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Sample records for severe metabolic acidosis

  1. Metabolic acidosis

    MedlinePlus

    ... of oxygen from shock , heart failure , or severe anemia Seizures Other causes of metabolic acidosis include: Kidney disease (distal renal tubular acidosis and proximal renal tubular acidosis) Poisoning ...

  2. Severe metabolic acidosis following assault chemical burn

    PubMed Central

    Roock, Sophie D; Deleuze, Jean-Paul; Rose, Thomas; Jennes, Serge; Hantson, Philippe

    2012-01-01

    Assault chemical burns are uncommon in northern Europe. Besides local toxicity, systemic manifestations are possible after strong acid exposure. A 40-year-old woman was admitted 1 h after a criminal assault with sulfuric acid. The total burned surface area was 35%, third degree. Injury was due to sulfuric acid (measured pH 0.9) obtained from a car battery. Immediate complications were obstructive dyspnea and metabolic acidosis. The admission arterial pH was 6.92, with total bicarbonate 8.6 mEq/l and base deficit 23.4 mEq/l. The correction of metabolic acidosis was achieved after several hours by the administration of bicarbonate and lactate buffers. The patient developed several burns-related complications (sepsis and acute renal failure). Cutaneous projections of strong acids may cause severe metabolic acidosis, particularly when copious irrigation and clothes removal cannot be immediately performed at the scene. PMID:22787349

  3. Severe metabolic acidosis following assault chemical burn.

    PubMed

    Roock, Sophie D; Deleuze, Jean-Paul; Rose, Thomas; Jennes, Serge; Hantson, Philippe

    2012-04-01

    Assault chemical burns are uncommon in northern Europe. Besides local toxicity, systemic manifestations are possible after strong acid exposure. A 40-year-old woman was admitted 1 h after a criminal assault with sulfuric acid. The total burned surface area was 35%, third degree. Injury was due to sulfuric acid (measured pH 0.9) obtained from a car battery. Immediate complications were obstructive dyspnea and metabolic acidosis. The admission arterial pH was 6.92, with total bicarbonate 8.6 mEq/l and base deficit 23.4 mEq/l. The correction of metabolic acidosis was achieved after several hours by the administration of bicarbonate and lactate buffers. The patient developed several burns-related complications (sepsis and acute renal failure). Cutaneous projections of strong acids may cause severe metabolic acidosis, particularly when copious irrigation and clothes removal cannot be immediately performed at the scene. PMID:22787349

  4. Shoshin beriberi with severe metabolic acidosis.

    PubMed

    Seta, T; Okuda, K; Toyama, T; Himeno, Y; Ohta, M; Hamada, M

    1981-09-01

    A case of Shoshin beriberi found in a patient with severe metabolic acidosis and shock was presented. We believe the metabolic acidosis in this case is ascribable to overproduction of pyruvate and lactate resulting from lack of thiamine due to preferential intake of sake, precooked food, and rice, and also to shock. The hemodynamic studies done after recovery from shock revealed that the cardiac output, which was initially high, decreased to a slightly low level and then increased to a normal level, concomitant with an increase in the peripheral vascular resistance after introductory administration of thiamine. After treatment with thiamine, all abnormalities disappeared. PMID:7280764

  5. Safe delivery of two parturient women in severe metabolic acidosis

    PubMed Central

    Shariffuddin, Ina Ismiarti; Rai, Vineya; Chan, Y K; Muniandy, Rajesh Kumar

    2014-01-01

    Care of an acutely ill parturient is particularly difficult when we have to balance the needs of both mother and the fetus to survive. The literature suggests there should be emphasis on stabilising the mother's condition. In dealing with metabolic acidosis, however, we believe delivering the baby early might not only relieve the threat of the acidosis on the mother, it may be the only way to deliver a live baby. We report two parturient women with severe metabolic acidosis which was considerably reduced very soon after the delivery and how our timely delivery resulted in the birth of two neurologically intact babies. PMID:24862427

  6. 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. PMID:17936961

  7. Severe metabolic acidosis in the alcoholic: differential diagnosis and management.

    PubMed

    Höjer, J

    1996-06-01

    1. A chronic alcoholic with severe metabolic acidosis presents a difficult diagnostic problem. The most common cause is alcoholic ketoacidosis, a syndrome with a typical history but often misleading laboratory findings. This paper will focus on this important and probably underdiagnosed syndrome. 2. The disorder occurs in alcoholics who have had a heavy drinking-bout culminating in severe vomiting, with resulting dehydration, starvation, and then a beta-hydroxybutyrate dominated ketoacidosis. 3. Awareness of this syndrome, thorough history-taking, physical examination and routine laboratory analyses will usually lead to a correct diagnosis. 4. The treatment is simply replacement of fluid, glucose, electrolytes and thiamine. Insulin or alkali should be avoided. 5. The most important differential diagnoses are diabetic ketoacidosis, lactic acidosis and salicylate, methanol or ethylene glycol poisoning, conditions which require quite different treatment. 6. The diagnostic management of unclear cases should always include toxicological tests, urine microscopy for calcium oxalate crystals and calculation of the serum anion and osmolal gaps. 7. It is suggested here, however, that the value of the osmolal gap should be considered against a higher reference limit than has previously been recommended. An osmolal gap above 25 mosm/kg, in a patient with an increased anion gap acidosis, is a strong indicator of methanol or ethylene glycol intoxication. PMID:8793530

  8. Starvation Ketoacidosis: A Cause of Severe Anion Gap Metabolic Acidosis in Pregnancy

    PubMed Central

    Venkatram, Sindhaghatta; Diaz-Fuentes, Gilda

    2014-01-01

    Pregnancy is a diabetogenic state characterized by relative insulin resistance, enhanced lipolysis, elevated free fatty acids and increased ketogenesis. In this setting, short period of starvation can precipitate ketoacidosis. This sequence of events is recognized as “accelerated starvation.” Metabolic acidosis during pregnancy may have adverse impact on fetal neural development including impaired intelligence and fetal demise. Short periods of starvation during pregnancy may present as severe anion gap metabolic acidosis (AGMA). We present a 41-year-old female in her 32nd week of pregnancy, admitted with severe AGMA with pH 7.16, anion gap 31, and bicarbonate of 5 mg/dL with normal lactate levels. She was intubated and accepted to medical intensive care unit. Urine and serum acetone were positive. Evaluation for all causes of AGMA was negative. The diagnosis of starvation ketoacidosis was established in absence of other causes of AGMA. Intravenous fluids, dextrose, thiamine, and folic acid were administered with resolution of acidosis, early extubation, and subsequent normal delivery of a healthy baby at full term. Rapid reversal of acidosis and favorable outcome are achieved with early administration of dextrose containing fluids. PMID:24963418

  9. [A rapidly fatal case of severe falciparum malaria complicated with high-level metabolic acidosis].

    PubMed

    Saito, Y; Takamori, M; Kimura, M

    2000-05-01

    A 67-year-old male was admitted with consciousness disturbance (JCS, III-200) after completing a 12-day tour to east Africa without malaria chemoprophylaxis. When he visited the hospital one day prior to the admission complaining of fever and a slightly sore throat, he did not mention the travel history. Soon after his travel history was revealed, blood films were prepared which showed abundant ring forms accompanied with a small number of trophozoites and schizonts of Plasmodium falciparum, with the parasitemia of 26%. Despite intravenous quinine infusion, first that of loading dose, his consciousness state (JCS, III-300), renal and hepatic functions and anemia (Hb, 5.8 g/dL) deteriorated progressively. Moreover, metabolic acidosis worsened with pH of 6.954, HCO3- of 3.4 mEq/L, BE of--27.0 mEq/L, PCO2 15.5 mmHg by arterial blood gas analysis, although he received a large volume of sodium bicarbonate solution. The patient died on the 4th day of his illness. According to the literature, it is suggested that the treatment of metabolic acidosis in severe faciparum malaria with sodium bicarbonate is sometimes harmful, since it can result in sodium overloading, which may then precipitate pulmonary edema/ARDS. However, alternative treatment regimens have not yet been established. Future investigation on the etiology and the proper treatment of metabolic acidosis associated with severe falciparum malaria is highly needed. PMID:10860364

  10. Successful recovery from iatrogenic severe hypernatremia and severe metabolic acidosis resulting from accidental use of inappropriate bicarbonate concentrate for hemodialysis treatment.

    PubMed

    Bhosale, Guruprasad P; Shah, Veena R

    2015-01-01

    Bicarbonate dialysis is the treatment modality of choice for correction of metabolic acidosis in chronic renal failure. However, improper selection of dialysate concentrate can result in life-threatening human errors. We report a case of iatrogenic severe hypernatremia (sodium 207 mEq/L) and severe metabolic acidosis (pH 6.65) that resulted due to accidental use of inappropriate bicarbonate concentrate for hemodialysis treatment. There was successful recovery in this patient with no neurological sequelae. To the best of our knowledge, this is the first case report in adults of severe hypernatremia along with severe metabolic acidosis due to error in the preparation of dialysis fluid. PMID:25579726

  11. 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

  12. Metabolic acidosis: neo-considerations for general surgeons.

    PubMed

    Martin, L C E; Abah, U; Bean, E; Gupta, S

    2012-11-01

    Hyperchloraemic metabolic acidosis is a documented complication of neobladder formation. However, it usually improves with time and is mild. Severe and persistent metabolic acidosis may manifest when patients undergo further surgery for other reasons. Neobladder formation following radical cystectomy or cystoprostatectomy is becoming increasingly common, and surgeons treating patients with neobladders should recognise and treat metabolic acidosis with intravenous fluids and bicarbonate. PMID:23131216

  13. Diagnostic Challenge in a Patient with Severe Anion Gap Metabolic Acidosis

    PubMed Central

    Tan, Eugene M.; Kalimullah, Ejaaz; Sohail, M. Rizwan; Ramar, Kannan

    2015-01-01

    The approach to the patient with acute renal failure and elevated anion and osmolal gap is difficult. Differential diagnoses include toxic alcohol ingestion, diabetic or starvation ketoacidosis, or 5-oxoproline acidosis. We present a 76-year-old female with type 2 diabetes mellitus, who was found at home in a confused state. Laboratory analysis revealed serum pH 6.84, bicarbonate 5.8 mmol/L, pCO2 29 mmHg, anion gap 22.2 mmol/L, osmolal gap 17.4 mOsm/kg, elevated beta-hydroxybutyrate (4.2 mmol/L), random blood sugar 213 mg/dL, creatinine 2.1 mg/dL, and potassium 7.5 mmol/L with no electrocardiogram (EKG) changes. Fomepizole and hemodialysis were initiated for presumed ethylene glycol or methanol ingestion. Drug screens returned negative for ethylene glycol, alcohols, and acetaminophen, but there were elevated urine levels of acetone (11 mg/dL). The acetaminophen level was negative, and 5-oxoproline was not analyzed. After 5 days in the intensive care unit (ICU), her mental status improved with supportive care. She was discharged to a nursing facility. Though a diagnosis was not established, our patient's presentation was likely due to starvation ketosis combined with chronic acetaminophen ingestion. Acetone ingestion is less likely. Overall, our case illustrates the importance of systematically approaching an elevated osmolal and anion gap metabolic acidosis. PMID:26113997

  14. Metabolic acidosis and the progression of chronic kidney disease

    PubMed Central

    2014-01-01

    Metabolic acidosis is a common complication of chronic kidney disease. Accumulating evidence identifies acidosis not only as a consequence of, but as a contributor to, kidney disease progression. Several mechanistic pathways have been identified in this regard. The dietary acid load, even in the absence of overt acidosis, may have deleterious effects. Several small trials now suggest that the treatment of acidosis with oral alkali can slow the progression of kidney disease. PMID:24708763

  15. 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 redirected away from several other critical metabolic processes, including ribose and glutathione synthesis. These alterations lead to both a decrease in cellular proliferation and increased sensitivity to ROS. Collectively, these data reveal a role for p53 in cellular metabolic reprogramming under acidosis, in order to permit increased bioenergetic capacity and ROS neutralization. Understanding the metabolic adaptations that cancer cells make under acidosis may present opportunities to generate anti-tumor therapeutic agents that are more tumor-specific. PMID:24359630

  16. 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

  17. Metabolic Acidosis of CKD: An Update.

    PubMed

    Kraut, Jeffrey A; Madias, Nicolaos E

    2016-02-01

    The kidney has the principal role in the maintenance of acid-base balance. Therefore, a decrease in renal ammonium excretion and a positive acid balance often leading to a reduction in serum bicarbonate concentration are observed in the course of chronic kidney disease (CKD). The decrease in serum bicarbonate concentration is usually absent until glomerular filtration rate decreases to <20 to 25mL/min/1.73 m(2), although it can develop with lesser degrees of decreased kidney function. Non-anion gap acidosis, high-anion gap acidosis, or both can be found at all stages of CKD. The acidosis can be associated with muscle wasting, bone disease, hypoalbuminemia, inflammation, progression of CKD, and increased mortality. Administration of base may decrease muscle wasting, improve bone disease, and slow the progression of CKD. Base is suggested when serum bicarbonate concentration is <22 mEq/L, but the target serum bicarbonate concentration is unclear. Evidence that increments in serum bicarbonate concentration > 24 mEq/L might be associated with worsening of cardiovascular disease adds complexity to treatment decisions. Further study of the mechanisms through which metabolic acidosis contributes to the progression of CKD, as well as the pathways involved in mediating the benefits and complications of base therapy, is warranted. PMID:26477665

  18. Altered contractile response of penis under hypoxia with metabolic acidosis.

    PubMed

    Moon, D G; Lee, D S; Kim, J J

    1999-10-01

    Previous studies concerning ischemic priapism revealed that hypoxia alters the erectile and contractile responses of penis. But the effects of accompanying acidosis on those responses have not been fully evaluated or understood yet. We performed this study to elucidate the role of acidosis on the trabecular smooth muscle contractility like in ischemic priapism. Under the general anesthesia, 55 mature male cats were conditioned to systemic metabolic acidosis by hypoventilation by animal ventilator. The changes of intracavernous pressure (ICP) to erectogenic agents (acetylcholine, L-arginine, prostaglandin E1: PGE1), erectolytic agents (epinephrine, thromboxane A2; TXA2), K channel-related drugs (pinacidil, 4-aminopyridine, tetraethylammonium; TEA, glibenclamide) and calcium ionophore were monitored at Set 1 (PO2 > 60 mmHg, pH > 7.25), Set 2 (PO2 < 30 mmHg, 7.25 > pH > 7.0), Set 3 (PO2 < 30 mmHg, pH < 7.0), and Set 4 (PO2 > 60 mmHg, pH < 7.0) in vivo. At Set 1 and Set 2, epinephrine, TXA2, and ionomycin decreased the ICP by acetylcholine or PGE1 (n = 9, P < 0.01). The decrease of ICP was in order of epinephrine, TXA2 and ionomycin. Acidosis reduced the increase of ICP to acetylcholine or PGE1 (n = 8, P < 0.01), TXA2 or ionomycin did not affect ICP under severe acidosis but epinephrine decreased ICP even under severe acidosis (n = 7, P < 0.05). Pretreatment of potassium channel blockers did not suppress the increase of ICP by erectogenic agents under acidosis (n = 6, P < 0.05). Pinacidil did not affect ICP under acidosis (n = 6, P < 0.01). These results suggest that acidosis impairs the contractile response of cavernous smooth muscle to erectolytic agents. It may be the results of the interference by [H+] with the intra and extracellular mechanisms that regulate the homeostasis of [Ca2]. Conclusively, besides hypoxia, acidosis is another limiting factor of trabecular smooth muscle contractility like in ischemic priapism. PMID:10553805

  19. Obscure Severe Infrarenal Aortoiliac Stenosis With Severe Transient Lactic Acidosis

    PubMed Central

    Nantsupawat, Teerapat; Mankongpaisarnrung, Charoen; Soontrapa, Suthipong; Limsuwat, Chok

    2013-01-01

    A 57-year-old man presented with sudden onset of leg pain, right-sided weakness, aphasia, confusion, drooling, and severe lactic acidosis (15 mmol/L). He had normal peripheral pulses and demonstrated no pain, pallor, poikilothermia, paresthesia, or paralysis. Empiric antibiotics, aspirin, full-dose enoxaparin, and intravenous fluid were initiated. Lactic acid level decreased to 2.5 mmol/L. The patient was subsequently extubated and was alert and oriented with no complaints of leg or abdominal pain. Unexpectedly, the patient developed cardiac arrest, rebound severe lactic acidosis (8.13 mmol/L), and signs of acute limb ischemia. Emergent computed tomography of the aorta confirmed infrarenal aortoiliac thrombosis. Transient leg pain and transient severe lactic acidosis can be unusual presentations of severe infrarenal aortoiliac stenosis. When in doubt, vascular studies should be implemented without delay to identify this catastrophic diagnosis. PMID:26425569

  20. 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. PMID:26776539

  1. 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

  2. Metabolic acidosis during parenteral nutrition: Pathophysiological mechanisms.

    PubMed

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

    2015-05-01

    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

  3. A rare cause of severe lactic acidosis.

    PubMed

    Saeed, Saad; Kuravi, Aditya; Rowley, Matt; Saeed, Marwa

    2015-01-01

    Sarcoidosis is a multisystem disease of unknown aetiology with a classic histology of non-caseating granulomas. It most often occurs in those below the age of 50 years, and has a female preponderance. The main targets, often symptomless, are the lung and hilar lymph nodes, although liver involvement is not uncommon. Hepatic sarcoidosis encompasses a broad spectrum of presentations, from asymptomatic hepatic granulomas with slight liver function test derangement to severe liver involvement with cholestasis, advanced liver cirrhosis or chronic liver failure. Mortality due to acute liver failure is far less common than lung and heart involvement. We describe a case of fulminant liver failure with multiorgan failure presenting initially with chronic non-specific symptoms, in addition to minimal abnormal investigations such as mild anaemia, neutrophil leucocytosis and mild obstructive liver dysfunction. Presenting features included confusion, hypotension, oliguria and rapidly deteriorating liver function with severe lactic acidosis. Postmortem examination confirmed extensive systemic sarcoidosis. PMID:25911351

  4. Pyroglutamic acid-induced metabolic acidosis: a case report.

    PubMed

    Luyasu, S; Wamelink, M M C; Galanti, L; Dive, A

    2014-06-01

    High anion gap metabolic acidosis due to pyroglutamic acid (5-oxoproline) is a rare complication of acetaminophen treatment (which depletes glutathione stores) and is often associated with clinically moderate to severe encephalopathy. Acquired 5-oxoprolinase deficiency (penicillins) or the presence of other risk factors of glutathione depletion such as malnutrition or sepsis seems to be necessary for symptoms development. We report the case of a 55-year-old women who developed a symptomatic overproduction of 5-oxoproline during flucloxacillin treatment for severe sepsis while receiving acetaminophen for fever control. Hemodialysis accelerated the clearance of the accumulated organic acid, and was followed by a sustained clinical improvement. PMID:24694265

  5. Acidosis

    MedlinePlus

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

  6. Severe lactic acidosis in a diabetic patient after ethanol abuse and floor cleaner intake.

    PubMed

    Hendrikx, Jeroen J M A; Lagas, Jurjen S; Daling, Ratana; Hooijberg, Jan Hendrik; Schellens, Jan H M; Beijnen, Jos H; Brandjes, Desiderius P M; Huitema, Alwin D R

    2014-11-01

    An intoxication with drugs, ethanol or cleaning solvents may cause a complex clinical scenario if multiple agents have been ingested simultaneously. The situation can become even more complex in patients with (multiple) co-morbidities. A 59-year-old man with type 2 diabetes mellitus (without treatment two weeks before the intoxication) intentionally ingested a substantial amount of ethanol along with ~750 mL of laminate floor cleaner containing citric acid. The patient was admitted with severe metabolic acidosis (both ketoacidosis and lactic acidosis, with serum lactate levels of 22 mM). He was treated with sodium bicarbonate, insulin and thiamine after which he recovered within two days. Diabetic ketoacidosis and lactic acidosis aggravated due to ethanol intoxication, thiamine deficiency and citrate. The high lactate levels were explained by excessive lactate formation caused by the combination of untreated diabetes mellitus, thiamine deficiency and ethanol abuse. Metabolic acidosis in diabetes is multi-factorial, and the clinical situation may be further complicated, when ingestion of ethanol and toxic agents are involved. Here, we reported a patient in whom diabetic ketoacidosis was accompanied by severe lactic acidosis as a result of citric acid and mainly ethanol ingestion and a possible thiamine deficiency. In the presence of lactic acidosis in diabetic ketoacidosis, physicians need to consider thiamine deficiency and ingestion of ethanol or other toxins. PMID:24717115

  7. Prevalence and Correlates of Metabolic Acidosis among Patients with Homozygous Sickle Cell Disease

    PubMed Central

    Maurel, Stéphane; Stankovic Stojanovic, Katia; Avellino, Virginie; Girshovich, Alexey; Letavernier, Emmanuel; Grateau, Gilles; Baud, Laurent; Girot, Robert; Lionnet, Francois

    2014-01-01

    Background and objectives Very few studies report acid base disorders in homozygous patients with sickle cell anemia (SCA) and describe incomplete renal acidosis rather than true metabolic acidosis, the prevalence of which is unknown and presumably low. This study aimed to assess the prevalence of metabolic acidosis and to identify its risk factors and mechanisms. Design, setting, participants, & measurements This study retrospectively analyzed 411 homozygous patients with SCA with a GFR≥60 ml/min per 1.73 m2, referred in a single center between 2007 and 2012. Acidosis and nonacidosis groups were compared for clinical and biologic data including SCA complications and hemolytic parameters. A subgroup of 65 patients with SCA, referred for a measured GFR evaluation in the setting of sickle cell–associated nephropathy, was further analyzed in order to better characterize metabolic acidosis. Results Metabolic acidosis was encountered in 42% of patients with SCA, with a higher prevalence in women (52% versus 27% in men; P<0.001). Several hemolytic biomarkers, such as lactate dehydrogenase, were different between the acidosis and nonacidosis groups (P=0.02 and P=0.03 in men and women, respectively), suggesting higher hemolytic activity in the former group. To note, fasting urine osmolality was low in the whole study population and was significantly lower in men with SCA in the acidosis group (392 versus 427 mOsm/kg; P=0.01). SCA subgroup analysis confirmed metabolic acidosis with a normal anion gap in 14 patients, characterized by a lower urinary pH (P<0.02) and no increase in urinary ammonium. Serum potassium, plasma renin, and aldosterone were similar between the two groups and thus could not explain impaired urinary ammonium excretion. Conclusions These results suggest that the prevalence of metabolic acidosis in patients with SCA is underestimated and related to impaired ammonium availability possibly due to an altered corticopapillary gradient. Future studies should evaluate whether chronic metabolic acidosis correction may be beneficial in this population, especially in bone remodeling. PMID:24458070

  8. Metabolic acidosis inhibits soft tissue calcification in uremic rats.

    PubMed

    Mendoza, F J; Lopez, I; Montes de Oca, A; Perez, J; Rodriguez, M; Aguilera-Tejero, E

    2008-02-01

    Metabolic acidosis is common in patients with chronic kidney disease, which is known to affect bone metabolism. We examined the effect of metabolic acidosis on the development of vascular and other soft-tissue calcifications in uremic rats treated with calcitriol. Extraskeletal calcification was measured in vivo, in control rats and rats with a remnant kidney model of uremia with or without ammonium chloride-induced acidosis. Soft-tissue calcification was assessed histologically, by measurement of the expression of the sodium-dependent phosphate cotransporter Pit-1 and by quantification of tissue calcium and phosphorus. Calcitriol administration to uremic rats resulted in significant deposition of material positive for von Kossa stain in the aorta, stomach, and kidney, elevated aortic calcium and phosphorus, increased aortic Pit-1 expression, and high mortality. Calcitriol-treated uremic rats with acidosis did not develop aortic or soft-tissue calcification, did not increase aortic Pit-1 expression, and had significantly lower mortality. Additionally, an acidotic environment prevented calcification of vascular smooth muscle cells in vitro. Our study shows that metabolic acidosis inhibits extraskeletal calcification. PMID:17989650

  9. Trimethoprim/Sulfamethoxazole-Induced Severe Lactic Acidosis: A Case Report and Review of the Literature.

    PubMed

    Bulathsinghala, Marie; Keefer, Kimberly; Van de Louw, Andry

    2016-04-01

    Propylene glycol (PG) is used as a solvent in numerous medications, including trimethoprim/sulfamethoxazole (TMP/SMX) and lorazepam, and is metabolized in the liver to lactic acid. Cases of lactic acidosis related to PG toxicity have been described and always involved large doses of benzodiazepines and PG. We present the first case of severe lactic acidosis after a 3-day course of TMP/SMX alone, involving allegedly safe amounts of PG.A 31-year-old female with neurofibromatosis and pilocytic astrocytoma, receiving temozolomide and steroids, was admitted to the intensive care unit for pneumonia and acute respiratory failure requiring intubation. Her initial hemodynamic and acid-base statuses were normal. She was treated with intravenous TMP/SMX for possible Pneumocystis jirovecii pneumonia and was successfully extubated on day 2. On day 3, she developed tachypnea and arterial blood gas analysis revealed a severe metabolic acidosis (pH 7.2, PCO2 19 mm Hg, bicarbonates 8 mEq/L) with anion gap of 25 mEq/L and lactate of 12.1 mmol/L. TMP/SMX was discontinued and the lactate decreased to 2.9 mmol/L within 24 hours while her plasma bicarbonates normalized, without additional intervention. The patient never developed hypotension or severe hypoxia, and her renal and liver functions were normal. No other cause for lactic acidosis was identified and it resolved after TMP/SMX cessation alone, suggesting PG toxicity.Although PG-related lactic acidosis is well recognized after large doses of lorazepam, clinicians should bear in mind that TMP/SMX contains PG as well and should suspect PG toxicity in patients developing unexplained metabolic acidosis while receiving TMP/SMX. PMID:27124045

  10. 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. PMID:24608516

  11. Catabolism in uremia: the impact of metabolic acidosis.

    PubMed

    Franch, H A; Mitch, W E

    1998-12-01

    Chronic metabolic acidosis stimulates the catabolism of bone and muscle in experimental animals and humans. The toxicity caused by acidosis involves changes in endocrine function and toxicity arising from the homeostatic responses that are activated by the body to maintain pH near normal levels. Glucocorticoids, insulin, insulin-like growth factor-1, and parathyroid hormone play important roles in the homeostatic responses of bone and muscle to acid. Bone buffering of acid and the resulting increase in renal calcium excretion leads to negative calcium balance. Activation of the ubiquitin-proteasome proteolytic system and branched-chain ketoacid dehydrogenase in muscle, along with hepatic glutamine synthesis in the liver and renal glutamine uptake, are homeostatic mechanisms that cause negative nitrogen balance and loss of muscle mass. Treating the acidosis of chronic renal insufficiency improves both bone and muscle metabolism by reducing the loss of calcium and protein and amino acids in the two organs, respectively. Thus, treating acidosis suppresses both bone and muscle catabolism in patients with normal and reduced renal function. PMID:11443773

  12. Chronic metabolic acidosis increases the serum concentration of 1,25-dihydroxyvitamin D in humans by stimulating its production rate. Critical role of acidosis-induced renal hypophosphatemia.

    PubMed Central

    Krapf, R; Vetsch, R; Vetsch, W; Hulter, H N

    1992-01-01

    Chronic metabolic acidosis results in metabolic bone disease, calcium nephrolithiasis, and growth retardation. The pathogenesis of each of these sequelae is poorly understood in humans. We therefore investigated the effects of chronic extrarenal metabolic acidosis on the regulation of 1,25-(OH)2D, parathyroid hormone, calcium, and phosphate metabolism in normal humans. Chronic extrarenal metabolic acidosis was induced by administering two different doses of NH4Cl [2.1 (low dose) and 4.2 (high dose) mmol/kg body wt per d, respectively] to four male volunteers each during metabolic balance conditions. Plasma [HCO3-] decreased by 4.5 +/- 0.4 mmol/liter in the low dose and by 9.1 +/- 0.3 mmol/liter (P < 0.001) in the high dose group. Metabolic acidosis induced renal hypophosphatemia, which strongly correlated with the severity of acidosis (Plasma [PO4] on plasma [HCO3-]; r = 0.721, P < 0.001). Both metabolic clearance and production rates of 1,25-(OH)2D increased in both groups. In the high dose group, the percentage increase in production rate was much greater than the percentage increase in metabolic clearance rate, resulting in a significantly increased serum 1,25-(OH)2D concentration. A strong inverse correlation was observed for serum 1,25-(OH)2D concentration on both plasma [PO4] (r = -0.711, P < 0.001) and plasma [HCO3-] (r = -0.725, P < 0.001). Plasma ionized calcium concentration did not change in either group whereas intact serum parathyroid hormone concentration decreased significantly in the high dose group. In conclusion, metabolic acidosis results in graded increases in serum 1,25-(OH)2D concentration by stimulating its production rate in humans. The increased production rate is explained by acidosis-induced hypophosphatemia/cellular phosphate depletion resulting at least in part from decreased renal tubular phosphate reabsorption. The decreased serum intact parathyroid hormone levels in more severe acidosis may be the consequence of hypophosphatemia and/or increased serum 1,25-(OH)2D concentrations. PMID:1469097

  13. 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. PMID:26904700

  14. 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:24700866

  15. Autophagic clearance of mitochondria in the kidney copes with metabolic acidosis.

    PubMed

    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; Isaka, Yoshitaka; Rakugi, Hiromi

    2014-10-01

    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:24700866

  16. Seizures, metabolic acidosis and coma resulting from acute isoniazid intoxication.

    PubMed

    Topcu, I; Yentur, E A; Kefi, A; Ekici, N Z; Sakarya, M

    2005-08-01

    Isoniazid is an anti-tuberculosis drug, used commonly for treatment and prophylaxis of tuberculosis. Acute isoniazid intoxication is characterized by a clinical triad consisting of metabolic acidosis resistant to treatment with sodium bicarbonate, seizures which may be fatal and refractory to standard anticonvulsant therapy, and coma. Treatment requires admission to the intensive care unit for ventilatory support, management of seizures and metabolic acidosis. Pyridoxine, in a dose equivalent to the amount of isoniazid ingested, is the only effective antidote. We report the successful treatment of two isoniazid intoxication cases: the case of a child developing an accidental acute isoniazid intoxication and an adult case of isoniazid intoxication with the intent of suicide. PMID:16119496

  17. Lentiform Fork Sign: a Magnetic Resonance Finding in a Case of Acute Metabolic Acidosis

    PubMed Central

    Grasso, Daniela; Borreggine, Carmela; Perfetto, Francesco; Bertozzi, Vincenzo; Trivisano, Marina; Specchio, Luigi Maria; Grilli, Gianpaolo; Macarini, Luca

    2014-01-01

    Summary We report a 33 year-old woman addicted to chronic unspecified solvents abuse with stupor, respiratory disorders, tetraplegia and severe metabolic acidosis. On admission an unenhanced cranial CT scan showed symmetrical hypodensities of both lentiform nuclei. MR imaging performed 12 hours after stupor demonstrates bilateral putaminal hemorrhagic necrosis, bilateral external capsule, corona radiata and deep cerebellar hyperintensities with right cingulate cortex involvement. DWI reflected bilateral putaminal hyperintensities with restricted water diffusion as to citotoxic edema and development of vasogenic edema in the external capsule recalling a fork. On day twenty, after specific treatments MRI demonstrated a bilateral putaminal marginal enhancement. Bilateral putaminal necrosis is a characteristic but non-specific radiological finding of methanol poisoning. Lentiform Fork sign is a rare MRI finding reported in literature in 22 patients with various conditions characterized by metabolic acidosis. Vasogenic edema may be due to the differences in metabolic vulnerability between neurons and astrocytes. We postulate that metabolic acidosis could have an important role to generate this sign. PMID:24976195

  18. Lentiform fork sign: a magnetic resonance finding in a case of acute metabolic acidosis.

    PubMed

    Grasso, Daniela; Borreggine, Carmela; Perfetto, Francesco; Bertozzi, Vincenzo; Trivisano, Marina; Specchio, Luigi Maria; Grilli, Gianpaolo; Macarini, Luca

    2014-06-01

    We report a 33 year-old woman addicted to chronic unspecified solvents abuse with stupor, respiratory disorders, tetraplegia and severe metabolic acidosis. On admission an unenhanced cranial CT scan showed symmetrical hypodensities of both lentiform nuclei. MR imaging performed 12 hours after stupor demonstrates bilateral putaminal hemorrhagic necrosis, bilateral external capsule, corona radiata and deep cerebellar hyperintensities with right cingulate cortex involvement. DWI reflected bilateral putaminal hyperintensities with restricted water diffusion as to citotoxic edema and development of vasogenic edema in the external capsule recalling a fork. On day twenty, after specific treatments MRI demonstrated a bilateral putaminal marginal enhancement. Bilateral putaminal necrosis is a characteristic but non-specific radiological finding of methanol poisoning. Lentiform Fork sign is a rare MRI finding reported in literature in 22 patients with various conditions characterized by metabolic acidosis. Vasogenic edema may be due to the differences in metabolic vulnerability between neurons and astrocytes. We postulate that metabolic acidosis could have an important role to generate this sign. PMID:24976195

  19. Treatment of Metabolic Acidosis in Patients With CKD

    PubMed Central

    Chen, Wei; Abramowitz, Matthew K.

    2013-01-01

    Metabolic acidosis is a common complication of chronic kidney disease and believed to contribute to a number of sequelae, including bone disease, altered protein metabolism, skeletal muscle wasting, and progressive GFR loss. Small trials in animal models and humans suggest a role for alkali therapy to lessen these complications. Recent studies support this notion, although more definitive evidence is needed on the long-term benefits of alkali therapy and the optimal serum bicarbonate level. The role of dietary modification should also be given greater consideration. In addition, potential adverse effects of alkali treatment must be taken into consideration, including sodium retention and the theoretical concern of promoting vascular calcification. This teaching case summarizes the rationale for and the benefits and complications of base therapy in patients with chronic kidney disease. PMID:23932089

  20. A preterm infant with intractable metabolic acidosis: a devastating presentation of Chryseobacterium meningosepticum meningitis.

    PubMed

    Eroğlu-Ertuğrul, Nesibe; Sürmeli-Onay, Özge; Yurdakök, Murat

    2014-01-01

    Sepsis-related mortality and morbidity are the leading issues that neonatal intensive care units struggle with worldwide. We report a preterm infant with septic shock and intractable metabolic acidosis whose postmortem microbiologic examination revealed Chryseobacterium meningosepticum meningitis. We would like to alert clinicians about this uncommon sepsis agent, and to call into question the treatment modalities for metabolic acidosis. PMID:26022592

  1. [5-0xoproline (pyroglutamic acid) acidosis and acetaminophen- a differential diagnosis in high anion gap metabolic acidosis].

    PubMed

    Weiler, Stefan; Bellmann, Romuald; Kullak-Ublick, Gerd A

    2015-12-01

    Rare cases of high anion gap metabolic acidosis during long-term paracetamol administration in therapeutic doses with causative 5-oxoproline (pyroglutamic acid} accumulation have been reported. Other concomitant risk factors such as malnutrition, alcohol abuse, renal or hepatic dysfunction, comedication with flue/oxacillin, vigabatrin, netilmicin or sepsis have been described. The etiology seems to be a drug-induced reversible inhibition of glutathione synthetase or 5-oxoprolinase leading to elevated serum and urine levels of 5-oxoproline. Other more frequent differential diagnoses, such as intoxications, ketoacidosis or lactic acidosis should be excluded. Causative substances should be stopped. 5-oxoproline concentrations in urine can be quantified to establish the diagnosis. Adverse drug reactions, which are not listed or insufficiently described in the respective Swiss product information, should be reported to the regional pharmacovigilance centres for early signal detection. 5-0 xoproline acidosis will be integrated as a potential adverse drug reaction in the Swiss product information for paracetamol. PMID:26654818

  2. Treatment options for lactic acidosis and metabolic crisis in children with mitochondrial disease.

    PubMed

    Danhauser, Katharina; Smeitink, Jan A M; Freisinger, Peter; Sperl, Wolfgang; Sabir, Hemmen; Hadzik, Berit; Mayatepek, Ertan; Morava, Eva; Distelmaier, Felix

    2015-05-01

    The mitochondrial pyruvate oxidation route is a tightly regulated process, which is essential for aerobic cellular energy production. Disruption of this pathway may lead to severe neurometabolic disorders with onset in early childhood. A frequent finding in these patients is acute and chronic lactic acidemia, which is caused by increased conversion of pyruvate via the enzyme lactate dehydrogenase. Under stable clinical conditions, this process may remain well compensated and does not require specific therapy. However, especially in situations with altered energy demands, such as febrile infections or longer periods of fasting, children with mitochondrial disorders have a high risk of metabolic decompensation with exacerbation of hyperlactatemia and severe metabolic acidosis. Unfortunately, no controlled studies regarding therapy of this critical condition are available and clinical outcome is often unfavorable. Therefore, the aim of this review was to formulate expert-based suggestions for treatment of these patients, including dietary recommendations, buffering strategies and specific drug therapy. However, it is important to keep in mind that a specific therapy for the underlying metabolic cause in children with mitochondrial diseases is usually not available and symptomatic therapy especially of severe lactic acidosis has its ethical limitations. PMID:25687154

  3. Acute diarrhea and metabolic acidosis caused by tuberculous vesico-rectal fistula

    PubMed Central

    Wei, Xiu-Qing; Zou, Yan; Wu, Zhi-E; Abassa, Kodjo-Kunale; Mao, Wei; Tao, Jin; Kang, Zhuang; Wen, Zhuo-Fu; Wu, Bin

    2014-01-01

    Acquired vesico-rectal fistula is an uncommon complication of pelvic malignant tumors, surgical injury, inflammatory disorders such as tuberculosis infection, radiotherapy and less commonly diverticulum of the urinary tract. The fistula is often identified by urinary tract abnormalities such as dysuria, recurrent urinary tract infection, pneumaturia, and fecaluria. Here, we report an unusual case of a patient with a vesico-rectal fistula of tuberculous origin, presenting with severe acute diarrhea, metabolic acidosis, hyperchloremia and hypokalemia while with only mild urinary tract symptoms. The patient was cured by tuberculostatic therapy. PMID:25386096

  4. A rare case of severe lactic acidosis in a preterm infant: lack of thiamine during total parenteral nutrition.

    PubMed

    Oguz, Serife Suna; Ergenekon, Ebru; Tmer, Leyla; Ko, Esin; Turan, Ozden; Onal, Esra; Trkyilmaz, Canan; Atalay, Yildiz

    2011-01-01

    Total parenteral nutrition (TPN) is a revolution in neonatal intensive care unit (NICU) care, but this therapy is not without problems. A 35-week-old, 1300 g female infant was transferred to our NICU because of bilious vomiting and feeding problems. When enteral feeding was started again, a severe condition similar to the previous one developed. On the 24th day, the patient underwent surgery with a diagnosis of Hirschprung's disease. One week before surgery, the parenteral solutions were composed without vitamins because intravenous vitamin supplements suitable for infants were not available. Thereafter, the patient suffered from severe hypoglycaemia, and sepsis started to develop, accompanied by a large anion gap and metabolic acidosis which is severe lactic acidosis refractory to massive doses of bicarbonate. The acidosis improved significantly when the patient was treated with thiamin. Although TPN is life saving in the NICU, meticulous attention must be paid while treating a patient with TPN, and all possible nutrients should be provided. In this report, a case of a preterm newborn requiring a prolonged period of TPN and complicated by serious lactic acidosis is presented and discussed. PMID:22145490

  5. Prevalence of Metformin Use and the Associated Risk of Metabolic Acidosis in US Diabetic Adults With CKD

    PubMed Central

    Kuo, Chin-Chi; Yeh, Hung-Chieh; Chen, Bradley; Tsai, Ching-Wei; Lin, Yu-Sheng; Huang, Chiu-Ching

    2015-01-01

    Abstract The use of metformin in chronic kidney disease (CKD) population has been intensely debated with conflicting evidence. Large population studies are needed to inform risk assessment and therapeutic decision-making. We evaluated the associations among metformin, metabolic acidosis, and CKD in a 10-year nationally representative noninstitutionalized civilian population in the United States. In this cross-sectional study, a total of 2279 diabetic adults aged 20 years or older in the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2012 were included and had measurements of serum bicarbonate, sodium, potassium, and chloride. The exposure was metformin use. The outcome was subclinical and severe metabolic acidosis defined by serum bicarbonate <23 mEq/L and anion gap > 16mEq/L and by serum bicarbonate < 20 mEq/L, respectively. The prevalence of metformin use decreased from 67.2% among CKD-1 and -2, 40.6% among CKD-3, to 1.3% among advanced CKD-4 and -5. Across CKD stages up to CKD-3b, we observed a tendency of lower levels of serum bicarbonate that was significant in metformin users with CKD-2 and CKD-3a and marginally significant with CKD-3b compared to nonmetformin users. The corresponding tendency of higher anion gap in metformin users with the estimated glomerular filtration rate >60 mL/min/1.73 m2 was also observed. In multiple linear regression analysis, metformin was significantly associated with decreased serum bicarbonate levels (β = −0.45, 95% CI: −0.73, −0.17) and increased serum anion gap levels (β = 0.40, 95% CI: 0.19, 0.61). The adjusted odds ratio of subclinical high anion gap and severe metabolic acidosis for metformin users was 1.68 (95% CI: 1.11, 2.55) and 1.31 (0.49, 3.47), respectively. The association between metformin and serum bicarbonate was significantly modified by CKD status. No interaction was found between metformin and CKD stages for serum anion gap and acidosis. Metformin is associated with subclinical metabolic acidosis but not with severe metabolic acidosis. The propensity of serum bicarbonate-lowering effect was intensified in advanced CKD; however, such tendency was not associated with the risk of clinically defined acidosis. Our findings highlight a potential of cautious expansion of metformin use among CKD-3b patients with diabetes meriting further investigations. PMID:26705203

  6. Different effects of respiratory and metabolic acidosis on preganglionic sympathetic nerve activity.

    PubMed

    Offner, B; Czachurski, J; König, S A; Seller, H

    1994-07-01

    We studied sympathetic nerve activity (SNA) responses, recorded in multifiber preparations of left third thoracic white ramus, to respiratory or isocapnic metabolic acidosis or to CO2 enhancement at constant pH in chloralose-anesthetized paralyzed artificially ventilated cats. Cardiopulmonary, baro-, and peripheral chemoreceptors were denervated by bilaterally cutting vagus and carotid sinus nerves. Acidosis was induced by either decreasing artificial ventilation or infusing HCl (0.5 M i.v.). Both respiratory and isocapnic metabolic acidosis induced a decrease in local extracellular pH, measured directly with pH-sensitive microelectrodes within medulla region containing sympathoexcitatory bulbospinal neurons. The magnitude of changes in medullary pH was independent of the way systemic acidosis was generated. Despite uniformity of changes in local medullary extracellular pH due to systemic respiratory or isocapnic metabolic acidosis, different responses were observed in preganglionic SNA. Isocapnic metabolic acidosis resulted in a slight increase in SNA, averaging 6.4% per 0.05 systemic pH unit decrease. In contrast, respiratory acidosis induced by decreasing artificial ventilation produced a more pronounced increase of SNA, reaching peak changes of approximately 70% compared with control level with normal blood gases, an average increase of 13% per 0.05 systemic pH unit decrease. We conclude that systemic CO2 and H+ concentrations represent different stimuli to sympathetic nervous system. Despite similar changes of local extracellular pH within rostral ventrolateral medulla during systemic acidosis, different responses of SNA suggest other sites or as yet unknown additional effects of CO2 as being responsible for excitation of sympathetic activity. PMID:7961230

  7. Infusion of sodium bicarbonate in experimentally induced metabolic acidosis does not provoke cerebrospinal fluid (CSF) acidosis in calves

    PubMed Central

    Abeysekara, Saman; Zello, Gordon A.; Lohmann, Katharina L.; Alcorn, Jane; Hamilton, Don L.; Naylor, Jonathan M.

    2012-01-01

    In a crossover study, 5 calves were made acidotic by intermittent intravenous infusion of isotonic hydrochloric acid (HCl) over approximately 24 h. This was followed by rapid (4 h) or slow (24 h) correction of blood pH with isotonic sodium bicarbonate (NaHCO3) to determine if rapid correction of acidemia produced paradoxical cerebrospinal fluid (CSF) acidosis. Infusion of HCl produced a marked metabolic acidosis with respiratory compensation. Venous blood pH (mean ± Sx) was 7.362 ± 0.021 and 7.116 ± 0.032, partial pressure of carbon dioxide (Pco2, torr) 48.8 ± 1.3 and 34.8 ± 1.4, and bicarbonate (mmol/L), 27.2 ± 1.27 and 11 ± 0.96; CSF pH was 7.344 ± 0.031 and 7.240 ± 0.039, Pco2 42.8 ± 2.9 and 34.5 ± 1.4, and bicarbonate 23.5 ± 0.91 and 14.2 ± 1.09 for the period before the infusion of hydrochloric acid and immediately before the start of sodium bicarbonate correction, respectively. In calves treated with rapid infusion of sodium bicarbonate, correction of venous acidemia was significantly more rapid and increases in Pco2 and bicarbonate in CSF were also more rapid. However, there was no significant difference in CSF pH. After 4 h of correction, CSF pH was 7.238 ± 0.040 and 7.256 ± 0.050, Pco2 44.4 ± 2.2 and 34.2 ± 2.1, and bicarbonate 17.8 ± 1.02 and 14.6 ± 1.4 for rapid and slow correction, respectively. Under the conditions of this experiment, rapid correction of acidemia did not provoke paradoxical CSF acidosis. PMID:22754090

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

    PubMed

    Kim, Se Young

    2015-12-01

    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

  9. 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

  10. Tumour-specific metabolic adaptation to acidosis is coupled to epigenetic stability in osteosarcoma cells.

    PubMed

    Chano, Tokuhiro; Avnet, Sofia; Kusuzaki, Katsuyuki; Bonuccelli, Gloria; Sonveaux, Pierre; Rotili, Dante; Mai, Antonello; Baldini, Nicola

    2016-01-01

    The glycolytic-based metabolism of cancers promotes an acidic microenvironment that is responsible for increased aggressiveness. However, the effects of acidosis on tumour metabolism have been almost unexplored. By using capillary electrophoresis with time-of-flight mass spectrometry, we observed a significant metabolic difference associated with glycolysis repression (dihydroxyacetone phosphate), increase of amino acid catabolism (phosphocreatine and glutamate) and urea cycle enhancement (arginino succinic acid) in osteosarcoma (OS) cells compared with normal fibroblasts. Noteworthy, metabolites associated with chromatin modification, like UDP-glucose and N(8)-acetylspermidine, decreased more in OS cells than in fibroblasts. COBRA assay and acetyl-H3 immunoblotting indicated an epigenetic stability in OS cells than in normal cells, and OS cells were more sensitive to an HDAC inhibitor under acidosis than under neutral pH. Since our data suggest that acidosis promotes a metabolic reprogramming that can contribute to the epigenetic maintenance under acidosis only in tumour cells, the acidic microenvironment should be considered for future therapies. PMID:27186436

  11. Tumour-specific metabolic adaptation to acidosis is coupled to epigenetic stability in osteosarcoma cells

    PubMed Central

    Chano, Tokuhiro; Avnet, Sofia; Kusuzaki, Katsuyuki; Bonuccelli, Gloria; Sonveaux, Pierre; Rotili, Dante; Mai, Antonello; Baldini, Nicola

    2016-01-01

    The glycolytic-based metabolism of cancers promotes an acidic microenvironment that is responsible for increased aggressiveness. However, the effects of acidosis on tumour metabolism have been almost unexplored. By using capillary electrophoresis with time-of-flight mass spectrometry, we observed a significant metabolic difference associated with glycolysis repression (dihydroxyacetone phosphate), increase of amino acid catabolism (phosphocreatine and glutamate) and urea cycle enhancement (arginino succinic acid) in osteosarcoma (OS) cells compared with normal fibroblasts. Noteworthy, metabolites associated with chromatin modification, like UDP-glucose and N8-acetylspermidine, decreased more in OS cells than in fibroblasts. COBRA assay and acetyl-H3 immunoblotting indicated an epigenetic stability in OS cells than in normal cells, and OS cells were more sensitive to an HDAC inhibitor under acidosis than under neutral pH. Since our data suggest that acidosis promotes a metabolic reprogramming that can contribute to the epigenetic maintenance under acidosis only in tumour cells, the acidic microenvironment should be considered for future therapies. PMID:27186436

  12. Infusion of sodium bicarbonate in experimentally induced metabolic acidosis does not provoke cerebrospinal fluid (CSF) acidosis in calves.

    PubMed

    Abeysekara, Saman; Zello, Gordon A; Lohmann, Katharina L; Alcorn, Jane; Hamilton, Don L; Naylor, Jonathan M

    2012-01-01

    In a crossover study, 5 calves were made acidotic by intermittent intravenous infusion of isotonic hydrochloric acid (HCl) over approximately 24 h. This was followed by rapid (4 h) or slow (24 h) correction of blood pH with isotonic sodium bicarbonate (NaHCO(3)) to determine if rapid correction of acidemia produced paradoxical cerebrospinal fluid (CSF) acidosis. Infusion of HCl produced a marked metabolic acidosis with respiratory compensation. Venous blood pH (mean ± S(x)) was 7.362 ± 0.021 and 7.116 ± 0.032, partial pressure of carbon dioxide (Pco(2), torr) 48.8 ± 1.3 and 34.8 ± 1.4, and bicarbonate (mmol/L), 27.2 ± 1.27 and 11 ± 0.96; CSF pH was 7.344 ± 0.031 and 7.240 ± 0.039, Pco(2) 42.8 ± 2.9 and 34.5 ± 1.4, and bicarbonate 23.5 ± 0.91 and 14.2 ± 1.09 for the period before the infusion of hydrochloric acid and immediately before the start of sodium bicarbonate correction, respectively. In calves treated with rapid infusion of sodium bicarbonate, correction of venous acidemia was significantly more rapid and increases in Pco(2) and bicarbonate in CSF were also more rapid. However, there was no significant difference in CSF pH. After 4 h of correction, CSF pH was 7.238 ± 0.040 and 7.256 ± 0.050, Pco(2) 44.4 ± 2.2 and 34.2 ± 2.1, and bicarbonate 17.8 ± 1.02 and 14.6 ± 1.4 for rapid and slow correction, respectively. Under the conditions of this experiment, rapid correction of acidemia did not provoke paradoxical CSF acidosis. PMID:22754090

  13. [Blood sugar and hypoxic dynamics in metabolic acidosis and alkalosis (experimental data)].

    PubMed

    Iluchev, D

    1975-01-01

    The dynamics of the glucose concentration and arterovenous glucose gradient was examined during different metabolic deviations in the acid-base balance. The metabolitic acidosis increased the level of sugar in the blood. A definite influence on the latter had the gravity of the acidosis and to a certain degree its pathogenetic form. The arterio-venous glucose difference changed from negative to positive with the increase of proton activity. The type of the peripheral hypoxic structure, formed during the state of acidosis influenced both the glucose gradient and its quantitative relations to the acid-base and oxygen indices. The sugar content in the blood during metabolitic alcalosis was not changed significantly. There was an increase in the arterio-venous gradient and inverse correlation between the glucose level and the arterio-venous oxygen difference with the increase of the bicarbonate concentration. PMID:4290

  14. 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 ischaemia. However, presynaptic muscarinic inhibition of noradrenaline release was not affected by hyperkalaemia, but was sensitive to metabolic inhibition and low degrees of acidosis. PMID:11884219

  15. 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.

  16. Construction and validation of a decision tree for treating metabolic acidosis in calves with neonatal diarrhea

    PubMed Central

    2012-01-01

    Background The aim of the present prospective study was to investigate whether a decision tree based on basic clinical signs could be used to determine the treatment of metabolic acidosis in calves successfully without expensive laboratory equipment. A total of 121 calves with a diagnosis of neonatal diarrhea admitted to a veterinary teaching hospital were included in the study. The dosages of sodium bicarbonate administered followed simple guidelines based on the results of a previous retrospective analysis. Calves that were neither dehydrated nor assumed to be acidemic received an oral electrolyte solution. In cases in which intravenous correction of acidosis and/or dehydration was deemed necessary, the provided amount of sodium bicarbonate ranged from 250 to 750 mmol (depending on alterations in posture) and infusion volumes from 1 to 6.25 liters (depending on the degree of dehydration). Individual body weights of calves were disregarded. During the 24 hour study period the investigator was blinded to all laboratory findings. Results After being lifted, many calves were able to stand despite base excess levels below −20 mmol/l. Especially in those calves, metabolic acidosis was undercorrected with the provided amount of 500 mmol sodium bicarbonate, which was intended for calves standing insecurely. In 13 calves metabolic acidosis was not treated successfully as defined by an expected treatment failure or a measured base excess value below −5 mmol/l. By contrast, 24 hours after the initiation of therapy, a metabolic alkalosis was present in 55 calves (base excess levels above +5 mmol/l). However, the clinical status was not affected significantly by the metabolic alkalosis. Conclusions Assuming re-evaluation of the calf after 24 hours, the tested decision tree can be recommended for the use in field practice with minor modifications. Calves that stand insecurely and are not able to correct their position if pushed require higher doses of sodium bicarbonate, if there is clinical evidence of a marked D-lactic acidosis. In those calves, determining the degree of loss of the palpebral reflex was identified as a useful decision criterion to provide an additional amount of 250 mmol sodium bicarbonate. This work demonstrates the clinical relevance of the discovery that D-lactate is responsible for most of the clinical signs expressed in neonatal diarrheic calves suffering from metabolic acidosis. PMID:23216654

  17. Hyperchloremic Metabolic Acidosis due to Cholestyramine: A Case Report and Literature Review

    PubMed Central

    Kamar, Fareed B.; McQuillan, Rory F.

    2015-01-01

    Cholestyramine is a bile acid sequestrant that has been used in the treatment of hypercholesterolemia, pruritus due to elevated bile acid levels, and diarrhea due to bile acid malabsorption. This medication can rarely cause hyperchloremic nonanion gap metabolic acidosis, a complication featured in this report of an adult male with concomitant acute kidney injury. This case emphasizes the caution that must be taken in prescribing cholestyramine to patients who may also be volume depleted, in renal failure, or taking spironolactone. PMID:26425378

  18. Hyperchloremic Metabolic Acidosis due to Cholestyramine: A Case Report and Literature Review.

    PubMed

    Kamar, Fareed B; McQuillan, Rory F

    2015-01-01

    Cholestyramine is a bile acid sequestrant that has been used in the treatment of hypercholesterolemia, pruritus due to elevated bile acid levels, and diarrhea due to bile acid malabsorption. This medication can rarely cause hyperchloremic nonanion gap metabolic acidosis, a complication featured in this report of an adult male with concomitant acute kidney injury. This case emphasizes the caution that must be taken in prescribing cholestyramine to patients who may also be volume depleted, in renal failure, or taking spironolactone. PMID:26425378

  19. Effect of metabolic acidosis on renal tubular sodium handling in rats as determined by lithium clearance.

    PubMed

    Menegon, L F; Figueiredo, J F; Gontijo, J A

    1998-10-01

    Systemic metabolic acidosis is known to cause a decrease in salt and water reabsorption by the kidney. We have used renal lithium clearance to investigate the effect of chronic, NH4Cl-induced metabolic acidosis on the renal handling of Na+ in male Wistar-Hannover rats (200-250 g). Chronic acidosis (pH 7.16 +/- 0.13) caused a sustained increase in renal fractional Na+ excretion (267.9 +/- 36.4%), accompanied by an increase in fractional proximal (113.3 +/- 3.6%) and post-proximal (179.7 +/- 20.2%) Na+ and urinary K+ (163.4 +/- 5.6%) excretion when compared to control and pair-fed rats. These differences occurred in spite of an unchanged creatinine clearance and Na+ filtered load. A lower final body weight was observed in the acidotic (232 +/- 4.6 g) and pair-fed (225 +/- 3.6 g) rats compared to the controls (258 +/- 3.7 g). In contrast, there was a significant increase in the kidney weights of acidotic rats (1.73 +/- 0.05 g) compared to the other experimental groups (control, 1.46 +/- 0.05 g; pair-fed, 1.4 +/- 0.05 g). We suggest that altered renal Na+ and K+ handling in acidotic rats may result from a reciprocal relationship between the level of metabolism in renal tubules and ion transport. PMID:9876297

  20. Prevalence of Metformin Use and the Associated Risk of Metabolic Acidosis in US Diabetic Adults With CKD: A National Cross-Sectional Study.

    PubMed

    Kuo, Chin-Chi; Yeh, Hung-Chieh; Chen, Bradley; Tsai, Ching-Wei; Lin, Yu-Sheng; Huang, Chiu-Ching

    2015-12-01

    The use of metformin in chronic kidney disease (CKD) population has been intensely debated with conflicting evidence. Large population studies are needed to inform risk assessment and therapeutic decision-making. We evaluated the associations among metformin, metabolic acidosis, and CKD in a 10-year nationally representative noninstitutionalized civilian population in the United States.In this cross-sectional study, a total of 2279 diabetic adults aged 20 years or older in the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2012 were included and had measurements of serum bicarbonate, sodium, potassium, and chloride. The exposure was metformin use. The outcome was subclinical and severe metabolic acidosis defined by serum bicarbonate <23 mEq/L and anion gap > 16mEq/L and by serum bicarbonate < 20 mEq/L, respectively.The prevalence of metformin use decreased from 67.2% among CKD-1 and -2, 40.6% among CKD-3, to 1.3% among advanced CKD-4 and -5. Across CKD stages up to CKD-3b, we observed a tendency of lower levels of serum bicarbonate that was significant in metformin users with CKD-2 and CKD-3a and marginally significant with CKD-3b compared to nonmetformin users. The corresponding tendency of higher anion gap in metformin users with the estimated glomerular filtration rate >60 mL/min/1.73 m was also observed. In multiple linear regression analysis, metformin was significantly associated with decreased serum bicarbonate levels (β = -0.45, 95% CI: -0.73, -0.17) and increased serum anion gap levels (β = 0.40, 95% CI: 0.19, 0.61). The adjusted odds ratio of subclinical high anion gap and severe metabolic acidosis for metformin users was 1.68 (95% CI: 1.11, 2.55) and 1.31 (0.49, 3.47), respectively. The association between metformin and serum bicarbonate was significantly modified by CKD status. No interaction was found between metformin and CKD stages for serum anion gap and acidosis.Metformin is associated with subclinical metabolic acidosis but not with severe metabolic acidosis. The propensity of serum bicarbonate-lowering effect was intensified in advanced CKD; however, such tendency was not associated with the risk of clinically defined acidosis. Our findings highlight a potential of cautious expansion of metformin use among CKD-3b patients with diabetes meriting further investigations. PMID:26705203

  1. 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. PMID:24855681

  2. Na+/H+ exchange in human lymphocytes and platelets in chronic and subacute metabolic acidosis.

    PubMed Central

    Reusch, H P; Reusch, R; Rosskopf, D; Siffert, W; Mann, J F; Luft, F C

    1993-01-01

    The effect of acid-base disturbances on sodium/proton (Na+/H+) exchange has been examined in animal models; however, few data are available from human studies. To test the effect of metabolic acidosis on Na+/H+ exchange in man, as well as to examine the relationship between Na+/H+ exchange and cytosolic calcium ([Ca2+]i), we measured both variables in patients with decreased renal function with mild metabolic acidosis (pH 7.34 +/- 0.06), in normal control subjects (pH 7.41 +/- 0.02), and in subjects before (pH 7.40 +/- 0.01), and after (pH 7.26 +/- 0.04) ammonium chloride (NH4Cl) 15 g for 5 d. Lymphocytes and platelets were loaded with the cytosolic pH (pHi) indicator 2'-7'-bis(carboxyethyl)-5,6-carboxyfluorescein and acidified to pH approximately 6.6 with propionic acid. To quantitate Na+/H+ exchange, dpHi/dt was determined at 1 min. [Ca2+]i was measured with fura-2. Na+/H+ exchange was significantly increased only in lymphocytes of patients with renal insufficiency. Neither intracellular pH (pHi) nor [Ca2+]i was different from controls. NH4Cl resulted in a significant increase in Na+/H+ exchange in lymphocytes, but not in platelets of normal subjects. Values of pHi and [Ca2+]i in either cell type remained unaffected. Since metabolic acidosis influenced Na+/H+ only in lymphocytes, but not in platelets, it is possible that protein synthesis may be involved in increasing Na+/H+ exchange. PMID:8394388

  3. Multiplexed microneedle-based biosensor array for characterization of metabolic acidosis.

    PubMed

    Miller, Philip R; Skoog, Shelby A; Edwards, Thayne L; Lopez, Deanna M; Wheeler, David R; Arango, Dulce C; Xiao, Xiaoyin; Brozik, Susan M; Wang, Joseph; Polsky, Ronen; Narayan, Roger J

    2012-01-15

    The development of a microneedle-based biosensor array for multiplexed in situ detection of exercise-induced metabolic acidosis, tumor microenvironment, and other variations in tissue chemistry is described. Simultaneous and selective amperometric detection of pH, glucose, and lactate over a range of physiologically relevant concentrations in complex media is demonstrated. Furthermore, materials modified with a cell-resistant (Lipidure(®)) coating were shown to inhibit macrophage adhesion; no signs of coating delamination were noted over a 48-h period. PMID:22265568

  4. Role of proton receptor OGR1 in bone response to metabolic acidosis?

    PubMed

    Jorgetti, Vanda; Drüeke, Tilman B; Ott, Susan M

    2016-03-01

    Chronic metabolic acidosis stimulates bone resorption, resulting in loss of calcium and bicarbonate from bone. Both osteoblasts and osteoclasts sense extracellular H(+) by the G-protein coupled receptor, OGR1, whose activation leads to increased bone resorption as well as decreased bone formation. Krieger et al. examined the effect of OGR1 knockout in mice. They found an unexpected increase in bone resorption, but nevertheless an increase in bone volume linked to enhanced bone formation. This discovery opens a window of opportunity to explore potential new anabolic treatments for patients with low bone mass. PMID:26880446

  5. Effect of chronic metabolic acidosis on bone density and bone architecture in vivo in rats.

    PubMed

    Gasser, Jürg A; Hulter, Henry N; Imboden, Peter; Krapf, Reto

    2014-03-01

    Chronic metabolic acidosis (CMA) might result in a decrease in vivo in bone mass based on its reported in vitro inhibition of bone mineralization, bone formation, or stimulation of bone resorption, but such data, in the absence of other disorders, have not been reported. CMA also results in negative nitrogen balance, which might decrease skeletal muscle mass. This study analyzed the net in vivo effects of CMA's cellular and physicochemical processes on bone turnover, trabecular and cortical bone density, and bone microarchitecture using both peripheral quantitative computed tomography and μCT. CMA induced by NH4Cl administration (15 mEq/kg body wt/day) in intact and ovariectomized (OVX) rats resulted in stable CMA (mean Δ[HCO3(-)]p = 10 mmol/l). CMA decreased plasma osteocalcin and increased TRAP5b in intact and OVX animals. CMA decreased total volumetric bone mineral density (vBMD) after 6 and 10 wk (week 10: intact normal +2.1 ± 0.9% vs. intact acidosis -3.6 ± 1.2%, P < 0.001), an effect attributable to a decrease in cortical thickness and, thus, cortical bone mass (no significant effect on cancellous vBMD, week 10) attributed to an increase in endosteal bone resorption (nominally increased endosteal circumference). Trabecular bone volume (BV/TV) decreased significantly in both CMA groups at 6 and 10 wk, associated with a decrease in trabecular number. CMA significantly decreased muscle cross-sectional area in the proximal hindlimb at 6 and 10 wk. In conclusion, chronic metabolic acidosis induces a large decrease in cortical bone mass (a prime determinant of bone fragility) in intact and OVX rats and impairs bone microarchitecture characterized by a decrease in trabecular number. PMID:24352505

  6. 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.

  7. Severity of ruminal acidosis in primiparous holstein cows during the periparturient period.

    PubMed

    Penner, G B; Beauchemin, K A; Mutsvangwa, T

    2007-01-01

    The objectives of this study were: 1) to determine the effect of providing additional prepartum concentrate on the occurrence and severity of ruminal acidosis (RA) and lactational performance during the periparturient period in primiparous cows; and 2) to characterize the occurrence and severity of RA during the periparturient period. We hypothesized that providing additional concentrate prepartum would reduce postpartum RA. Fourteen ruminally cannulated Holstein heifers were paired by expected calving date and body condition score. The heifers were assigned to 1 of 2 prepartum feeding regimens: 1) a control treatment consisting of a far-off diet (forage:concentrate, F:C = 80:20) fed from d -60 to d -25 and a close-up diet (F:C = 54:46) fed from d -24 until parturition; or 2) a high-concentrate (HC) feeding program consisting of 4 prepartum diets, HC-1 (F:C = 68:32) fed from d -60 to d -43, HC-2 (F:C = 60:40) fed from d -42 to d -25, HC-3 (F:C = 52:48) fed from d -24 to d -13, and HC-4 (F:C = 46:54) fed from d -12 until parturition. All cows received the same lactation diet postpartum. Ruminal pH was measured continuously from d -5 to d +5, and for 3 consecutive days starting on d +17 +/- 1.2, d +37 +/- 1.4, and d +58 +/- 1.5 relative to parturition using an indwelling ruminal pH system. Ruminal acidosis was considered to occur when ruminal pH was <5.8 (total RA). Ruminal acidosis was further partitioned into: 1) mild RA (5.8 > ruminal pH > 5.5), 2) moderate RA (5.5 > ruminal pH > 5.2), and 3) acute RA (ruminal pH < 5.2). Feeding additional concentrate prepartum did not reduce postpartum RA. In fact, cows fed the HC treatment had more daily episodes of acute RA than cows fed the control treatment. Day relative to parturition affected the occurrence and severity of RA; RA increased following parturition and was sustained thereafter. The DM intake during the last 5 d of gestation was lower for cows fed the HC treatment compared with cows fed the control treatment, but lactational performance was not affected. We conclude that, under the conditions imposed, feeding additional concentrate prepartum does not reduce postpartum RA. Furthermore, the incidence and severity of RA increases immediately postpartum, emphasizing the need to develop and implement feeding strategies that reduce this risk. PMID:17183105

  8. Reversal of severe lactic acidosis with thiamine in a renal allograft recipient.

    PubMed

    Kumar, K Nanda; Shah, Veena R; Parikh, Beena K; Sonde, Sumedha

    2015-07-01

    A 48-year-old female patient with end-stage renal failure developed unexplained severe lactic acidosis (LA) associated with hyperglycemia during robotic-assisted laparoscopic renal transplantation. Initial treatment with sodium bicarbonate and insulin infusion were ineffective in treating acidemia. Postoperatively, intravenous administration of thiamine resulted in rapid improvement of LA and blood sugar levels. Uremia and chronic hemodialysis might be the causes behind the quantitative/qualitative deficiency of thiamine unmasked during the surgical stress. Though a rare entity, acute thiamine deficiency should be considered in the differential diagnosis of unexplained severe LA in patients with chronic kidney disease and hemodialysis who undergo major surgery or admitted to critical illness care units. PMID:26180438

  9. Reversal of severe lactic acidosis with thiamine in a renal allograft recipient

    PubMed Central

    Kumar, K. Nanda; Shah, Veena R.; Parikh, Beena K.; Sonde, Sumedha

    2015-01-01

    A 48-year-old female patient with end-stage renal failure developed unexplained severe lactic acidosis (LA) associated with hyperglycemia during robotic-assisted laparoscopic renal transplantation. Initial treatment with sodium bicarbonate and insulin infusion were ineffective in treating acidemia. Postoperatively, intravenous administration of thiamine resulted in rapid improvement of LA and blood sugar levels. Uremia and chronic hemodialysis might be the causes behind the quantitative/qualitative deficiency of thiamine unmasked during the surgical stress. Though a rare entity, acute thiamine deficiency should be considered in the differential diagnosis of unexplained severe LA in patients with chronic kidney disease and hemodialysis who undergo major surgery or admitted to critical illness care units. PMID:26180438

  10. 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

  11. 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. PMID:24694986

  12. Gene expression profile of duodenal epithelial cells in response to chronic metabolic acidosis.

    PubMed

    Wongdee, Kannikar; Teerapornpuntakit, Jarinthorn; Riengrojpitak, Suda; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

    2009-01-01

    Chronic metabolic acidosis (CMA) affects ion transport, permeability, and metabolism of the intestinal absorptive cells. Most effects of CMA on the intestine are long-term adaptations at genomic level. To identify the CMA-regulated genes, the Illumina's microarray featuring high-performance BeadArray technology was performed on RNA samples from the rat duodenal epithelial cells exposed to long-standing acidemia. After 21 days of CMA, we found 423 transcripts upregulated and 261 transcripts downregulated. Gene ontology analysis suggested effects of CMA on cellular processes, such as cell adhesion, proliferation, fuel metabolism, and biotransformation. Interestingly, 27 upregulated transcripts (e.g., Aqp1, Cacnb1, Atp1a2, Kcnab2, and Slc2a1) and 13 downregulated transcripts (e.g., Slc17a7, Slc9a4, and Slc30a3) are involved in the absorption of water, ions, and nutrients. Some upregulated genes, such as Slc38a5 and Slc1a7 encoding glutamine transporters, may be parts of the total body adaptation to alleviate negative nitrogen balance. Therefore, the present results provided a novel genome-wide information for further investigations of the mechanism of CMA effect on the intestine. PMID:18979233

  13. Intra-operative correction of acidosis, coagulopathy and hypothermia in combat casualties with severe haemorrhagic shock.

    PubMed

    Morrison, J J; Ross, J D; Poon, H; Midwinter, M J; Jansen, J O

    2013-08-01

    We assessed acidosis, coagulopathy and hypothermia, before and after surgery in 51 combat troops operated on for severe blast injury. Patients were transfused a median (IQR [range]) of 27 (17-38 [5-84]) units of red cell concentrate, 27 (16-38 [4-83]) units of plasma, 2.0 (0.5-3.5 [0-13.0]) units of cryoprecipitate and 4 (2-6 [0-17]) pools of platelets. The pH, base excess, prothrombin time and temperature increased: from 7.19 (7.10-7.29 [6.50-7.49]) to 7.45 (7.40-7.51 [7.15-7.62]); from -9.0 (-13.5 to -4.5 [-28 to -2]) mmol.l⁻¹ to 4.5 (1.0-8.0 [-7 to +11]) mmol.l⁻¹; from 18 (15-21 [9-24]) s to 14 (11-18 [9-21]) s; and from 36.1 (35.1-37.1 [33.0-38.1]) °C to 37.4 (37.0-37.9 [36.0-38.0]) °C, respectively. Contemporary intra-operative resuscitation strategies can normalise the physiological derangements caused by haemorrhagic shock. PMID:23724784

  14. 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

  15. The role of dietary acid load and mild metabolic acidosis in insulin resistance in humans.

    PubMed

    Williams, Rebecca S; Kozan, Pinar; Samocha-Bonet, Dorit

    2016-05-01

    Type 2 diabetes is increasingly being recognised as a global health crisis (World Health Organisation). Insulin resistance is closely associated with obesity and precedes the development of type 2 diabetes. However, there is now increasing evidence to suggest that diet itself may independently be associated with type 2 diabetes risk. A diet with a high acid load (or high potential renal net acid load, PRAL) can result in a decrease in pH towards the lower end of the normal physiological range, which may in turn lead to the development of insulin resistance. Conversely, reducing dietary acid load (the so called 'alkaline diet') may be protective and prevent the onset of type 2 diabetes. Here, we explore the influence of dietary acid load on the development of mild metabolic acidosis and induction of insulin resistance. Whilst large prospective cohort studies link high dietary acid load or low serum bicarbonate with the development of type 2 diabetes, the effect of a diet with a low acid (or high alkaline) load remains unclear. Further interventional studies are required to investigate the influence of dietary composition on the body's acid/base balance, insulin resistance and incidence of type 2 diabetes. PMID:26363101

  16. 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 1.0% NaOH treatments of DDGS. In the current study, feeding DDGS treated with NaOH did not increase fiber digestibility nor was it necessary to alleviate a possible metabolic acidosis. Alkali treatment of DDGS did not increase average ruminal pH or blood pH. PMID:27065141

  17. The relationship between rumen acidosis resistance and expression of genes involved in regulation of intracellular pH and butyrate metabolism of ruminal epithelial cells in steers.

    PubMed

    Schlau, N; Guan, L L; Oba, M

    2012-10-01

    Past research has focused on the prevention and management of subacute rumen acidosis by manipulating the ration; however, the severity of acidosis varies even among animals fed a common high-grain diet. The objectives of this study were to compare the ruminal volatile fatty acid (VFA) profile and expression of genes involved in the metabolism of butyrate, the VFA most extensively metabolized by the ruminal epithelium, and intracellular pH regulation in ruminal epithelial cells between acidosis-resistant (AR) and acidosis-susceptible (AS) steers. Acidosis indexes (area per day under pH 5.8 divided by dry matter intake) were measured for 17 steers fed a common high-grain diet, and the 3 steers with the lowest (1.4 ± 1.2 pH∙min/kg) and the 3 with the highest values (23.9 ± 7.4 pH∙min/kg) were classified as AR and AS, respectively, and used in the subsequent study. The steers were force-fed a diet containing 85% grain at 60% of the expected daily intake (5.8 ± 0.8 and 5.6 ± 0.6 kg for AR and AS, respectively) within 30 min. Mean ruminal pH over the postprandial 6-h period was higher for AR compared with AS (6.02 vs. 5.55), and mean total VFA concentration was 74% for AR compared with AS (122 vs. 164 mM). Molar proportion of butyrate in the ruminal fluid was 139% higher for AR compared with AS (17.5 vs. 7.33 mol/100 mol of VFA). Expression of monocarboxylate cotransporter isoform 1, sodium hydrogen exchanger isoforms 1 and 2, and anion exchangers (downregulated in adenoma and putative anion exchanger, isoform 1) did not differ between AR and AS steers. However, expression of sodium hydrogen exchanger isoform 3, which imports Na(+) to the epithelial cell and exports H(+) to the rumen, was 176% higher in AR steers than in AS steers. Higher ruminal pH for AR might be partly due to a faster rate of VFA absorption, lower VFA production, or both. PMID:22863095

  18. Severe lactic acidosis and multiorgan failure due to thiamine deficiency during total parenteral nutrition.

    PubMed

    Ramsi, Musaab; Mowbray, Claire; Hartman, Gary; Pageler, Natalie

    2014-01-01

    A 16-year-old perioperative paediatric patient presented with refractory lactic acidosis and multiorgan failure due to thiamine-deficient total parenteral nutrition during a recent national multivitamin shortage. Urgent empiric administration of intravenous thiamine resulted in prompt recovery from this life-threatening condition. Despite readily available treatment, a high index of suspicion is required to prevent cardiovascular collapse and mortality. PMID:24895398

  19. Downregulation of claudin-2 expression in renal epithelial cells by metabolic acidosis.

    PubMed

    Balkovetz, Daniel F; Chumley, Phillip; Amlal, Hassane

    2009-09-01

    Chronic metabolic acidosis (CMA) is associated with an inhibition of fluid reabsorption in the renal proximal tubule. The effects of CMA on paracellular transport across the renal epithelial tight junction (TJ) is unknown. Claudin-2 is a transmembrane TJ-associated protein which confers TJ paracellular permeability to Na(+). We examined the effects of CMA on the expression of TJ transport proteins using both in vivo and in vitro models of CMA. The results showed downregulation of claudin-2 mRNA and protein expression in the cortex of rats subjected to the NH(4)Cl loading model of CMA. Madin-Darby canine kidney (MDCK) and HK-2 cells are models of renal epithelial cells and express claudin-2 protein in their TJ. We examined the effects of acidic pH exposure on the expression of claudin-2 in MDCK and HK-2 renal epithelial cells. Exposure of MDCK cells to pH 6.96 medium caused a significant and reversible decrease in claudin-2 protein abundance. A dose-response analysis of acidic medium exposure of MDCK and HK-2 cells demonstrated a downregulation of claudin-2 protein. The downregulation effect of acidic pH is specific to claudin-2 expression as the expression of other TJ-associated proteins (i.e., claudin-1, -3, -4, and -7, occludin, and zonula occludens-1) remained unchanged compared with control pH (7.40). Collectively, these data demonstrate that CMA downregulates the expression of claudin-2 likely through a direct effect of acidic pH. Potential physiological significance of these changes is discussed. PMID:19587148

  20. An Unusual Initial Presentation of Sjögren’s Syndrome: Severe Hypokalemic Paralysis Secondary to Distal Renal Tubular Acidosis

    PubMed Central

    Sengul, Erkan; Bunul, Fatih; Yazici, Ayten; Sengul, Aysun; Dindar, Sevim; Halhalli, Gökçen Selma Kilic; Binnetoglu, Emine

    2013-01-01

    Sjögren’s syndrome is mainly affects the exocrine glands. Patients usually complain of persistent dryness of the mouth and eyes. However, nonexocrine organs such as the kidneys are often affected in these patients. Distal renal tubular acidosis (dRTA) and interstitiel nephritis are common in Sjögren’s syndrome. Nonetheless, severe hypokalemia and paralysis secondary to dRTA are unusual initial manifestation of Sjögren’s syndrome. Here, we describe a case of a 48 year old women admitted to the emergency setting with severe hypokalemic paralysis and diagnosed Sjögren’s syndrome. PMID:25610283

  1. Incidence, prevalence, severity, and risk factors for ruminal acidosis in feedlot steers during backgrounding, diet transition, and finishing.

    PubMed

    Castillo-Lopez, E; Wiese, B I; Hendrick, S; McKinnon, J J; McAllister, T A; Beauchemin, K A; Penner, G B

    2014-07-01

    The objective of this study was to determine the incidence, prevalence, severity, and risk factors for ruminal acidosis in feedlot steers during backgrounding, diet transition, and finishing. Steers were purchased from a local auction market (n = 250; mean ± SD; 330 ± 20.0 kg initial BW) and were grouped together with 28 steers fitted with a ruminal cannula (248 ± 25.5 kg initial BW). Steers were randomly allocated to 1 of 8 pens (3 to 4 cannulated steers per pen with a total of 35 steers/pen). The feeding period (143 d) was divided into 4 phases: backgrounding (BKGD; d 1 to 20), diet transition (TRAN; d 21 to 40), and the first (FIN1; d 41 to 91) and second half (FIN2; d 92 to 143) of finishing. The BKGD diet contained (% DM) barley silage (45.7%), barley grain (41.6%), canola meal (4.2%), and a pelleted mineral and vitamin supplement (8.5%). Steers were transitioned to a finishing diet containing (% DM) barley silage (5%), barley grain (80.9%), canola meal (4.9%), and a pelleted mineral and vitamin supplement (9.2%) using 4 transition diets. Feed was offered to achieve 5% refusals (as-is basis). Ruminal pH was recorded in cannulated steers every 10 min throughout the study, and feed refusals and BW were recorded at 2 wk intervals. Mean ruminal pH (P < 0.01) was 6.4, 6.3, 6.2, and 6.0 ± 0.01 during the BKGD, TRAN, FIN1, and FIN2, respectively. The duration (P < 0.01) pH < 5.5 was 4.1, 12.1, 78.7, and 194 ± 9.4 min/d during BKGD, TRAN, FIN1, and FIN2, respectively. Using a threshold of ruminal pH < 5.5 for at least 180 min to diagnose ruminal acidosis, incidence was defined as the number of times steers experienced ruminal acidosis during each period and prevalence was defined as the percentage of steers that experienced acidosis during each period. On average, the incidence rate (P < 0.01) of ruminal acidosis was 0.1, 0.3, 6.7, and 14.8 ± 0.97 episodes during BKGD, TRAN, FIN1, and FIN2, respectively. In the same order, the prevalence (P < 0.01) was 0.7, 1.7, 15.4, and 37.8 ± 2.0%. Based on multiple regression, factors associated with prevalence of ruminal acidosis and the duration pH < 5.5 were feeding phase (P < 0.01) and DMI (P < 0.01). Overall, the greatest incidence, prevalence, and severity of ruminal acidosis were observed towards the end of the finishing phase and were associated with days on feed and DMI. PMID:24879761

  2. 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.

  3. 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. PMID:26648089

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

    PubMed Central

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

    2015-01-01

    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. PMID:26648089

  5. Role of the carotid bodies in the respiratory compensation for the metabolic acidosis of exercise in humans.

    PubMed Central

    Rausch, S M; Whipp, B J; Wasserman, K; Huszczuk, A

    1991-01-01

    1. In response to an acute exercise-induced metabolic acidosis, the fall of arterial pH is constrained by the magnitude of the compensatory hyperventilation. To determine the role of the carotid bodies in this regulatory process, subjects performed prolonged (24 min) square-wave cycle ergometry from a background of unloaded cycling at inspired oxygen fractions (FI,O2) of 0.12 O2 (high carotid body gain), 0.21 O2 (normal carotid body gain) and 0.80 O2 (low carotid body gain). The work rates were selected to provide the same exercise intensity, despite the different inspirates; i.e. resulting in a constant increase in arterial blood [lactate] (delta [L-] approximately 4 mequiv l-1. 2. Ventilatory and pulmonary gas exchange variables were computed breath-by-breath and arterial blood was sampled at intervals throughout the tests and analysed subsequently for [lactate], [pyruvate], arterial partial pressures of oxygen and carbon dioxide (PO2, PCO2), pH, [bicarbonate] and [potassium]. 3. Hypoxia markedly reduced, and hyperoxia magnified, the transient decrease in arterial pH following exercise onset. However, there was a slow acid-base compensatory component, even when carotid chemosensitivity was suppressed by hyperoxia. We therefore conclude that, in humans, carotid body chemosensitivity plays a dominant role in constraining variations of arterial pH in response to the acute metabolic acidosis of heavy exercise, but that secondary-presumably central chemosensory-mechanisms subserve a slower compensatory role. PMID:1822563

  6. 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. PMID:25987732

  7. The progestin etonogestrel enhances the respiratory response to metabolic acidosis in newborn rats. Evidence for a mechanism involving supramedullary structures.

    PubMed

    Loiseau, Camille; Osinski, Diane; Joubert, Fanny; Straus, Christian; Similowski, Thomas; Bodineau, Laurence

    2014-05-01

    Central congenital hypoventilation syndrome is a neuro-respiratory disease characterized by the dysfunction of the CO2/H(+) chemosensitive neurons of the retrotrapezoid nucleus/parafacial respiratory group. A recovery of CO2/H(+) chemosensitivity has been observed in some central congenital hypoventilation syndrome patients coincidental with contraceptive treatment by a potent progestin, desogestrel (Straus et al., 2010). The mechanisms of this progestin effect remain unknown, although structures of medulla oblongata, midbrain or diencephalon are known to be targets for progesterone. In the present study, on ex vivo preparations of central nervous system of newborn rats, we show that acute exposure to etonogestrel (active metabolite of desogestrel) enhanced the increased respiratory frequency induced by metabolic acidosis via a mechanism involving supramedullary structures located in pontine, mesencephalic or diencephalic regions. PMID:24686181

  8. Lactic Acidosis in a Patient with Type 2 Diabetes Mellitus.

    PubMed

    Weisberg, Lawrence S

    2015-08-01

    Lactic acidosis occurs when lactate production exceeds its metabolism. There are many possible causes of lactic acidosis, and in any given patient, several causes may coexist. This Attending Rounds presents a case in point. Metformin's role in the pathogenesis of lactic acidosis in patients with diabetes mellitus is complex, as the present case illustrates. The treatment of lactic acidosis is controversial, except for the imperative to remedy its underlying cause. The use of sodium bicarbonate to treat the often alarming metabolic derangements may be quite efficacious in that regard but is of questionable benefit to patients. Renal replacement therapies (RRTs) have particular appeal in this setting for a variety of reasons, but their effect on clinical outcomes is untested. PMID:25762524

  9. Effects of seasonal vitamin D deficiency and respiratory acidosis on bone metabolism markers in submarine crewmembers during prolonged patrols.

    PubMed

    Holy, Xavier; Collombet, Jean-Marc; Labarthe, Frédéric; Granger-Veyron, Nicolas; Bégot, Laurent

    2012-02-01

    The aim of the study was to determine the seasonal influence of vitamin D status on bone metabolism in French submariners over a 2-mo patrol. Blood samples were collected as follows: prepatrol and patrol days 20, 41, and 58 on crewmembers from both a winter (WP; n = 20) and a summer patrol (SP; n = 20), respectively. Vitamin D status was evaluated for WP and SP. Moreover, extended parameters for acid-base balance (Pco(2), pH, and bicarbonate), bone metabolism (bone alkaline phosphatase and COOH-terminal telopeptide of type I collagen), and mineral homeostasis (parathyroid hormone, ionized calcium and phosphorus) were scrutinized. As expected, SP vitamin D status was higher than WP vitamin D status, regardless of the considered experimental time. A mild chronic respiratory acidosis (CRA) was identified in both SP and WP submariners, up to patrol day 41. Such an occurrence paired up with an altered bone remodeling coupling (decreased bone alkaline phosphatase-to-COOH-terminal telopeptide of type I collagen ratio). At the end of the patrol (day 58), a partial compensation of CRA episode, combined with a recovered normal bone remodeling coupling, was observed in SP, not, however, in WP submariners. The mild CRA episode displayed over the initial 41-day submersion period was mainly induced by a hypercapnia resulting from the submarine-enriched CO(2) level. The correlated impaired bone remodeling may imply a physiological attempt to compensate this acidosis via bone buffering. On patrol day 58, the discrepancy observed in terms of CRA compensation between SP and WP may result from the seasonal influence on vitamin D status. PMID:22134698

  10. Metabolic bone disease (anticonvulsant osteomalacia) and renal tubular acidosis in tuberous sclerosis.

    PubMed

    Radó, J P; Haris, A

    1993-07-01

    The characteristics triad of tuberous sclerosis-adenoma sebaceum, mental deficiency and epilepsy-associated with distal-type renal tubular acidosis was combined with anticonvulsant osteomalacia in a 41-year-old woman. In addition to the specific bone lesions of tuberous sclerosis, the bone disease was caused by an adverse effect of a drug and possibly also by the renal disorder leading to significant musculoskeletal disability. In response to calcium carbonicum and 1-25-dihydroxyvitamin D therapy the musculoskeletal disability healed and the abnormal biochemical markers of anticonvulsant osteomalacia disappeared. The present observation draws attention to the increased hazard threatening patients on chronic anticonvulsant therapy simultaneously suffering from renal diseases. PMID:8286838

  11. 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. PMID:26349936

  12. Respiratory acidosis

    MedlinePlus

    ... when the lungs cannot remove all of the carbon dioxide the body produces. This causes body fluids, especially ... Acute respiratory acidosis is a condition in which carbon dioxide builds up very quickly, before the kidneys can ...

  13. Lactic acidosis

    MedlinePlus

    ... caused by certain diseases, such as: AIDS Cancer Kidney failure Respiratory failure Sepsis A common medicine used to treat diabetes called metformin can also cause lactic acidosis. If you take this medicine, have ...

  14. Changes in mRNAs for enzymes of glutamine metabolism in kidney and liver during ammonium chloride acidosis.

    PubMed

    Schoolwerth, A C; deBoer, P A; Moorman, A F; Lamers, W H

    1994-09-01

    Changes in protein and mRNAs for enzymes of glutamine metabolism were determined in rat kidney cortex at different times after induction of NH4Cl acidosis. After NH4Cl, phosphoenolpyruvate carboxykinase (PEPCK) mRNA increased 16-fold by 10 h (P < 0.05) and then returned to control levels by 30 h. In situ hybridization (ISH) showed that PEPCK mRNA was confined to medullary rays; after NH4Cl, expression of PEPCK expanded throughout the cortex, reaching a maximal intensity at 10 h. Phosphate-dependent glutaminase (PDG) and glutamate dehydrogenase (GDH) mRNAs increased 8- and 2.6-fold, respectively (both P < 0.05), by 10 h before decreasing; the increased expression was confirmed by ISH. Immunohistochemistry showed that increased PEPCK, PDG, and GDH protein occurred at variable times after the rise in mRNAs. The increase was confined to proximal tubules and was sustained, a finding noted also by Western blot analysis. In contrast, glutamine synthase protein and mRNA, confined to deep cortex and outer medullar, did not change after NH4Cl. These studies reveal striking changes in PEPCK and PDG mRNAs in rat renal cortex during acidosis. The ISH pattern suggested that increased amounts of PEPCK were synthesized in recruited cells which contained little enzyme under physiological conditions. mRNA levels for PEPCK, PDG, and GDH peaked at 10 h before returning to control levels. Despite the decrease in mRNAs, a sustained increase in proteins was noted. PMID:7916534

  15. Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function.

    PubMed

    Lange, Christian M; Bojunga, Jörg; Hofmann, Wolf Peter; Wunder, Katrin; Mihm, Ulrike; Zeuzem, Stefan; Sarrazin, Christoph

    2009-12-01

    Entecavir is a potent nucleoside inhibitor of the hepatitis B virus (HBV) polymerase with a high antiviral efficacy and a high genetic barrier to viral resistance. After approval in 2006, knowledge on the side effect profile in patients with advanced liver disease and impaired liver function is still limited. Here, we report on 16 patients with liver cirrhosis and chronic hepatitis B who were treated with entecavir. Five of these patients developed lactic acidosis during entecavir treatment. All patients who developed lactic acidosis had highly impaired liver function (Model for End-Stage Liver Disease [MELD] score >or= 20). Lactic acidosis (lactate 26-200 mg/dL, pH 7.02-7.40, base excess -5 mmol/L to -18 mmol/L) occurred between 4 and 240 days after treatment initiation with entecavir. Lactic acidosis was lethal in one patient but resolved in the other cases after termination/interruption of entecavir treatment. No increased lactate serum concentrations were observed during treatment with entecavir in the other 11 patients with chronic hepatitis B and liver cirrhosis who all had MELD scores below 18. The MELD score correlated with the development of lactic acidosis (P < 0.005) as well as its single parameters bilirubin, international normalized ratio, and creatinine. In contrast, Child-Pugh Score did not correlate with the development of lactic acidosis. Our data indicate that entecavir should be applied cautiously in patients with impaired liver function. PMID:19937695

  16. Severe encephalopathy, lactic acidosis, vegetative instability and neuropathy with 5-Fluorouracil treatment - pyrimidine degradation defect or beriberi?

    PubMed

    Rosen, A; van Kuilenburg, A; Assmann, B; Kuhlen, M; Borkhardt, A

    2011-05-01

    We present the case of a 19-year-old female with nasopharyngeal carcinoma, who received two courses of chemotherapy with 5-fluorouracil (5-FU) in combination with folic acid and cisplatin. Upon developing esophageal strictures in the course of her radiotherapy, she required total parenteral nutrition. In the course of therapy, the patient developed severe multisystem failure with encephalopathy, lactic acidosis, vegetative instability and neuropathy. The treatment with 5-FU can lead to severe toxicity due to enzyme deficiencies in the degradation of pyrimidines, but it can also lead to thiamine deficiency with the classic symptoms of beriberi. Beriberi is a rare disorder, usually attributed to malnutrition or alcoholism. 5-FU has been shown to induce thiamine depletion. Reduced food intake or total parenteral nutrition devoid of vitamin supplements may aggravate symptoms. We were unable to find a genetic cause for increased 5-FU toxicity in our patient, ruling out deficiencies of dihydropyrimidine dehydrogenase, dihydropyrimidinase or ?-ureidopropionase and double-strand break repair deficits. We come to the conclusion that, even without any definable enzyme deficiency, treatment with 5-FU can lead to high toxicity due to thiamine deficiency if vitamin supplementation is not undertaken. PMID:21941485

  17. 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

  18. Rumen microbial abundance and fermentation profile during severe subacute ruminal acidosis and its modulation by plant derived alkaloids in vitro.

    PubMed

    Mickdam, Elsayed; Khiaosa-Ard, Ratchaneewan; Metzler-Zebeli, Barbara U; Klevenhusen, Fenja; Chizzola, Remigius; Zebeli, Qendrim

    2016-06-01

    Rumen microbiota have important metabolic functions for the host animal. This study aimed at characterizing changes in rumen microbial abundances and fermentation profiles using a severe subacute ruminal acidosis (SARA) in vitro model, and to evaluate a potential modulatory role of plant derived alkaloids (PDA), containing quaternary benzophenanthridine and protopine alkaloids, of which sanguinarine and chelerythrine were the major bioactive compounds. Induction of severe SARA strongly affected the rumen microbial composition and fermentation variables without suppressing the abundance of total bacteria. Protozoa and fungi were more sensitive to the low ruminal pH condition than bacteria. Induction of severe SARA clearly depressed degradation of fiber (P < 0.001), which came along with a decreased relative abundance of fibrolytic Ruminococcus albus and Fibrobacter succinogenes (P < 0.001). Under severe SARA conditions, the genus Prevotella, Lactobacillus group, Megasphaera elsdenii, and Entodinium spp. (P < 0.001) were more abundant, whereas Ruminobacter amylophilus was less abundant. SARA largely suppressed methane formation (-70%, P < 0.001), although total methanogenic 16S rRNA gene abundance was not affected. According to principal component analysis, Methanobrevibacter spp. correlated to methane concentration. Addition of PDA modulated ruminal fermentation under normal conditions such as enhanced (P < 0.05) concentration of total SCFA, propionate and valerate, and increased (P < 0.05) degradation of crude protein compared with the unsupplemented control diet. Our results indicate strong shifts in the microbial community during severe SARA compared to normal conditions. Supplementation of PDA positively modulates ruminal fermentation under normal ruminal pH conditions. PMID:26868619

  19. [Kidney transplants from donors burdened metabolic acidosis in the course of poisoning with methanol and carbon monoxide].

    PubMed

    Kołaciński, Zbigniew; Skrzypek-Mikulska, Agnieszka; Pitrus, Ewelina; Matych, Józef; Winnicka, Renata; Czyzewska, Sylwia; Krakowiak, Anna

    2013-01-01

    The question of obtaining organs from donors who died of methanol poisoning has been discussed in the medical literature for many years. The results of such transplants published so far are very optimistic. However, the possibility of permanent and significant injury to transplanted organs caused by poisons or its metabolites raises serious concerns regarding the procedure. The long-term effects of intensive treatment of poisoning need to be considered as well. Metabolic acidosis and high blood osmolality are agents with recognized damaging potential impairing organ function at cellular level. The study traced the fate of kidney transplants from 13 donors who died of methanol poisoning and one isoned with carbon monoxide. The donors group consisted of 12 men and 2 women, of mean age 49 years (SD +/- 7.93). The kidneys were transplanted 20 men and 8 women. The mean age of recipients was 50.29 years (SD +/- 12.9). At the time of admission to the Department of Toxicology all donors presented with profound metabolic acidosis and high plasma osmolality (mean 434.71 mOsm/kg H2O (SD +/- 73.29). Metabolic acidosis was treated high doses of sodium bicarbonate (mean infusion volume of was 409 ml) before the HD procedure. Blood methanol levels were between 125 and 470 mg% (mean 317.23 SD +/- 136.83). The carboxyhaemoglobin concentration of in the donor poisoned with carbon monoxide was 47.2%. Transplantation was performed after confirmation of the brain death, the period of cold ischemia (CIT) ranged from 6 to 22 hours (mean 16.06 hours; SD +/- 3.99). Kidneys have taken function immediately after transplantation in 21 recipients. In seven cases, patients required two or three HD procedures. A total of 16 dialysis were performed post-transplants. In the group of patients, the mean glomerular filtration rate (GFR) at 3 months after transplantation was 46.71 ml/min/1.73m2 (SD +/- 10.89). During the 18 months follow-up a constant upward trend to the mean GFR 50.55 was noticed. In the group of donors, the mean blood urea concentration (BUN) 3 months after transplantation was 61.43 mg/dL, including 7 patients with BUN within the range of 80-100 mg/dL. At 18 months post transplant, the average concentration was 42.36 mg/dL, with no cases exceeding 55 mg/dL. Similarly, serum creatinine level normalized with the mean value of 3.01 mg/dL at 3 months and 1.68 mg/dL at 18 months post the procedure. There was no case exceeding 2 mg/dL. One recipient died of a heart attack after a period of more than 18 months after transplantation. However, the transplant was efficiently active at all times (GFR 56-60 ml). PMID:24466684

  20. Enzymatic and functional evidence for adaptation of the vacuolar H(+)-ATPase in proximal tubule apical membranes from rats with chronic metabolic acidosis.

    PubMed

    Chambrey, R; Paillard, M; Podevin, R A

    1994-02-01

    The present work examined the effects of chronic metabolic acidosis on the vacuolar proton-translocating adenosine triphosphatase (H(+)-ATPase) activity both in rat renal cortical homogenates and in their luminal membranes. Moreover, to assess the effect of acidosis on H+ transport by the apical H(+)-ATPase, we have developed a detergent-dilution procedure, resulting in the formation of sealed vesicles having this enzyme at their external surface. NH4Cl loading for 4 days had no effect on homogenates H(+)-ATPase activity, estimated with either N-ethylmaleimide or bafilomycin A1. In contrast, H(+)-ATPase activities were increased significantly by about 30% in both native apical membranes prepared by Ca2+ aggregation and detergent-treated luminal vesicles from acidotic animal. Kinetic analysis revealed that this stimulation was solely through changes in the Vmax for ATP. In membranes prepared by Mg2+ aggregation, acidosis also caused significant stimulation of the H(+)-ATPase activity. In addition, the initial rate of ATP-induced intravesicular acidification was 25% higher in reoriented H(+)-ATPase vesicles from acidotic rats, whereas passive proton permeability was identical in both groups. Finally, both vesicle enrichments and yields of luminal markers and de-enrichments and yields of intracellular membrane markers were identical in the two groups. These results provide enzymatic and functional evidence suggesting that chronic acidosis induces an adaptative change in the rat brush border H(+)-ATPase. PMID:8106360

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

    PubMed Central

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

    2016-01-01

    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. PMID:26728390

  2. Metabolic Multianalyte Microphysiometry Reveals Extracellular Acidosis is an Essential Mediator of Neuronal Preconditioning

    PubMed Central

    2012-01-01

    Metabolic adaptation to stress is a crucial yet poorly understood phenomenon, particularly in the central nervous system (CNS). The ability to identify essential metabolic events which predict neuronal fate in response to injury is critical to developing predictive markers of outcome, for interpreting CNS spectroscopic imaging, and for providing a richer understanding of the relevance of clinical indices of stress which are routinely collected. In this work, real-time multianalyte microphysiometry was used to dynamically assess multiple markers of aerobic and anaerobic respiration through simultaneous electrochemical measurement of extracellular glucose, lactate, oxygen, and acid. Pure neuronal cultures and mixed cultures of neurons and glia were compared following a 90 min exposure to aglycemia. This stress was cytotoxic to neurons yet resulted in no appreciable increase in cell death in age-matched mixed cultures. The metabolic profile of the cultures was similar in that aglycemia resulted in decreases in extracellular acidification and lactate release in both pure neurons and mixed cultures. However, oxygen consumption was only diminished in the neuron enriched cultures. The differences became more pronounced when cells were returned to glucose-containing media upon which extracellular acidification and oxygen consumption never returned to baseline in cells fated to die. Taken together, these data suggest that lactate release is not predictive of neuronal survival. Moreover, they reveal a previously unappreciated relationship of astrocytes in maintaining oxygen uptake and a correlation between metabolic recovery of neurons and extracellular acidification. PMID:22860220

  3. Lactate Clearance and Vasopressor Seem to Be Predictors for Mortality in Severe Sepsis Patients with Lactic Acidosis Supplementing Sodium Bicarbonate: A Retrospective Analysis

    PubMed Central

    Kim, Eun Bin; Jeong, Hyo Jin; Son, Young Ki; An, Won Suk

    2015-01-01

    Introduction Initial lactate level, lactate clearance, C-reactive protein, and procalcitonin in critically ill patients with sepsis are associated with hospital mortality. However, no study has yet discovered which factor is most important for mortality in severe sepsis patients with lactic acidosis. We sought to clarify this issue in patients with lactic acidosis who were supplementing with sodium bicarbonate. Materials and Methods Data were collected from a single center between May 2011 and April 2014. One hundred nine patients with severe sepsis and lactic acidosis who were supplementing with sodium bicarbonate were included. Results The 7-day mortality rate was 71.6%. The survivors had higher albumin levels and lower SOFA, APACHE II scores, vasopressor use, and follow-up lactate levels at an elapsed time after their initial lactate levels were checked. In particular, a decrement in lactate clearance of at least 10% for the first 6 hours, 24 hours, and 48 hours of treatment was more dominant among survivors than non-survivors. Although the patients who were treated with broad-spectrum antibiotics showed higher illness severity than those who received conventional antibiotics, there was no significant mortality difference. 6-hour, 24-hour, and 48-hour lactate clearance (HR: 4.000, 95% CI: 1.309–12.219, P = 0.015) and vasopressor use (HR: 4.156, 95% CI: 1.461–11.824, P = 0.008) were significantly associated with mortality after adjusting for confounding variables. Conclusions Lactate clearance at a discrete time point seems to be a more reliable prognostic index than initial lactate value in severe sepsis patients with lactic acidosis who were supplementing with sodium bicarbonate. Careful consideration of vasopressor use and the initial application of broad-spectrum antibiotics within the first 48 hours may be helpful for improving survival, and further study is warranted. PMID:26692209

  4. Acute isoniazid intoxication: seizures, acidosis and coma.

    PubMed

    Temmerman, W; Dhondt, A; Vandewoude, K

    1999-08-01

    Isoniazid (INH) is the most widely used of the antituberculosis drugs. An acute overdose is potentially fatal and is characterized by the clinical triad of repetitive seizures unresponsive to the usual anticonvulsants, metabolic acidosis with a high anion gap and coma. The diagnosis of INH overdose should be considered in any patient who presents with an unexplained metabolic acidosis and convulsions. The cornerstone of therapy consists in pyridoxine (vitamin B6) and the dose should be equal to the amount of INH ingested. When conservative therapy fails or in case of renal insufficiency, dialysis must be considered. Severe central nervous toxicity can also be caused by chronic ingestion of higher than therapeutic doses of INH. In those cases pyridoxine-therapy can be useful as well. In the present paper a case of acute overdose of INH is reported, followed by a review of the literature. PMID:10544512

  5. Anorexia nervosa, laxative abuse, hypopotassemia and distal renal tubular acidosis.

    PubMed

    Pines, A; Kaplinsky, N; Olchovsky, D; Frankl, O; Goldfarb, D; Iaina, A

    1985-01-01

    A case of anorexia nervosa in a 28-year-old woman with laxative abuse, hypopotassemia and severe metabolic acidosis, is described. The diagnosis of classical renal tubular acidosis, Type I, was confirmed by our inability to decrease urinary pH beyond 5.5 and to increase ammonia excretion during an ammonium chloride loading test. A bicarbonate loading test and normal plasma aldosterone with high renin activity excluded proximal renal tubular acidosis, hyporeninemic-hypoaldosteronemic renal tubular acidosis and Bartter's syndrome. The inability to increase ammonium excretion during severe metabolic acidosis following ammonium chloride loading did not favor the possibility of a transient physiological adaptation of ammoniagenesis at the tubular cell level, related to potassium depletion. Although mental disorder, laxative abuse, abstinence from food intake and severe potassium depletion intermingled in a vicious cycle, we assume that one of the following possibilities may explain the clinical presentation in our patient: either two separated and unrelated disorders, or laxative abuse as the cause of renal tubular acidification impairment. PMID:3972559

  6. Relationship of severity of subacute ruminal acidosis to rumen fermentation, chewing activities, sorting behavior, and milk production in lactating dairy cows fed a high-grain diet.

    PubMed

    Gao, X; Oba, M

    2014-05-01

    The objectives of the current study were to evaluate the variation in severity of subacute ruminal acidosis (SARA) among lactating dairy cows fed a high-grain diet and to determine factors characterizing animals that are tolerant to high-grain diets. Sixteen ruminally cannulated late-lactating dairy cows (days in milk=282 ± 33.8; body weight=601 ± 75.9 kg) were fed a high-grain diet consisting of 35% forage and 65% concentrate mix. After 17 d of diet adaptation, chewing activities were monitored for a 24-h period and ruminal pH was measured every 30s for 72 h. Acidosis index, defined as the severity of SARA (area of pH <5.8) divided by dry matter intake (DMI), was determined for individual animals to assess the severity of SARA normalized for a feed intake level. Although all cows were fed the same diet, minimum pH values ranged from 5.16 to 6.04, and the acidosis index ranged from 0.0 to 10.9 pH · min/kg of DMI. Six cows with the lowest acidosis index (0.04 ± 0.61 pH · min/kg) and 4 with the highest acidosis index (7.67 ± 0.75 pH · min/kg) were classified as animals that were tolerant and susceptible to the high-grain diet, respectively. Total volatile fatty acid concentration and volatile fatty acid profile were not different between the groups. Susceptible animals sorted against long particles, whereas tolerant animals did not (sorting index=87.6 vs. 97.9, respectively). However, the tolerant cows had shorter total chewing time (35.8 vs. 45.1 min/kg of DMI). In addition, although DMI, milk yield, and milk component yields did not differ between the groups, milk urea nitrogen concentration was higher for tolerant cows compared with susceptible cows (12.8 vs. 8.6 mg/dL), which is possibly attributed to less organic matter fermentation in the rumen of tolerant cows. These results suggest that a substantial variation exists in the severity of SARA among lactating dairy cows fed the same high-grain diet, and that cows tolerant to the high-grain diet might be characterized by less sorting behavior but less chewing time, and higher milk urea nitrogen concentration. PMID:24612805

  7. Gastric bypass in obese rats causes bone loss, vitamin D deficiency, metabolic acidosis, and elevated peptide YY

    PubMed Central

    Canales, Benjamin K.; Schafer, Anne L.; Shoback, Dolores M.; Carpenter, Thomas O.

    2014-01-01

    Background Metabolic bone disease and bariatric surgery have long been interconnected. The objective of this study is to better understand the mechanisms of bone mass loss after Roux-en-Y gastric bypass (RYGB) surgery. We evaluated mineral homeostasis and bone mass in diet-induced obese (DIO) rats after RYGB or sham surgery. Methods Twelve DIO male Sprague Dawley rats underwent RYGB (n = 8) or sham (n = 4) surgery at 21 weeks of age. Postoperatively, animals ate an ad libitum 40% fat, normal calcium diet and were euthanized 22 weeks later. Serum and urine chemistries, insulin, leptin, bone turnover markers (BTM), and calciotropic and gut hormones were measured before and 22 weeks after surgery. Femurs were analyzed using microcomputed tomography (CT). Results Compared to sham, RYGB animals had lower serum bicarbonate, calcium, 25-hydroxyvitamin D, insulin, and leptin levels with higher serum parathyroid hormone, peptide YY, and urinary calcium at 43 weeks of age. Sham control rats gained weight and had coupled decreases in formation (P1 NP and OC) and unchanged resorption (CTX) BTMs. Comparatively, RYGB animals had higher serum CTX and OC but even lower P1 NP levels than controls. CT revealed lower trabecular bone volume, number, and thickness and lower cortical bone volume, thickness, and moment of inertia relative to controls. Conclusion In rats with DIO, long-term RYGB-associated bone resorption appears to be driven in part by vitamin D malabsorption and secondary hyperparathyroidism. Other mechanisms, such as chronic acidosis, changes in fat-secreted hormones, and persistently elevated gut-derived hormone peptide YY, may also contribute to observed bone mass differences. Further investigation of these potential contributors to bone loss may lead to new targets for skeletal maintenance after RYGB. PMID:24969093

  8. Evaluation of the systemic innate immune response and metabolic alterations of nonlactating cows with diet-induced subacute ruminal acidosis.

    PubMed

    Rodríguez-Lecompte, J C; Kroeker, A D; Ceballos-Márquez, A; Li, S; Plaizier, J C; Gomez, D E

    2014-12-01

    Subacute ruminal acidosis (SARA) increases lipopolysaccharide endotoxin in the rumen, which might translocate into the systemic circulation, triggering a cascade of clinical and immunological alterations. The objective of this study was to characterize the clinical immune and metabolic responses to ruminal-derived lipopolysaccharide in nonlactating cows induced with SARA using 2 challenges, a grain-based SARA challenge (GBSC) or an alfalfa-pellet SARA challenge (APSC). Six dry, nonlactating Holstein cows were used in a 3 × 3 Latin square arrangement of treatments with 4-wk experimental cycles. All cows received the control diet containing 70% forage and 30% mixed concentrates (dry matter basis) for 3 wk. In wk 4, cows received a control diet, GBSC (38% wheat-barley pellets, 32% other mixed concentrate, and 30% forages), or APSC (45% mixed concentrate, 32% alfalfa pellets, and 23% other forages). Total plasma proteins and immunology-related proteins, acute phase proteins, blood cells, serum chemistry, mRNA gene expression of peripheral blood cell surface markers, and selected proinflammatory cytokines were evaluated. Ruminal pH was lower in both groups with induced SARA compared with a control group. Ruminal endotoxins were higher in GBSC; however, plasma endotoxin was not detected in any study group. No significant differences in feed intake, rectal temperature, white blood cell counts, or differentials were found between control and SARA challenge groups; changes in glucose, urea, Ca, and Mg were observed in SARA groups. Total plasma proteins were lower in both SARA groups, and acute phase proteins were higher in GBSC. The expression of CD14, MD2, and TLR4 mRNA in peripheral blood leukocytes was not affected by SARA induction. The induction of SARA as a result of GBSC or APSC challenge was successful; however, LPS was not detected in plasma. Changes in clinical, metabolic, and inflammatory responses were not observed in the SARA-challenged cows, suggesting that, in this study, SARA was not associated with a systemic response to inflammation. PMID:25459907

  9. Transient feeding of a concentrate-rich diet increases the severity of subacute ruminal acidosis in dairy cattle.

    PubMed

    Pourazad, P; Khiaosa-Ard, R; Qumar, M; Wetzels, S U; Klevenhusen, F; Metzler-Zebeli, B U; Zebeli, Q

    2016-02-01

    The objective of this study was to investigate the effect of the pattern of concentrate-rich feeding on subacute ruminal acidosis (SARA), its severity, and the corresponding changes in VFA concentration. Eight rumen-cannulated Holstein cows were assigned to a 2 × 2 crossover design with 2 SARA challenge models and 2 experimental runs ( = 8 per treatment). Each run lasted for 40 d, consisting of a 6-d baseline, a 6-d gradual grain adaptation, and a 28-d SARA challenge period. The 2 SARA challenge models were transient (TRA) and persistent (PER) SARA. Initially, all cows were subjected to a forage-only diet (baseline) and gradually switched to 60% concentrate (DM basis). Then, cows in the PER model were continuously challenged for 28 d, whereas cows in the TRA model had a 7-d break from the SARA diet and were fed the forage-only diet after the first 7 d of SARA challenge. Thereafter, the TRA cows were rechallenged with the SARA diet. Wireless ruminal pH sensors were used to obtain ruminal pH profiles and temperature over the experimental period. For the determination of VFA, free ruminal liquid (FRL) and particle-associated ruminal liquid (PARL) were collected once for the baseline and twice (d 20 and 40 for the PER model) or 3 times (d 13, 30, and 40 for the TRA model) during SARA, each time at 0, 4, and 8 h after the morning feeding. Cows in both models experienced SARA albeit with day-to-day variation. From the start until the first 7-d SARA, cows of both models had similar pH profiles, but during the rechallenge, SARA was more severe in the TRA model than in the PER model based on lower daily mean ruminal pH (5.93 vs. 6.15; SEM 0.058) and double the amount of time at pH < 5.8 (497 vs. 278 min; SEM 68.61, < 0.05). Mean ruminal temperature was raised during SARA compared with the baseline (38.9 vs. 38.7°C; SEM 0.057, < 0.001). Concentrations of VFA increased with increasing time after feeding ( < 0.001). In general, SARA challenge (d 40 vs. the baseline), but not the challenge model, altered VFA concentrations and profile of both FRL and PARL by increasing the amounts of propionate and butyrate, whereas total VFA concentration was less affected. Proportions of VFA shifted over the duration of SARA challenge with more propionate but less acetate and butyrate proportions with advancing days of SARA challenge, leading to the values of the last SARA day being different from the earlier days ( < 0.05). In conclusion, the TRA condition led to the higher severity of SARA, but factors beyond feed intake and VFA alterations seemed to play a role. PMID:27065143

  10. Distal renal tubular acidosis

    MedlinePlus

    Renal tubular acidosis - distal; Renal tubular acidosis type I; Type I RTA; RTA - distal; Classical RTA ... excreting it into the urine. Distal renal tubular acidosis (Type I RTA) is caused by a defect ...

  11. Acute kidney injury with oxalate deposition in a patient with a high anion gap metabolic acidosis and a normal osmolal gap

    PubMed Central

    Alhamad, Tarek; Blandon, Jimena; Meza, Ana T.; Bilbao, Jorge E.; Hernandez, German T.

    2013-01-01

    Background: Ethylene glycol ingestion can lead to acute kidney injury from tubular deposition of oxalate crystals.  The diagnosis of ethylene glycol intoxication is based on a history of ingestion, clinical examination, high anion gap metabolic acidosis, high osmolal gap, and a measured serum level of ethylene glycol.  However, depending on the delay in time from ingestion to arrival to a hospital, the osmolal gap may become normal, thereby creating a confusing clinic picture for the treating clinician. Case: A 71 year-old man with a history of alcohol abuse had been unconscious for an unknown period of time.  Upon hospitalization, he was found to have a high anion gap metabolic acidosis but a normal serum osmolal gap and subsequently developed acute kidney injury.  The serum lactic acid and glucose levels were unremarkable, and there were no ketones in the serum. Urine analysis showed numerous red blood cells and calcium oxalate crystals.  The renal biopsy showed multiple oxalate crystals in the renal tubules demonstrating birefringence under polarized light. Given the history of alcohol abuse, the clinical presentation, the unexplained high anion gap metabolic acidosis, and the biopsy findings, ethylene glycol intoxication was deemed the most likely diagnosis. Conclusions: In cases of ethylene glycol intoxication, a high serum osmolal gap is supportive of ethylene glycol intoxication, but a normal serum osmolal gap does not exclude the diagnosis, especially when the time of ingestion is unknown. Physicians should be aware of potentially normal serum osmolal gap values in cases of ethylene glycol intoxication. PMID:24475441

  12. Metabolic management of severe acute pancreatitis.

    PubMed

    Windsor, J A; Hammodat, H

    2000-06-01

    The metabolic management of severe acute pancreatitis involves early identification of patients with severe pancreatitis, aggressive fluid resuscitation, organ support, and careful monitoring in an intensive care environment. Recent evidence has helped to define the roles of enteral feeding, prophylactic antibiotics, endoscopic retrograde cholangiopancreatography, computed tomography, and fine-needle aspiration for bacteriology. The most difficult decision in the management of these patients is whether surgery is required and which of the complementary approaches to necrosectomy and drainage is appropriate. Key metabolic events in the acinar cell, pancreas, and intestines are now being unraveled, as is the basis for the systemic manifestations and organ dysfunction associated with pancreatitis. This gives hope for the development of more specific metabolic interventions, which will likely target the maintenance of intestinal integrity and function, preservation of pancreatic microcirculation, and balanced modulation of the inflammatory response. PMID:10773118

  13. 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 ad libitum. Bunk management strategy has the potential to decrease DMI and ADG when steers managed on a clean bunk program are restricted relative to traditional, ad libitum bunk programs. Monensin helps control intake patterns for individuals, but increasing concentration above currently approved levels in this study seemed to have little effect. PMID:14601891

  14. Lactic Acidosis in Sepsis: It's Not All Anaerobic: Implications for Diagnosis and Management.

    PubMed

    Suetrong, Bandarn; Walley, Keith R

    2016-01-01

    Increased blood lactate concentration (hyperlactatemia) and lactic acidosis (hyperlactatemia and serum pH < 7.35) are common in patients with severe sepsis or septic shock and are associated with significant morbidity and mortality. In some patients, most of the lactate that is produced in shock states is due to inadequate oxygen delivery resulting in tissue hypoxia and causing anaerobic glycolysis. However, lactate formation during sepsis is not entirely related to tissue hypoxia or reversible by increasing oxygen delivery. In this review, we initially outline the metabolism of lactate and etiology of lactic acidosis; we then address the pathophysiology of lactic acidosis in sepsis. We discuss the clinical implications of serum lactate measurement in diagnosis, monitoring, and prognostication in acute and intensive care settings. Finally, we explore treatment of lactic acidosis and its impact on clinical outcome. PMID:26378980

  15. Bone Density Is Directly Associated With Glomerular Filtration and Metabolic Acidosis but Do Not Predict Fragility Fractures in Men With Moderate Chronic Kidney Disease.

    PubMed

    Lima, Guilherme Alcantara Cunha; Paranhos-Neto, Francisco de Paula; Silva, Luciana Colonese; de Mendonça, Laura Maria Carvalho; Delgado, Alvimar Gonçalves; Leite, Maurilo; Gomes, Carlos Perez; Farias, Maria Lucia Fleiuss

    2016-04-01

    Hyperparathyroidism, vitamin D deficiency, increased fibroblast growth factor-23 (FGF-23), and metabolic acidosis promote bone fragility in chronic kidney disease (CKD). Although useful in predicting fracture risk in the general population, the role of dual-energy X-ray absorptiometry (DXA) in CKD remains uncertain. This cross-sectional study included 51 men aged 50-75 yr with moderate CKD. The stage 4 CKD patients had higher levels of parathyroid hormone (p < 0.001), FGF-23 (p = 0.029), and lowest 25-hydroxyvitamin D (p = 0.016), bicarbonate (p < 0.001), total femur (p = 0.003), and femoral neck (p = 0.011) T-scores compared with stage 3 CKD patients. Total femur and femoral neck T-scores were directly correlated with serum bicarbonate (p = 0.003, r = 0.447 and p = 0.005, r = 0.427, respectively) and estimated glomerular filtration rate (p = 0.024, r = 0.325 and p = 0.003, r = 0.313, respectively) but were not significantly associated with parathyroid hormone, 25-hydroxyvitamin D, or FGF-23. Only 3.9% of the participants had osteoporosis on DXA scan, whereas 31.4% reported a low-impact fracture. Our data point to a pivotal role of metabolic acidosis for bone impairment and to the inadequacy of DXA to evaluate bone fragility in CKD patients. PMID:24709549

  16. L-Arginine Affects Aerobic Capacity and Muscle Metabolism in MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-Like Episodes) Syndrome

    PubMed Central

    Rodan, Lance H.; Wells, Greg D.; Banks, Laura; Thompson, Sara; Schneiderman, Jane E.; Tein, Ingrid

    2015-01-01

    Objective To study the effects of L-arginine (L-Arg) on total body aerobic capacity and muscle metabolism as assessed by 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) in patients with MELAS (Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes) syndrome. Methods We performed a case control study in 3 MELAS siblings (m.3243A>G tRNAleu(UUR) in MTTL1 gene) with different % blood mutant mtDNA to evaluate total body maximal aerobic capacity (VO2peak) using graded cycle ergometry and muscle metabolism using 31P-MRS. We then ran a clinical trial pilot study in MELAS sibs to assess response of these parameters to single dose and a 6-week steady-state trial of oral L-Arginine. Results At baseline (no L-Arg), MELAS had lower serum Arg (p = 0.001). On 31P-MRS muscle at rest, MELAS subjects had increased phosphocreatine (PCr) (p = 0.05), decreased ATP (p = 0.018), and decreased intracellular Mg2+ (p = 0.0002) when compared to matched controls. With L-arginine therapy, the following trends were noted in MELAS siblings on cycle ergometry: (1) increase in mean % maximum work at anaerobic threshold (AT) (2) increase in % maximum heart rate at AT (3) small increase in VO2peak. On 31P-MRS the following mean trends were noted: (1) A blunted decrease in pH after exercise (less acidosis) (2) increase in Pi/PCr ratio (ADP) suggesting increased work capacity (3) a faster half time of PCr recovery (marker of mitochondrial activity) following 5 minutes of moderate intensity exercise (4) increase in torque. Significance These results suggest an improvement in aerobic capacity and muscle metabolism in MELAS subjects in response to supplementation with L-Arg. Intramyocellular hypomagnesemia is a novel finding that warrants further study. Classification of Evidence Class III evidence that L-arginine improves aerobic capacity and muscle metabolism in MELAS subjects. Trial Registration ClinicalTrials.gov NCT01603446. PMID:25993630

  17. [Resistance training reduces the metabolic acidosis and hepatic and renal hypertrophy caused by the consumption of a high protein diet in rats].

    TOXLINE Toxicology Bibliographic Information

    Aparicio VA; Nebot E; Kapravelou G; Sánchez C; Porres JM; López Jurado M; Aranda P

    2011-11-01

    INTRODUCTION: High protein (HP) diet consumption may adversely affect metabolic acidosis and hepatic and renal health. Despite such potentially adverse effect, there are only few studies analyzing the effects of resistance training on the parameters that could be altered by such diets.MATERIAL AND METHODS: A total of 32 adult male Wistar rats were randomly distributed in 4 experimental groups (n = 8): normoprotein or HP diets, with or without resistance training. Diets were based on a whey protein hydrolyzate, and the experimental period lasted for 90 days.RESULTS AND DISCUSSION: Consumption of HP diets and resistance training significantly affected food intake, body composition and plasmatic levels of total cholesterol and triglycerides. Consumption of HP diets led to a considerable increase in liver and kidney weight (P < 0.001), urinary volume and acidity, as well as in the urinary excretion of Ca, with a parallel reduction in the urinary excretion of citrate (P < 0.05). The buffering action of resistance training on such diet-induced alterations was especially evident in the levels of hepatic and plasma triglycerides, plasmatic urea, and in liver and kidney weight (P < 0.001).CONCLUSION: Resistance training had a protective action against alterations of hepatic and renal health status and some metabolic parameters like hepatic and plasma triglycerides.

  18. Fuel metabolism during severe rowing exercise

    SciTech Connect

    Hoyt, R.W.; Lubowitz, J.; Asakura, T.; Stein, T.P.

    1986-03-01

    Eight elite oarsmen were studied during and after six min of severe ergometer exercise. Power output averaged 380 +/- 28 watts. Serial venous blood samples and gas exchange measurements were obtained during exercise. In 4 of the 8 subjects, a primed periodic oral dose of the tracer (6,6-/sup 2/H/sub 2/)glucose was used to determine the effects of severe exercise on glucose metabolism. During exercise, the levels of lactate progressively increased to 12.2 +/- 1.3 mM (SE). There was little change in isotopic glucose enrichment during exercise (from 2.95 +/- 0.30 to 2.55 +/- 0.23 atom percent excess, APE). During recovery, isotopic glucose enrichment decreased significantly to 1.40 +/- 0.14 APE, indicating a substantial post-exercise plasma glucose flux. There were significant post-exercise increases in plasma glucose accumulation (from 84 +/- 5 to 131 +/- 3 mg/dl) and insulin concentration (0.57 +/- 0.08 to 1.34 +/- 0.15 ng/ml). These results suggest that muscle glycogen is the primary source of fuel during six minutes of maximal rowing exercise.

  19. 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 E1? 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 E1? in brain, muscle, and liver compared to saline-treated mice. By means of recombinant enzymes, we showed that phenylbutyrate prevents phosphorylation of E1? 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

  20. A homozygous mutation in LYRM7/MZM1L associated with early onset encephalopathy, lactic acidosis, and severe reduction of mitochondrial complex III activity.

    PubMed

    Invernizzi, Federica; Tigano, Marco; Dallabona, Cristina; Donnini, Claudia; Ferrero, Ileana; Cremonte, Maurizio; Ghezzi, Daniele; Lamperti, Costanza; Zeviani, Massimo

    2013-12-01

    Mutations in nuclear genes associated with defective complex III (cIII) of the mitochondrial respiratory chain are rare, having been found in only two cIII assembly factors and, as private changes in single families, three cIII structural subunits. Recently, human LYRM7/MZM1L, the ortholog of yeast MZM1, has been identified as a new assembly factor for cIII. In a baby patient with early onset, severe encephalopathy, lactic acidosis and profound, isolated cIII deficiency in skeletal muscle, we identified a disease-segregating homozygous mutation (c.73G>A) in LYRM7/MZM1L, predicting a drastic change in a highly conserved amino-acid residue (p.Asp25Asn). In a mzm1? yeast strain, the expression of a mzm1(D25N) mutant allele caused temperature-sensitive respiratory growth defect, decreased oxygen consumption, impaired maturation/stabilization of the Rieske Fe-S protein, and reduced complex III activity and amount. LYRM7/MZM1L is a novel disease gene, causing cIII-defective, early onset, severe mitochondrial encephalopathy. PMID:24014394

  1. A Homozygous Mutation in LYRM7/MZM1L Associated with Early Onset Encephalopathy, Lactic Acidosis, and Severe Reduction of Mitochondrial Complex III Activity

    PubMed Central

    Invernizzi, Federica; Tigano, Marco; Dallabona, Cristina; Donnini, Claudia; Ferrero, Ileana; Cremonte, Maurizio; Ghezzi, Daniele; Lamperti, Costanza; Zeviani, Massimo

    2013-01-01

    Mutations in nuclear genes associated with defective complex III (cIII) of the mitochondrial respiratory chain are rare, having been found in only two cIII assembly factors and, as private changes in single families, three cIII structural subunits. Recently, human LYRM7/MZM1L, the ortholog of yeast MZM1, has been identified as a new assembly factor for cIII. In a baby patient with early onset, severe encephalopathy, lactic acidosis and profound, isolated cIII deficiency in skeletal muscle, we identified a disease-segregating homozygous mutation (c.73G>A) in LYRM7/MZM1L, predicting a drastic change in a highly conserved amino-acid residue (p.Asp25Asn). In a mzm1Δ yeast strain, the expression of a mzm1D25N mutant allele caused temperature-sensitive respiratory growth defect, decreased oxygen consumption, impaired maturation/stabilization of the Rieske Fe–S protein, and reduced complex III activity and amount. LYRM7/MZM1L is a novel disease gene, causing cIII-defective, early onset, severe mitochondrial encephalopathy. PMID:24014394

  2. The Use of Sodium Bicarbonate in the Treatment of Acidosis in Sepsis: A Literature Update on a Long Term Debate

    PubMed Central

    Velissaris, Dimitrios; Karamouzos, Vasilios; Ktenopoulos, Nikolaos; Pierrakos, Charalampos; Karanikolas, Menelaos

    2015-01-01

    Introduction. Sepsis and its consequences such as metabolic acidosis are resulting in increased mortality. Although correction of metabolic acidosis with sodium bicarbonate seems a reasonable approach, there is ongoing debate regarding the role of bicarbonates as a therapeutic option. Methods. We conducted a PubMed literature search in order to identify published literature related to the effects of sodium bicarbonate treatment on metabolic acidosis due to sepsis. The search included all articles published in English in the last 35 years. Results. There is ongoing debate regarding the use of bicarbonates for the treatment of acidosis in sepsis, but there is a trend towards not using bicarbonate in sepsis patients with arterial blood gas pH > 7.15. Conclusions. Routine use of bicarbonate for treatment of severe acidemia and lactic acidosis due to sepsis is subject of controversy, and current opinion does not favor routine use of bicarbonates. However, available evidence is inconclusive, and more studies are required to determine the potential benefit, if any, of bicarbonate therapy in the sepsis patient with acidosis. PMID:26294968

  3. Renal tubular acidosis due to the milk-alkali syndrome.

    PubMed

    Rochman, J; Better, O S; Winaver, J; Chaimowitz, C; Barzilai, A; Jacobs, R

    1977-06-01

    A 60-year-old man with a history of excessive ingestion of calcium carbonate presented with azotemia, hypercalcemia and hyperphosphatemia. His acid-base status was initially normal. Following the cessation of calcium carbonate treatment, the hypercalcemia and azotemia disappeared, and the patient was found to be in metabolic acidosis with blunted acid excretion and a urine pH of 6.1. Kidney biopsy showed focal tubular calcification; the tubular damage was apparently caused by hypercalcemia and had resulted in renal tubular acidosis. During the three months of observation since that time there has been a tendecy for spontaneous remission of the renal tubular acidosis. Impaired renal hydrogen ion excretion prevented the development of metabolic alkalosis despite ingestion of alkali initially, and was later responsible for the metabolic acidosis. Renal tubular acidosis occurring as a sequel to the milk-alkali syndrome may aggravate the danger of nephrocalcinosis in this syndrome. PMID:885714

  4. Lactate clearance and metabolic aspects of continuous high-volume hemofiltration.

    PubMed

    Cheungpasitporn, Wisit; Zand, Ladan; Dillon, John J; Qian, Qi; Leung, Nelson

    2015-08-01

    Lactic acidosis is associated with high morbidity and mortality in hospitalized patients. Treatment of lactic acidosis is targeted on correcting the underlying causes and optimizing adequate oxygen delivery to the tissues. Even though evidence is lacking, continuous renal replacement therapy (CRRT) and dialysis have been advocated as treatments for lactic acidosis. We report a 28-year-old Caucasian male with a history of hemophagocytic lymphohistiocytosis who presented with septic shock, severe lactic acidosis and multiple organ failure. Metabolic acidosis was corrected after bicarbonate therapy and CRRT with a hemofiltration rate of 7 L/h (58 mL/kg/h). Lactate clearance was calculated to be 79 mL/min. Compared with reported rates of lactate overproduction in septic shock, the rate of lactate clearance is quite small. Our case suggests that CRRT with high-volume hemofiltration is not effective for severe lactic acidosis. Lactic acidosis alone should not be considered as a nonrenal indication for CRRT. PMID:26251702

  5. Lactate clearance and metabolic aspects of continuous high-volume hemofiltration

    PubMed Central

    Cheungpasitporn, Wisit; Zand, Ladan; Dillon, John J.; Qian, Qi; Leung, Nelson

    2015-01-01

    Lactic acidosis is associated with high morbidity and mortality in hospitalized patients. Treatment of lactic acidosis is targeted on correcting the underlying causes and optimizing adequate oxygen delivery to the tissues. Even though evidence is lacking, continuous renal replacement therapy (CRRT) and dialysis have been advocated as treatments for lactic acidosis. We report a 28-year-old Caucasian male with a history of hemophagocytic lymphohistiocytosis who presented with septic shock, severe lactic acidosis and multiple organ failure. Metabolic acidosis was corrected after bicarbonate therapy and CRRT with a hemofiltration rate of 7 L/h (58 mL/kg/h). Lactate clearance was calculated to be 79 mL/min. Compared with reported rates of lactate overproduction in septic shock, the rate of lactate clearance is quite small. Our case suggests that CRRT with high-volume hemofiltration is not effective for severe lactic acidosis. Lactic acidosis alone should not be considered as a nonrenal indication for CRRT. PMID:26251702

  6. Protein metabolism in severe childhood malnutrition

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The major clinical syndromes of severe childhood malnutrition (SCM) are marasmus (non-oedematous SCM), kwashiorkor and marasmic-kwashiorkor (oedematous SCM). Whereas treatment of marasmus is straightforward and the associated mortality is low, kwashiorkor and marasmic-kwashiorkor are difficult to tr...

  7. Metabolic syndrome in patients with severe mental illness in Gorgan

    PubMed Central

    Kamkar, Mohammad Zaman; Sanagoo, Akram; Zargarani, Fatemeh; Jouybari, Leila; Marjani, Abdoljalal

    2016-01-01

    Background: Metabolic syndrome is commonly associated with cardiovascular diseases and psychiatric mental illness. Hence, we aimed to assess the metabolic syndrome among severe mental illness (SMI). Materials and Methods: The study included 267 patients who were referred to the psychiatric unit at 5th Azar Education Hospital of Golestan University of Medical Sciences in Gorgan, Iran. Results: The mean waist circumference, systolic and diastolic blood pressure, triglyceride and fasting blood glucose levels were significantly higher in the SMI with metabolic syndrome, but the high density lipoprotein (HDL)-cholesterol was significantly lower. The prevalence of metabolic syndrome in SMI patients was 20.60%. There were significant differences in the mean of waist circumference, systolic (except for women) and diastolic blood pressure, triglyceride, HDL-cholesterol and fasting blood glucose in men and women with metabolic syndrome when compared with subjects without metabolic syndrome. The prevalence of metabolic syndrome in SMI women was higher than men. The most age distribution was in range of 30-39 years old. The most prevalence of metabolic syndrome was in age groups 50-59 years old. The prevalence of metabolic syndrome was increased from 30 to 59 years old. Conclusion: The prevalence of metabolic syndrome in patients with SMI in Gorgan is almost similar to those observed in Asian countries. The prevalence of metabolic syndrome was lower than western countries. These observations may be due to cultural differences in the region. It should be mention that the families of mental illness subjects in our country believe that their patients must be cared better than people without mental illness. These findings of this study suggest that mental illness patients are at risk of metabolic syndrome. According to our results, risk factors such as age and gender differences may play an important role in the presence of metabolic syndrome. In our country, women do less physical activity than men; therefore, the incidence of metabolic syndrome is higher among women. PMID:27003972

  8. Effect of oral sodium bicarbonate supplementation on progression of chronic kidney disease in patients with chronic metabolic acidosis: study protocol for a randomized controlled trial (SoBic-Study)

    PubMed Central

    2013-01-01

    Background Overt chronic metabolic acidosis in patients with chronic kidney disease develops after a drop of glomerular filtration rate to less than approximately 25 mL/min/1.73 m2. The pathogenic mechanism seems to be a lack of tubular bicarbonate production, which in healthy individuals neutralizes the acid net production. As shown in several animal and human studies the acidotic milieu alters bone and vitamin D metabolism, induces muscle wasting, and impairs albumin synthesis, aside from a direct alteration of renal tissue by increasing angiotensin II, aldosteron and endothelin kidney levels. Subsequent studies testing various therapeutic approaches in very selected study populations showed that oral supplementation of the lacking bicarbonate halts progression of decline of renal function. However, due to methodological limitations of these studies further investigations are of urgent need to ensure the validity of this therapeutic concept. Methods/Design The SoBic-study is a single-center, randomized, controlled, open-label clinical phase IV study performed at the nephrological outpatient service of the Medical University of Vienna. Two-hundred patients classified to CKD stage 3 or 4 with two separate measurements of HCO3- of <21 mmol/L will be 1:1 randomized to either receive a high dose of oral sodium bicarbonate with a serum target HCO3- level of 24 ± 1 mmol/L or receive a rescue therapy of sodium bicarbonate with a serum target level of 20 ± 1 mmol/L. The follow up will be for two years. The primary outcome is the effect of sodium bicarbonate supplementation on renal function measured by means of estimated glomerular filtration rates (4-variable-MDRD-equation) after two years. Secondary outcomes are change in markers of bone metabolism between groups, death rates between groups, and the number of subjects proceeding to renal replacement therapy across groups. Adverse events, such as worsening of arterial hypertension due to the additional sodium consumption, will be accurately monitored. Discussion We hypothesize that sufficiently balanced acid–base homeostasis leads to a reduction of decline of renal function in patients with chronic kidney disease. The concept of an exogenous bicarbonate supplementation to substitute the lacking endogenous bicarbonate has existed for a long time, but has never been investigated sufficiently to state clear treatment guidelines. Trial registration EUDRACT Number: 2012-001824-36 PMID:23826760

  9. A Review of metabolic staging in severely injured patients

    PubMed Central

    2010-01-01

    An interpretation of the metabolic response to injury in patients with severe accidental or surgical trauma is made. In the last century, various authors attributed a meaning to the post-traumatic inflammatory response by using teleological arguments. Their interpretations of this response, not only facilitates integrating the knowledge, but also the flow from the bench to the bedside, which is the main objective of modern translational research. The goal of the current review is to correlate the metabolic changes with the three phenotypes -ischemia-reperfusion, leukocytic and angiogenic- that the patients express during the evolution of the systemic inflammatory response. The sequence in the expression of multiple metabolic systems that becomes progressively more elaborate and complex in severe injured patients urges for more detailed knowledge in order to establish the most adequate metabolic support according to the evolutive phase. Thus, clinicians must employ different treatment strategies based on the different metabolic phases when caring for this challenging patient population. Perhaps, the best therapeutic option would be to favor early hypometabolism during the ischemia-reperfusion phase, to boost the antienzymatic metabolism and to reduce hypermetabolism during the leukocytic phase through the early administration of enteral nutrition and the modulation of the acute phase response. Lastly, the early epithelial regeneration of the injured organs and tissues by means of an oxidative metabolism would reduce the fibrotic sequelae in these severely injured patients. PMID:20478066

  10. Stimulation by in vivo and in vitro metabolic acidosis of expression of rBSC-1, the Na+-K+(NH4+)-2Cl- cotransporter of the rat medullary thick ascending limb.

    PubMed

    Attmane-Elakeb, A; Mount, D B; Sibella, V; Vernimmen, C; Hebert, S C; Bichara, M

    1998-12-11

    To assess whether metabolic acidosis per se regulates rBSC-1, the rat medullary thick ascending limb (MTAL) apical Na+-K+(NH4+)-2Cl- cotransporter, rat MTALs were incubated for 16 h in an acid 1:1 mixture of Ham's nutrient mixture F-12 and Dulbecco's modified Eagle's medium. Cotransport activity was estimated in intact cells and membrane vesicles by intracellular pH and 22Na+ uptake measurements, respectively; rBSC-1 protein was quantified by immunoblotting analysis and mRNA by quantitative reverse transcription-polymerase chain reaction. As compared with incubation at pH approximately 7.35, acid incubation (pH approximately 7.10) up-regulated by 35-100% rBSC-1 transport activity in cells and membrane vesicles, and rBSC-1 protein and mRNA abundance. In contrast, acid incubation did not alter alkaline phosphatase and Na+/K+-ATPase enzyme activities or beta-actin protein abundance. After 3 h of in vivo chronic metabolic acidosis (CMA) rBSC-1 mRNA abundance increased in freshly harvested MTALs, which was accompanied after 1-6 days of CMA with enhanced rBSC-1 protein abundance. These results demonstrate that both in vivo and in vitro CMA stimulate rBSC-1 expression, which would contribute to the adaptive increase in MTAL absorption and urinary excretion of NH4+ in response to CMA. PMID:9837954

  11. Positive Correlation between Severity of Blepharospasm and Thalamic Glucose Metabolism.

    PubMed

    Murai, Hideki; Suzuki, Yukihisa; Kiyosawa, Motohiro; Wakakura, Masato; Mochizuki, Manabu; Ishiwata, Kiichi; Ishii, Kenji

    2011-01-01

    A 43-year-old woman with drug-related blepharospasm was followed up for 22 months. She had undergone etizolam treatment for 19 years for indefinite complaints. We examined her cerebral glucose metabolism 5 times (between days 149 and 688 since presentation), using positron emission tomography, and identified regions of interest in the thalamus, caudate nucleus, putamen, and primary somatosensory area on both sides. The severity of the blepharospasm was evaluated by PET scanning using the Wakakura classification. Sixteen women (mean age 42.4 ± 11.7 years) were examined as normal controls. The thalamic glucose metabolism in our patient was significantly increased on days 149, 212, and 688. The severity of the blepharospasm was positively correlated with the thalamic glucose metabolism, suggesting that the severity of blepharospasms reflects thalamic activity. PMID:22110436

  12. Positive Correlation between Severity of Blepharospasm and Thalamic Glucose Metabolism

    PubMed Central

    Murai, Hideki; Suzuki, Yukihisa; Kiyosawa, Motohiro; Wakakura, Masato; Mochizuki, Manabu; Ishiwata, Kiichi; Ishii, Kenji

    2011-01-01

    A 43-year-old woman with drug-related blepharospasm was followed up for 22 months. She had undergone etizolam treatment for 19 years for indefinite complaints. We examined her cerebral glucose metabolism 5 times (between days 149 and 688 since presentation), using positron emission tomography, and identified regions of interest in the thalamus, caudate nucleus, putamen, and primary somatosensory area on both sides. The severity of the blepharospasm was evaluated by PET scanning using the Wakakura classification. Sixteen women (mean age 42.4 ± 11.7 years) were examined as normal controls. The thalamic glucose metabolism in our patient was significantly increased on days 149, 212, and 688. The severity of the blepharospasm was positively correlated with the thalamic glucose metabolism, suggesting that the severity of blepharospasms reflects thalamic activity. PMID:22110436

  13. Acquired distal renal tubular acidosis in man.

    PubMed

    Better, O S

    1982-10-01

    Distal renal tubular acidosis (dRTA) may complicate renal transplantation, liver cirrhosis, and obstructive uropathy. Indeed, its occurrence may be an early clue to an episode of rejection of the graft or to obstructive uropathy. The mechanism in most patients with dRTA is impaired distal secretion of protons. In some patients, however, back leak of protons from tubular lumen to blood may abolish distal tubular ability to maintain urine to blood proton gradients. In patients with obstructive uropathy the spectrum of tubular acidosis is widened by the occurrence of additional defects in tubular secretion of potassium and impairment of hydrogen ion secretion secondary to hypoaldosteronism. Hyperkalemia is also seen in "voltage dependent" states such as following the administration of lithium and amiloride. Hyperkalemia per se is conducive to acidosis by a combination of extrarenal and several intrarenal mechanisms. PMID:6755051

  14. Trauma triggering thyrotoxic crisis with lactic acidosis

    PubMed Central

    Prosser, Jennifer S.; Quan, Dan K.

    2015-01-01

    Thyrotoxic crisis (TC) is defined as a life-threatening exacerbation of the hyperthyroid state that causes multiple autonomic and metabolic disturbances. It is considered to be an endocrine emergency that must be urgently diagnosed and treated. We describe a case of TC precipitated by trauma with a resultant lactic acidosis. The patient is a 24-year-old male with a history of hyperthyroidism who presented to the emergency department following a motor vehicle accident. The patient was initially tachycardic and hypertensive, however, was afebrile. Initial laboratory analysis showed an anion gap of 26, lactic acid 7.6, free T4 5.61 and thyroid stimulating hormone < 0.015. A diagnosis of TC was made, and he was treated with intravenous fluids, propranolol, and methimazole with improvement of tachycardia and lactic acidosis. We discuss the features of this case, which reviews the presentations of TC as well as its metabolic sequelae. PMID:26604530

  15. 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. PMID:26345674

  16. Glucose and pyruvate metabolism in severe chronic obstructive pulmonary disease

    PubMed Central

    Hsu, Jean W.-C.; Bandi, Venkata; Hanania, Nicola A.; Kheradmand, Farrah; Jahoor, Farook

    2012-01-01

    The mechanisms leading to weight loss in patients with chronic obstructive pulmonary disease (COPD) are poorly understood but may involve alterations in macronutrient metabolism. Changes in muscle oxidative capacity and lactate production during exercise suggest glucose metabolism may be altered in COPD subjects. The objective of this study was to determine differences in the rates of glucose production and clearance, the rate of glycolysis (pyruvate production), and oxidative and nonoxidative pyruvate disposal in subjects with severe COPD compared with healthy controls. The in vivo rates of glucose production and clearance were measured in 14 stable outpatients with severe COPD (seven with low and seven with preserved body mass indexes) and 7 healthy controls using an intravenous infusion of [2H2]glucose. Additionally, pyruvate production and oxidative and non-oxidative pyruvate disposal were measured using intravenous infusions of [13C]bicarbonate and [13C]pyruvate. Endogenous glucose flux and glucose clearance were significantly faster in the combined COPD subjects (P = 0.002 and P < 0.001, respectively). This difference remained significant when COPD subjects were separated by body mass index. Pyruvate flux and oxidation were significantly higher in the combined COPD subjects than controls (P = 0.02 for both), but there was no difference in nonoxidative pyruvate disposal or plasma lactate concentrations between the two groups. In subjects with severe COPD, there are alterations in glucose metabolism leading to increased glucose production and faster glucose metabolism by glycolysis and oxidation compared with controls. However, no difference in glucose conversion to lactate via pyruvate reduction is observed. PMID:22016370

  17. The nephrologist's role in metformin-induced lactic acidosis.

    PubMed

    Gómez-Navarro, L; de Arriba, G; Sánchez-Heras, M; Pérez del Valle, K M; Hernández-Sevillano, B; Basterrechea, M A; Tallón, S; Torres-Guinea, M; Rodríguez-Palomares, J R

    2011-01-01

    Metformin is an antihyperglycemic agent commonly used in diabetic patients. It is very effective and is able to reduce the plasma glucose and HbA1C. However, in some patients, specially those with comorbidities, metformin can provoke severe lactic acidosis with high morbimortality. Treatment of the lactic acidosis induced by metformin is based on the use of supportive general measures; in severe cases, procedures of extrarrenal purification like hemodialysis or continuous hemodiafiltration have been successfully used. PMID:21959726

  18. The dental management of troublesome twos: renal tubular acidosis and rampant caries

    PubMed Central

    B, Sandhyarani; Huddar, Dayanand; Patil, Anil; Sankeshwari, Banashree

    2013-01-01

    Renal tubular acidosis is a group of disorders in which there is metabolic acidosis due to defect in renal tubular acidification mechanism to maintain normal plasma bicarbonate and blood pH. Irrespective of organ system involved, oral cavity often reflects the disease occurring anywhere in the body. Thus congenital chronic renal diseases, causing acid–base disturbances affects development and structure of the teeth. Chronic renal tubular acidosis causes enamel defects, dental caries, oral candidiasis, angular cheilitis, etc. We hereby present an unusual case report of a 4-year-old boy suffering from renal tubular acidosis associated with rampant caries, whose full mouth rehabilitation has been done. PMID:23667245

  19. Hemodynamic and Metabolic Correlates of Perinatal White Matter Injury Severity

    PubMed Central

    Riddle, Art; Maire, Jennifer; Cai, Victor; Nguyen, Thuan; Gong, Xi; Hansen, Kelly; Grafe, Marjorie R.; Hohimer, A. Roger; Back, Stephen A.

    2013-01-01

    Background and Purpose Although the spectrum of perinatal white matter injury (WMI) in preterm infants is shifting from cystic encephalomalacia to milder forms of WMI, the factors that contribute to this changing spectrum are unclear. We hypothesized that the variability in WMI quantified by immunohistochemical markers of inflammation could be correlated with the severity of impaired blood oxygen, glucose and lactate. Methods We employed a preterm fetal sheep model of in utero moderate hypoxemia and global severe but not complete cerebral ischemia that reproduces the spectrum of human WMI. Since there is small but measurable residual brain blood flow during occlusion, we sought to determine if the metabolic state of the residual arterial blood was associated with severity of WMI. Near the conclusion of hypoxia-ischemia, we recorded cephalic arterial blood pressure, blood oxygen, glucose and lactate levels. To define the spectrum of WMI, an ordinal WMI rating scale was compared against an unbiased quantitative image analysis protocol that provided continuous histo-pathological outcome measures for astrogliosis and microgliosis derived from the entire white matter. Results A spectrum of WMI was observed that ranged from diffuse non-necrotic lesions to more severe injury that comprised discrete foci of microscopic or macroscopic necrosis. Residual arterial pressure, oxygen content and blood glucose displayed a significant inverse association with WMI and lactate concentrations were directly related. Elevated glucose levels were the most significantly associated with less severe WMI. Conclusions Our results suggest that under conditions of hypoxemia and severe cephalic hypotension, WMI severity measured using unbiased immunohistochemical measurements correlated with several physiologic parameters, including glucose, which may be a useful marker of fetal response to hypoxia or provide protection against energy failure and more severe WMI. PMID:24416093

  20. Examining the relationship between diet-induced acidosis and cancer

    PubMed Central

    2012-01-01

    Increased cancer risk is associated with select dietary factors. Dietary lifestyles can alter systemic acid-base balance over time. Acidogenic diets, which are typically high in animal protein and salt and low in fruits and vegetables, can lead to a sub-clinical or low-grade state of metabolic acidosis. The relationship between diet and cancer risk prompts questions about the role of acidosis in the initiation and progression of cancer. Cancer is triggered by genetic and epigenetic perturbations in the normal cell, but it has become clear that microenvironmental and systemic factors exert modifying effects on cancer cell development. While there are no studies showing a direct link between diet-induced acidosis and cancer, acid-base disequilibrium has been shown to modulate molecular activity including adrenal glucocorticoid, insulin growth factor (IGF-1), and adipocyte cytokine signaling, dysregulated cellular metabolism, and osteoclast activation, which may serve as intermediary or downstream effectors of carcinogenesis or tumor promotion. In short, diet-induced acidosis may influence molecular activities at the cellular level that promote carcinogenesis or tumor progression. This review defines the relationship between dietary lifestyle and acid-base balance and discusses the potential consequences of diet-induced acidosis and cancer occurrence or progression. PMID:22853725

  1. Haploinsufficiency of the Ammonia Transporter Rhcg Predisposes to Chronic Acidosis

    PubMed Central

    Bourgeois, Soline; Bounoure, Lisa; Christensen, Erik I.; Ramakrishnan, Suresh K.; Houillier, Pascal; Devuyst, Olivier; Wagner, Carsten A.

    2013-01-01

    Ammonia secretion by the collecting duct (CD) is critical for acid-base homeostasis and, when defective, causes distal renal tubular acidosis (dRTA). The Rhesus protein RhCG mediates NH3 transport as evident from cell-free and cellular models as well as from Rhcg-null mice. Here, we investigated in a Rhcg mouse model the metabolic effects of Rhcg haploinsufficiency, the role of Rhcg in basolateral NH3 transport, and the mechanisms of adaptation to the lack of Rhcg. Both Rhcg+/+ and Rhcg+/? mice were able to handle an acute acid load, whereas Rhcg?/? mice developed severe metabolic acidosis with reduced ammonuria and high mortality. However, chronic acid loading revealed that Rhcg+/? mice did not fully recover, showing lower blood HCO3? concentration and more alkaline urine. Microperfusion studies demonstrated that transepithelial NH3 permeability was reduced by 80 and 40%, respectively, in CDs from Rhcg?/? and Rhcg+/? mice compared with controls. Basolateral membrane permeability to NH3 was reduced in CDs from Rhcg?/? mice consistent with basolateral Rhcg localization. Rhcg?/? responded to acid loading with normal expression of enzymes and transporters involved in proximal tubular ammoniagenesis but reduced abundance of the NKCC2 transporter responsible for medullary accumulation of ammonium. Consequently, tissue ammonium content was decreased. These data demonstrate a role for apical and basolateral Rhcg in transepithelial NH3 transport and uncover an incomplete dRTA phenotype in Rhcg+/? mice. Haploinsufficiency or reduced expression of RhCG may underlie human forms of (in)complete dRTA. PMID:23281477

  2. Acidosis Promotes Bcl-2 Family-mediated Evasion of Apoptosis

    PubMed Central

    Ryder, Christopher; McColl, Karen; Zhong, Fei; Distelhorst, Clark W.

    2012-01-01

    Acidosis arises in solid and lymphoid malignancies secondary to altered nutrient supply and utilization. Tumor acidosis correlates with therapeutic resistance, although the mechanism behind this effect is not fully understood. Here we show that incubation of lymphoma cell lines in acidic conditions (pH 6.5) blocks apoptosis induced by multiple cytotoxic metabolic stresses, including deprivation of glucose or glutamine and treatment with dexamethasone. We sought to examine the role of the Bcl-2 family of apoptosis regulators in this process. Interestingly, we found that acidic culture causes elevation of both Bcl-2 and Bcl-xL, while also attenuating glutamine starvation-induced elevation of p53-up-regulated modulator of apoptosis (PUMA) and Bim. We confirmed with knockdown studies that these shifts direct survival decisions during starvation and acidosis. Importantly, the promotion of a high anti- to pro-apoptotic Bcl-2 family member ratio by acidosis renders cells exquisitely sensitive to the Bcl-2/Bcl-xL antagonist ABT-737, suggesting that acidosis causes Bcl-2 family dependence. This dependence appears to be mediated, in part, by the acid-sensing G protein-coupled receptor, GPR65, via a MEK/ERK pathway. PMID:22685289

  3. Acidosis Promotes Metastasis Formation by Enhancing Tumor Cell Motility.

    PubMed

    Riemann, A; Schneider, B; Gndel, D; Stock, C; Gekle, M; Thews, O

    2016-01-01

    The tumor microenvironment is characterized by hypoxia, acidosis as well as other metabolic and biochemical alterations. Its role in cancer progression is increasingly appreciated especially on invasive capacity and the formation of metastasis. The effect of acidosis on metastasis formation of two rat carcinoma cell lines was studied in the animal model. In order to analyze the pH dependency of different steps of metastasis formation, invasiveness, cell adhesion and migration of AT-1 prostate cancer cells as well as possible underlying cell signaling pathways were studied in vitro.Acidosis significantly increased the formation of lung metastases of both tumor cell lines in vivo. In vitro, extracellular acidosis neither enhanced invasiveness nor affected cell adhesion to a plastic or to an endothelial layer. However, cellular motility was markedly elevated at pH 6.6 and this effect was sustained even when extracellular pH was switched back to pH 7.4. When analyzing the underlying mechanism, a prominent role of ROS in the induction of migration was observed. Signaling through the MAP kinases ERK1/2 and p38 as well as Src family kinases was not involved. Thus, cancer cells in an acidic microenvironment can acquire enhanced motility, which is sustained even if the tumor cells leave their acidic microenvironment e.g. by entering the blood stream. This increase depended on elevated ROS production and may contribute to the augmented formation of metastases of acidosis-primed tumor cells in vivo. PMID:26782215

  4. Neurological damage arising from intrapartum hypoxia/acidosis.

    PubMed

    Rei, M; Ayres-de-Campos, D; Bernardes, J

    2016-01-01

    Complications occurring at any level of foetal oxygen supply will result in hypoxaemia, and this may ultimately lead to hypoxia/acidosis and neurological damage. Hypoxic-ischaemic encephalopathy (HIE) is the short-term neurological dysfunction caused by intrapartum hypoxia/acidosis, and this diagnosis requires the presence of a number of findings, including the confirmation of newborn metabolic acidosis, low Apgar scores, early imaging evidence of cerebral oedema and the appearance of clinical signs of neurological dysfunction in the first 48 h of life. Cerebral palsy (CP) consists of a heterogeneous group of nonprogressive movement and posture disorders, frequently accompanied by cognitive and sensory impairments, epilepsy, nutritional deficiencies and secondary musculoskeletal lesions. Although CP is the most common long-term neurological complication associated with intrapartum hypoxia/acidosis, >80% of cases are caused by other phenomena. Data on minor long-term neurological deficits are scarce, but they suggest that less serious intellectual and motor impairments may result from intrapartum hypoxia/acidosis. This chapter focuses on the existing evidence of neurological damage associated with poor foetal oxygenation during labour. PMID:26148854

  5. Molecular Pathophysiology of Renal Tubular Acidosis

    PubMed Central

    Pereira, P.C.B; Miranda, D.M; Oliveira, E.A; Silva, A.C. Simões e

    2009-01-01

    Renal tubular acidosis (RTA) is characterized by metabolic acidosis due to renal impaired acid excretion. Hyperchloremic acidosis with normal anion gap and normal or minimally affected glomerular filtration rate defines this disorder. RTA can also present with hypokalemia, medullary nephrocalcinosis and nephrolitiasis, as well as growth retardation and rickets in children, or short stature and osteomalacia in adults. In the past decade, remarkable progress has been made in our understanding of the molecular pathogenesis of RTA and the fundamental molecular physiology of renal tubular transport processes. This review summarizes hereditary diseases caused by mutations in genes encoding transporter or channel proteins operating along the renal tubule. Review of the molecular basis of hereditary tubulopathies reveals various loss-of-function or gain-of-function mutations in genes encoding cotransporter, exchanger, or channel proteins, which are located in the luminal, basolateral, or endosomal membranes of the tubular cell or in paracellular tight junctions. These gene mutations result in a variety of functional defects in transporter/channel proteins, including decreased activity, impaired gating, defective trafficking, impaired endocytosis and degradation, or defective assembly of channel subunits. Further molecular studies of inherited tubular transport disorders may shed more light on the molecular pathophysiology of these diseases and may significantly improve our understanding of the mechanisms underlying renal salt homeostasis, urinary mineral excretion, and blood pressure regulation in health and disease. The identification of the molecular defects in inherited tubulopathies may provide a basis for future design of targeted therapeutic interventions and, possibly, strategies for gene therapy of these complex disorders. PMID:19721811

  6. Deficiency of the α Subunit of Succinate–Coenzyme A Ligase Causes Fatal Infantile Lactic Acidosis with Mitochondrial DNA Depletion

    PubMed Central

    Ostergaard, Elsebet ; Christensen, Ernst ; Kristensen, Elisabeth ; Mogensen, Bodil ; Duno, Morten ; Shoubridge, Eric A. ; Wibrand, Flemming 

    2007-01-01

    Fatal infantile lactic acidosis is a severe metabolic disorder characterized by the onset of lactic acidosis within the 1st d of life and early death. We found a combined respiratory-chain enzyme deficiency associated with mitochondrial DNA (mtDNA) depletion in a small consanguineous family with this disorder. To identify the disease-causing gene, we performed single-nucleotide polymorphism homozygosity mapping and found homozygous regions on four chromosomes. DNA sequencing revealed a homozygous 2-bp deletion in SUCLG1, a gene that encodes the α subunit of the Krebs-cycle enzyme succinate–coenzyme A ligase (SUCL). The mtDNA depletion is likely explained by decreased mitochondrial nucleoside diphosphate kinase (NDPK) activity resulting from the inability of NDPK to form a complex with SUCL. PMID:17668387

  7. Proximal Tubule Function and Response to Acidosis

    PubMed Central

    2014-01-01

    Summary The human kidneys produce approximately 160–170 L of ultrafiltrate per day. The proximal tubule contributes to fluid, electrolyte, and nutrient homeostasis by reabsorbing approximately 60%–70% of the water and NaCl, a greater proportion of the NaHCO3, and nearly all of the nutrients in the ultrafiltrate. The proximal tubule is also the site of active solute secretion, hormone production, and many of the metabolic functions of the kidney. This review discusses the transport of NaCl, NaHCO3, glucose, amino acids, and two clinically important anions, citrate and phosphate. NaCl and the accompanying water are reabsorbed in an isotonic fashion. The energy that drives this process is generated largely by the basolateral Na+/K+-ATPase, which creates an inward negative membrane potential and Na+-gradient. Various Na+-dependent countertransporters and cotransporters use the energy of this gradient to promote the uptake of HCO3− and various solutes, respectively. A Na+-dependent cotransporter mediates the movement of HCO3− across the basolateral membrane, whereas various Na+-independent passive transporters accomplish the export of various other solutes. To illustrate its homeostatic feat, the proximal tubule alters its metabolism and transport properties in response to metabolic acidosis. The uptake and catabolism of glutamine and citrate are increased during acidosis, whereas the recovery of phosphate from the ultrafiltrate is decreased. The increased catabolism of glutamine results in increased ammoniagenesis and gluconeogenesis. Excretion of the resulting ammonium ions facilitates the excretion of acid, whereas the combined pathways accomplish the net production of HCO3− ions that are added to the plasma to partially restore acid-base balance. PMID:23908456

  8. Fatal Tenofovir-Associateacd Lactic Acidosis: A Case Report

    PubMed Central

    Hashim, Hasriza; Sahari, Narisa Sulaiman; Sazlly Lim, Sazlyna Mohd; Hoo, Fan Kee

    2015-01-01

    Introduction: The introduction of highly active antiretroviral therapy (HAART), in 1996, has resulted in marked reductions in the rate of illness and death, due to HIV infection. The HAART has transformed HIV infection into a manageable chronic disease. However, although many regimens lower plasma viral load, to below the limit of detection, in most patients, maintaining viral load suppression remains challenging, because of adverse effects and toxicity in the long term, which can lead to non-adherence, virologic failure and drug resistance. Although rare, lactic acidosis often develops fatal complications, as reported in several human immunodeficiency virus infected patients treated with nucleoside reverse transcriptase inhibitors (NRTIs). The purpose of this paper is to report a case of tenofovir induced lactic acidosis and review the literature. Case Presentation: A 52-year-old Malay gentleman, with hepatitis C virus and HIV infection was admitted to the intensive care unit for severe lactic acidosis, with concurrent Escherichia coli bacteremia with multiorgan dysfunction. The patient was started on highly active antiretroviral therapy, which included tenofovir, 5 weeks before presentation. Antimicrobial therapy, continuous veno-venous hemofiltration, and other supportive treatments were instituted. However, the patient eventually succumbed to his illness. Conclusions: It is essential for clinicians to be able to recognize the signs and symptoms of lactic acidosis in NRTIs treated HIV patients, as an early diagnosis is important to institute treatment. PMID:26568856

  9. Lactobacillus GG does not affect D-lactic acidosis in diarrheic calves, in a clinical setting.

    PubMed

    Ewaschuk, Julia B; Zello, Gordon A; Naylor, Jonathan M

    2006-01-01

    D-lactate, produced by gastrointestinal fermentation, is a major contributor to metabolic acidosis in diarrheic calves. Lactobacillus rhamnosus GG survives gastrointestinal transit in the neonatal calf and does not produce D-lactate. To determine whether this probiotic reduces gastrointestinal D-lactate production or severity of diarrhea or both, 48 calves (mean, 11 days old; range, 2-30 days) admitted to the clinic for treatment of diarrhea were randomly allocated to 2 groups. The experimental group was given Lactobacillus rhamnosus GG (1 x 10(11) cfu/d) PO, dissolved in milk or oral electrolyte solution, in addition to clinic treatment protocols; the other group served as a control. Serum and fecal samples were obtained at admission and at 24 and 48 hours after initial administration of Lactobacillus rhamnosus GG. All samples were analyzed for D- and L-lactate by using high-pressure liquid chromatography. Feces were also analyzed for pathogens, Lactobacillus rhamnosus GG recovery, and dry matter. D-lactic acidemia (>3 mmol/L) was present in 37/48 calves at admission. Lactobacillus rhamnosus GG was recovered in the feces of 13 experimental calves and 0 control calves 24 hours after administration. No difference in serum or fecal D- or L-lactate between the groups was detected at any time point. After therapy, D-lactic acidosis was absent at 48 hours in all but 1 calf. No relation between fecal pathogen (viral, bacterial, or protozoal) and degree of D-lactic acidosis was observed. The reduction in mortality and greater fecal dry matter in Lactobacillus rhamnosus GG-treated calves was not statistically significant. PMID:16734098

  10. Sulfur amino acid metabolism in children with severe childhood undernutrition: methionine kinetics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Children with edematous but not nonedematous severe childhood undernutrition (SCU) have lower plasma and erythrocyte-free concentrations of cysteine and methionine, which suggests a decreased availability of methionine for cysteine synthesis. We propose that methionine production and metabolism will...

  11. 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.

  12. 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. PMID:25193912

  13. The Effect of Treatment of Acidosis on Calcium Balance in Patients with Chronic Azotemic Renal Disease*

    PubMed Central

    Litzow, John R.; Lemann, Jacob; Lennon, Edward J.

    1967-01-01

    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 NaHCO3 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. PMID:6018764

  14. 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

  15. Effect of induced ruminal acidosis on blood variables in heifers

    PubMed Central

    2013-01-01

    Background Ruminal acidosis is responsible for the onset of different pathologies in dairy and feedlot cattle, but there are major difficulties in the diagnosis. This study modelled the data obtained from various blood variables to identify those that could indicate the severity of ruminal acidosis. Six heifers were fed three experimental rations throughout three periods. The diets were characterised by different starch levels: high starch (HS), medium starch (MS) and low starch, as the control diet (CT). Ruminal pH values were continuously measured using wireless sensors and compared with pH measurements obtained by rumenocentesis. Blood samples were analysed for complete blood count, biochemical profile, venous blood gas, blood lipopolysaccharide (LPS) and LPS-binding proteins (LBP). Results The regression coefficient comparing the ruminal pH values, obtained using the two methods, was 0.56 (P = 0.040). Feeding the CT, MS and HS led to differences in the time spent below the 5.8, 5.5 and 5.0 pH thresholds and in several variables, including dry matter intake (7.7 vs. 6.9 vs. 5.1 kg/d; P = 0.002), ruminal nadir pH (5.69 vs. 5.47 vs. 5.44; P = 0.042), mean ruminal pH (6.50 vs. 6.34 vs. 6.31; P = 0.012), haemoglobin level (11.1 vs. 10.9 vs. 11.4 g/dL; P = 0.010), platelet count (506 vs. 481 vs. 601; P = 0.008), HCO3- (31.8 vs. 31.3 vs. 30.6 mmol/L; P = 0.071) and LBP (5.9 vs. 9.5 vs. 10.5 μg/mL; P < 0.001). A canonical discriminant analysis (CDA) was used to classify the animals into four ruminal pH classes (normal, risk of acidosis, subacute ruminal acidosis and acute ruminal acidosis) using haemoglobin, mean platelet volume, β-hydroxybutyrate, glucose and reduced haemoglobin. Conclusions Although additional studies are necessary to confirm the reliability of these discriminant functions, the use of plasma variables in a multifactorial model appeared to be useful for the evaluation of ruminal acidosis severity. PMID:23647881

  16. Rumen microbiome composition determined using two nutritional models of subacute ruminal acidosis.

    PubMed

    Khafipour, Ehsan; Li, Shucong; Plaizier, Jan C; Krause, Denis O

    2009-11-01

    Subacute ruminal acidosis (SARA) is a metabolic disease in dairy cattle that occurs during early and mid-lactation and has traditionally been characterized by low rumen pH, but lactic acid does not accumulate as in acute lactic acid acidosis. It is hypothesized that factors such as increased gut permeability, bacterial lipopolysaccharides, and inflammatory responses may have a role in the etiology of SARA. However, little is known about the nature of the rumen microbiome during SARA. In this study, we analyzed the microbiome of 64 rumen samples taken from eight lactating Holstein dairy cattle using terminal restriction fragment length polymorphisms (TRFLP) of 16S rRNA genes and real-time PCR. We used rumen samples from two published experiments in which SARA had been induced with either grain or alfalfa pellets. The results of TRFLP analysis indicated that the most predominant shift during SARA was a decline in gram-negative Bacteroidetes organisms. However, the proportion of Bacteroidetes organisms was greater in alfalfa pellet-induced SARA than in mild or severe grain-induced SARA (35.4% versus 26.0% and 16.6%, respectively). This shift was also evident from the real-time PCR data for Prevotella albensis, Prevotella brevis, and Prevotella ruminicola, which are members of the Bacteroidetes. The real-time PCR data also indicated that severe grain-induced SARA was dominated by Streptococcus bovis and Escherichia coli, whereas mild grain-induced SARA was dominated by Megasphaera elsdenii and alfalfa pellet-induced SARA was dominated by P. albensis. Using discriminant analysis, the severity of SARA and degree of inflammation were highly correlated with the abundance of E. coli and not with lipopolysaccharide in the rumen. We thus suspect that E. coli may be a contributing factor in disease onset. PMID:19783747

  17. Management of Moderate to Severe Psoriasis in Patients with Metabolic Comorbidities

    PubMed Central

    Gisondi, Paolo; Galvan, Arturo; Idolazzi, Luca; Girolomoni, Giampiero

    2015-01-01

    Psoriasis is a chronic inflammatory skin disease affecting 2–3% of worldwide population. The extent of skin involvement is variable, ranging from a few localized plaques to generalized involvement. Moderate to severe psoriasis (>10% of body surface area) is frequently associated with psoriatic arthritis and metabolic diseases, like abdominal obesity, diabetes, non-alcoholic fatty liver disease, dyslipidemia, metabolic syndrome, and chronic kidney disease. A common genetic background as well as several acquired risk factors links psoriasis to comorbidities. From a clinical prespective, the understanding of the patients in the context of these comorbidities is very important to ensure that treatment is tailored to meet the individual patient needs. Indeed, some pharmacological treatments may negatively affect cardio-metabolic comorbidities, and have important interactions with drugs that are commonly used to treat them. Non-pharmacological intervention such as diet, smoking cessation, and physical exercise could both improve the response to treatments for psoriasis and reduce the cardiovascular risk. PMID:25654080

  18. Severe acute oxidant exposure: morphological damage and aerobic metabolism in the lung

    SciTech Connect

    Montgomery, M.R.; Teuscher, F.; LaSota, I.; Niewoehner, D.E.

    1986-09-01

    Groups of male rats were exposed to acute doses of oxygen, ozone, or paraquat which produced equivalent mortality (25-30%) over a 28 day post-exposure period. Quantitative evaluation of morphological changes indicated the primary response to be edema and inflammation with only slight fibrosis being apparent by the end of the observation period. Aerobic pulmonary metabolism was inhibited in lungs from animals exposed to oxygen and ozone as evidenced by decreased oxygen consumption; however, this was transient and O/sub 2/ consumption returned to normal within 24 hours after removal from the exposure chamber. Conversely, treatment with paraquat caused an immediate, transient stimulation of O/sub 2/ consumption. Glucose metabolism was unaltered by the gas exposures and, as previously reported, was initially stimulated by paraquat treatment. In vitro, only paraquat altered both O/sub 2/ consumption and glucose metabolism when added to lung slice preparations; ozone had no effect. Oxygen did not alter O/sub 2/ consumption but caused a slight biphasic response in glucose metabolism. Aerobic metabolism is relatively unchanged by these doses of oxygen and ozone which result in the death of 25-30% of all treated animals. Even though paraquat produces similar morphologic changes, it may represent a more severe metabolic insult than ''equivalent'' doses of oxygen or ozone. Also, if interstitial pulmonary fibrosis is a desired result of experimental exposure, rats may not be a suitable model for oxidant induced lung injury.

  19. [The characteristics of changes in lipid metabolism indices of patients with severe mechanical trauma].

    PubMed

    Moroz, V V; Bessekeev, A A; Molchanova, L V; Shcherbakova, L N

    2003-01-01

    The paper contains the study results of some lipid-metabolism indices in patients with severe mechanical injury. Changing concentrations of total cholesterol, triglycerides and of different lipoprotein fractions in blood plasma are demonstrated. It was established that the investigated lipid-metabolism indices reflect a degree of liver malfunction in severely impaired homeostasis. It can be stated on the basis of comparing the study results with the clinical outcome that the dynamic concentration of total cholesterol in blood plasma is an important prognostication factor. Changing ratios of high-density lipoproteins, low-density lipoproteins and extra-low-density lipoproteins were observed in survivors yet by day 15, which is indicative of a commencing dislipidemia. PMID:14991968

  20. Methemoglobinemia associated with acidosis of probable renal origin.

    PubMed

    Sager, S; Grayson, G H; Feig, S A

    1995-01-01

    We describe an infant who had methemoglobinemia related to acidosis, probably on the basis of renal tubular acidosis. Methemoglobinemia may indicate the presence of a clinically significant underlying disorder. PMID:7815226

  1. Chronic administration of Eucommia leaf stimulates metabolic function of rats across several organs.

    PubMed

    Fujikawa, Takahiko; Hirata, Tetsuya; Wada, Atsunori; Kawamura, Naomi; Yamaguchi, Yasuyo; Fujimura, Katsuyuki; Ueda, Taro; Yurugi, Yutaka; Soya, Hideaki; Nishibe, Sansei

    2010-12-01

    Eucommia bark (Eucommia ulmoides Oliver) has been used as an herbal medicine, and more recently, the plant's leaves have been widely used to prepare tea which may have anti-obesity properties. We used a metabolic syndrome-like rat model, produced by feeding a 35% high-fat diet (HFD), to examine potential anti-obesity and anti-metabolic syndrome effects and mechanisms of chronic administration of Eucommia leaf as an extract or green leaf powder. Eighty rats were studied for 3 months in ten groups. Both forms of Eucommia leaves minimised increases in body weight and visceral fat in a dose-dependent fashion. Increases in plasma levels of TAG and NEFA, and insulin resistance secondary to HFD were lessened by both forms of Eucommia leaf. Concomitantly, an increase in plasma adiponectin levels and suppression of plasma resistin and TNF-α levels were confirmed. Real-time PCR studies showed that both forms of Eucommia leaf enhanced metabolic function across several organs, including diminishing ATP production (white adipose tissue), accelerating β-oxidation (liver) and increasing the use of ketone bodies/glucose (skeletal muscle), all of which may exert anti-obesity effects under HFD conditions. These findings suggest that chronic administration of either form of Eucommia leaves stimulates the metabolic function in rats across several organs. The anti-obesity and anti-metabolic syndrome activity in this rat model may be maintained through secretion and regulation of adipocytokines that depend on the accumulation of visceral fat to improve insulin resistance or hyperlipaemia. PMID:20691136

  2. 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

  3. Maple Bark Biochar Affects Rhizoctonia solani Metabolism and Increases Damping-Off Severity.

    PubMed

    Copley, Tanya R; Aliferis, Konstantinos A; Jabaji, Suha

    2015-10-01

    Many studies have investigated the effect of biochar on plant yield, nutrient uptake, and soil microbial populations; however, little work has been done on its effect on soilborne plant diseases. To determine the effect of maple bark biochar on Rhizoctonia damping-off, 11 plant species were grown in a soilless potting substrate amended with different concentrations of biochar and inoculated or not with Rhizoctonia solani anastomosis group 4. Additionally, the effect of biochar amendment on R. solani growth and metabolism in vitro was evaluated. Increasing concentrations of maple bark biochar increased Rhizoctonia damping-off of all 11 plant species. Using multivariate analyses, we observed positive correlations between biochar amendments, disease severity and incidence, abundance of culturable bacterial communities, and physicochemical parameters. Additionally, biochar amendment significantly increased R. solani growth and hyphal extension in vitro, and altered its primary metabolism, notably the mannitol and tricarboxylic acid cycles and the glycolysis pathway. One or several organic compounds present in the biochar, as identified by gas chromatography-mass spectrometry analysis, may be metabolized by R. solani. Taken together, these results indicate that future studies on biochar should focus on the effect of its use as an amendment on soilborne plant pathogens before applying it to soils. PMID:25938176

  4. Comparison of metabolic substrates in alligators and several birds of prey.

    PubMed

    Sweazea, Karen L; McMurtry, John P; Elsey, Ruth M; Redig, Patrick; Braun, Eldon J

    2014-08-01

    On average, avian blood glucose concentrations are 1.5-2 times those of mammals of similar mass and high concentrations of insulin are required to lower blood glucose. Whereas considerable data exist for granivorous species, few data are available for plasma metabolic substrate and glucoregulatory hormone concentrations for carnivorous birds and alligators. Birds and mammals with carnivorous diets have higher metabolic rates than animals consuming diets with less protein whereas alligators have low metabolic rates. Therefore, the present study was designed to compare substrate and glucoregulatory hormone concentrations in several birds of prey and a phylogenetically close relative of birds, the alligator. The hypothesis was that the combination of carnivorous diets and high metabolic rates favored the evolution of greater protein and fatty acid utilization leading to insulin resistance and high plasma glucose concentrations in carnivorous birds. In contrast, it was hypothesized that alligators would have low substrate utilization attributable to a low metabolic rate. Fasting plasma substrate and glucoregulatory hormone concentrations were compared for bald eagles (Haliaeetus leucocephalus), great horned owls (Bubo virginianus), red-tailed hawks (Buteo jamaicensis), and American alligators (Alligator mississippiensis). Avian species had high circulating β-hydroxybutyrate (10-21 mg/dl) compared to alligators (2.81 ± 0.16 mg/dl). In mammals high concentrations of this byproduct of fatty acid utilization are correlated with insulin resistance. Fasting glucose and insulin concentrations were positively correlated in eagles whereas no relationship was found between these variables for owls, hawks or alligators. Additionally, β-hydroxybutyrate concentrations were low in alligators. Similar to carnivorous mammals, ingestion of a high protein diet may have favored the utilization of fatty acids and protein for energy thereby promoting the development of insulin resistance and gluconeogenesis-induced high plasma glucose concentrations during periods of fasting in birds of prey. PMID:25043840

  5. Acidosis Activation of the Proton-Sensing GPR4 Receptor Stimulates Vascular Endothelial Cell Inflammatory Responses Revealed by Transcriptome Analysis

    PubMed Central

    Dong, Lixue; Li, Zhigang; Leffler, Nancy R.; Asch, Adam S.; Chi, Jen-Tsan; Yang, Li V.

    2013-01-01

    Acidic tissue microenvironment commonly exists in inflammatory diseases, tumors, ischemic organs, sickle cell disease, and many other pathological conditions due to hypoxia, glycolytic cell metabolism and deficient blood perfusion. However, the molecular mechanisms by which cells sense and respond to the acidic microenvironment are not well understood. GPR4 is a proton-sensing receptor expressed in endothelial cells and other cell types. The receptor is fully activated by acidic extracellular pH but exhibits lesser activity at the physiological pH 7.4 and minimal activity at more alkaline pH. To delineate the function and signaling pathways of GPR4 activation by acidosis in endothelial cells, we compared the global gene expression of the acidosis response in primary human umbilical vein endothelial cells (HUVEC) with varying level of GPR4. The results demonstrated that acidosis activation of GPR4 in HUVEC substantially increased the expression of a number of inflammatory genes such as chemokines, cytokines, adhesion molecules, NF-?B pathway genes, and prostaglandin-endoperoxidase synthase 2 (PTGS2 or COX-2) and stress response genes such as ATF3 and DDIT3 (CHOP). Similar GPR4-mediated acidosis induction of the inflammatory genes was also noted in other types of endothelial cells including human lung microvascular endothelial cells and pulmonary artery endothelial cells. Further analyses indicated that the NF-?B pathway was important for the acidosis/GPR4-induced inflammatory gene expression. Moreover, acidosis activation of GPR4 increased the adhesion of HUVEC to U937 monocytic cells under a flow condition. Importantly, treatment with a recently identified GPR4 antagonist significantly reduced the acidosis/GPR4-mediated endothelial cell inflammatory response. Taken together, these results show that activation of GPR4 by acidosis stimulates the expression of a wide range of inflammatory genes in endothelial cells. Such inflammatory response can be suppressed by GPR4 small molecule inhibitors and hold potential therapeutic value. PMID:23613998

  6. Type B lactic acidosis: a rare but life threatening hematologic emergency. A case illustration and brief review

    PubMed Central

    Claudino, Wederson M; Dias, Ajoy; Tse, William; Sharma, Vivek R

    2015-01-01

    Major strides have been made in improving the treatment of medical emergencies associated with malignancies. Nonetheless, metabolic emergencies in cancer patients can often times be life-threatening. Type B lactic acidosis is a rare but potentially fatal paraneoplastic phenomenon that has been described in association with hematologic and solid malignancies and portends a poor prognosis if not rapidly recognized and treated. It is believed that this occurs as a result of cancer cells switching their glucose metabolism from an oxidative oxygen- dependent pathway towards a glycolytic phenotype, also known as the Warburg effect. Though rare, it is important to consider this entity in the differential diagnosis of type B lactic acidosis since prompt identification and treatment may help improve outcomes in this otherwise fatal process. We present a case of type B lactic acidosis in a patient with chronic lymphocytic leukemia along with a brief review of the literature. PMID:26171281

  7. Severe Obesity Shifts Metabolic Thresholds but Does Not Attenuate Aerobic Training Adaptations in Zucker Rats

    PubMed Central

    Rosa, Thiago S.; Simões, Herbert G.; Rogero, Marcelo M.; Moraes, Milton R.; Denadai, Benedito S.; Arida, Ricardo M.; Andrade, Marília S.; Silva, Bruno M.

    2016-01-01

    Severe obesity affects metabolism with potential to influence the lactate and glycemic response to different exercise intensities in untrained and trained rats. Here we evaluated metabolic thresholds and maximal aerobic capacity in rats with severe obesity and lean counterparts at pre- and post-training. Zucker rats (obese: n = 10, lean: n = 10) were submitted to constant treadmill bouts, to determine the maximal lactate steady state, and an incremental treadmill test, to determine the lactate threshold, glycemic threshold and maximal velocity at pre and post 8 weeks of treadmill training. Velocities of the lactate threshold and glycemic threshold agreed with the maximal lactate steady state velocity on most comparisons. The maximal lactate steady state velocity occurred at higher percentage of the maximal velocity in Zucker rats at pre-training than the percentage commonly reported and used for training prescription for other rat strains (i.e., 60%) (obese = 78 ± 9% and lean = 68 ± 5%, P < 0.05 vs. 60%). The maximal lactate steady state velocity and maximal velocity were lower in the obese group at pre-training (P < 0.05 vs. lean), increased in both groups at post-training (P < 0.05 vs. pre), but were still lower in the obese group at post-training (P < 0.05 vs. lean). Training-induced increase in maximal lactate steady state, lactate threshold and glycemic threshold velocities was similar between groups (P > 0.05), whereas increase in maximal velocity was greater in the obese group (P < 0.05 vs. lean). In conclusion, lactate threshold, glycemic threshold and maximal lactate steady state occurred at similar exercise intensity in Zucker rats at pre- and post-training. Severe obesity shifted metabolic thresholds to higher exercise intensity at pre-training, but did not attenuate submaximal and maximal aerobic training adaptations. PMID:27148063

  8. Enkephalins and hormonal-metabolic reactions in experimental stress depending on its severity

    SciTech Connect

    Lishmanov, Y.B.; Alekminskaya, L.A.; Lasukova, T.V.

    1985-08-01

    The aim of this investigation was to study the action of enkephalins on changes in hormonal-metabolic constants in stress of varied severity. Catecholamine excretion with the urine was determined fluorometrically, serum cortisol and insulin concentrations were measured radioimmunologically and glucose was determined by the standard orthotoluidine method. The results of the investigation indicate that enkephalins have a modulating effect on various hormonal mechanisms of adaptation stress. The results confirm that the physiological action of the peptide regulator depends on the functional state of the biological systems and it may differ sharply, even to the extent of diametrically opposite effects.

  9. The metabolic effects of moderately severe upper gastrointestinal haemorrhage in man.

    PubMed Central

    Foster, K. J.; Alberti, K. G.; Binder, C.; Holdstock, G.; Karran, S. J.; Smith, C. L.; Talbot, S.; Turnell, D. C.

    1982-01-01

    The metabolic effects of moderately severe gastrointestinal haemorrhage were investigated in man. Before resuscitation, patients had raised circulating concentrations of glucose, lactate, alanine, glycerol and cortisol. After urgent operation for haemorrhage, metabolite concentrations were similar to those of control patients having elective abdominal surgery, but insulin concentrations were higher and cortisol lower in haemorrhage patients. There were no significant differences in nitrogen excretion between haemorrhage patients and their controls, but urinary 3-methyl-histidine excretion by haemorrhage patients was lower indicating decreased muscle protein breakdown. Decreased amino acid release from muscle might account for previously reported imparied wound healing after haemorrhage. PMID:7045838

  10. Interactions between sleep, circadian function, and glucose metabolism: implications for risk and severity of diabetes.

    PubMed

    Reutrakul, Sirimon; Van Cauter, Eve

    2014-04-01

    Sleep disturbances, including sleep insufficiency and sleep fragmentation, have been linked to abnormal glucose metabolism and increased diabetes risk. Well-controlled laboratory studies have provided insights regarding the underlying mechanisms. Several large prospective studies suggest that these sleep disturbances are associated with an increased risk of incident diabetes. Obstructive sleep apnea, which combines sleep fragmentation and hypoxemia, is a major risk factor for insulin resistance and possibly diabetes. Whether glycemic control in type 2 diabetes patients can be improved by treating sleep apnea remains controversial. Recently, sleep disturbances during pregnancy and their relationship to gestational diabetes and hyperglycemia have received considerable attention owing to potential adverse effects on maternal and fetal health. Additionally, evidence from animal models has identified disruption of the circadian system as a putative risk factor for adverse metabolic outcomes. The purpose of this review is to provide an update on the current state of knowledge linking sleep disturbances, circadian dysfunction, and glucose metabolism. Experimental, prospective, and interventional studies are discussed. PMID:24628249

  11. The effect of LLLT on bone metabolism in children with severe cerebral palsy (a secondary publication)

    PubMed Central

    2014-01-01

    Background and aims: It is said that the average frequency of bone fracture in hospitalized children with severe cerebral palsy (unable to remain seated) is 1% (0.2 to 2.0%). Cerebral palsy patients' bones are known to be vulnerable to fracture, and refractory bone atrophy may be observed. However, the effect of low level laser therapy (LLLT) on bone density or bone metabolism has not been fully investigated. In recent years, tests for bone density or bone metabolism markers have become available. Material and methods: In this study, we evaluated changes in bone density and bone metabolism markers in 4 children with severe cerebral palsy who underwent LLLT for an average of 22 days. Results: B-ALP, a marker of ossification, increased 1 month after the start of irradiation in 3 of the 4 subjects and returned to a level close to the pre-irradiation level 2 months after the start of irradiation. In the remaining subjects in whom B-ALP failed to increase, B-ALP had been low before irradiation. Urinary N-terminal telopeptide (NTx) levels, a marker of bone resorption, decreased in 3 of the 4 subjects after the start of irradiation and remained low even 10 months later. Serum NTx levels tended to decrease in 3 of the 4 subjects. The levels of serum NTx/Crea, Deoxy-Pyridinoline (DPd) and DPd/Crea (DPd/Crea) also decreased in 3 of the 4 subjects. Transient decreases in intact parathyroid hormone (PTH) levels were observed in all 4 cases. Changes were particularly apparent in 2 cases: one with high NTx levels, which showed enhanced bone resorption, and one with high PTH levels, probably due to a vitamin D (VitD) deficiency. Although the metacarpal bone density measured by DIP was found to be lower than in normal children, there were no changes due to LLLT. Conclusion: These results suggest that LLLT has a positive influence on bone metabolism in that it temporarily increases bone formation and suppresses bone resorption while also tending to improve secondary hyperparathyroidism caused by VitD deficiency. Enhanced bone resorption in the case with high NTx levels was noteworthy, together with marked changes in the case with high PTH levels due to VitD deficiency. These positive influences on bone metabolism merit attention as potential new indications of LLLT. PMID:25705079

  12. Lactic acidosis following intentional overdose by inhalation of salmeterol and fluticasone.

    PubMed

    Manara, Alessandro; Hantson, Philippe; Vanpee, Dominique; Thys, Frédéric

    2012-11-01

    Salmeterol, a long-acting β2-adrenergic receptor agonist used for the treatment of asthma and chronic obstructive pulmonary disease, has an adverse effects profile that is similar to that of salbutamol and other β2-agonists. We report a sympathomimetic syndrome with metabolic acidosis and hyperlactatemia after intentional inhalation of salmeterol in a suicide attempt. A 16-year-old female patient was admitted to the emergency department approximately 2 hours after having inhaled 60 puffs of a combination of salmeterol xinafoate 25 μg and fluticasone propionate 50 μg. She presented in an anxious state with complaints of palpitations and chest pain. The electrocardiogram demonstrated sinus tachycardia and ST-segment depression in the inferior and anterolateral leads. Laboratory findings showed hypokalemia, hypophosphatemia, and lactic acidosis. Cardiac troponin I and creatine kinase MB remained within the normal range. Treatment was supportive and included intravenous fluids and cautious potassium supplementation. The next day, electrocardiographic and laboratory findings returned to normal. We hypothesize that stimulation of β2-adrenergic receptors by inhalation of salmeterol caused this patient's lactic acidosis. This observation is consistent with the hypothesis that the hyperlactatemia observed during asthma attacks is due in part to the administration of high doses of β2-agonists. Salmeterol overdose by inhalation appears to be sufficient to cause lactic acidosis. PMID:23131487

  13. 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. PMID:23581267

  14. Down-sizing of neuronal network activity and density of presynaptic terminals by pathological acidosis are efficiently prevented by Diminazene Aceturate.

    PubMed

    de Ceglia, Roberta; Chaabane, Linda; Biffi, Emilia; Bergamaschi, Andrea; Ferrigno, Giancarlo; Amadio, Stefano; Del Carro, Ubaldo; Mazzocchi, Nausicaa; Comi, Giancarlo; Bianchi, Veronica; Taverna, Stefano; Forti, Lia; D'Adamo, Patrizia; Martino, Gianvito; Menegon, Andrea; Muzio, Luca

    2015-03-01

    Local acidosis is associated with neuro-inflammation and can have significant effects in several neurological disorders, including multiple sclerosis, brain ischemia, spinal cord injury and epilepsy. Despite local acidosis has been implicated in numerous pathological functions, very little is known about the modulatory effects of pathological acidosis on the activity of neuronal networks and on synaptic structural properties. Using non-invasive MRI spectroscopy we revealed protracted extracellular acidosis in the CNS of Experimental Autoimmune Encephalomyelitis (EAE) affected mice. By multi-unit recording in cortical neurons, we established that acidosis affects network activity, down-sizing firing and bursting behaviors as well as amplitudes. Furthermore, a protracted acidosis reduced the number of presynaptic terminals, while it did not affect the postsynaptic compartment. Application of the diarylamidine Diminazene Aceturate (DA) during acidosis significantly reverted both the loss of neuronal firing and bursting and the reduction of presynaptic terminals. Finally, in vivo DA delivery ameliorated the clinical disease course of EAE mice, reducing demyelination and axonal damage. DA is known to block acid-sensing ion channels (ASICs), which are proton-gated, voltage-insensitive, Na(+) permeable channels principally expressed by peripheral and central nervous system neurons. Our data suggest that ASICs activation during acidosis modulates network electrical activity and exacerbates neuro-degeneration in EAE mice. Therefore pharmacological modulation of ASICs in neuroinflammatory diseases could represent a new promising strategy for future therapies aimed at neuro-protection. PMID:25499583

  15. A Heterozygous ZMPSTE24 Mutation Associated with Severe Metabolic Syndrome, Ectopic Fat Accumulation, and Dilated Cardiomyopathy.

    PubMed

    Galant, Damien; Gaborit, Bénédicte; Desgrouas, Camille; Abdesselam, Ines; Bernard, Monique; Levy, Nicolas; Merono, Françoise; Coirault, Catherine; Roll, Patrice; Lagarde, Arnaud; Bonello-Palot, Nathalie; Bourgeois, Patrice; Dutour, Anne; Badens, Catherine

    2016-01-01

    ZMPSTE24 encodes the only metalloprotease, which transforms prelamin into mature lamin A. Up to now, mutations in ZMPSTE24 have been linked to Restrictive Dermopathy (RD), Progeria or Mandibulo-Acral Dysplasia (MAD). We report here the phenotype of a patient referred for severe metabolic syndrome and cardiomyopathy, carrying a mutation in ZMPSTE24. The patient presented with a partial lipodystrophic syndrome associating hypertriglyceridemia, early onset type 2 diabetes, and android obesity with truncal and abdominal fat accumulation but without subcutaneous lipoatrophy. Other clinical features included acanthosis nigricans, liver steatosis, dilated cardiomyopathy, and high myocardial and hepatic triglycerides content. Mutated fibroblasts from the patient showed increased nuclear shape abnormalities and premature senescence as demonstrated by a decreased Population Doubling Level, an increased beta-galactosidase activity and a decreased BrdU incorporation rate. Reduced prelamin A expression by siRNA targeted toward LMNA transcripts resulted in decreased nuclear anomalies. We show here that a central obesity without subcutaneous lipoatrophy is associated with a laminopathy due to a heterozygous missense mutation in ZMPSTE24. Given the high prevalence of metabolic syndrome and android obesity in the general population, and in the absence of familial study, the causative link between mutation and phenotype cannot be formally established. Nevertheless, altered lamina architecture observed in mutated fibroblasts are responsible for premature cellular senescence and could contribute to the phenotype observed in this patient. PMID:27120622

  16. Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy

    PubMed Central

    Risson, Valérie; Mazelin, Laetitia; Roceri, Mila; Sanchez, Hervé; Moncollin, Vincent; Corneloup, Claudine; Richard-Bulteau, Hélène; Vignaud, Alban; Baas, Dominique; Defour, Aurélia; Freyssenet, Damien; Tanti, Jean-François; Le-Marchand-Brustel, Yannick; Ferrier, Bernard; Conjard-Duplany, Agnès; Romanino, Klaas; Bauché, Stéphanie; Hantaï, Daniel; Mueller, Matthias; Kozma, Sara C.; Thomas, George; Rüegg, Markus A.; Ferry, Arnaud; Pende, Mario; Bigard, Xavier; Koulmann, Nathalie

    2009-01-01

    Mammalian target of rapamycin (mTOR) is a key regulator of cell growth that associates with raptor and rictor to form the mTOR complex 1 (mTORC1) and mTORC2, respectively. Raptor is required for oxidative muscle integrity, whereas rictor is dispensable. In this study, we show that muscle-specific inactivation of mTOR leads to severe myopathy, resulting in premature death. mTOR-deficient muscles display metabolic changes similar to those observed in muscles lacking raptor, including impaired oxidative metabolism, altered mitochondrial regulation, and glycogen accumulation associated with protein kinase B/Akt hyperactivation. In addition, mTOR-deficient muscles exhibit increased basal glucose uptake, whereas whole body glucose homeostasis is essentially maintained. Importantly, loss of mTOR exacerbates the myopathic features in both slow oxidative and fast glycolytic muscles. Moreover, mTOR but not raptor and rictor deficiency leads to reduced muscle dystrophin content. We provide evidence that mTOR controls dystrophin transcription in a cell-autonomous, rapamycin-resistant, and kinase-independent manner. Collectively, our results demonstrate that mTOR acts mainly via mTORC1, whereas regulation of dystrophin is raptor and rictor independent. PMID:20008564

  17. New insights into the metabolic and nutritional determinants of severe combined immunodeficiency

    PubMed Central

    Field, Martha S; Kamynina, Elena; Watkins, David; Rosenblatt, David S; Stover, Patrick J

    2015-01-01

    Human mutations in MTHFD1 have recently been identified in patients with severe combined immunodeficiency (SCID). SCID results from inborn errors of metabolism that cause impaired T- and B-cell proliferation and function. One of the most common causes of SCID is adenosine deaminase (ADA) deficiency, which ultimately inhibits DNA synthesis and cell division. MTHFD1 has been shown to translocate to the nucleus during S-phase of the cell cycle; this localization is critical for synthesis of thymidyate (dTMP or the “T” base in DNA) and subsequent progression through the cell cycle and cell proliferation. Identification of MTHFD1 mutations that are associated with SCID highlights the potential importance of adequate dTMP synthesis in the etiology of SCID. PMID:27123375

  18. Direct transfer of rainbow trout to seawater induces several changes in kidney carbohydrate metabolism.

    PubMed

    Soengas, J L; Fuentes, J; Andrés, M D; Aldegunde, M

    1994-12-01

    The levels of glycogen and glucose, and the activities of several key enzymes of glycogenolysis, glycolysis, gluconeogenesis and the pentose phosphate shunt were assessed in kidneys of rainbow trout (Oncorhynchus mykiss) of two sizes (80 and 140 g) after transfer to seawater (28 p.p.t.) during 7 days. The results indicated changes, mainly size-independent, in kidney carbohydrate metabolism during transfer of rainbow trout to seawater. An enhanced glycogenolysis and a concomitant increase in gluconeogenic enzyme activity were clearly observed in kidneys of both sizes of animals during transfer to seawater. Changes are suggested to be related to the known role of kidney as a glucose producer tissue thus satisfying, at least in part, the high energetic requirements of the osmoregulatory work performed by other tissues using glucose as fuel, such as the gills, during adaptation to seawater. PMID:7754164

  19. 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 development of PEM, are noteworthy contributions. Since the 1940s, outstanding and often-cited review articles have made JAS a highly visible source of information on these disorders. Thus, JAS has played a significant role as a repository for information pertaining to metabolic and digestive disorders in cattle and other ruminants, and it will no doubt continue to be a premier resource for information on these conditions during the second century of the American Society of Animal Science. PMID:18344294

  20. [A case of favourable outcome of the treatment of extremely severe acute poisoning with methanol].

    PubMed

    Batotsyrenov, B V; Livanov, G A; Vasil'ev, S A; Fedorov, A V; Antrianov, A Iu

    2013-01-01

    A case of favourable outcome of the treatment of extremely severe acute poisoning after prolonged exposure to lethal doses of methanol is reported. The complex treatment included urgent and effective elimination of the poison (multiple gastric lavage, hemodialysis), antidote therapy (administration of ethanol), correction of decompensated metabolic acidosis (alkali therapy and infusion therapy with reamberin). These measures had beneficial effect on the clinical course of poisoning and ensured its favourable outcome. PMID:25696956

  1. [Cardiac and metabolic risk factors in severe mental disorders. Task of a prevention manager].

    PubMed

    Lederbogen, F; Schwarz, P; Häfner, S; Schweiger, U; Bohus, M; Deuschle, M

    2015-07-01

    People with severe mental disorders have a reduction in life expectancy of 13-30 % compared with the general population. This severe disadvantage is primarily due to an increased prevalence of cardiac and metabolic disorders, especially coronary heart disease (CHD) and type 2 diabetes mellitus and are the result of untoward health behavior characterized by smoking, low levels of physical activity and unhealthy dietary habits. Obesity, arterial hypertension and lipid disorders are also associated with this behavior and further increase the risk of CHD and type 2 diabetes. Thus, people with mental disorders constitute a population with a high risk of cardiovascular events. Appropriate measures for prevention and therapy are urgently indicated but rarely applied. This article presents new organizational structures to overcome this deficit with a prevention manager playing a central role in organizing and applying preventive and therapeutic care. Results from cardiology and diabetic medicine have shown the effectiveness of pooling this responsibility. The measure has the potential to reduce the increased mortality of people with severe mental disorders. PMID:25591753

  2. Ruminant Nutrition Symposium: Productivity, digestion, and health responses to hindgut acidosis in ruminants.

    PubMed

    Gressley, T F; Hall, M B; Armentano, L E

    2011-04-01

    Microbial fermentation of carbohydrates in the hindgut of dairy cattle is responsible for 5 to 10% of total-tract carbohydrate digestion. When dietary, animal, or environmental factors contribute to abnormal, excessive flow of fermentable carbohydrates from the small intestine, hindgut acidosis can occur. Hindgut acidosis is characterized by increased rates of production of short-chain fatty acids including lactic acid, decreased digesta pH, and damage to gut epithelium as evidenced by the appearance of mucin casts in feces. Hindgut acidosis is more likely to occur in high-producing animals fed diets with relatively greater proportions of grains and lesser proportions of forage. In these animals, ruminal acidosis and poor selective retention of fermentable carbohydrates by the rumen will increase carbohydrate flow to the hindgut. In more severe situations, hindgut acidosis is characterized by an inflammatory response; the resulting breach of the barrier between animal and digesta may contribute to laminitis and other disorders. In a research setting, effects of increased hindgut fermentation have been evaluated using pulse-dose or continuous abomasal infusions of varying amounts of fermentable carbohydrates. Continuous small-dose abomasal infusions of 1 kg/d of pectin or fructans into lactating cows resulted in decreased diet digestibility and decreased milk fat percentage without affecting fecal pH or VFA concentrations. The decreased diet digestibility likely resulted from increased bulk in the digestive tract or from increased digesta passage rate, reducing exposure of the digesta to intestinal enzymes and epithelial absorptive surfaces. The same mechanism is proposed to explain the decreased milk fat percentage because only milk concentrations of long-chain fatty acids were decreased. Pulse-dose abomasal fructan infusions (1 g/kg of BW) into steers resulted in watery feces, decreased fecal pH, and increased fecal VFA concentrations, without causing an inflammatory response. Daily 12-h abomasal infusions of a large dose of starch (~4 kg/d) have also induced hindgut acidosis as indicated by decreased fecal pH and watery feces. On the farm, watery or foamy feces or presence of mucin casts in feces may indicate hindgut acidosis. In summary, hindgut acidosis occurs because of relatively high rates of large intestinal fermentation, likely due to digestive dysfunction in other parts of the gut. A better understanding of the relationship of this disorder to other animal health disorders is needed. PMID:21415422

  3. 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

  4. Hypercapnic acidosis attenuates endotoxin-induced acute lung injury.

    PubMed

    Laffey, John G; Honan, Dave; Hopkins, Natalie; Hyvelin, Jean-Marc; Boylan, John F; McLoughlin, Paul

    2004-01-01

    Deliberate induction of prophylactic hypercapnic acidosis protects against lung injury after in vivo ischemia-reperfusion and ventilation-induced lung injury. However, the efficacy of hypercapnic acidosis in sepsis, the commonest cause of clinical acute respiratory distress syndrome, is not known. We investigated whether hypercapnic acidosis--induced by adding CO2 to inspired gas--would be protective against endotoxin-induced lung injury in an in vivo rat model. Prophylactic institution of hypercapnic acidosis (i.e., induction before endotoxin instillation) attenuated the decrement in arterial oxygenation, improved lung compliance, and attenuated alveolar neutrophil infiltration compared with control conditions. Therapeutic institution of hypercapnic acidosis, that is, induction after endotoxin instillation, attenuated the decrement in oxygenation, improved lung compliance, and reduced alveolar neutrophil infiltration and histologic indices of lung injury. Therapeutic hypercapnic acidosis attenuated the endotoxin-induced increase in the higher oxides of nitrogen and nitrosothiols in the lung tissue and epithelial lining fluid. Lung epithelial lining fluid nitrotyrosine concentrations were increased with hypercapnic acidosis. We conclude that hypercapnic acidosis attenuates acute endotoxin-induced lung injury, and is efficacious both prophylactically and therapeutically. The beneficial actions of hypercapnic acidosis were not mediated by inhibition of peroxynitrite-induced nitration within proteins. PMID:12958048

  5. The monitoring, prevention and treatment of sub-acute ruminal acidosis (SARA): a review.

    PubMed

    Enemark, Jörg M D

    2008-04-01

    Sub-acute ruminal acidosis (SARA) has become an increasing problem in well-managed, high yielding dairy herds and the monitoring of groups of cows for signs of the condition is now crucial. Rumenocentesis may be ethically questionable but the technique remains the most reliable means of diagnosing SARA. Continuous measurement of ruminal pH may however be possible in the future. Parameters reflecting the metabolic acidosis caused by SARA are also promising tools, and measurement of milk fat content may be useful in individual mid-lactation cows although it is less valuable for bulk tank milk samples. The prevention of SARA includes the establishment of feeding and management guidelines seeking to minimize rumen acidotic load. Regular monitoring may facilitate early recognition of the condition and limit economic losses. Some degree of SARA may however be inevitable and presents a challenge to the dairy industry as consumers become increasingly concerned about the welfare of production animals. PMID:18343172

  6. 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.

  7. Fatal neonatal encephalopathy and lactic acidosis caused by a homozygous loss-of-function variant in COQ9.

    PubMed

    Danhauser, Katharina; Herebian, Diran; Haack, Tobias B; Rodenburg, Richard J; Strom, Tim M; Meitinger, Thomas; Klee, Dirk; Mayatepek, Ertan; Prokisch, Holger; Distelmaier, Felix

    2016-03-01

    Coenzyme Q10 (CoQ10) has an important role in mitochondrial energy metabolism by way of its functioning as an electron carrier in the respiratory chain. Genetic defects disrupting the endogenous biosynthesis pathway of CoQ10 may lead to severe metabolic disorders with onset in early childhood. Using exome sequencing in a child with fatal neonatal lactic acidosis and encephalopathy, we identified a homozygous loss-of-function variant in COQ9. Functional studies in patient fibroblasts showed that the absence of the COQ9 protein was concomitant with a strong reduction of COQ7, leading to a significant accumulation of the substrate of COQ7, 6-demethoxy ubiquinone10. At the same time, the total amount of CoQ10 was severely reduced, which was reflected in a significant decrease of mitochondrial respiratory chain succinate-cytochrome c oxidoreductase (complex II/III) activity. Lentiviral expression of COQ9 restored all these parameters, confirming the causal role of the variant. Our report on the second COQ9 patient expands the clinical spectrum associated with COQ9 variants, indicating the importance of COQ9 already during prenatal development. Moreover, the rescue of cellular CoQ10 levels and respiratory chain complex activities by CoQ10 supplementation points to the importance of an early diagnosis and immediate treatment. PMID:26081641

  8. Effects of HIV Infection on the Metabolic and Hormonal Status of Children with Severe Acute Malnutrition

    PubMed Central

    Hornik, Christoph P.; Kiyimba, Tonny; Bain, James; Muehlbauer, Michael; Kiboneka, Elizabeth; Stevens, Robert; St. Peter, John V.; Newgard, Christopher B.; Bartlett, John; Freemark, Michael

    2014-01-01

    Background HIV infection occurs in 30% of children with severe acute malnutrition in sub-Saharan Africa. Effects of HIV on the pathophysiology and recovery from malnutrition are poorly understood. Methods We conducted a prospective cohort study of 75 severely malnourished Ugandan children. HIV status/CD4 counts were assessed at baseline; auxologic data and blood samples were obtained at admission and after 14 days of inpatient treatment. We utilized metabolomic profiling to characterize effects of HIV infection on metabolic status and subsequent responses to nutritional therapy. Findings At admission, patients (mean age 16.3 mo) had growth failure (mean W/H z-score −4.27 in non-edematous patients) that improved with formula feeding (mean increase 1.00). 24% (18/75) were HIV-infected. Nine children died within the first 14 days of hospitalization; mortality was higher for HIV-infected patients (33% v. 5%, OR = 8.83). HIV-infected and HIV-negative children presented with elevated NEFA, ketones, and even-numbered acylcarnitines and reductions in albumin and amino acids. Leptin, adiponectin, insulin, and IGF-1 levels were low while growth hormone, cortisol, and ghrelin levels were high. At baseline, HIV-infected patients had higher triglycerides, ketones, and even-chain acylcarnitines and lower leptin and adiponectin levels than HIV-negative patients. Leptin levels rose in all patients following nutritional intervention, but adiponectin levels remained depressed in HIV-infected children. Baseline hypoleptinemia and hypoadiponectinemia were associated with increased mortality. Conclusions Our findings suggest a critical interplay between HIV infection and adipose tissue storage and function in the adaptation to malnutrition. Hypoleptinemia and hypoadiponectinemia may contribute to high mortality rates among malnourished, HIV-infected children. PMID:25050734

  9. Hyperhomocysteinemia as a metabolic disorder parameter is independently associated with the severity of coronary heart disease

    PubMed Central

    Liu, Chenggui; Yang, Yinzhong; Peng, Duanliang; Chen, Linong; Luo, Jun

    2015-01-01

    Objectives: To study the associations between hyperhomocysteinemia (HHcy) and the severity of coronary heart disease (CHD). Methods: We retrospectively analyzed metabolic parameters, anthropometric variables, and life style habits in 292 CHD patients of different categories, and 100 controlled non-CHD patients with chest pain symptoms who were hospitalized in the Department of Cardiovascular Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China between October 2013 and September 2014. Results: The prevalence of HHcy in CHD patients was 79.1%, while only 5% of non-CHD patients had elevated serum homocysteine (Hcy) concentrations. The prevalence of HHcy significantly increased from 5% in non-CHD controls to 66% in the stable angina pectoris (SAP) group, to 81.9% in the unstable angina pectoris group, and to 93.15% in the acute myocardial infarction (AMI) group (p<0.001). After adjusting for confounding factors, multivariate logistic regression analysis showed that HHcy was independently associated with CHD category (AMI versus SAP, odds ratio [6.38], 95% confidence interval; 1.18-34.46). The Hcy was negatively correlated with folic acid (r=-0.67, p<0.001) and vitamin B12 (r=-0.56, p<0.001). Of the CHD patients with HHcy, 51.1% had low folic acid and 42% had low vitamin B12, 7 or 5 times higher than that of CHD patients with normal-low Hcy concentrations (p<0.001). Conclusion: Hyperhomocysteinemia is independently associated with the severity of CHD, and significantly correlated with low status of folic acid and vitamin B12 in CHD patients. PMID:26108589

  10. Diet-induced acidosis: is it real and clinically relevant?

    PubMed

    Pizzorno, Joseph; Frassetto, Lynda A; Katzinger, Joseph

    2010-04-01

    The concept of diet-induced 'acidosis' as a cause of disease has been a subject of interest for more than a century. The present article reviews the history of our evolving understanding of physiological pH, the physiological support for the concept of 'acidosis', the causes of acidosis, how it is recognised, its short-term effects as well as the long-term clinical relevance of preventative measures, and the research support for normalisation of pH. Further, we suggest differentiation of the terms 'acidosis' and 'acidaemia' as a way to resolve the conflation of these topics which has led to confusion and controversy. The available research makes a compelling case that diet-induced acidosis, not diet-induced acidaemia, is a real phenomenon, and has a significant, clinical, long-term pathophysiological effect that should be recognised and potentially counterbalanced by dietary means. PMID:20003625

  11. 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.

  12. Gingival overgrowth caused by vitamin C deficiency associated with metabolic syndrome and severe periodontal infection: a case report.

    PubMed

    Omori, Kazuhiro; Hanayama, Yoshihisa; Naruishi, Koji; Akiyama, Kentaro; Maeda, Hiroshi; Otsuka, Fumio; Takashiba, Shogo

    2014-12-01

    It has been suggested that vitamin C deficiency/scurvy is associated with gingival inflammatory changes; however, the disorder is very infrequently encountered in the modern era. Here, we report a case of extensive gingival overgrowth caused by vitamin C deficiency associated with metabolic syndrome and severe periodontal infection. PMID:25548632

  13. Functional Metabolomics Uncovers Metabolic Alterations Associated to Severe Oxidative Stress in MCF7 Breast Cancer Cells Exposed to Ascididemin

    PubMed Central

    Morvan, Daniel

    2013-01-01

    Marine natural products are a source of promising agents for cancer treatment. However, there is a need to improve the evaluation of their mechanism of action in tumors. Metabolomics of the response to anti-tumor agents is a tool to reveal candidate biomarkers and metabolic targets. We used two-dimensional high-resolution magic angle spinning proton-NMR spectroscopy-based metabolomics to investigate the response of MCF7 breast cancer cells to ascididemin, a marine alkaloid and lead molecule for anti-cancer treatment. Ascididemin induced severe oxidative stress and apoptosis within 48 h of exposure. Thirty-three metabolites were quantified. Metabolic response involved downregulation of glycolysis and the tricarboxylic acid cycle, and phospholipid metabolism alterations. Candidate metabolic biomarkers of the response of breast cancer cells to ascididemin were proposed including citrate, gluconate, polyunsaturated fatty acids, glycerophospho-choline and -ethanolamine. In addition, candidate metabolic targets were identified. Overall, the response to Asc could be related to severe oxidative stress and anti-inflammatory effects. PMID:24152560

  14. Normal liver enzymes are correlated with severity of metabolic syndrome in a large population based cohort

    PubMed Central

    Kälsch, Julia; Bechmann, Lars P.; Heider, Dominik; Best, Jan; Manka, Paul; Kälsch, Hagen; Sowa, Jan-Peter; Moebus, Susanne; Slomiany, Uta; Jöckel, Karl-Heinz; Erbel, Raimund; Gerken, Guido; Canbay, Ali

    2015-01-01

    Key features of the metabolic syndrome are insulin resistance and diabetes. The liver as central metabolic organ is not only affected by the metabolic syndrome as non-alcoholic fatty liver disease (NAFLD), but may contribute to insulin resistance and metabolic alterations. We aimed to identify potential associations between liver injury markers and diabetes in the population-based Heinz Nixdorf RECALL Study. Demographic and laboratory data were analyzed in participants (n = 4814, age 45 to 75y). ALT and AST values were significantly higher in males than in females. Mean BMI was 27.9 kg/m2 and type-2-diabetes (known and unkown) was present in 656 participants (13.7%). Adiponectin and vitamin D both correlated inversely with BMI. ALT, AST, and GGT correlated with BMI, CRP and HbA1c and inversely correlated with adiponectin levels. Logistic regression models using HbA1c and adiponectin or HbA1c and BMI were able to predict diabetes with high accuracy. Transaminase levels within normal ranges were closely associated with the BMI and diabetes risk. Transaminase levels and adiponectin were inversely associated. Re-assessment of current normal range limits should be considered, to provide a more exact indicator for chronic metabolic liver injury, in particular to reflect the situation in diabetic or obese individuals. PMID:26269425

  15. Normal liver enzymes are correlated with severity of metabolic syndrome in a large population based cohort.

    PubMed

    Kälsch, Julia; Bechmann, Lars P; Heider, Dominik; Best, Jan; Manka, Paul; Kälsch, Hagen; Sowa, Jan-Peter; Moebus, Susanne; Slomiany, Uta; Jöckel, Karl-Heinz; Erbel, Raimund; Gerken, Guido; Canbay, Ali

    2015-01-01

    Key features of the metabolic syndrome are insulin resistance and diabetes. The liver as central metabolic organ is not only affected by the metabolic syndrome as non-alcoholic fatty liver disease (NAFLD), but may contribute to insulin resistance and metabolic alterations. We aimed to identify potential associations between liver injury markers and diabetes in the population-based Heinz Nixdorf RECALL Study. Demographic and laboratory data were analyzed in participants (n = 4814, age 45 to 75 y). ALT and AST values were significantly higher in males than in females. Mean BMI was 27.9 kg/m(2) and type-2-diabetes (known and unkown) was present in 656 participants (13.7%). Adiponectin and vitamin D both correlated inversely with BMI. ALT, AST, and GGT correlated with BMI, CRP and HbA1c and inversely correlated with adiponectin levels. Logistic regression models using HbA1c and adiponectin or HbA1c and BMI were able to predict diabetes with high accuracy. Transaminase levels within normal ranges were closely associated with the BMI and diabetes risk. Transaminase levels and adiponectin were inversely associated. Re-assessment of current normal range limits should be considered, to provide a more exact indicator for chronic metabolic liver injury, in particular to reflect the situation in diabetic or obese individuals. PMID:26269425

  16. Severe Ketoacidosis Associated with Canagliflozin (Invokana): A Safety Concern

    PubMed Central

    Gelaye, Alehegn; Haidar, Abdallah; Kassab, Christina; Kazmi, Syed; Sinha, Prabhat

    2016-01-01

    Canagliflozin (Invokana) is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor that was first introduced in 2013 for the treatment of type 2 diabetes mellitus (DM). Though not FDA approved yet, its use in type 1 DM has been justified by the fact that its mechanism of action is independent of insulin secretion or action. However, some serious side effects, including severe anion gap metabolic acidosis and euglycemic diabetic ketoacidosis (DKA), have been reported. Prompt identification of the causal association and initiation of appropriate therapy should be instituted for this life threatening condition. PMID:27088018

  17. Severe Ketoacidosis Associated with Canagliflozin (Invokana): A Safety Concern.

    PubMed

    Gelaye, Alehegn; Haidar, Abdallah; Kassab, Christina; Kazmi, Syed; Sinha, Prabhat

    2016-01-01

    Canagliflozin (Invokana) is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor that was first introduced in 2013 for the treatment of type 2 diabetes mellitus (DM). Though not FDA approved yet, its use in type 1 DM has been justified by the fact that its mechanism of action is independent of insulin secretion or action. However, some serious side effects, including severe anion gap metabolic acidosis and euglycemic diabetic ketoacidosis (DKA), have been reported. Prompt identification of the causal association and initiation of appropriate therapy should be instituted for this life threatening condition. PMID:27088018

  18. MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis

    ClinicalTrials.gov

    2016-01-22

    Mucopolysaccharidosis I; Mucopolysaccharidosis II; Mucopolysaccharidosis VI; Mucopolysaccharidosis VII; Hurler Syndrome; Hunter Syndrome; Maroteaux Lamy Syndrome; Sly Syndrome; Glycoprotein Metabolic Disorders; Alpha Mannosidosis; Fucosidosis; Aspartylglucosaminuria; Adrenoleukodystrophy; Peroxisomal Disorders; Osteopetrosis; Sphingolipidosis; Gangliosidosis; Globoid Cell Leukodystrophy; Metachromatic Leukodystrophy; Niemann Pick B; Niemann Pick C Subtype 2; I-cell Disease

  19. 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. PMID:26937408

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

    PubMed Central

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

    2015-01-01

    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.

  1. 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)

  2. Side Effects of HIV Medicines: HIV and Lactic Acidosis

    MedlinePlus

    Side Effects of HIV Medicines HIV and Lactic Acidosis (Last updated 1/7/2016; last reviewed 1/7/ ... blood. The condition is a rare but serious side effect of some HIV medicines. All HIV medicines in ...

  3. Drug-induced haemolysis, renal failure, thrombocytopenia and lactic acidosis in patients with HIV and cryptococcal meningitis: a diagnostic challenge.

    PubMed

    Camara-Lemarroy, Carlos R; Flores-Cantu, Hazael; Calderon-Hernandez, Hector J; Diaz-Torres, Marco A; Villareal-Velazquez, Hector J

    2015-12-01

    Patients with HIV are at risk of both primary and secondary haematological disorders. We report two cases of patients with HIV and cryptococcal meningitis who developed severe haemolytic anaemia, thrombocytopenia, renal failure and lactic acidosis while on treatment with amphotericin B and co-trimoxazole. PMID:25614519

  4. Acidosis differently modulates the inflammatory program in monocytes and macrophages.

    PubMed

    Riemann, Anne; Wuling, Hanna; Loppnow, Harald; Fu, Hang; Reime, Sarah; Thews, Oliver

    2016-01-01

    Inflammation, ischemia or the microenvironment of solid tumors is often accompanied by a reduction of extracellular pH (acidosis) that stresses the cells and acts on cellular signaling and transcription. The effect of acidosis on the expression of various inflammatory markers, on functional parameters (migration, phagocytic activity) and on signaling pathways involved was studied in monocytic cells and macrophages. In monocytic cell lines acidosis led to a reduction in expression of most of the inflammatory mediators, namely IL-1, IL-6, TNF-?, MCP-1, COX-2 and osteopontin. In primary human monocytes MCP-1 and TNF-? were reduced but COX-2 and IL-6 were increased. In RAW264.7 macrophage cell line IL-1, COX-2 and iNOS expression was increased, whereas MCP-1 was reduced similar to the effect in monocytic cells. For primary human monocyte-derived macrophages the regulation of inflammatory markers by acidosis depended on activation state, except for the acidosis-induced downregulation of MCP-1 and TNF-?. Acidosis affected functional immune cell behavior when looking at phagocytic activity which was increased in a time-dependent manner, but cellular motility was not changed. Neither ERK1/2 nor CREB signaling was stimulated by the reduction of extracellular pH. However, p38 was activated by acidosis in RAW264.7 cells and this activation was critical for the induction of IL-1, COX-2 and iNOS expression. In conclusion, acidosis may impede the recruitment of immune cells, but fosters inflammation when macrophages are present by increasing the level of COX-2 and iNOS and by functionally forcing up the phagocytic activity. PMID:26499398

  5. Plasma prolactin concentration increases after hypercapnia acidosis.

    PubMed

    Rojas Vega, S; Strder, H K; Hollmann, W

    2003-10-01

    Responses of plasma prolactin (PRL) concentration to alterations in carbon dioxide pressure ( pCO(2)) induced by 4 min of rebreathing out of a bag with 6 l gas initially containing a concentration of 93% O(2) and 7% CO(2) (hypercapnia hyperoxia; HH) and 4 min of voluntary hyperventilation (VH) at a respiratory rate of 28 - 32 per minute were investigated in ten males. During rebreathing in HH, an augmentation of pCO(2) from 40.2 +/- 2.1 to 63.7 +/- 5.4 mmHg and a decrease of pH from 7.4 +/- 0.02 to 7.32 +/- 0.04 were found in capillary blood (p < 0.01). Neither breathing frequency (BF) nor plasma PRL changed during this period. After two minutes of post-rebreathing, pCO(2) and pH returned to basal values. BF increased from 2 min of rebreathing (12.4 +/- 1.9 breath/min) until 11 min of recovery period (18.1 +/- 4.9 breath/min) (p < 0.01), while plasma PRL increased from end of rebreathing (11.59 +/- 1.49 ng/dl) to 11 min of recovery period (13.63 +/- 1.97 ng/dl) (p < 0.01). In VH, hyperventilation decreased pCO (2) from 39.91 +/- 2.62 to 21.73 +/- 2.59 mmHg (p < 0.01) and increased pH from 7.39 +/- 0.04 to 7.58 +/- 0.04 (p < 0.01) in capillary blood. After four minutes of recovery from hyperventilation, pH and pCO(2) were back to their basal values. No changes in plasma PRL were found throughout VH. This present pilot study's new finding is that plasma PRL increases after hypercapnia acidosis. This indicates that acidosis-induced central chemoreflex function increases phrenic nerve activity based on serotonergic modulation, leading to an augmentation of BF. As serotonin is also the main PRL-releasing factor, this might have had the collateral effect of causing PRL release and delayed appearance in the peripheral circulation. PMID:14605994

  6. 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 ...

  7. Low Cerebral Glucose Metabolism: A Potential Predictor for the Severity of Vascular Parkinsonism and Parkinson’s Disease

    PubMed Central

    Xu, Yunqi; Wei, Xiaobo; Liu, Xu; Liao, Jinchi; Lin, Jiaping; Zhu, Cansheng; Meng, Xiaochun; Xie, Dongsi; Chao, Dongman; Fenoy, Albert J; Cheng, Muhua; Tang, Beisha; Zhang, Zhuohua; Xia, Ying; Wang, Qing

    2015-01-01

    This study explored the association between cerebral metabolic rates of glucose (CMRGlc) and the severity of Vascular Parkinsonism (VP) and Parkinson’s disease (PD). A cross-sectional study was performed to compare CMRGlc in normal subjects vs. VP and PD patients. Twelve normal subjects, 22 VP, and 11 PD patients were evaluated with the H&Y and MMSE, and underwent 18F-FDG measurements. Pearson’s correlations were used to identify potential associations between the severity of VP/PD and CMRGlc. A pronounced reduction of CMRGlc in the frontal lobe and caudate putamen was detected in patients with VP and PD when compared with normal subjects. The VP patients displayed a slight CMRGlc decrease in the caudate putamen and frontal lobe in comparison with PD patients. These decreases in CMRGlc in the frontal lobe and caudate putamen were significantly correlated with the VP patients’ H&Y, UPDRS II, UPDRS III, MMSE, cardiovascular, and attention/memory scores. Similarly, significant correlations were observed in patients with PD. This is the first clinical study finding strong evidence for an association between low cerebral glucose metabolism and the severity of VP and PD. Our findings suggest that these changes in glucose metabolism in the frontal lobe and caudate putamen may underlie the pathophysiological mechanisms of VP and PD. As the scramble to find imaging biomarkers or predictors of the disease intensifies, a better understanding of the roles of cerebral glucose metabolism may give us insight into the pathogenesis of VP and PD. PMID:26618044

  8. Hearing impairment in association with distal renal tubular acidosis among Saudi children.

    PubMed

    Zakzouk, S M; Sobki, S H; Mansour, F; al Anazy, F H

    1995-10-01

    A follow-up of seven patients with the autosomal recessive inherited syndrome of distal renal tubular acidosis (RTA) and sensorineural hearing loss is described. Five patients were diagnosed as having primary distal renal tubular acidosis and rickets, four were found to have severe sensorineural hearing loss of over 80 dB: two of which are brothers. Two patients were diagnosed as having secondary distal renal acidosis due to a genetic disorder called osteopetrosis; they are brothers and their audiograms showed a mild conductive hearing loss of an average 35 dB bilaterally. All patients had growth retardation with improvement due to alkaline therapy but their hearing loss was not affected by the medication. The pedigrees of two families with half sibs showed the familial incidence for consanguineous marriage. Consanguinity was found to be positive in five out of the seven patients. The tribal tradition in Saudi Arabia fosters consanguineous marriages for cultural and social reasons and pre-arranged marriages are still seen. PMID:7499943

  9. Association of LIPA gene polymorphisms with obesity-related metabolic complications among severely obese patients.

    PubMed

    Guénard, Frédéric; Houde, Alain; Bouchard, Luigi; Tchernof, André; Deshaies, Yves; Biron, Simon; Lescelleur, Odette; Biertho, Laurent; Marceau, Simon; Pérusse, Louis; Vohl, Marie-Claude

    2012-10-01

    The lipase A, lysosomal acid, cholesterol esterase enzyme (LIPA) is involved in the hydrolysis of triglycerides (TGs) and cholesteryl esters (CEs) delivered to lysosomes. LIPA deficiency in human causes two distinct phenotypes characterized by intracellular storage of CE and derangements in the control of cholesterol production, namely the Wolman disease (WD) and the CE storage disease (CESD). To test the potential association of LIPA gene polymorphisms with obesity-related metabolic complications, promoter, exons, and intronic flanking regions of the LIPA gene were first sequenced in 25 individuals. From the 14 common polymorphisms identified, 12 tagging single-nucleotide polymorphisms (tSNPs) were genotyped in a cohort of 1,751 obese individuals. After adjustments for the effect of age, sex, diabetes, and medication, the C allele of SNP rs1051338 was associated with lower blood pressure (BP; systolic (SBP) P = 0.004; diastolic (DBP) P = 0.006). Three of the tested SNPs were associated with modifications of the plasma lipid profile. The G/G genotype of rs2071509 was associated with higher high-density lipoprotein cholesterol (HDL-C) levels (P = 0.009) and minor allele of rs1131706 was also associated with higher HDL-C (P = 0.004) and an association between rs3802656 and total cholesterol (total-C)/HDL-C ratio was identified (P = 0.04). These results thus suggest that LIPA polymorphisms contribute to the interindividual variability observed in obesity-related metabolic complications. PMID:22395809

  10. Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPARγ

    PubMed Central

    Wang, Fenfen; Mullican, Shannon E.; DiSpirito, Joanna R.; Peed, Lindsey C.; Lazar, Mitchell A.

    2013-01-01

    Adipose tissue is an important metabolic organ, the dysfunction of which is associated with the development of obesity, diabetes mellitus, and cardiovascular disease. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is considered the master regulator of adipocyte differentiation and function. Although its cell-autonomous role in adipogenesis has been clearly demonstrated in cell culture, previous fat-specific knockouts of the murine PPARγ gene did not demonstrate a dramatic phenotype in vivo. Here, using Adipoq–Cre mice to drive adipose-specific recombination, we report a unique fat-specific PPARγ knockout (PPARγ FKO) mouse model with almost no visible brown and white adipose tissue at age 3 mo. As a consequence, PPARγ FKO mice had hugely enlarged pancreatic islets, massive fatty livers, and dramatically elevated levels of blood glucose and serum insulin accompanied by extreme insulin resistance. PPARγ FKO mice also exhibited delayed hair coat formation associated with absence of dermal fat, disrupted mammary gland development with loss of mammary fat pads, and high bone mass with loss of bone marrow fat, indicating the critical roles of adipose PPARγ in these tissues. Together, our data reveal the necessity of fat PPARγ in adipose formation, whole-body metabolic homeostasis, and normal development of fat-containing tissues. PMID:24167256

  11. Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity

    PubMed Central

    2011-01-01

    Background The relationship between relative metabolic disturbances and developmental disorders is an emerging research focus. This study compares the nutritional and metabolic status of children with autism with that of neurotypical children and investigates the possible association of autism severity with biomarkers. Method Participants were children ages 5-16 years in Arizona with Autistic Spectrum Disorder (n = 55) compared with non-sibling, neurotypical controls (n = 44) of similar age, gender and geographical distribution. Neither group had taken any vitamin/mineral supplements in the two months prior to sample collection. Autism severity was assessed using the Pervasive Development Disorder Behavior Inventory (PDD-BI), Autism Treatment Evaluation Checklist (ATEC), and Severity of Autism Scale (SAS). Study measurements included: vitamins, biomarkers of vitamin status, minerals, plasma amino acids, plasma glutathione, and biomarkers of oxidative stress, methylation, sulfation and energy production. Results Biomarkers of children with autism compared to those of controls using a t-test or Wilcoxon test found the following statistically significant differences (p < 0.001): Low levels of biotin, plasma glutathione, RBC SAM, plasma uridine, plasma ATP, RBC NADH, RBC NADPH, plasma sulfate (free and total), and plasma tryptophan; also high levels of oxidative stress markers and plasma glutamate. Levels of biomarkers for the neurotypical controls were in good agreement with accessed published reference ranges. In the Autism group, mean levels of vitamins, minerals, and most amino acids commonly measured in clinical care were within published reference ranges. A stepwise, multiple linear regression analysis demonstrated significant associations between several groups of biomarkers with all three autism severity scales, including vitamins (adjusted R2 of 0.25-0.57), minerals (adj. R2 of 0.22-0.38), and plasma amino acids (adj. R2 of 0.22-0.39). Conclusion The autism group had many statistically significant differences in their nutritional and metabolic status, including biomarkers indicative of vitamin insufficiency, increased oxidative stress, reduced capacity for energy transport, sulfation and detoxification. Several of the biomarker groups were significantly associated with variations in the severity of autism. These nutritional and metabolic differences are generally in agreement with other published results and are likely amenable to nutritional supplementation. Research investigating treatment and its relationship to the co-morbidities and etiology of autism is warranted. PMID:21651783

  12. Acidosis promotes Bcl-2 family-mediated evasion of apoptosis: involvement of acid-sensing G protein-coupled receptor Gpr65 signaling to Mek/Erk.

    PubMed

    Ryder, Christopher; McColl, Karen; Zhong, Fei; Distelhorst, Clark W

    2012-08-10

    Acidosis arises in solid and lymphoid malignancies secondary to altered nutrient supply and utilization. Tumor acidosis correlates with therapeutic resistance, although the mechanism behind this effect is not fully understood. Here we show that incubation of lymphoma cell lines in acidic conditions (pH 6.5) blocks apoptosis induced by multiple cytotoxic metabolic stresses, including deprivation of glucose or glutamine and treatment with dexamethasone. We sought to examine the role of the Bcl-2 family of apoptosis regulators in this process. Interestingly, we found that acidic culture causes elevation of both Bcl-2 and Bcl-xL, while also attenuating glutamine starvation-induced elevation of p53-up-regulated modulator of apoptosis (PUMA) and Bim. We confirmed with knockdown studies that these shifts direct survival decisions during starvation and acidosis. Importantly, the promotion of a high anti- to pro-apoptotic Bcl-2 family member ratio by acidosis renders cells exquisitely sensitive to the Bcl-2/Bcl-xL antagonist ABT-737, suggesting that acidosis causes Bcl-2 family dependence. This dependence appears to be mediated, in part, by the acid-sensing G protein-coupled receptor, GPR65, via a MEK/ERK pathway. PMID:22685289

  13. Loss of inherited genomic imprints in mice leads to severe disruption in placental lipid metabolism

    PubMed Central

    Himes, K. P.; Young, A.; Koppes, E.; Stolz, D.; Barak, Y.; Sadovsky, Y.; Chaillet, J.R.

    2015-01-01

    Introduction Monoallelic expression of imprinted genes is necessary for placental development and normal fetal growth. Differentially methylated domains (DMDs) largely determine the parental-specific monoallelic expression of imprinted genes. Maternally derived DNA (cytosine-5-) -methyltransferase 1o (DNMT1o) maintains DMDs during the eight-cell stage of development. DNMT1o-deficient mouse placentas have a generalized disruption of genomic imprints. Previous studies have demonstrated that DNMT1o deficiency alters placental morphology and broadens the embryonic weight distribution in late gestation. Lipids are critical for fetal growth. Thus, we assessed the impact of disrupted imprinting on placental lipids. Methods Lipids were quantified from DNMT1o-deficient mouse placentas and embryos at E17.5 using a modified Folch method. Expression of select genes critical for lipid metabolism was quantified with RT-qPCR. Mitochondrial morphology was assessed by TEM and mitochondrial aconitase and cytoplasmic citrate concentrations quantified. DMD methylation was determined by EpiTYPER. Results We found that DNMT1o deficiency is associated with increased placental triacylglycerol levels. Neither fetal triacylglycerol concentrations nor expression of select genes that mediate placental lipid transport were different from wild type. Placental triacylglycerol accumulation was associated with impaired beta-oxidation and abnormal citrate metabolism with decreased mitochondrial aconitase activity and increased cytoplasmic citrate concentrations. Loss of methylation at the MEST DMD was strongly associated with placental triacylglycerol accumulation. Discussion A generalized disruption of genomic imprints leads to triacylglycerol accumulation and abnormal mitochondrial function. This could stem directly from a loss of methylation at a given DMD, such as MEST, or represent a consequence of abnormal placental development. PMID:25662615

  14. [POSSIBILITY OF CORRECTION OF METABOLIC DISORDERS WITH REAMBERIN IN ACUTE PERIOD OF TRAUMATIC INJURY].

    PubMed

    Gerasimov, L V; Marchenkov, Yu V; Volkov, D P; Rodionov, E P; Izmajlov, V V

    2015-01-01

    56 patients at the age of 18-60 years with severe trauma were examined. Influence of the polyelectrolytic (Reamberin)solution on an acid-base state, osmolarity and electrolytic composition of plasma in the acute posttraumatic period was evaluated. It was found that patients, who was treated by isotonic sodium chloride solution and Ringer's solution, had metabolic acidosis and hyperchloremia. In contrast, in the reamberin group 82% of patients had lower concentrations of chloride and had nothing acid-base disturbances on the second day after trauma. Reamberin didn't influence on plasma osmolarity and the rate of metabolic alkalosis during the acute period of a trauma. PMID:27025136

  15. Bone and metabolic complications of urinary diversions.

    PubMed

    Cano Megías, Marta; Muñoz Delgado, Eva Golmayo

    2015-02-01

    Hyperchloremic metabolic acidosis is a complication of urinary diversion using ileum or colon. Its prevalence ranges from 25% and 46% depending on the procedure used and renal function of the patient. It is a consequence of intestinal fluid and electrolyte exchange between intestinal mucosa and urine. The main mechanism is absorption of ammonium and chloride from urine. Long-term chronic metabolic acidosis in these patients may lead to impaired bone metabolism and osteomalacia. Regular monitoring of pH, chlorine, bicarbonate, and calcium-phosphorus metabolism is therefore essential for early diagnosis and treatment. PMID:25481805

  16. Effect of metabolic alkalosis on respiratory function in patients with chronic obstructive lung disease.

    PubMed Central

    Bear, R.; Goldstein, M.; Phillipson, E.; Ho, M.; Hammeke, M.; Feldman, R.; Handelsman, S.; Halperin, M.

    1977-01-01

    Eleven instances of a mixed acid-base disorder consisting of chronic respiratory acidosis and metabolic alkalosis were recognized in eight patients with chronic obstructive lung disease and carbon dioxide retention. Correction of the metabolic alkalosis led to substantial improvement in blood gas values and clinical symptoms. Patients with mixed chronic respiratory acidosis and metabolic alkalosis constitute a common subgroup of patients with chronic obstructive lung disease and carbon dioxide retention; these patients benefit from correction of the metabolic alkalosis. PMID:21028

  17. Hemodynamic and metabolic basis of impaired exercise tolerance in patients with severe left ventricular dysfunction

    SciTech Connect

    Roubin, G.S.; Anderson, S.D.; Shen, W.F.; Choong, C.Y.; Alwyn, M.; Hillery, S.; Harris, P.J.; Kelly, D.T. )

    1990-04-01

    Hemodynamic and metabolic changes were measured at rest and during exercise in 23 patients with chronic heart failure and in 6 control subjects. Exercise was limited by leg fatigue in both groups and capacity was 40% lower in the patients with failure. At rest, comparing patients with control subjects, heart rate and right atrial and pulmonary wedge pressure were higher; cardiac output, stroke volume and work indexes and ejection fraction were lower; mean arterial and right atrial pressure and systemic resistance were similar. During all phases of exercise in patients with heart failure, pulmonary wedge pressure and systemic vascular resistance were higher and pulmonary vascular resistance remained markedly elevated compared with values in control subjects. Cardiac output was lower in the patients with failure, but appeared to have the same physiologic distribution in both groups during exercise. Although arterial-femoral venous oxygen content difference was higher in patients with heart failure, this increase did not compensate for the reduced blood flow. Even though the maximal oxygen consumption was significantly reduced, femoral venous lactate and pH values were higher than values in control subjects, but femoral venous pH was similar in both groups at their respective levels of maximal exercise. Ejection fraction was lower in those with heart failure at rest and did not increase with exercise. Ventilation in relation to oxygen consumption was higher in patients with failure than in control subjects.

  18. The prevalence of metabolic syndrome amongst patients with severe mental illness in the community in Hong Kong – a cross sectional study

    PubMed Central

    2013-01-01

    Background Patients with severe mental illness are at increased risk of developing metabolic disorders. The risk of metabolic syndrome in the Hong Kong general population is lower than that observed in western countries; however the prevalence of metabolic syndrome in patients with severe mental illness in Hong Kong is unknown. Method This cross-sectional study aimed to estimate the prevalence of metabolic syndrome in patients with severe mental illness in Hong Kong and to identify the relationships between metabolic syndrome and socio-demographic, clinical and lifestyle factors. Results A total of 139 patients with a diagnosis of severe mental illness participated in the study. The unadjusted prevalence of metabolic syndrome was 35%. The relative risk of metabolic syndrome in comparison with the general Hong Kong population was 2.008 (95% CI 1.59-2.53, p < 0.001). In a logistic regression model sleep disruption and being prescribed first generation antipsychotics were significantly associated with the syndrome, whilst eating less than 3 portions of fruit/vegetables per day and being married were weakly associated. Conclusion The results demonstrate that metabolic syndrome is highly prevalent and that physical health inequalities in patients with severe mental illness in Hong Kong are similar to those observed in western countries. The results provide sufficient evidence to support the need for intervention studies in this setting and reinforce the requirement to conduct regular physical health checks for all patients with severe mental illness. PMID:23506322

  19. 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 BH. Principles of Anatomy and Physiology . 14th ed. Hoboken, NJ: John H Wiley and Sons; 2013: ...

  20. Nutritional and Pharmacological Modulation of the Metabolic Response of Severely Burned Patients: Review of the Literature (Part II)*.

    PubMed

    Atiyeh, B S; Gunn, S W A; Dibo, S A

    2008-09-30

    Severe burn patients are some of the most challenging critically ill patients, with an extreme state of physiological stress and an overwhelming systemic metabolic response. Increased energy expenditure to cope with this insult necessitates mobilization of large amounts of substrate from fat stores and active muscle for repair and fuel, leading to catabolism. The hypermetabolic response can last for as long as nine months to one year after injury and is associated with impaired wound healing, increased infection risks, erosion of lean body mass, hampered rehabilitation, and delayed reintegration of burn survivors into society. Reversal of the hypermetabolic response by manipulating the patient's physiological and biochemical environment through the administration of specific nutrients, growth factors, or other agents, often in pharmacological doses, is emerging as an essential component of the state of the art in severe burn management. Early enteral nutritional support, control of hyperglycaemia, blockade of catecholamine response, and use of anabolic steroids have all been proposed to attenuate hypermetabolism or to blunt catabolism associated with severe burn injury. The present study is a literature review of the proposed nutritional and metabolic therapeutic measures in order to determine evidence-based best practice. Unfortunately, the present state of our knowledge does not allow the formulation of clear-cut guidelines. Only general trends can be outlined which will certainly have some practical applications but above all will dictate future research in the field. PMID:21991122

  1. Nutritional and pharmacological modulation of the metabolic response of severely burned patients: review of the literature (part 1).

    PubMed

    Atiyeh, B S; Gunn, S W A; Dibo, S A

    2008-06-30

    Severe burn patients are some of the most challenging critically ill patients, with an extreme state of physiological stress and an overwhelming systemic metabolic response. Increased energy expenditure to cope with this insult necessitates mobilization of large amounts of substrate from fat stores and active muscle for repair and fuel, leading to catabolism. The hypermetabolic response can last for as long as nine months to one year after injury and is associated with impaired wound healing, increased infection risks, erosion of lean body mass, hampered rehabilitation, and delayed reintegration of burn survivors into society. Reversal of the hypermetabolic response by manipulating the patient's physiological and biochemical environment through the administration of specific nutrients, growth factors, or other agents, often in pharmacological doses, is emerging as an essential component of the state of the art in severe burn management. Early enteral nutritional support, control of hyperglycaemia, blockade of catecholamine response, and use of anabolic steroids have all been proposed to attenuate hypermetabolism or to blunt catabolism associated with severe burn injury. The present study is a literature review of the proposed nutritional and metabolic therapeutic measures in order to determine evidence-based best practice. Unfortunately, the present state of our knowledge does not allow the formulation of clear-cut guidelines. Only general trends can be outlined which will certainly have some practical applications but above all will dictate future research in the field. PMID:21991114

  2. Nutritional and Pharmacological Modulation of the Metabolic Response of Severely Burned Patients: Review of the Literature (Part III)*.

    PubMed

    Atiyeh, B S; Gunn, S W A; Dibo, S A

    2008-12-31

    Severe burn patients are some of the most challenging critically ill patients, with an extreme state of physiological stress and an overwhelming systemic metabolic response. Increased energy expenditure to cope with this insult necessitates mobilization of large amounts of substrate from fat stores and active muscle for repair and fuel, leading to catabolism. The hypermetabolic response can last for as long as nine months to one year after injury and is associated with impaired wound healing, increased infection risks, erosion of lean body mass, hampered rehabilitation, and delayed reintegration of burn survivors into society.Reversal of the hypermetabolic response by manipulating the patient's physiological and biochemical environment through the administration of specific nutrients, growth factors, or other agents, often in pharmacological doses, is emerging as an essential component of the state of the art in severe burn management. Early enteral nutritional support, control of hyperglycaemia, blockade of catecholamine response, and use of anabolic steroids have all been proposed to attenuate hypermetabolism or to blunt catabolism associated with severe burn injury. The present study is a literature review of the proposed nutritional and metabolic therapeutic measures in order to determine evidence-based best practice. Unfortunately, the present state of our knowledge does not allow the formulation of clear-cut guidelines. Only general trends can be outlined which will certainly have some practical applications but above all will dictate future research in the field. PMID:21991133

  3. Sulfur amino acid metabolism in children with severe childhood undernutrition: cysteine kinetics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Children with edematous but not nonedematous severe childhood undernutrition (SCU) have lower plasma and erythrocyte-free concentrations of cysteine, the rate-limiting precursor of glutathione synthesis. We propose that these lower cysteine concentrations are due to reduced production secondary to s...

  4. Unique metabolic characteristics of the major syndromes of severe childhood malnutrition

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The major clinical syndromes of severe childhood malnutrition (SCM) are marasmus, kwashiorkor and marasmic-kwashiorkor. Whereas treatment of marasmus is straightforward and the associated mortality is low, kwashiorkor and marasmic-kwashiorkor are difficult to treat and have high morbidity and mortal...

  5. Sjgrens, Renal Tubular Acidosis And Osteomalacia - An Asian Indian Series

    PubMed Central

    Sandhya, Pulukool; Danda, Debashish; Rajaratnam, Simon; Thomas, Nihal

    2014-01-01

    Objective: To study the profile of Renal Tubular Acidosis (RTA) in Asian Indian patients with Primary Sjgren's Syndrome (pSS). Methods: The Electronic medical records of patients with a diagnosis of pSS seen between 2003 and 2010 at our tertiary care teaching hospital were screened for RTA. Clinical features, immunological profile, acid-base balance and electrolyte status, 25-hydroxyvitamin D (25(OH) D3) levels, histopathological changes in minor salivary gland biopsy samples and radiological findings were retrieved. RTA was diagnosed in cases of hyperchloremic metabolic acidosis with urinary pH values higher than 5.5. Those with known features suggestive of RTA including hypokalemic paralysis, hyperchloremia and nephrocalcinosis without acidosis were defined as incomplete RTA. Results: Of the 380 patients with clinically suspected pSS, 25 had RTA. The median age was 32 (18-60) years. Nineteen patients had complete RTA. Six had incomplete RTA. Only 10 patients (40%) had symptoms related to RTA at presentation. Sixteen patients (64%) had present or past history of hypokalemic paralysis. Pseudofractures were seen in 7 patients and an additional 2 had subclinical radiological osteomalacia. Majority of the patients (61.2%) had a normal 25(OH) D3 level. Those with osteomalacia had significantly lower serum phosphate, blood ph and higher alkaline phosphatase. Serum calcium and 25(OH) D3 levels were not significantly different between patients with osteomalacia and those without. Conclusion: Most patients were asymptomatic for RTA inspite of clinically overt and elicitable features. Skeletal manifestation was a common finding in patients with Sjgren and RTA, despite normal levels of 25 (OH) D3 in a majority. PMID:25584094

  6. 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

  7. Differential impacts of elevated CO2 and acidosis on the energy budget of gill and liver cells from Atlantic cod, Gadus morhua.

    PubMed

    Stapp, L S; Kreiss, C M; Pörtner, H O; Lannig, G

    2015-09-01

    Ocean acidification impacts fish and other marine species through increased seawater PCO2 levels (hypercapnia). Knowledge of the physiological mechanisms mediating effects in various tissues of fish is incomplete. Here we tested the effects of extracellular hypercapnia and acidosis on energy metabolism of gill and liver cells of Atlantic cod. Exposure media mimicked blood conditions in vivo, either during normo- or hypercapnia and at control or acidic extracellular pH (pHe). We determined metabolic rate and energy expenditure for protein biosynthesis, Na(+)/K(+)-ATPase and H(+)-ATPase and considered nutrition status by measurements of metabolic rate and protein biosynthesis in media with and without free amino acids (FAA). Addition of FAA stimulated hepatic but not branchial oxygen consumption. Normo- and hypercapnic acidosis as well as hypercapnia at control pHe depressed metabolic stimulation of hepatocytes. In gill cells, acidosis depressed respiration independent of PCO2 and FAA levels. For both cell types, depressed respiration was not correlated with the same reduction in energy allocated to protein biosynthesis or Na(+)/K(+)-ATPase. Hepatic energy expenditure for protein synthesis and Na(+)/K(+)-ATPase was even elevated at acidic compared to control pHe suggesting increased costs for ion regulation and cellular reorganization. Hypercapnia at control pHe strongly reduced oxygen demand of branchial Na(+)/K(+)-ATPase with a similar trend for H(+)-ATPase. We conclude that extracellular acidosis triggers metabolic depression in gill and metabolically stimulated liver cells. Additionally, hypercapnia itself seems to limit capacities for metabolic usage of amino acids in liver cells while it decreases the use and costs of ion regulatory ATPases in gill cells. PMID:26005104

  8. Lactic acidosis complicating treatment of ketosis of labour.

    PubMed Central

    Ames, A C; Cobbold, S; Maddock, J

    1975-01-01

    Hypertonic glucose, fructose, and sorbitol solutions were given intravenously to women in the first stage of labour who had ketonuria and ketonaemia as evidenced by a raised blood acetoacetate and 3-hydrosybutyrate. There was no difference in the antiketogenic action of these, which was rapid and effective, but when compared with a control group who were given normal saline they had a high incidence of hyperlactataemia, and nine out of 28 patients developed lactic acidosis after the infusions. The "lactatogenic" effect was shared by all three substrates, and when they are used in the treatment of ketosis of labour, and the mother develops lactic acidosis, they might exacerbate pre-existing lactic acidosis and precipitate fetal distress. PMID:1203699

  9. Local and systemic consequences of severe ischemia and reperfusion of the skeletal muscle. Physiopathology and prevention.

    PubMed

    Defraigne, J O; Pincemail, J

    1998-08-01

    Revascularization of a limb after a severe and prolonged period of ischemia may be associated with high rates of mortality and amputation, because of the development of a postrevascularization syndrome, regardless the cause of occlusion (ischemia, trauma, iatrogenic) or the methods used to achieve reperfusion (fibrinolysis, surgery, resuscitative therapy). This "revascularization" syndrome includes several complications, both local (explosive swelling of the limb, compartment syndrome and skeletal muscle infarction (rhabdomyolysis) and general (acidosis, hypercalcemia, hypovolaemic shock, renal, hepatointestinal and pulmonary failures, arrhythmias and cardiac arrest (multiple organ dysfunction). Current therapies are directed against complications after they occurred, once revascularization is completed: fasciotomy, mannitol and diuretics administration for forced diuresis, fluid administration to correct hypovolaemia, use of resins, insulin and glucose or haemodialysis to deal with hypercalcemia, administration of buffers (THAM, bicarbonate) to correct acidosis, control of hypercalcaemia with orthophosphates and calcitonin.... Nevertheless, a substantial percentage of the injury is generated upon reperfusion and the muscle may remain viable after prolonged period of ischemia. Intra and extraacellular swelling, tissue acidosis, free radical mediated damage, loss of adenine nucleotide precursors, and intracellular calcium overload have been suggested to be the mechanisms responsible for reperfusion injury. Careful control of both the composition and the physical conditions of the initial reperfusion (controlled reperfusion) may result, in selected cases, in improvements in the metabolism, structure and function of the limb after reperfusion. PMID:9779243

  10. Metabolic and Hormonal Changes of Severely Burned Children Receiving Long-Term Oxandrolone Treatment

    PubMed Central

    Przkora, Rene; Jeschke, Marc G.; Barrow, Robert E.; Suman, Oscar E.; Meyer, Walter J.; Finnerty, Celeste C.; Sanford, Arthur P.; Lee, Jong; Chinkes, David L.; Mlcak, Ronald P.; Herndon, David N.

    2005-01-01

    Objective: When given to children for 1 year after a severe burn, oxandrolone significantly improves lean body mass, bone mineral content, and muscle strength. The beneficial effects of oxandrolone on height and weight were observed 1 year after treatment was discontinued. To study the efficacy of oxandrolone in severely burned children for 12 months after burn and 12 months after the drug was discontinued. Summary Background Data: Oxandrolone attenuates body catabolism during the acute phase after burn. It is unclear whether oxandrolone would have any beneficial effects during long-term treatment or if there were any effects after the drug was stopped. Methods: Sixty-one children with 40% total body surface area burns were enrolled in this study. Patients were randomized into those to receive oxandrolone (n = 30) or placebo (n = 31) for the first 12 months. Treatment was discontinued after 12 months, and the patients were studied without the drug for the following 12 months. At discharge and 6, 12, 18, and 24 months after burn, height, weight, body composition, resting energy expenditure, muscle strength, and serum human growth hormone, insulin-like growth factor-I (IGF-1), IGF binding protein-3, insulin, cortisol, parathyroid hormone, tri-iodothyronine uptake (T3 uptake), and free thyroxine index (FTI) were measured. Statistical analysis used Tukey multiple comparison test. Significance was accepted at P < 0.05. Results: Oxandrolone improved lean body mass, bone mineral content and muscle strength compared with controls during treatment, P < 0.05. Serum IGF-1, T3 uptake, and FTI were significantly higher during drug treatment compared with controls, P < 0.05. Significant increases in height and weight with oxandrolone were observed after the end of treatment. Conclusions: Oxandrolone improved body composition and strength in severely burned children during the 12 months of treatment. Its effect on height and weight continued after treatment was discontinued. PMID:16135924

  11. Prevalence of biopsy-proven non-alcoholic fatty liver disease in severely obese subjects without metabolic syndrome.

    PubMed

    Qureshi, K; Abrams, G A

    2016-04-01

    Obesity is a major risk factor for non-alcoholic fatty liver disease (NAFLD). NAFLD encompasses simple fatty liver (FL) and non-alcoholic steatohepatitis (NASH) in its spectrum. NASH can progress to liver cirrhosis and is associated with liver cancer. Not all obese subjects have insulin resistance (IR) or develop metabolic syndrome (MS). This study evaluates the prevalence of NAFLD in severely obese subjects without MS. We retrospectively reviewed 445 charts from our database of severely obese subjects with clinical suspicion of NAFLD and who were selected for laparoscopic Roux-en-Y gastric bypass surgery. One hundred five subjects who did not have MS, as defined by the International Diabetes Foundation, based on comprehensive pre-operative metabolic evaluation were included. Liver biopsy specimens were evaluated for NAFLD. 24% of morbidly obese (mean body mass index [BMI] 48 kg m(-2) ) adult subjects (mean age 38 years) who underwent bariatric surgery did not have MS. NAFLD was identified in 77 (73%) on liver biopsy, out of which 59 (56%) were labelled as FL and 18 (17%) had histological diagnosis of NASH. Age, gender, race and BMI were the same among all groups. Among NAFLD subjects, 22% did not have any additional metabolic component of MS, while 36% had low high-density lipoprotein, 27% had hypertension, 8% had high triglycerides and 6% had hyperglycaemia. IR calculated by HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) and diagnosis of hyperglycaemia was statistically higher in NASH group compared to those who did not have NASH. NAFLD is highly prevalent in morbidly obese individuals who undergo bariatric surgery despite the absence of MS. Diagnosis of hyperglycaemia in such subjects suggests the presence of IR and may have underlying NASH, which is a progressive form of NAFLD. PMID:26856683

  12. INCREASED HEPATIC SYNTHESIS AND DYSREGULATION OF CHOLESTEROL METABOLISM IS ASSOCIATED WITH THE SEVERITY OF NONALCOHOLIC FATTY LIVER DISEASE

    PubMed Central

    Min, Hae-Ki; Kapoor, Ashwani; Fuchs, Michael; Mirshahi, Faridoddin; Zhou, Huiping; Maher, James; Kellum, John; Warnick, Russell; Contos, Melissa J; Sanyal, Arun J.

    2012-01-01

    SUMMARY Nonalcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular and liver-related mortality. NAFLD is characterized by both triglyceride and free cholesterol (FC) accumulation without a corresponding increment in cholesterol esters. The aim of this study was to evaluate the expression of cholesterol metabolic genes in NAFLD and relate these to disease phenotype. NAFLD was associated with increased SREBP-2 maturation, HMG CoA reductase (HMGCR) expression and decreased phosphorylation of HMGCR. Cholesterol synthesis was increased as measured by the circulating desmosterol:cholesterol ratio. miR-34a, a microRNA increased in NAFLD, inhibited sirtuin-1 with downstream dephosphorylation of AMP kinase and HMGCR. Cholesterol ester hydrolase was increased while ACAT-2 remained unchanged. LDL receptor expression was significantly decreased and similar in NAFLD subjects on or off statins. HMGCR expression was correlated with FC, histologic severity of NAFLD and LDL-cholesterol. These data demonstrate dysregulated cholesterol metabolism in NAFLD which may contribute to disease severity and cardiovascular risks. PMID:22560219

  13. Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease.

    PubMed

    Min, Hae-Ki; Kapoor, Ashwani; Fuchs, Michael; Mirshahi, Faridoddin; Zhou, Huiping; Maher, James; Kellum, John; Warnick, Russell; Contos, Melissa J; Sanyal, Arun J

    2012-05-01

    Nonalcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular and liver-related mortality. NAFLD is characterized by both triglyceride and free cholesterol (FC) accumulation without a corresponding increment in cholesterol esters. The aim of this study was to evaluate the expression of cholesterol metabolic genes in NAFLD and relate these to disease phenotype. NAFLD was associated with increased SREBP-2 maturation, HMG CoA reductase (HMGCR) expression and decreased phosphorylation of HMGCR. Cholesterol synthesis was increased as measured by the circulating desmosterol:cholesterol ratio. miR-34a, a microRNA increased in NAFLD, inhibited sirtuin-1 with downstream dephosphorylation of AMP kinase and HMGCR. Cholesterol ester hydrolase was increased while ACAT-2 remained unchanged. LDL receptor expression was significantly decreased and similar in NAFLD subjects on or off statins. HMGCR expression was correlated with FC, histologic severity of NAFLD and LDL-cholesterol. These data demonstrate dysregulated cholesterol metabolism in NAFLD which may contribute to disease severity and cardiovascular risks. PMID:22560219

  14. Metabolism

    MedlinePlus

    ... Some 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 ...

  15. Characterization of the interaction between local cerebral metabolic rate for glucose and acid-base index in ischemic rat brain employing a double-isotope methodology

    SciTech Connect

    Peek, K.E.H.

    1988-01-01

    The association between increases in cerebral glucose metabolism and the development of acidosis is largely inferential, based on reports linking hyperglycemia with poor neurological outcome, lactate accumulation, and the severity of acidosis. We measured local cerebral metabolic rate for glucose (lCMRglc) and an index of brain pH-the acid-base index (ABI)-concurrently and characterized their interaction in a model of focal cerebral ischemia in rats in a double-label autoradiographic study, using ({sup 14}C)2-deoxyglucose and ({sup 14}C)dimethyloxazolidinedione. Computer-assisted digitization and analysis permitted the simultaneous quantification of the two variables on a pixel-by-pixel basis in the same brain slices.

  16. The effect of cyclical and severe heat stress on growth performance and metabolism in Afshari lambs.

    PubMed

    Mahjoubi, E; Yazdi, M Hossein; Aghaziarati, N; Noori, G R; Afsarian, O; Baumgard, L H

    2015-04-01

    The extent to which reduced feed intake contributes to decreased growth during heat stress (HS) in the ovine model is not clear. To evaluate the impact of decreased DMI on performance, we conducted an experiment on growing lambs experiencing a cyclical but extensive heat load. Sixteen intact male Afshari lambs (40.1 ± 1.9 kg) were used in a completely randomized design in 2 periods. In period 1, all 16 lambs were housed in thermal neutral (TN) conditions (22.2 ± 3.1°C and a temperature-humidity index [THI] of 67.9 ± 3.2) and fed at libitum for 8 d. In period 2 (P2), which lasted 9 d, 8 lambs were subjected to a cyclical HS condition (33.0 to 45.0°C and a THI of more than 80 at least for 24 h/d and more than 90 for 8 h/d). The other 8 lambs were maintained in TN conditions but pair-fed (pair-fed thermal neutral [PFTN]) to the HS lambs. During each period, DMI and water intake were measured daily. Respiration rate, rectal temperature, and skin temperature at the shoulder, rump, and front and rear leg were recorded at 0700 and 1400 h daily. Dry matte intake declined (17.5%; P < 0.01) in HS lambs and, by design, the temporal pattern and magnitude of reduced feed intake was similar in the PFTN controls. Water intake increased (19%; P < 0.05) during P2 in HS but not in the PFTN controls. Heat stress increased the 0700 and 1400 h skin temperature at the shoulder (5 and 9.2%), rump (6.2 and 10.3%), rear (6 and 9.2%), and front leg (6.5 and 9.8%) and respiratory rates (84 and 163% [P < 0.01]at 0700 and 1400 h, respectfully), but only the 1400 h rectal temperature was increased (P < 0.01; 0.65°C) in HS lambs. Neither environment nor period affected blood urea nitrogen and glucose concentrations. However, circulating NEFA and insulin were increased and declined (P < 0.01) in PFTN lambs, respectively, but neither variable was altered in the HS lambs. Growth was reduced in P2 for lambs in both treatments, but despite being on a similar reduced plane of nutrition, the HS lambs' ADG was more than 2-fold greater than the PFTN controls. These results indicate that HS markedly alters the energetics of weight gain during growth and that the effects of HS are dependent on the severity of the heat load. PMID:26020185

  17. Metabolic Syndrome in South African Patients with Severe Mental Illness: Prevalence and Associated Risk Factors

    PubMed Central

    Saloojee, Shamima; Burns, Jonathan K; Motala, Ayesha A

    2016-01-01

    Background There is a surge of cardiovascular disease (CVD) in Africa. CVD is the leading cause of mortality among patients with severe mental illness (SMI) in developed countries, with little evidence from the African context. Objective To determine the prevalence and risk factors for MetS among South African patients with SMI. Method In a cross sectional study, individuals with SMI treated with antipsychotics and a control group without a mental illness, matched for age, gender and ethnicity were evaluated for MetS using the 2009 Joint Interim statement (JIS) criteria. Results Of the 276 study group subjects, 65.9% were male, 84.1% black African, 9.1% white, 5.4% of Indian descent and 1.5% coloured (mixed race) with a mean age of 34.7 years (±12.5). Schizophrenia was the most common diagnosis (73.2%) and 40% were taking first generation antipsychotics. The prevalence of MetS was 23.2% (M: 15.4%, F: 38.3%) in the study group and 19.9% (M: 11.9%, F: 36.3%) in the control group (p = 0.4). MetS prevalence was significantly higher in study subjects over 55 years compared to controls (p = 0.03). Increased waist circumference (p< 0.001) and low high density lipoprotein (HDL) cholesterol (p = 0.003) were significantly more prevalent in study subjects compared to controls. In study subjects, risk factors associated with MetS included age (OR: 1.09, 95% CI 1.06–1.12, p < 0.001), female gender (OR: 2.19, 95% CI 1.06–4.55, p = 0.035) and Indian descent (OR: 5.84, 95% CI 1.66–20.52, p = 0.006) but not class of antipsychotic (p = 0.26). Conclusion The overall MetS prevalence was not increased in patients with SMI compared to controls; however, the higher prevalence of the individual components (HDL cholesterol and waist circumference) suggests an increased risk for CVD, especially in patients over 55 years. PMID:26882230

  18. 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.

  19. Ruminant Nutrition Symposium: Acidosis: new insights into the persistent problem.

    PubMed

    Oba, M; Wertz-Lutz, A E

    2011-04-01

    The Ruminant Nutrition Symposium titled "Acidosis: New insights into the persistent problem" was held at the Joint Annual Meeting of the American Dairy Science Association, American Society of Animal Science, Poultry Science Association, Asociación Mexicana de Producción Animal, Western Section-ASAS, and the Canadian Society of Animal Science in Denver, Colorado, July 11 to 15, 2010. The objective of the symposium was to provide the ruminant nutrition community with new insights and perspectives from recent research findings on acidosis. Under modern production systems, ruminants are fed high-grain diets to maximize their energy intake and productivity. However, feeding highly fermentable diets often causes excess fermentation and results in accumulation of fermentation acids in the rumen, leading to a decrease in feed intake, poor feed efficiency, liver abscesses, and lameness in feedlot cattle or lactating dairy cows. Although our understanding of nutritional factors (i.e., effects of type and processing method of grains and importance of physically effective fiber) affecting rumen pH have increased substantially over the past few decades, rumen acidosis has continued to be a common problem in the ruminant livestock industry. The symposium program was organized to review recent research findings in acidosis with more emphasis on physiological aspects, and provide novel insights into the persistent problem. PMID:21148789

  20. Severe hyperkalemia as a complication of timolol, a topically applied beta-adrenergic antagonist

    SciTech Connect

    Swenson, E.R.

    1986-06-01

    Severe hyperkalemia occurred in a patient with radiation pneumonitis and glaucoma shortly after beginning prednisone therapy. There was no evidence of renal failure, diabetes, acidosis, increased potassium intake, or significant tissue trauma. Medications having adverse effects on potassium metabolism were considered, and the patient's use of timolol maleate eyedrops was discontinued. His serum potassium level normalized despite continuation of the prednisone therapy. He became hyperkalemic on rechallenge with timolol and normokalemic following its withdrawal. This case indicates that the potential for beta-blocker-induced hyperkalemia exists even with topical appreciation.

  1. Acidosis Blocks CCAAT/Enhancer-Binding Protein Homologous Protein (CHOP)- and c-Jun-Mediated Induction of p53-Upregulated Mediator of Apoptosis (PUMA) during Amino Acid Starvation

    PubMed Central

    Ryder, Christopher B.; McColl, Karen; Distelhorst, Clark W.

    2012-01-01

    Cancer cells must avoid succumbing to a variety of noxious conditions within their surroundings. Acidosis is one such prominent feature of the tumor microenvironment that surprisingly promotes tumor survival and progression. We recently reported that acidosis prevents apoptosis of starved or stressed lymphoma cells through regulation of several Bcl-2 family members (Ryder et al., JBC, 2012). Mechanistic studies in that work focused on the acid-mediated upregulation of anti-apoptotic Bcl-2 and Bcl-xL, while additionally showing inhibition of glutamine starvation-induced expression of pro-apoptotic PUMA by acidosis. Herein we report that amino acid (AA) starvation elevates PUMA, an effect that is blocked by extracellular acidity. Knockdown studies confirm that PUMA induction during AA starvation requires expression of both CHOP and c-Jun. Interestingly, acidosis strongly attenuates AA starvation-mediated c-Jun expression, which correlates with PUMA repression. As c-Jun exerts a tumor suppressive function in this and other contexts, its inhibition by acidosis has broader implications for survival of cancer cells in the acidic tumor milieu. PMID:23261451

  2. Changes in the Rumen Epimural Bacterial Diversity of Beef Cattle as Affected by Diet and Induced Ruminal Acidosis

    PubMed Central

    Petri, R. M.; Schwaiger, T.; Penner, G. B.; Beauchemin, K. A.; Forster, R. J.; McKinnon, J. J.

    2013-01-01

    Little is known about the nature of the rumen epithelial adherent (epimural) microbiome in cattle fed different diets. Using denaturing gradient gel electrophoresis (DGGE), quantitative real-time PCR (qPCR), and pyrosequencing of the V3 hypervariable coding region of 16S rRNA, epimural bacterial communities of 8 cattle were profiled during the transition from a forage to a high-concentrate diet, during acidosis, and after recovery. A total of 153,621 high-quality gene sequences were obtained, with populations exhibiting less taxonomic variability among individuals than across diets. The bacterial community composition exhibited clustering (P < 0.03) by diet, with only 14 genera, representing >1% of the rumen epimural population, differing (P ≤ 0.05) among diets. During acidosis, levels of Atopobium, Desulfocurvus, Fervidicola, Lactobacillus, and Olsenella increased, while during the recovery, Desulfocurvus, Lactobacillus, and Olsenella reverted to levels similar to those with the high-grain diet and Sharpea and Succinivibrio reverted to levels similar to those with the forage diet. The relative abundances of bacterial populations changed during diet transition for all qPCR targets except Streptococcus spp. Less than 5% of total operational taxonomic units (OTUs) identified exhibited significant variability across diets. Based on DGGE, the community structures of epithelial populations differed (P ≤ 0.10); segregation was most prominent for the mixed forage diet versus the grain, acidotic challenge, and recovery diets. Atopobium, cc142, Lactobacillus, Olsenella, RC39, Sharpea, Solobacterium, Succiniclasticum, and Syntrophococcus were particularly prevalent during acidosis. Determining the metabolic roles of these key genera in the rumens of cattle fed high-grain diets could define a clinical microbial profile associated with ruminal acidosis. PMID:23584771

  3. Severe Acute Malnutrition in Childhood: Hormonal and Metabolic Status at Presentation, Response to Treatment, and Predictors of Mortality

    PubMed Central

    Bartz, Sarah; Mody, Aaloke; Hornik, Christoph; Bain, James; Muehlbauer, Michael; Kiyimba, Tonny; Kiboneka, Elizabeth; Stevens, Robert; Bartlett, John; St Peter, John V.; Newgard, Christopher B.

    2014-01-01

    Objective: Malnutrition is a major cause of childhood morbidity and mortality. To identify and target those at highest risk, there is a critical need to characterize biomarkers that predict complications prior to and during treatment. Methods: We used targeted and nontargeted metabolomic analysis to characterize changes in a broad array of hormones, cytokines, growth factors, and metabolites during treatment of severe childhood malnutrition. Children aged 6 months to 5 years were studied at presentation to Mulago Hospital and during inpatient therapy with milk-based formulas and outpatient supplementation with ready-to-use food. We assessed the relationship between baseline hormone and metabolite levels and subsequent mortality. Results: Seventy-seven patients were enrolled in the study; a subset was followed up from inpatient treatment to the outpatient clinic. Inpatient and outpatient therapies increased weight/height z scores and induced striking changes in the levels of fatty acids, amino acids, acylcarnitines, inflammatory cytokines, and various hormones including leptin, insulin, GH, ghrelin, cortisol, IGF-I, glucagon-like peptide-1, and peptide YY. A total of 12.2% of the patients died during hospitalization; the major biochemical factor predicting mortality was a low level of leptin (P = .0002), a marker of adipose tissue reserve and a critical modulator of immune function. Conclusions: We have used metabolomic analysis to provide a comprehensive hormonal and metabolic profile of severely malnourished children at presentation and during nutritional rehabilitation. Our findings suggest that fatty acid metabolism plays a central role in the adaptation to acute malnutrition and that low levels of the adipose tissue hormone leptin associate with, and may predict, mortality prior to and during treatment. PMID:24606092

  4. The impact of leucine infusion on skeletal muscle amino acid and energy metabolism in severely traumatized patients.

    PubMed

    Lennmarken, C; Skullman, S; Wirén, M; Vinnars, E; Larsson, J

    1992-06-01

    The response to trauma is associated with increased energy requirements and net protein breakdown. The branched chain aminoacids, especially leucine, are considered to act by serving as a fuel for muscle tissue and by stimulating synthesis of proteins and controlling protein breakdown. Such results have been obtained mainly from in vitro studies. The present study was designed to evaluate the pharmacological effect of leucine infusion on muscle energy/amino acid metabolism in man after severe multiple trauma. 16 patients were studied and randomly allocated into 2 groups. Group 1 was given fat and 20% glucose while group 2 received 6 g N in form of leucine dissolved in 10% glucose solution and fat. The patients received 40 kcal/kg/24 h over an 8 day period after trauma. Biochemical analyses, muscle biopsies (energy substrates, electrolytes, amino acids), nitrogen balance and 3-methyl histidine excretion in urine were evaluated. Biochemical data revealed a significant increase (p < 0.05) of serum urea in group 2 day 4 and 8 after trauma. Muscle intracellular electrolytes (K(+), Mg(2+)) and energy substrates (ATP, phosphocreatine) showed a similar decrease in both groups. The intracellular muscle amino acids displayed a pattern known to be related to trauma without differences between the groups. The cumulative nitrogen balance 8 days after the injury was -93.5 g N +/- 10.1 (SEM) in group 1 and -73 g N +/- 7.5 in group 2. The 3-methylhistidine excretion was markedly increased similar in both groups. The present study demonstrated no significant pharmacological effect of leucine administration on muscle metabolism, nitrogen balance or 3-methylhistidine excretion in severely traumatized patients. Conventional balanced amino acid solutions are probably optimal to meet the patients actual requirements. PMID:16839989

  5. Why are dairy cows not able to cope with the subacute ruminal acidosis?

    PubMed

    Brzozowska, A M; Sloniewski, K; Oprzadek, J; Sobiech, P; Kowalski, Z M

    2013-01-01

    One of the largest challenges for the dairy industry is to provide cows with a diet which is highly energetic but does not negatively affect their rumens' functions. In highly productive dairy cows, feeding diets rich in readily fermentable carbohydrates provides energy precursors needed for maximum milk production, but simultaneously decreases ruminal pH, leading to a widespread prevalence of subacute ruminal acidosis. Maximizing milk production without triggering rumen acidosis still challenges dairy farmers, who try to prevent prolonged bouts of low ruminal pH mainly by proper nutrition and management practices. The animals try to avoid overeating fermentable feeds, as it causes negative consequences by disturbing digestive processes. The results of several experiments show that ruminants, including sheep and beef cattle, are able to modify some aspects of feeding behaviour in order to adjust nutrient intake to their needs and simultaneously prevent physiological disturbances. Particularly, such changes (e.g., increased preference for fibrous feeds, reduced intake of concentrates) were observed in animals, which were trying to prevent the excessive drop of rumen fluid pH. Thanks to a specific mechanism called "the postingestive feedback", animals should be able to work out such a balance in intake, so they do not suffer either from hunger or from negative effects of over-ingesting the fermentable carbohydrates. This way, an acidosis should not be a frequent problem in ruminants. However, prolonged periods of excessively decreased rumen pH are still a concern in dairy cows. It raises a question, why the regulation of feed intake by postingestive feedback does not help to maintain stable rumen environment in dairy cows? PMID:24597322

  6. Analysis of metabolic flux phenotypes for two Arabidopsis mutants with severe impairment in seed storage lipid synthesis

    SciTech Connect

    Lonien, J.; Schwender, J.

    2009-11-01

    Major storage reserves of Arabidopsis (Arabidopsis thaliana) seeds are triacylglycerols (seed oils) and proteins. Seed oil content is severely reduced for the regulatory mutant wrinkled1 (wri1-1; At3g54320) and for a double mutant in two isoforms of plastidic pyruvate kinase (pkp{beta}{sub 1}pkp{alpha}; At5g52920 and At3g22960). Both already biochemically well-characterized mutants were now studied by {sup 13}C metabolic flux analysis of cultured developing embryos based on comparison with their respective genetic wild-type backgrounds. For both mutations, in seeds as well as in cultured embryos, the oil fraction was strongly reduced while the fractions of proteins and free metabolites increased. Flux analysis in cultured embryos revealed changes in nutrient uptakes and fluxes into biomass as well as an increase in tricarboxylic acid cycle activity for both mutations. While in both wild types plastidic pyruvate kinase (PK{sub p}) provides most of the pyruvate for plastidic fatty acid synthesis, the flux through PK{sub p} is reduced in pkp{beta}{sub 1}pkp{alpha} by 43% of the wild-type value. In wri1-1, PK{sub p} flux is even more reduced (by 82%), although the genes PKp{beta}{sub 1} and PKp{alpha} are still expressed. Along a common paradigm of metabolic control theory, it is hypothesized that a large reduction in PK{sub p} enzyme activity in pkp{beta}{sub 1}pkp{alpha} has less effect on PK{sub p} flux than multiple smaller reductions in glycolytic enzymes in wri1-1. In addition, only in the wri1-1 mutant is the large reduction in PK{sub p} flux compensated in part by an increased import of cytosolic pyruvate and by plastidic malic enzyme. No such limited compensatory bypass could be observed in pkp{beta}{sub 1}pkp{alpha}.

  7. Effects of alternate fasting or very low calorie diet and low calorie diet on metabolic syndrome in severely obese patients

    PubMed Central

    Tančić-Gajić, M; Vujović, S; Vukčević, M; Ivović, M; Drezgić, M; Marina, LV; Stojanović, M; Arizanović, Z; Nenezić, A; Micić, D

    2012-01-01

    Background and Aim: Weight loss improves the metabolic syndrome (MetS) features and related clinical abnormalities in obese subjects. The aim of this study was to assess the effects of a non-surgical therapeutic program on the MetS in severely obese patients. Patients and Methods: Sixty-four extremely obese patients were involved in the therapeutic program, which consisted of two alternating phases: the three-week therapeutic fasting or semi-fasting in hospital conditions and the low calorie diet with dosed physical activity in outpatient conditions. At the baseline we measured: anthropometric parameters, blood pressure and lipid profile. Subjects underwent an oral glucose tolerance test and insulin resistance/sensitivity was evaluated by the homeostasis model assessment and the oral glucose insulin sensitivity. After weight reduction by at least 10%, all mentioned assessments were repeated. Results: None of the patients had significant adverse effects. Forty-one patients aged 43.0±11.5 years completed the study. The mean weight loss was 27 kg or 18% of the initial weight (p<0.01), which was followed by a significant decrease of the insulin resistance, the overall prevalence of MetS (32%) and all MetS parameters, without the significant change in high-density lipoprotein. This weight loss pogram substantially improves the MetS in extremely obese patients. Conclusion: The tailored alternating either fasting or semi- fasting should be considered as an optional approach to manage extreme obesity and related metabolic abnormality. PMID:23935313

  8. Metabolic and electrolyte disturbance after cardiac arrest: How to deal with it.

    PubMed

    Bellomo, Rinaldo; Märtensson, Johan; Eastwood, Glenn Matthew

    2015-12-01

    Cardiac arrest (CA) is a sudden, severe event that causes a cascade of metabolic and electrolyte disturbances throughout the body triggered by a loss of cardiac output. Metabolic disturbances are primarily in the form of mixed metabolic and respiratory acidosis; dysglycaemia; and states of deficiency or excess in potassium, calcium, magnesium and lactate. It is known that persistent metabolic disturbances are associated with poor patient outcome following resuscitation from CA, but this might simply be a reflection of the severity of illness. Moreover, contemporary evidence for the management of metabolic disturbances to improve outcomes in these patients is scarce. Moreover, metabolic disturbances during the early post-resuscitation period remain poorly understood in terms of severity, duration and the influence of their post-resuscitation care and treatment on outcome. Although sufficient data suggest that extreme metabolic disturbances such as hypoglycaemia, severe hyperglycaemia, severe hypokalaemia and hyperkalaemia and hypomagnesaemia likely have a devastating effect and should be avoided, randomised controlled trial evidence is clearly need for the management of metabolic and electrolyte derangements in resuscitated CA patients. PMID:26670818

  9. Cellular acidosis inhibits assembly, disassembly, and motility of stress granules.

    PubMed

    Chudinova, E M; Nadezhdina, E S; Ivanov, P A

    2012-11-01

    Stress granules (SGs) are large ribonucleoprotein (RNP)-containing particles that form in cytoplasm in response to a variety of acute changes in the cellular environment. One of the general parameters of the cell environment is pH. In some diseases, as well as in muscle fatigue, tissue acidosis occurs, leading to decrease in intracellular pH. Here we studied whether decrease in pH causes the formation of SGs in cultured animal cells, whether it affects the formation of the SGs under the action of arsenite and, if such effects occur, what are the mechanisms of the influence of acidosis. Acidosis was simulated by decreasing the pH of the culture medium, which acidified the cytoplasm. We found that medium acidification to pH 6.0 in itself did not cause formation of SGs in cells. Moreover, acidification prevented the formation of SGs under treatment with sodium arsenite or sodium arsenite together with the proteasome inhibitor MG132, and it inhibited the dissociation of preformed SGs under the influence of cycloheximide. We established that pH decrease did not affect the phosphorylation of eIF2α that occurs under the action of sodium arsenite, and even caused such phosphorylation by itself. We also found that the velocity of SG motion in cytoplasm at acidic pH was very low, and the mobile fraction of SG-incorporated PABP protein revealed by FRAP was decreased. We suppose that acidic pH impairs biochemical processes favoring assembly of RNPs in stress conditions and RNP dissociation on the termination of stress. Thus, in acidosis the reaction of the cellular translation apparatus to stress is modified. PMID:23240565

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

    PubMed

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

    2014-06-01

    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

  11. 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

  12. Mechanism of diminished contractile response to catecholamines during acidosis

    SciTech Connect

    Marsh, J.D.; Margolis, T.I.; Kim, D. Harvard Medical School, Boston, MA )

    1988-01-01

    To examined mechanisms of diminished contractile response to catecholamines during acidosis, the authors studied contractile properties, {beta}-adrenergic receptor properties, and intracellular pH of intact, cultured myocardial cells from chick embryo ventricle at pH 7.4 and 6.8. On changing the superfusing buffer from pH 7.4 to 6.8 there was a decline in contractile amplitude to 80% of control by 20 min. Fluorimetrically determined intracellular pH declined over a similar time course from 7.11 {plus minus} 0.05 to 6.96 {plus minus} 0.07. After 45 min at pH 6.8 the contractile response to 1 {mu}M isoproterenol was less than half of the response at pH 7.4. Antagonist and agonist ligand-binding properties of the {beta}-adrenergic receptor were determined in the intact cells under conditions identical to those for the contractility studies. With the use of the hydrophilic antagonist ({sup 3}H)CGP-12177 that selectively labels cell-surface receptors, agonist competition studies demonstrated that acidosis had no significant effect on antagonist or agonist affinity but decreased {beta}-receptor number from 21 {plus minus} 3 to 11 {plus minus} 3 fmol/mg protein. It is probably that a decline in the number of {beta}-receptors on the cell surface contributes to contractile hyporesponsiveness to catecholamines during acidosis.

  13. Effect of strain and diet upon constitutive and chemically induced activities of several xenobiotic-metabolizing enzymes in rats.

    PubMed

    Stott, W T; Kan, H L; McFadden, L G; Sparrow, B R; Gollapudi, B B

    2004-06-01

    The response of animals in toxicity studies reflects a complex interaction of a number of variables, some intrinsic to a particular study design and others resulting from the treatment itself. The influences of strain and diet upon constitutive and benzo(a)pyrene (B(a)P) induced activities of several hepatic Phase I and II enzymes were studied in a multifactoral design. Male and female CDF and Crl:CD rats were fed a standard rodent diet ad libitum, a 75% of ad libitum restricted feeding regimen or a phytoestrogen-free diet for approximately 3 weeks. During the last five days of the study, rats were administered either corn oil (vehicle) or 15 mg/kg/day B(a)P via oral gavage. The constitutive activities of hepatic CYP1A1, CYP1A2, CYP2B1/2, and mixed isoforms of UDP-glucuronosyl transferase, sulfotransferase, and glutathione-S-transferase varied significantly by feeding regimen and strain. Responses to B(a)P administration were also observed to be influenced by diet and strain in a manner similar to that observed for constitutive activities. These findings point out the potentially significant interactions of relatively commonly encountered variables that may affect results of hazard testing, especially when employing near metabolically saturating dosages of test chemicals. PMID:15135211

  14. More sensitivity of cortical GABAergic neurons than glutamatergic neurons in response to acidosis.

    PubMed

    Liu, Hua; Li, Fang; Wang, Chunyan; Su, Zhiqiang

    2016-05-25

    Acidosis impairs brain functions. Neuron-specific mechanisms underlying acidosis-induced brain dysfunction remain elusive. We studied the sensitivity of cortical GABAergic neurons and glutamatergic neurons to acidosis by whole-cell recording in brain slices. The acidification to the neurons was induced by perfusing artificial cerebral spinal fluid with lower pH. This acidification impairs excitability and synaptic transmission in the glutamatergic and GABAergic neurons. Acidosis impairs spiking capacity in the GABAergic neurons more than in the glutamatergic neurons. Acidosis also strengthens glutamatergic synaptic transmission and attenuates GABAergic synaptic transmission on the GABAergic neurons more than the glutamatergic neurons, which results in the functional impairment of these GABAergic neurons. This acidosis-induced dysfunction predominantly in the cortical GABAergic neurons drives the homeostasis of neuronal networks toward overexcitation and exacerbates neuronal impairment. PMID:27116702

  15. Ruminal acidosis and the rapid onset of ruminal parakeratosis in a mature dairy cow: a case report.

    PubMed

    Steele, Michael A; AlZahal, Ousama; Hook, Sarah E; Croom, Jim; McBride, Brian W

    2009-01-01

    A mature dairy cow was transitioned from a high forage (100% forage) to a high-grain (79% grain) diet over seven days. Continuous ruminal pH recordings were utilized to diagnose the severity of ruminal acidosis. Additionally, blood and rumen papillae biopsies were collected to describe the structural and functional adaptations of the rumen epithelium. On the final day of the grain challenge, the daily mean ruminal pH was 5.41+/-0.09 with a minimum of 4.89 and a maximum of 6.31. Ruminal pH was under 5.0 for 130 minutes (2.17 hours) which is characterized as the acute form of ruminal acidosis in cattle. The grain challenge increased blood beta-hydroxybutyrate by 1.8 times and rumen papillae mRNA expression of 3-hydroxy-3-methylglutaryl-coenzyme A synthase by 1.6 times. Ultrastructural and histological adaptations of the rumen epithelium were imaged by scanning electron and light microscopy. Rumen papillae from the high grain diet displayed extensive sloughing of the stratum corneum and compromised cell adhesion as large gaps were apparent between cells throughout the strata. This case report represents a rare documentation of how the rumen epithelium alters its function and structure during the initial stage of acute acidosis. PMID:19840395

  16. Ruminal acidosis and the rapid onset of ruminal parakeratosis in a mature dairy cow: a case report

    PubMed Central

    Steele, Michael A; AlZahal, Ousama; Hook, Sarah E; Croom, Jim; McBride, Brian W

    2009-01-01

    A mature dairy cow was transitioned from a high forage (100% forage) to a high-grain (79% grain) diet over seven days. Continuous ruminal pH recordings were utilized to diagnose the severity of ruminal acidosis. Additionally, blood and rumen papillae biopsies were collected to describe the structural and functional adaptations of the rumen epithelium. On the final day of the grain challenge, the daily mean ruminal pH was 5.41 ± 0.09 with a minimum of 4.89 and a maximum of 6.31. Ruminal pH was under 5.0 for 130 minutes (2.17 hours) which is characterized as the acute form of ruminal acidosis in cattle. The grain challenge increased blood beta-hydroxybutyrate by 1.8 times and rumen papillae mRNA expression of 3-hydroxy-3-methylglutaryl-coenzyme A synthase by 1.6 times. Ultrastructural and histological adaptations of the rumen epithelium were imaged by scanning electron and light microscopy. Rumen papillae from the high grain diet displayed extensive sloughing of the stratum corneum and compromised cell adhesion as large gaps were apparent between cells throughout the strata. This case report represents a rare documentation of how the rumen epithelium alters its function and structure during the initial stage of acute acidosis. PMID:19840395

  17. Effects on breathing of focal acidosis at multiple medullary raphe sites in awake goats.

    PubMed

    Hodges, M R; Martino, P; Davis, S; Opansky, C; Pan, L G; Forster, H V

    2004-12-01

    To gain insight into why there are chemoreceptors at widespread sites in the brain, mircrotubules were chronically implanted at two or three sites in the medullary raphe nuclei of adult goats (n = 7). After >2 wk, microdialysis (MD) probes were inserted into the microtubules to create focal acidosis (FA) in the awake state using mock cerebral spinal fluid (mCSF) equilibrated with 6.4% (pH = 7.3), 50% (pH = 6.5), or 80% CO(2) (pH = 6.3), where MD with 50 and 80% CO(2) reduces tissue pH by 0.1 and 0.18 pH unit, respectively. There were no changes in all measured variables with MD with 6.4% at single or multiple raphe sites (P > 0.05). During FA at single raphe sites, only 80% CO(2) elicited physiological changes as inspiratory flow was 16.9% above (P < 0.05) control. However, FA with 50 and 80% CO(2) at multiple sites increased (P < 0.05) inspiratory flow by 18.4 and 30.1%, respectively, where 80% CO(2) also increased (P < 0.05) tidal volume, heart rate, CO(2) production, and O(2) consumption. FA with 80% CO(2) at multiple raphe sites also led to hyperventilation (-2 mmHg), indicating that FA had effects on breathing independent of an increased metabolic rate. We believe these findings suggest that the large ventilatory response to a global respiratory brain acidosis reflects the cumulative effect of stimulation at widespread chemoreceptor sites rather than a large stimulation at a single site. Additionally, focal acidification of raphe chemoreceptors appears to activate an established thermogenic response needed to offset the increased heat loss associated with the CO(2) hyperpnea. PMID:15322068

  18. EARS2 mutations cause fatal neonatal lactic acidosis, recurrent hypoglycemia and agenesis of corpus callosum.

    PubMed

    Danhauser, Katharina; Haack, Tobias B; Alhaddad, Bader; Melcher, Marlen; Seibt, Annette; Strom, Tim M; Meitinger, Thomas; Klee, Dirk; Mayatepek, Ertan; Prokisch, Holger; Distelmaier, Felix

    2016-06-01

    Mitochondrial aminoacyl tRNA synthetases are essential for organelle protein synthesis. Genetic defects affecting the function of these enzymes may cause pediatric mitochondrial disease. Here, we report on a child with fatal neonatal lactic acidosis and recurrent hypoglycemia caused by mutations in EARS2, encoding mitochondrial glutamyl-tRNA synthetase 2. Brain ultrasound revealed agenesis of corpus callosum. Studies on patient-derived skin fibroblasts showed severely decreased EARS2 protein levels, elevated reactive oxygen species (ROS) production, and altered mitochondrial morphology. Our report further illustrates the clinical spectrum of the severe neonatal-onset form of EARS2 mutations. Moreover, in this case the live-cell parameters appeared to be more sensitive to mitochondrial dysfunction compared to standard diagnostics, which indicates the potential relevance of fibroblast studies in children with mitochondrial diseases. PMID:26780086

  19. Severe necrosis of oesophageal and gastric mucosa in fatal methanol poisoning.

    PubMed

    Cascallana, José L; Gordo, Verónica; Montes, Rosario

    2012-07-10

    Methanol is a potent neurotoxic substance that causes severe metabolic acidosis and serious neurological disorders. Most of the cases are accidental exposures to drinking beverages contaminated with methanol. There are few articles reporting pure methanol intoxication; however, it is well known that small quantities of pure methanol causes blindness and death, the minimum lethal dose being 50-100 ml.A case report is presented of a 67-year-old woman, who committed suicide by ingestion of 500 ml of absolute methanol. Despite symptomatic and supportive intensive care, the woman died 23 h after hospital admission due to metabolic acidosis and multiple organ dysfunction syndrome. A complete medico-legal autopsy was performed. Grossly, there was complete detachment of the oesophagus mucosa and brownish discolouration of the gastric mucosa. Histological findings showed diffuse haemorrhagic necrosis of the stomach mucosa and intense acute inflammatory infiltration of the lamina propria. To our knowledge, this is the first autopsy report of such severe digestive injuries. A discussion and review of the recent literature on the subject are given. PMID:22398189

  20. Type-B lactic acidosis associated with progressive multiple myeloma

    PubMed Central

    Abdullah, Sameer Y.; Ali, Moaath K.; Sabha, Marwa M.

    2015-01-01

    We report a 64-year-old lady with stage II, Immunoglobulin-G lambda multiple myeloma (MM) (standard risk), who presented with type-B lactic acidosis (LA), and multi-organ dysfunction associating myeloma progression, and ending in imminent death. In the context of literature review of all previously reported similar cases, this report highlights and discusses the association of type-B LA and MM (especially progressive disease), and also emphasizes the poor outcome. Early recognition of this condition with intensive supportive care, and treatment of multiple myeloma may improve outcomes. PMID:25719593

  1. 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.

  2. Repeated ruminal acidosis challenges in lactating dairy cows at high and low risk for developing acidosis: feeding, ruminating, and lying behavior.

    PubMed

    DeVries, T J; Beauchemin, K A; Dohme, F; Schwartzkopf-Genswein, K S

    2009-10-01

    An experiment was conducted to determine whether the susceptibility to ruminal acidosis, as defined through differences in days in milk (DIM), milk production level, and ration composition, influences cow feeding, ruminating, and lying behavior and whether these behaviors change during an acute bout of ruminal acidosis. Eight ruminally cannulated cows were assigned to 1 of 2 acidosis risk levels: low risk (LR, mid-lactation cows fed a 60:40 forage:concentrate ratio diet) or high risk (HR, early lactation cows fed a 45:55 forage:concentrate diet). As a result, diets were intentionally confounded with DIM and milk production to represent 2 different acidosis risk scenarios. Cows were exposed to an acidosis challenge in each of three 14-d periods. Each period consisted of 3 baseline days, a feed restriction day (restricting total mixed ration to 50% of ad libitum intake), an acidosis challenge day (1 h meal of 4 kg of ground barley/wheat before allocating the total mixed ration), and a recovery phase. Feeding, rumination, and standing/lying behavior were recorded for 2 baseline days, on the challenge day, and 1 and 4 d after the challenge day for each cow. Across the study, there were no differences in measures of standing, lying, or feeding behavior between the 2 groups of cows. The HR cows did, on average, spend less time ruminating (491 vs. 555 min/d) than the LR cows, resulting in a lesser percentage of observed cows ruminating across the day (44.6 vs. 48.1%). The acidosis challenge resulted in changes in behavior in all cows. Compared with the baseline, feeding time increased on the first day after the challenge (395 vs. 310 min/d), whereas lying time decreased (565 vs. 634 min/d). Rumination time decreased the first day following the challenge (436 min/d) relative to the baseline (533 min/d), but increased the following day (572 min/d). Fewer cows were observed to be ruminating at a given time on the first day following the challenge as compared with the baseline period. Despite this, on a herd level, numerous observations of the proportion of cows ruminating at any one time would need to be taken to accurately detect an acute bout of acidosis using changes in rumination behavior. Overall, these results suggest that risk of acidosis may have little overall effect on general behavior, with the exception of rumination. Furthermore, an acute bout of acidosis alters behavioral patterns of lactating dairy cows, particularly rumination behavior, and identification of these changes in behavior through repeated measurements may assist in the detection of an acidosis event within a herd. PMID:19762825

  3. A fatal adverse effect of cefazolin administration: severe brain edema in a patient with multiple meningiomas

    PubMed Central

    Tribuddharat, Sirirat; Sathitkarnmanee, Thepakorn; Kitkhuandee, Amnat; Theerapongpakdee, Sunchai; Ngamsaengsirisup, Kriangsak; Chanthawong, Sarinya

    2016-01-01

    Cefazolin is commonly administered before surgery as a prophylactic antibiotic. Hypersensitivity to cefazolin is not uncommon, and the symptoms mostly include urticaria, skin reaction, diarrhea, vomiting, and transient neutropenia, which are rarely life threatening. We present a rare case of fatal cefazolin hypersensitivity in a female who was diagnosed with multiple meningiomas and scheduled for craniotomy and tumor removal. Immediately after cefazolin IV administration, the patient developed acute hypertensive crisis, which resolved within 10 minutes after the treatment. This was followed by unexplained metabolic acidosis. The patient then developed severe brain edema 100 minutes later. The patient had facial edema when her face was exposed for the next 30 minutes. A computed tomography scan revealed global brain edema with herniation. She was admitted to the intensive care unit for symptomatic treatment and died 10 days after surgery from multiorgan failure. The serum IgE level was very high (734 IU/mL). Single-dose administration of cefazolin for surgical prophylaxis may lead to rare, fatal adverse reaction. The warning signs are sudden, unexplained metabolic acidosis, hypertensive crisis, tachycardia, and facial angioedema predominating with or without cutaneous symptoms like urticaria. PMID:26929668

  4. A fatal adverse effect of cefazolin administration: severe brain edema in a patient with multiple meningiomas.

    PubMed

    Tribuddharat, Sirirat; Sathitkarnmanee, Thepakorn; Kitkhuandee, Amnat; Theerapongpakdee, Sunchai; Ngamsaengsirisup, Kriangsak; Chanthawong, Sarinya

    2016-01-01

    Cefazolin is commonly administered before surgery as a prophylactic antibiotic. Hypersensitivity to cefazolin is not uncommon, and the symptoms mostly include urticaria, skin reaction, diarrhea, vomiting, and transient neutropenia, which are rarely life threatening. We present a rare case of fatal cefazolin hypersensitivity in a female who was diagnosed with multiple meningiomas and scheduled for craniotomy and tumor removal. Immediately after cefazolin IV administration, the patient developed acute hypertensive crisis, which resolved within 10 minutes after the treatment. This was followed by unexplained metabolic acidosis. The patient then developed severe brain edema 100 minutes later. The patient had facial edema when her face was exposed for the next 30 minutes. A computed tomography scan revealed global brain edema with herniation. She was admitted to the intensive care unit for symptomatic treatment and died 10 days after surgery from multiorgan failure. The serum IgE level was very high (734 IU/mL). Single-dose administration of cefazolin for surgical prophylaxis may lead to rare, fatal adverse reaction. The warning signs are sudden, unexplained metabolic acidosis, hypertensive crisis, tachycardia, and facial angioedema predominating with or without cutaneous symptoms like urticaria. PMID:26929668

  5. Glucose Metabolism and Pancreatic Defects in Spinal Muscular Atrophy

    PubMed Central

    Bowerman, Melissa; Swoboda, Kathryn J.; Michalski, John-Paul; Wang, Gen-Sheng; Reeks, Courtney; Beauvais, Ariane; Murphy, Kelley; Woulfe, John; Screaton, Robert A.; Scott, Fraser W.; Kothary, Rashmi

    2014-01-01

    Objective Spinal muscular atrophy (SMA) is the number 1 genetic killer of young children. It is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. Although SMA is primarily a motor neuron disease, metabolism abnormalities such as metabolic acidosis, abnormal fatty acid metabolism, hyperlipidemia, and hyperglycemia have been reported in SMA patients. We thus initiated an in-depth analysis of glucose metabolism in SMA. Methods Glucose metabolism and pancreas development were investigated in the Smn2B/− intermediate SMA mouse model and type I SMA patients. Results Here, we demonstrate in an SMA mouse model a dramatic cell fate imbalance within pancreatic islets, with a predominance of glucagon-producing α cells at the expense of insulin-producing β cells. These SMA mice display fasting hyperglycemia, hyperglucagonemia, and glucose resistance. We demonstrate similar abnormalities in pancreatic islets from deceased children with the severe infantile form of SMA in association with supportive evidence of glucose intolerance in at least a subset of such children. Interpretation Our results indicate that defects in glucose metabolism may play an important contributory role in SMA pathogenesis. PMID:22926856

  6. Over-nutrient environment during both prenatal and postnatal development increases severity of islet injury, hyperglycemia, and metabolic disorders in the offspring.

    PubMed

    Li, Lei; Xue, Jing; Li, Hongyan; Ding, Jian; Wang, Yanyun; Wang, Xietong

    2015-09-01

    Prenatal and postnatal over-nutrition has emerged as a new health issue contributing to metabolic disorders in early development of the offspring. Accumulating evidence has suggested that adverse prenatal and postnatal environments gave rise to the predisposition to metabolic syndromes including hyperglycemia, obesity, and diabetes. However, little research has concentrated on the effects of exposures to both adverse conditions before and after birth of the offspring. In this study, we aimed to investigate whether prenatal and postnatal over-nutrition is able to cause metabolic disorders to female mice feed on high-fat/fructose diet (HFFD) as well as their offspring. Female mice were fed on either HFFD or a normal chow diet (NC), while their offspring were divided into four experimental groups as NC/NC, HFFD/NC, NC/HFFD, and HFFD/HFFD (prenatal/postnatal diet order), respectively. Both NC/HFFD and HFFD/HFFD offspring exhibited obvious body weight and fat content gain, hyperglycemia, and severe insulin resistance. Interestingly, when compared to NC/HFFD offspring, the HFFD/HFFD offspring exhibited more severe alterations in their metabolism and dysfunctions on pancreatic β-cells, suggesting a potential impact of prenatal HFFD on the programming of pancreatic β-cell deficiency in the fetus. Meanwhile, the results from HFFD/NC mice indicated that a balance diet after birth partially compensated the adverse prenatal HFFD impact. In conclusion, this study demonstrated that prenatal and postnatal over-nutrition increases severity of islet injury, hyperglycemia, and metabolic disorders in the offspring. PMID:26048534

  7. Seizure-induced damage to substantia nigra and globus pallidus is accompanied by pronounced intra- and extracellular acidosis

    SciTech Connect

    Inamura, K.; Smith, M.L.; Hansen, A.J.; Siesjoe, B.K. )

    1989-12-01

    Status epilepticus of greater than 30-min duration in rats gives rise to a conspicuous lesion in the substantia nigra pars reticulata (SNPR) and globus pallidus (GP). The objective of the present study was to explore whether the lesion, which encompasses necrosis of both neurons and glial cells, is related to intra- and extracellular acidosis. Using the flurothyl model previously described to produce seizures, we assessed regional pH values with the autoradiographic 5,5-dimethyl(2-14C)oxazolidine-2,4-dione technique. Regional pH values were assessed in animals with continuous seizures for 20 and 60 min, as well as in those allowed to recover for 30 and 120 min after seizure periods of 20 or 60 min. In additional animals, changes in extracellular fluid pH (pHe) were measured with ion-selective microelectrodes, and extracellular fluid (ECF) volume was calculated from the diffusion profile for electrophoretically administered tetramethylammonium. In structures such as the neocortex and the hippocampus, which show intense metabolic activation during seizures, status epilepticus of 20- and 60-min duration was accompanied by a reduction of the composite tissue pH (pHt) of 0.2-0.3 unit. Recovery of pHt was observed upon termination of seizures. In SNPR and in GP, the acidosis was marked to excessive after 20 and 60 min of seizures (delta pHt approximately 0.6 after 60 min).

  8. Different patterns of testicular in vitro metabolism of (/sup 14/C)testosterone in several Betta (Anabantoidei, Belontiidae) species

    SciTech Connect

    Leitz, T.

    1987-07-01

    Testicular tissues of Betta picta, Betta smaragdina, and the short-finned variety of Betta splendens were incubated with (/sup 14/C)testosterone at 27 degrees for 120 min and the metabolites were isolated and characterized by paper and thin-layer chromatography and eventually by crystallization to constant specific activity. The metabolic profiles of the species were totally different. The short-finned B. splendens formed mainly 11-ketotestosterone (51.4%) as does the veiltail variety. B. smaragdina was the only species which formed considerable amounts of conjugates (24.3%), whereas in B. picta almost exclusively reduced (5 beta-) compounds (66.2%) were metabolites of testosterone. The results are discussed to be attributable to differences in testicular steroid metabolism. The significance of this observation remains unclear.

  9. Different patterns of testicular in vitro metabolism of [14C]testosterone in several Betta (Anabantoidei, Belontiidae) species.

    PubMed

    Leitz, T

    1987-07-01

    Testicular tissues of Betta picta, Betta smaragdina, and the short-finned variety of Betta splendens were incubated with [14C]testosterone at 27 degrees for 120 min and the metabolites were isolated and characterized by paper and thin-layer chromatography and eventually by crystallization to constant specific activity. The metabolic profiles of the species were totally different. The short-finned B. splendens formed mainly 11-ketotestosterone (51.4%) as does the veiltail variety. B. smaragdina was the only species which formed considerable amounts of conjugates (24.3%), whereas in B. picta almost exclusively reduced (5 beta-) compounds (66.2%) were metabolites of testosterone. The results are discussed to be attributable to differences in testicular steroid metabolism. The significance of this observation remains unclear. PMID:3623068

  10. Measurement of urinary free and acylcarnitines: quantitative acylcarnitine profiling in normal humans and in several patients with metabolic errors

    SciTech Connect

    Montgomery, J.A.; Mamer, O.A.

    1989-01-01

    A method for determining urinary concentrations of carnitine and acylcarnitine esters is described that employs fast atom bombardment mass spectrometry, stable isotope dilution techniques, and a novel deutero-methyl esterification that permits unambiguous identification and quantitation of free carnitine and acylcarnitines. It is rapid, does not require chromatographic or other isolation procedures, and is immune to analyte losses in sample preparation. Urinary concentrations are reported for adult control subjects and for others with various metabolic disorders.

  11. Modeling and simulation of the main metabolism in Escherichia coli and its several single-gene knockout mutants with experimental verification

    PubMed Central

    2010-01-01

    Background It is quite important to simulate the metabolic changes of a cell in response to the change in culture environment and/or specific gene knockouts particularly for the purpose of application in industry. If this could be done, the cell design can be made without conducting exhaustive experiments, and one can screen out the promising candidates, proceeded by experimental verification of a select few of particular interest. Although several models have so far been proposed, most of them focus on the specific metabolic pathways. It is preferred to model the whole of the main metabolic pathways in Escherichia coli, allowing for the estimation of energy generation and cell synthesis, based on intracellular fluxes and that may be used to characterize phenotypic growth. Results In the present study, we considered the simulation of the main metabolic pathways such as glycolysis, TCA cycle, pentose phosphate (PP) pathway, and the anapleorotic pathways using enzymatic reaction models of E. coli. Once intracellular fluxes were computed by this model, the specific ATP production rate, the specific CO2 production rate, and the specific NADPH production rate could be estimated. The specific ATP production rate thus computed was used for the estimation of the specific growth rate. The CO2 production rate could be used to estimate cell yield, and the specific NADPH production rate could be used to determine the flux of the oxidative PP pathway. The batch and continuous cultivations were simulated where the changing patterns of extracellular and intra-cellular metabolite concentrations were compared with experimental data. Moreover, the effects of the knockout of such pathways as Ppc, Pck and Pyk on the metabolism were simulated. It was shown to be difficult for the cell to grow in Ppc mutant due to low concentration of OAA, while Pck mutant does not necessarily show this phenomenon. The slower growth rate of the Ppc mutant was properly estimated by taking into account the lower specific ATP production rate. In the case of Pyk mutant, the enzyme level regulation was made clear such that Pyk knockout caused PEP concentration to be up-regulated and activated Ppc, which caused the increase in MAL concentration and backed up reduced PYR through Mez, resulting in the phenotypic growth characteristics similar to the wild type. Conclusions It was shown to be useful to simulate the main metabolism of E. coli for understanding metabolic changes inside the cell in response to specific pathway gene knockouts, considering the whole main metabolic pathways. The comparison of the simulation result with the experimental data indicates that the present model could simulate the effect of the specific gene knockouts to the changes in the metabolisms to some extent. PMID:21092096

  12. Effect of several doses of zeolite A on feed intake, energy metabolism and on mineral metabolism in dairy cows around calving.

    PubMed

    Grabherr, H; Spolders, M; Fürll, M; Flachowsky, G

    2009-04-01

    The object of the present study was to determine the influence of different zeolite A doses on dry matter intake (DMI) and mineral metabolism, and to evaluate an optimum dosage for preventing hypocalcaemia. Eighty pregnant dry cows were assigned to four groups (I-IV). They were fed a total mixed ration (TMR) ad libitum. Groups II, III and IV received an average daily dose of 12, 23 and 43 g zeolite A/kg DM for the last 2 weeks prepartum. Individually DMI was recorded daily. Blood and urine samples were taken before, during and after zeolite A supplementation. Serum was analysed for Ca, Mg, P(i), K, non-esterified fatty acids and beta-hydroxybutyrate (BHB). Urine was analysed for Ca, Mg, P(i), K and net acid-base excretion (NABE). After calving, milk yield (fat corrected milk) and milk composition were determined. During zeolite A supplementation, mean DMI of Group IV (7.3 +/- 1.3 kg/cow/day) was significantly lower compared to Groups I-III (10.1, 10.9, 9.5 kg/cow/day). The reduced feed intake of Group IV resulted in significantly increased BHB as well as decreased NABE after calving. Zeolite A supplementation in higher doses (III and IV) had a stabilizing effect on Ca metabolism around calving for older cows, whereas cows in Groups I and II showed a subclinical hypocalcaemia. The mean serum Mg concentration decreased significantly in older cows in Group IV at calving. The mean P(i) concentration in cows of Group IV decreased into ranges of hypophosphataemia already 1 week after beginning of zeolite A feeding. The mean DMI postpartum as well as the milk yield was not affected by zeolite A supplementation. Feeding of 23 g zeolite A/kg DM TMR prepartum proved to be an adequate dosage for reducing subclinical hypocalcaemia frequency without significant effects on feed intake and P(i) concentration in serum. PMID:19320935

  13. Identification of elevated urea as a severe, ubiquitous metabolic defect in the brain of patients with Huntington's disease.

    PubMed

    Patassini, Stefano; Begley, Paul; Reid, Suzanne J; Xu, Jingshu; Church, Stephanie J; Curtis, Maurice; Dragunow, Mike; Waldvogel, Henry J; Unwin, Richard D; Snell, Russell G; Faull, Richard L M; Cooper, Garth J S

    Huntington's disease (HD) is a neurodegenerative disorder wherein the aetiological defect is a mutation in the Huntington's gene (HTT), which alters the structure of the huntingtin protein through the lengthening of a polyglutamine tract and initiates a cascade that ultimately leads to dementia and premature death. However, neurodegeneration typically manifests in HD only in middle age, and processes linking the causative mutation to brain disease are poorly understood. Here, our objective was to elucidate further the processes that cause neurodegeneration in HD, by measuring levels of metabolites in brain regions known to undergo varying degrees of damage. We applied gas-chromatography/mass spectrometry-based metabolomics in a case-control study of eleven brain regions in short post-mortem-delay human tissue from nine well-characterized HD patients and nine controls. Unexpectedly, a single major abnormality was evident in all eleven brain regions studied across the forebrain, midbrain and hindbrain, namely marked elevation of urea, a metabolite formed in the urea cycle by arginase-mediated cleavage of arginine. Urea cycle activity localizes primarily in the liver, where it functions to incorporate protein-derived amine-nitrogen into urea for recycling or urinary excretion. It also occurs in other cell-types, but systemic over-production of urea is not known in HD. These findings are consistent with impaired local urea regulation in brain, by up-regulation of synthesis and/or defective clearance. We hypothesize that defective brain urea metabolism could play a substantive role in the pathogenesis of neurodegeneration, perhaps via defects in osmoregulation or nitrogen metabolism. Brain urea metabolism is therefore a target for generating novel monitoring/imaging strategies and/or therapeutic interventions aimed at ameliorating the impact of HD in patients. PMID:26522227

  14. Metabolic programming of obesity by energy restriction during the perinatal period: different outcomes depending on gender and period, type and severity of restriction

    PubMed Central

    Picó, Catalina; Palou, Mariona; Priego, Teresa; Sánchez, Juana; Palou, Andreu

    2012-01-01

    Epidemiological studies in humans and controlled intervention studies in animals have shown that nutritional programming in early periods of life is a phenomenon that affects metabolic and physiological functions throughout life. The phenotypes of health or disease are hence the result of the interaction between genetic and environmental factors, starting right from conception. In this sense, gestation and lactation are disclosed as critical periods. Continuous food restriction during these stages may lead to permanent adaptations with lasting effects on the metabolism of the offspring and may influence the propensity to develop different chronic diseases associated with obesity. However, the different outcomes of these adaptations on later health may depend on factors such as the type, duration, period, and severity of the exposure to energy restriction conditions, and they are, in part, gender specific. A better understanding of the factors and mechanisms involved in metabolic programming, and their effects, may contribute significantly to the prevention of obesity, which is considered to be one of the major health concerns of our time. Here, the different outcomes of maternal food restriction during gestation and lactation in the metabolic health of offspring, as well as potential mechanisms underlying these effects are reviewed. PMID:23189059

  15. Genealogy Profiling through Strain Improvement by Using Metabolic Network Analysis: Metabolic Flux Genealogy of Several Generations of Lysine-Producing Corynebacteria

    PubMed Central

    Wittmann, Christoph; Heinzle, Elmar

    2002-01-01

    A comprehensive approach of metabolite balancing, 13C tracer studies, gas chromatography-mass spectrometry, matrix-assisted laser desorption ionization-time of flight mass spectrometry, and isotopomer modeling was applied for comparative metabolic network analysis of a genealogy of five successive generations of lysine-producing Corynebacterium glutamicum. The five strains examined (C. glutamicum ATCC 13032, 13287, 21253, 21526, and 21543) were previously obtained by random mutagenesis and selection. Throughout the genealogy, the lysine yield in batch cultures increased markedly from 1.2 to 24.9% relative to the glucose uptake flux. Strain optimization was accompanied by significant changes in intracellular flux distributions. The relative pentose phosphate pathway (PPP) flux successively increased, clearly corresponding to the product yield. Moreover, the anaplerotic net flux increased almost twofold as a consequence of concerted regulation of C3 carboxylation and C4 decarboxylation fluxes to cover the increased demand for lysine formation; thus, the overall increase was a consequence of concerted regulation of C3 carboxylation and C4 decarboxylation fluxes. The relative flux through isocitrate dehydrogenase dropped from 82.7% in the wild type to 59.9% in the lysine-producing mutants. In contrast to the NADPH demand, which increased from 109 to 172% due to the increasing lysine yield, the overall NADPH supply remained constant between 185 and 196%, resulting in a decrease in the apparent NADPH excess through strain optimization. Extrapolated to industrial lysine producers, the NADPH supply might become a limiting factor. The relative contributions of PPP and the tricarboxylic acid cycle to NADPH generation changed markedly, indicating that C. glutamicum is able to maintain a constant supply of NADPH under completely different flux conditions. Statistical analysis by a Monte Carlo approach revealed high precision for the estimated fluxes, underlining the fact that the observed differences were clearly strain specific. PMID:12450803

  16. Assimilation, Accumulation, and Metabolism of Dinophysistoxins (DTXs) and Pectenotoxins (PTXs) in the Several Tissues of Japanese Scallop Patinopecten yessoensis

    PubMed Central

    Matsushima, Ryoji; Uchida, Hajime; Nagai, Satoshi; Watanabe, Ryuichi; Kamio, Michiya; Nagai, Hiroshi; Kaneniwa, Masaki; Suzuki, Toshiyuki

    2015-01-01

    Japanese scallops, Patinopecten yessoensis, were fed with the toxic dinoflagellate Dinophysis fortii to elucidate the relative magnitude of assimilation, accumulation, and metabolism of diarrhetic shellfish toxins (DSTs) and pectenotoxins (PTXs). Three individual scallops were separately exposed to cultured D. fortii for four days. The average cell number of D. fortii assimilated by each individual scallop was 7.7 × 105. Dinophysistoxin-1 (DTX1), pectenotoxin-2 (PTX2) and their metabolites were analyzed by liquid chromatography tandem mass spectrometry (LC/MS/MS) and the toxin content in individual tissues (digestive gland, adductor muscle, gill, gonad, mantle, and the others), feces and the seawater medium were quantified. Toxins were almost exclusively accumulated in the digestive gland with only low levels being detected in the gills, mantles, gonads, and adductor muscles. DTX1 and PTX2 were the dominant toxins in the D. fortii cells fed to the scallops, whereas the dominant toxins detected in the digestive gland of scallops were PTX6 and esterified acyl-O-DTX1 (DTX3). In other tissues PTX2 was the dominant toxin observed. The ratio of accumulated to assimilated toxins was 21%–39% and 7%–23% for PTXs and DTXs respectively. Approximately 54%–75% of PTX2 and 52%–70% of DTX1 assimilated by the scallops was directly excreted into the seawater mainly without metabolic transformation. PMID:26633503

  17. Lactic acidosis and diastolic hypotension after intermittent albuterol nebulization in a pediatric patient

    PubMed Central

    Saadia, Tehila A.; George, Mathew; Lee, Haesoon

    2015-01-01

    We describe a case of 13-year-old female with intermittent asthma who developed lactic acidosis and diastolic hypotension after receiving intermittent albuterol nebulizer treatment. She presented to the emergency department (ED) with sudden onset of shortness of breath and chest pain. She received two albuterol nebulizer treatments at home without symptomatic relief. She was treated in the ED with intermittent albuterol nebulization for a total of 22.5 mg over the next 5 hours. A decrease in diastolic blood pressure from 60 mmHg to 40 mmHg was noted after the treatment. Blood lactate level was 5.9 mmol/L. She recovered from it and was discharged to home but she had recurrence of shortness of breath and presented to the ED two days later. She was treated with albuterol nebulization for a total of 17.5 mg over the next two and half hours and developed diastolic hypotension again, as low as 30 mm Hg. After discontinuation of albuterol nebulization, her BP normalized. Cardiopulmonary and metabolic side effects of continuous albuterol therapy have been reported in the recent medical literature. Our patient, however, developed these adverse effects on intermittent albuterol nebulizer treatment. It is important for the pediatrician to recognize the adverse effects of β2-agonist therapy to avoid carrying out extensive workup for hypotension and hyperlactatemia prolonging hospital stay. PMID:26744665

  18. A combined high CYP2D6-CYP2C19 metabolic capacity is associated with the severity of suicide attempt as measured by objective circumstances.

    PubMed

    Peñas-Lledó, E; Guillaume, S; Naranjo, M E G; Delgado, A; Jaussent, I; Blasco-Fontecilla, H; Courtet, P; LLerena, A

    2015-04-01

    This study examined, for the first time, whether a high CYP2D6-CYP2C19 metabolic capacity combination increases the likelihood of suicidal intent severity in a large study cohort. Survivors of a suicide attempt (n=587; 86.8% women) were genotyped for CYP2C19 (*2, *17) and CYP2D6 (*3, *4, *4xN, *5, *6, *10, wtxN) genetic variation and evaluated with the Beck Suicide Intent Scale (SIS). Patients with a high CYP2D6-CYP2C19 metabolic capacity showed an increased risk for a severe suicide attempt (P<0.01) as measured by the SIS-objective circumstance subscale (odds ratio (OR)=1.37; 95% confidence interval (CI)=1.05-1.78; P=0.02) after adjusting for confounders (gender, age, level of studies, marital status, mental disorders, tobacco use, family history of suicide, personal history of attempts and violence of the attempt). Importantly, the risk was greater in those without a family history of suicide (OR=1.82; CI=1.19-2.77; P=0.002). Further research is warranted to evaluate whether the observed relationship is mediated by the role of CYP2D6 and CYP2C19 involvement in the endogenous physiology or drug metabolism or both. PMID:25113522

  19. X-linked adrenoleukodystrophy: very long-chain fatty acid metabolism is severely impaired in monocytes but not in lymphocytes.

    PubMed

    Weber, Franziska D; Wiesinger, Christoph; Forss-Petter, Sonja; Regelsberger, Günther; Einwich, Angelika; Weber, Willi H A; Köhler, Wolfgang; Stockinger, Hannes; Berger, Johannes

    2014-05-15

    X-linked adrenoleukodystrophy (X-ALD) is a fatal neurodegenerative disease caused by mutations in the ABCD1 gene, encoding a member of the peroxisomal ABC transporter family. The ABCD1 protein transports CoA-activated very long-chain fatty acids (VLCFAs) into peroxisomes for degradation via β-oxidation. In the severest form, X-ALD patients suffer from inflammatory demyelination of the brain. As the extent of the metabolic defect in the main immune cells is unknown, we explored their phenotypes concerning mRNA expression pattern of the three peroxisomal ABC transporters, VLCFA accumulation and peroxisomal β-oxidation. In controls, ABCD1 expression was high in monocytes, intermediate in B cells and low in T cells; ABCD2 expression was extremely low in monocytes, intermediate in B cells and highest in T cells; ABCD3 mRNA was equally distributed. In X-ALD patients, the expression patterns remained unaltered; accordingly, monocytes, which lack compensatory VLCFA transport by ABCD2, displayed the severest biochemical phenotype with a 6-fold accumulation of C26:0 and a striking 70% reduction in peroxisomal β-oxidation activity. In contrast, VLCFA metabolism was close to control values in B cells and T cells, supporting the hypothesis that sufficient ABCD2 is present to compensate for ABCD1 deficiency. Thus, the vulnerability of the main immune cell types is highly variable in X-ALD. Based on these results, we propose that in X-ALD the halt of inflammation after allogeneic hematopoietic stem cell transplantation relies particularly on the replacement of the monocyte lineage. Additionally, these findings support the concept that ABCD2 is a target for pharmacological induction as an alternative therapeutic strategy. PMID:24363066

  20. 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

  1. Perinatal risk factors for severe injury in neonates treated with whole-body hypothermia for encephalopathy

    PubMed Central

    Wayock, Christopher P.; Meserole, Rachel L.; Saria, Suchi; Jennings, Jacky M.; Huisman, Thierry A. G. M.; Northington, Frances J.; Graham, Ernest M.

    2016-01-01

    Objective Our objective was to identify perinatal risk factors that are available within 1 hour of birth that are associated with severe brain injury after hypothermia treatment for suspected hypoxic-ischemic encephalopathy. Study Design One hundred nine neonates at ≥35 weeks' gestation who were admitted from January 2007 to September 2012 with suspected hypoxic-ischemic encephalopathy were treated with whole-body hypothermia; 98 of them (90%) underwent brain magnetic resonance imaging (MRI) at 7-10 days of life. Eight neonates died before brain imaging. Neonates who had severe brain injury, which was defined as death or abnormal MRI results (cases), were compared with surviving neonates with normal MRI (control subjects). Logistic regression models were used to identify risk factors that were predictive of severe injury. Results Cases and control subjects did not differ with regard to gestational age, birthweight, mode of delivery, or diagnosis of non-reassuring fetal heart rate before delivery. Cases were significantly (P ≤ .05) more likely to have had an abruption, a cord and neonatal arterial gas level that showed metabolic acidosis, lower platelet counts, lower glucose level, longer time to spontaneous respirations, intubation, chest compressions in the delivery room, and seizures. In multivariable logistic regression, lower initial neonatal arterial pH (P = .004), spontaneous respiration at >30 minutes of life (P = .002), and absence of exposure to oxytocin (P = .033) were associated independently with severe injury with 74.3% sensitivity and 74.4% specificity. Conclusion Worsening metabolic acidosis at birth, longer time to spontaneous respirations, and lack of exposure to oxytocin correlated with severe brain injury in neonates who were treated with whole-body hypothermia. These risk factors may help quickly identify neonatal candidates for time-sensitive investigational therapies for brain neuroprotection. PMID:24657795

  2. Severe Sepsis in Severely Malnourished Young Bangladeshi Children with Pneumonia: A Retrospective Case Control Study

    PubMed Central

    Chisti, Mohammod Jobayer; Salam, Mohammed Abdus; Bardhan, Pradip Kumar; Faruque, Abu S. G.; Shahid, Abu S. M. S. B.; Shahunja, K. M.; Das, Sumon Kumar; Hossain, Md Iqbal; Ahmed, Tahmeed

    2015-01-01

    Background In developing countries, there is no published report on predicting factors of severe sepsis in severely acute malnourished (SAM) children having pneumonia and impact of fluid resuscitation in such children. Thus, we aimed to identify predicting factors for severe sepsis and assess the outcome of fluid resuscitation of such children. Methods In this retrospective case-control study SAM children aged 0–59 months, admitted to the Intensive Care Unit (ICU) of the Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh from April 2011 through July 2012 with history of cough or difficult breathing and radiologic pneumonia, who were assessed for severe sepsis at admission constituted the study population. We compared the pneumonic SAM children with severe sepsis (cases = 50) with those without severe sepsis (controls = 354). Severe sepsis was defined with objective clinical criteria and managed with fluid resuscitation, in addition to antibiotic and other supportive therapy, following the standard hospital guideline, which is very similar to the WHO guideline. Results The case-fatality-rate was significantly higher among the cases than the controls (40% vs. 4%; p<0.001). In logistic regression analysis after adjusting for potential confounders, lack of BCG vaccination, drowsiness, abdominal distension, acute kidney injury, and metabolic acidosis at admission remained as independent predicting factors for severe sepsis in pneumonic SAM children (p<0.05 for all comparisons). Conclusion and Significance We noted a much higher case fatality among under-five SAM children with pneumonia and severe sepsis who required fluid resuscitation in addition to standard antibiotic and other supportive therapy compared to those without severe sepsis. Independent risk factors and outcome of the management of severe sepsis in our study children highlight the importance for defining optimal fluid resuscitation therapy aiming at reducing the case fatality in such children. PMID:26440279

  3. [Nail changes associated with distal renal tubular acidosis in pediatric patients].

    PubMed

    Cardona-Hernndez, Miguel ngel; Fierro-Arias, Leonel; Jurado-Santa Cruz, Fermn; Gonzlez-Gonzlez, Maribet; Rivera-Martnez, Mnica Olivia; De la Torre-Garca, Mnica Elizabeth; Cabrera-Prez, Ana Luisa

    2015-01-01

    Renal tubular acidosis is a disease prevalent in childhood, responsible for a decrease in growth due inadequate acid-base levels regulation. It is well known that systemic conditions can generate or accompany nail changes by different pathophysiologic mechanisms, however no one has ever found or reported any association of onychopathy with renal tubular acidosis so far. That is why we would like to share our experience on this topic. PMID:26526475

  4. Effects of nitric oxide donors on cybrids harbouring the mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) A3243G mitochondrial DNA mutation

    PubMed Central

    2005-01-01

    Reactive nitrogen and oxygen species (O2•−, H2O2, NO• and ONOO−) have been strongly implicated in the pathophysiology of neurodegenerative and mitochondrial diseases. In the present study, we examined the effects of nitrosative and/or nitrative stress generated by DETA-NO {(Z)-1-[2-aminoethyl-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate}, SIN-1 (3-morpholinosydnonimine hydrochloride) and SNP (sodium nitroprusside) on U87MG glioblastoma cybrids carrying wt (wild-type) and mutant [A3243G (Ala3243→Gly)] mtDNA (mitochondrial genome) from a patient suffering from MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes). The mutant cybrids had reduced activity of cytochrome c oxidase, significantly lower ATP level and decreased mitochondrial membrane potential. However, endogenous levels of reactive oxygen species were very similar in all cybrids regardless of whether they carried the mtDNA defects or not. Furthermore, the cybrids were insensitive to the nitrosative and/or nitrative stress produced by either DETA-NO or SIN-1 alone. Cytotoxicity, however, was observed in response to SNP treatment and a combination of SIN-1 and glucose-deprivation. The mutant cybrids were significantly more sensitive to these insults compared with the wt controls. Ultrastructural examination of dying cells revealed several characteristic features of autophagic cell death. We concluded that nitrosative and/or nitrative stress alone were insufficient to trigger cytotoxicity in these cells, but cell death was observed with a combination of metabolic and nitrative stress. The vulnerability of the cybrids to these types of injury correlated with the cellular energy status, which were compromised by the MELAS mutation. PMID:15969653

  5. [Non-fatal hyperkalemia in lactic acidosis due to metformin overdose. Report of one case].

    PubMed

    Díaz, Rienzi; Vega, Jorge; Goecke, Helmuth

    2015-03-01

    We report a 74-year-old man with diabetes mellitus type 2 and hypertension, who recently underwent coronary bypass surgery due to severe triple vessel disease receiving cardiological and combined antidiabetic therapy, including metformin 4 g/day. He was admitted with abdominal pain, nausea, vomiting, diarrhea and loss of consciousness. At admission, he was disoriented and agitated with signs of poor perfusion. His blood pressure was 80/70 mmHg, pulse rate 40 beats/min, respiratory rate 20-breaths/min, and axillary temperature 35 °C. Biochemical profile revealed an extreme hyperkalemia of 15.4 mEq/L (double checked), elevated creatinine, uremia and brain natriuretic peptide; hypoglycemia (blood glucose 68 mg/dl) and normal C Reactive Protein. Arterial blood gases revealed severe lactic acidemia. The electrocardiogram showed sinus bradycardia, simple AV block, widened QRS with prominent T wave and prolonged QT. He was admitted to the Intensive Care Unit (ICU) with the suspicion of lactic acidosis associated with metformin, receiving fluid management, intravenous hypertonic glucose plus insulin and sodium bicarbonate, mechanical ventilation, vasopressor therapy, a temporary pacemaker lead, in addition to continuous venovenous hemodiafiltration. Two days later, the patient experienced a significant clinical improvement with normalization of the acid-base status, plasma lactate and potassium levels. On day 9, diuresis was recovered, creatinine and uremia returned to normal levels and the patient was discharged from the ICU. PMID:26005828

  6. Clinical review: Renal tubular acidosis – a physicochemical approach

    PubMed Central

    Ring, Troels; Frische, Sebastian; Nielsen, Søren

    2005-01-01

    The Canadian physiologist PA Stewart advanced the theory that the proton concentration, and hence pH, in any compartment is dependent on the charges of fully ionized and partly ionized species, and on the prevailing CO2 tension, all of which he dubbed independent variables. Because the kidneys regulate the concentrations of the most important fully ionized species ([K+], [Na+], and [Cl-]) but neither CO2 nor weak acids, the implication is that it should be possible to ascertain the renal contribution to acid–base homeostasis based on the excretion of these ions. One further corollary of Stewart's theory is that, because pH is solely dependent on the named independent variables, transport of protons to and from a compartment by itself will not influence pH. This is apparently in great contrast to models of proton pumps and bicarbonate transporters currently being examined in great molecular detail. Failure of these pumps and cotransporters is at the root of disorders called renal tubular acidoses. The unquestionable relation between malfunction of proton transporters and renal tubular acidosis represents a problem for Stewart theory. This review shows that the dilemma for Stewart theory is only apparent because transport of acid–base equivalents is accompanied by electrolytes. We suggest that Stewart theory may lead to new questions that must be investigated experimentally. Also, recent evidence from physiology that pH may not regulate acid–base transport is in accordance with the concepts presented by Stewart. PMID:16356241

  7. Lack of cytosolic glutamine synthetase1;2 in vascular tissues of axillary buds causes severe reduction in their outgrowth and disorder of metabolic balance in rice seedlings.

    PubMed

    Ohashi, Miwa; Ishiyama, Keiki; Kusano, Miyako; Fukushima, Atsushi; Kojima, Soichi; Hanada, Atsushi; Kanno, Keiichi; Hayakawa, Toshihiko; Seto, Yoshiya; Kyozuka, Junko; Yamaguchi, Shinjiro; Yamaya, Tomoyuki

    2015-01-01

    The development and elongation of active tillers in rice was severely reduced by a lack of cytosolic glutamine synthetase1;2 (GS1;2), and, to a lesser extent, lack of NADH-glutamate synthase1 in knockout mutants. In situ hybridization using the basal part of wild-type seedlings clearly showed that expression of OsGS1;2 was detected in the phloem companion cells of the nodal vascular anastomoses and large vascular bundles of axillary buds. Accumulation of lignin, visualized using phloroglucin HCl, was also observed in these tissues. The lack of GS1;2 resulted in reduced accumulation of lignin. Re-introduction into the mutants of OsGS1;2 cDNA under the control of its own promoter successfully restored the outgrowth of tillers and lignin deposition to wild-type levels. Transcriptomic analysis using a 5 mm basal region of rice shoots showed that the GS1;2 mutants accumulated reduced amounts of mRNAs for carbon and nitrogen metabolism, including C1 unit transfer in lignin synthesis. Although a high content of strigolactone in rice roots is known to reduce active tiller number, the reduction of outgrowth of axillary buds observed in the GS1;2 mutants was independent of the level of strigolactone. Thus metabolic disorder caused by the lack of GS1;2 resulted in a severe reduction in the outgrowth of axillary buds and lignin deposition. PMID:25429996

  8. Development of Metabolic Indicators of Burn Injury: Very Low Density Lipoprotein (VLDL) and Acetoacetate Are Highly Correlated to Severity of Burn Injury in Rats

    PubMed Central

    Izamis, Maria-Louisa; Uygun, Korkut; Sharma, Nripen S.; Uygun, Basak; Yarmush, Martin L.; Berthiaume, Francois

    2012-01-01

    Hypermetabolism is a significant sequela to severe trauma such as burns, as well as critical illnesses such as cancer. It persists in parallel to, or beyond, the original pathology for many months as an often-fatal comorbidity. Currently, diagnosis is based solely on clinical observations of increased energy expenditure, severe muscle wasting and progressive organ dysfunction. In order to identify the minimum number of necessary variables, and to develop a rat model of burn injury-induced hypermetabolism, we utilized data mining approaches to identify the metabolic variables that strongly correlate to the severity of injury. A clustering-based algorithm was introduced into a regression model of the extent of burn injury. As a result, a neural network model which employs VLDL and acetoacetate levels was demonstrated to predict the extent of burn injury with 88% accuracy in the rat model. The physiological importance of the identified variables in the context of hypermetabolism, and necessary steps in extension of this preliminary model to a clinically utilizable index of severity of burn injury are outlined. PMID:24957642

  9. Reversible lactic acidosis in a newborn with thiamine transporter-2 deficiency.

    PubMed

    Pérez-Dueñas, Belén; Serrano, Mercedes; Rebollo, Mónica; Muchart, Jordi; Gargallo, Eva; Dupuits, Celine; Artuch, Rafael

    2013-05-01

    Thiamine transporter-2 deficiency is a recessive disease caused by mutations in the SLC19A3 gene. Patients manifest acute episodes of encephalopathy; symmetric lesions in the cortex, basal ganglia, thalami or periaqueductal gray matter, and a dramatic response to biotin or thiamine. We report a 30-day-old patient with mutations in the SLC19A3 gene who presented with acute encephalopathy and increased level of lactate in the blood (8.6 mmol/L) and cerebrospinal fluid (7.12 mmol/L), a high excretion of α-ketoglutarate in the urine, and increased concentrations of the branched-chain amino acids leucine and isoleucine in the plasma. MRI detected bilateral and symmetric cortico-subcortical lesions involving the perirolandic area, bilateral putamina, and medial thalami. Some lesions showed low apparent diffusion coefficient values suggesting an acute evolution; others had high values likely to be subacute or chronic, most likely related to the perinatal period. After treatment with thiamine and biotin, irritability and opisthotonus disappeared, and the patient recovered consciousness. Biochemical disturbances also disappeared within 48 hours. After discontinuing biotin, the patient remained stable for 6 months on thiamine supplementation (20 mg/kg/day). The examination revealed subtle signs of neurologic sequelae, and MRI showed necrotic changes and volume loss in some affected areas. Our observations suggest that patients with thiamine transporter 2 deficiency may be vulnerable to metabolic decompensation during the perinatal period, when energy demands are high. Thiamine defects should be excluded in newborns and infants with lactic acidosis because prognosis largely depends on the time from diagnosis to thiamine supplementation. PMID:23589815

  10. A Promoter Polymorphism of the Vitamin D Metabolism Gene Cyp24a1 is Associated with Severe Atopic Dermatitis in Adults.

    PubMed

    Hallau, Jana; Hamann, Lutz; Schumann, Ralf R; Worm, Margitta; Heine, Guido

    2016-03-01

    Atopic dermatitis (AD) is a chronic inflammatory skin disease in which genetic and environmental factors result in impaired epidermal barrier functioning and an altered immune response. Vitamin D influences these 2 pathomechanisms, and beneficial results have been suggested in AD. The aim of this study was to investigate the potential roles of the 2 essential vitamin D metabolizing enzymes. The frequencies of 6 common polymorphisms in the genes encoding the vitamin D synthesizing enzyme Cyp27b1 or the inactivating enzyme Cyp24a1 were assessed in 281 patients with AD and 278 healthy donors in a case-control setting. The Cyp24a1 rs2248359-major C allele was significantly over-represented in patients with AD compared with controls, which was more pronounced in patients with severe AD. In addition, haplotypes of the Cyp24a1 and Cyp27b1 genes were associated with AD. These data support that vitamin D mediates beneficial functions in AD and suggest that future studies on the impact of vitamin D on AD should consider the individual genotypes of the vitamin D metabolizing enzymes. PMID:26315479

  11. RMND1 deficiency associated with neonatal lactic acidosis, infantile onset renal failure, deafness, and multiorgan involvement.

    PubMed

    Janer, Alexandre; van Karnebeek, Clara Dm; Sasarman, Florin; Antonicka, Hana; Al Ghamdi, Malak; Shyr, Casper; Dunbar, Mary; Stockler-Ispiroglu, Sylvia; Ross, Colin J; Vallance, Hilary; Dionne, Janis; Wasserman, Wyeth W; Shoubridge, Eric A

    2015-10-01

    RMND1 is an integral inner membrane mitochondrial protein that assembles into a large 240?kDa complex to support translation of the 13 polypeptides encoded on mtDNA, all of which are essential subunits of the oxidative phosphorylation (OXPHOS) complexes. Variants in RMND1 produce global defects in mitochondrial translation and were first reported in patients with severe neurological phenotypes leading to mortality in the first months of life. Using whole-exome sequencing, we identified compound heterozygous RMND1 variants in a 4-year-old patient with congenital lactic acidosis, severe myopathy, hearing loss, renal failure, and dysautonomia. The levels of mitochondrial ribosome proteins were reduced in patient fibroblasts, causing a translation defect, which was rescued by expression of the wild-type cDNA. RMND1 was almost undetectable by immunoblot analysis in patient muscle and fibroblasts. BN-PAGE analysis showed a severe combined OXPHOS assembly defect that was more prominent in patient muscle than in fibroblasts. Immunofluorescence experiments showed that RMND1 localizes to discrete foci in the mitochondrial network, juxtaposed to RNA granules where the primary mitochondrial transcripts are processed. RMND1 foci were not detected in patient fibroblasts. We hypothesize that RMND1 acts to anchor or stabilize the mitochondrial ribosome near the sites where the mRNAs are matured, spatially coupling post-transcriptional handling mRNAs with their translation, and that loss of function variants in RMND1 are associated with a unique constellation of clinical phenotypes that vary with the severity of the mitochondrial translation defect. PMID:25604853

  12. Ethanol metabolism, cirrhosis and alcoholism.

    PubMed

    Lieber, C S

    1997-01-01

    Alcohol-induced tissue damage results from associated nutritional deficiencies as well as some direct toxic effects, which have now been linked to the metabolism of ethanol. The main pathway involves liver alcohol dehydrogenase which catalyzes the oxidation of ethanol to acetaldehyde, with a shift to a more reduced state, and results in metabolic disturbances, such as hyperlactacidemia, acidosis, hyperglycemia, hyperuricemia and fatty liver. More severe toxic manifestations are produced by an accessory pathway, the microsomal ethanol oxidizing system involving an ethanol-inducible cytochrome P450 (2E1). After chronic ethanol consumption, there is a 4- to 10-fold induction of 2E1, associated not only with increased acetaldehyde generation but also with production of oxygen radicals that promote lipid peroxidation. Most importantly, 2E1 activates many xenobiotics to toxic metabolites. These include solvents commonly used in industry, anaesthetic agents, medications such as isoniazid, over the counter analgesics (acetaminophen), illicit drugs (cocaine), chemical carcinogens, and even vitamin A and its precursor beta-carotene. Furthermore, enhanced microsomal degradation of retinoids (together with increased hepatic mobilization) promotes their depletion and associated pathology. Induction of 2E1 also yields increased acetaldehyde generation, with formation of protein adducts, resulting in antibody production, enzyme inactivation, decreased DNA repair, impaired utilization of oxygen, glutathione depletion, free radical-mediated toxicity, lipid peroxidation, and increased collagen synthesis. New therapies include adenosyl-L-methionine which, in baboons, replenishes glutathione, and attenuates mitochondrial lesions. In addition, polyenylphosphatidylcholine (PPC) fully prevents ethanol-induced septal fibrosis and cirrhosis, opposes ethanol-induced hepatic phospholipid depletion, decreased phosphatidylethanolamine methyltransferase activity and activation of hepatic lipocytes, whereas its dilinoleoyl species increases collagenase activity. Current clinical trials with PPC are targeted on susceptible populations, namely heavy drinkers at precirrhotic stages. PMID:9028626

  13. Does high-dose metformin cause lactic acidosis in type 2 diabetic patients after CABG surgery? A double blind randomized clinical trial

    PubMed Central

    Baradari, Afshin Gholipour; Habibi, Mohammad Reza; Khezri, Hadi Darvishi; Aarabi, Mohsen; Khademloo, Mohammad; Jalali, Zahra; Ghafari, Rahman

    2011-01-01

    Metformin is a dimethyl biguanide oral anti-hyperglycemic agent. Lactic acidosis due to metformin is a fatal metabolic condition that limits its use in patients in poor clinical condition, consequently reducing the number of patients who benefit from this medication. In a double blind randomized clinical trial, we investigated 200 type 2 diabetic patients after coronary artery bypass surgery in the open heart ICU of the Mazandaran Heart Center, and randomly assigned them to equal intervention and control groups. The intervention group received regular insulin infusion along with 2 metformin 500 mg tablets every twelve hours, while the control group received only intravenous insulin with 2 placebo tablets every twelve hours. Lactate level, pH, base excess, blood glucose and serum creatinine were measured over five 12 h periods, with data averaged for each period. The primary outcome in this study was high lactate levels. Comparison between the 2 groups was made by independent Student’s t-test. To compare changes in multiple measures in each group and analysis of group interaction, a repeated measurement ANOVA test was used. There was no significant difference between the 2 groups regarding pH, base excess, or bicarbonate intake (P>0.05). No patient showed lactic acidosis in either group. Lactate levels were 23.0 vs 23.4 in the insulin-metformin and insulin only groups when the study was started, respectively. At the end of the study, those levels were 18.7 vs 18.9, respectively. In addition, the ANOVA repeated measurement test did not show a significant difference in terms of changes in the amount of lactate level between the 2 groups during the five measurement tests of the study period (P>0.05). High-dose metformin (1,000 mg twice daily with insulin) does not cause lactic acidosis in type 2 diabetic patients after coronary artery bypass surgery. PMID:21977308

  14. Impact of buffering hypercapnic acidosis on cell wounding in ventilator-injured rat lungs

    PubMed Central

    Caples, Sean M.; Rasmussen, Deborah L.; Lee, Won Y.; Wolfert, Marla Z.; Hubmayr, Rolf D.

    2009-01-01

    We measured the effects of raising perfusate pH on ventilator-induced cell wounding and repair in ex vivo mechanically ventilated hypercapnic rat lungs. Lungs were randomized to one of three perfusate groups: 1) unbuffered hypercapnic acidosis, 2) bicarbonate-buffered hypercapnia, or 3) tris-hydroxymethyl aminomethane (THAM)-buffered hypercapnia. The membrane-impermeant label propidium iodide was added to the perfusate either during or after injurious ventilation providing a means to subsequently identify transiently wounded and permanently wounded cells in optical sections of subpleural alveoli. Normalizing perfusate pH in hypercapnic preparations attenuated ventilator-induced cell injury, particularly in THAM-buffered preparations. This was observed despite greater amounts of edema and impaired lung mechanics compared with other treatment groups. Protective effects of buffering of hypercapnic acidosis on injury and repair were subsequently confirmed in a cell scratch model. We conclude that buffering of hypercapnic acidosis attenuates plasma cell injury induced by mechanical hyperinflation. PMID:18996901

  15. Relationship between synovial fluid biomarkers of articular cartilage metabolism and the patient's perspective of outcome depends on the severity of articular cartilage damage following ACL trauma.

    PubMed

    Wasilko, Scott M; Tourville, Timothy W; DeSarno, Michael J; Slauterbeck, James R; Johnson, Robert J; Struglics, André; Beynnon, Bruce D

    2016-05-01

    Anterior cruciate ligament (ACL) trauma often occurs in combination with injury to the articular cartilage of the knee, this can result in earlier radiographic evidence of post traumatic osteoarthritis (OA) of the knee compared to the contralateral, ACL intact knee; however, the biomechanical and biological mechanisms associated with the onset and progression of this disease are not understood. We sought to gain insight into the mechanisms by determining the relationship between articular cartilage injury associated with ACL trauma and the expression of synovial fluid biomarkers of articular cartilage metabolism, and to evaluate the relationship between these biomarkers and the patient's perspective of the outcomes. Synovial fluid samples were acquired from 39 ACL injured subjects at an average of 10 weeks after injury, and 32 control subjects with normal knees (documented with clinical exam and MRI assessment). Subjects in the ACL-injured group were classified as low-risk for future OA if they displayed an International Cartilage Repair Society (ICRS) Grade 2 articular cartilage lesion or less and high-risk for future OA if they had an ICRS Grade 3A articular cartilage lesion. The patient's perspective of the injury was evaluated with the Knee Injury and Osteoarthritis Outcomes Score (KOOS). There were no significant differences in mean concentrations of the markers of type II collagen metabolism (CPII, C2C, and C1,2C) or the aggrecan breakdown Alanine-Arginine-Glycine-Serine (ARGS) -fragment between control subjects and the subjects in the low- and high-risk groups (p-value range: 0.80-0.43). Associations between ARGS-aggrecan concentration and KOOS subscales of symptoms and pain were significantly different between the low- and high-risk groups (p = 0.03 and p = 0.01, respectively). Likewise, there was strong evidence in support of an association between the markers of type II collagen metabolism (C1,2C and CPII concentrations) and the KOOS subscale of pain between the low- and high-risk groups (p = 0.051 and 0.077, correspondingly). In ACL injured subjects with concomitant Grade 3A articular cartilage injuries, concentrations of synovial fluid ARGS-aggrecan were directly associated with improvements in KOOS symptoms and pain. These findings suggest the possible involvement of ARGS-aggrecan in a localized tissue repair response involving an increase in aggrecan turnover following severe knee trauma. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:820-827, 2016. PMID:26497486

  16. Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension

    PubMed Central

    Christou, Helen; Reslan, Ossama M.; Mam, Virak; Tanbe, Alain F.; Vitali, Sally H.; Touma, Marlin; Arons, Elena; Mitsialis, S. Alex; Kourembanas, Stella

    2012-01-01

    Pulmonary hypertension (PH) is characterized by pulmonary arteriolar remodeling with excessive pulmonary vascular smooth muscle cell (VSMC) proliferation. This results in decreased responsiveness of pulmonary circulation to vasodilator therapies. We have shown that extracellular acidosis inhibits VSMC proliferation and migration in vitro. Here we tested whether induction of nonhypercapnic acidosis in vivo ameliorates PH and the underlying pulmonary vascular remodeling and dysfunction. Adult male Sprague-Dawley rats were exposed to hypoxia (8.5% O2) for 2 wk, or injected subcutaneously with monocrotaline (MCT, 60 mg/kg) to develop PH. Acidosis was induced with NH4Cl (1.5%) in the drinking water 5 days prior to and during the 2 wk of hypoxic exposure (prevention protocol), or after MCT injection from day 21 to 28 (reversal protocol). Right ventricular systolic pressure (RVSP) and Fulton's index were measured, and pulmonary arteriolar remodeling was analyzed. Pulmonary and mesenteric artery contraction to phenylephrine (Phe) and high KCl, and relaxation to acetylcholine (ACh) and sodium nitroprusside (SNP) were examined ex vivo. Hypoxic and MCT-treated rats demonstrated increased RVSP, Fulton's index, and pulmonary arteriolar thickening. In pulmonary arteries of hypoxic and MCT rats there was reduced contraction to Phe and KCl and reduced vasodilation to ACh and SNP. Acidosis prevented hypoxia-induced PH, reversed MCT-induced PH, and resulted in reduction in all indexes of PH including RVSP, Fulton's index, and pulmonary arteriolar remodeling. Pulmonary artery contraction to Phe and KCl was preserved or improved, and relaxation to ACh and SNP was enhanced in NH4Cl-treated PH animals. Acidosis alone did not affect the hemodynamics or pulmonary vascular function. Phe and KCl contraction and ACh and SNP relaxation were not different in mesenteric arteries of all groups. Thus nonhypercapnic acidosis ameliorates experimental PH, attenuates pulmonary arteriolar thickening, and enhances pulmonary vascular responsiveness to vasoconstrictor and vasodilator stimuli. Together with our finding that acidosis decreases VSMC proliferation, the results are consistent with the possibility that nonhypercapnic acidosis promotes differentiation of pulmonary VSMCs to a more contractile phenotype, which may enhance the effectiveness of vasodilator therapies in PH. PMID:22287610

  17. Lactic acidosis induced by metformin in a chronic hemodialysis patient with diabetes mellitus type 2.

    PubMed

    Altun, Eda; Kaya, Bülent; Paydaş, Saime; Sarıakçalı, Barış; Karayaylalı, Ibrahim

    2014-04-01

    Metformin is a biguanide group oral antidiabetic drug used for the treatment of type 2 diabetes mellitus. Nausea, vomiting, diarrhea, abdominal pain, and anorexia are the most common adverse effects encountered during treatment. Lactic acidosis is a serious side effect seen with metformin use, and while the incidence of lactic acidosis is similar to other oral antidiabetics, metformin is not recommended to patients with certain risk factors, such as cardiovascular, pulmonary, and renal and liver failure. We describe a chronic hemodialysis patient treated with metformin, presenting to the nephrology department with altered mental status. PMID:24299454

  18. Proximal renal tubular acidosis: a not so rare disorder of multiple etiologies

    PubMed Central

    Haque, Syed K.; Ariceta, Gema; Batlle, Daniel

    2012-01-01

    Proximal renal tubular acidosis (RTA) (Type II RTA) is characterized by a defect in the ability to reabsorb HCO3 in the proximal tubule. This is usually manifested as bicarbonate wastage in the urine reflecting that the defect in proximal tubular transport is severe enough that the capacity for bicarbonate reabsorption in the thick ascending limb of Henle's loop and more distal nephron segments is overwhelmed. More subtle defects in proximal bicarbonate transport likely go clinically unrecognized owing to compensatory reabsorption of bicarbonate distally. Inherited proximal RTA is more commonly autosomal recessive and has been associated with mutations in the basolateral sodium-bicarbonate cotransporter (NBCe1). Mutations in this transporter lead to reduced activity and/or trafficking, thus disrupting the normal bicarbonate reabsorption process of the proximal tubules. As an isolated defect for bicarbonate transport, proximal RTA is rare and is more often associated with the Fanconi syndrome characterized by urinary wastage of solutes like phosphate, uric acid, glucose, amino acids, low-molecular-weight proteins as well as bicarbonate. A vast array of rare tubular disorders may cause proximal RTA but most commonly it is induced by drugs. With the exception of carbonic anhydrase inhibitors which cause isolated proximal RTA, drug-induced proximal RTA is associated with Fanconi syndrome. Drugs that have been recently recognized to cause severe proximal RTA with Fanconi syndrome include ifosfamide, valproic acid and various antiretrovirals such as Tenofovir particularly when given to human immunodeficiency virus patients receiving concomitantly protease inhibitors such as ritonavir or reverse transcriptase inhibitors such as didanosine. PMID:23235953

  19. A 44-year-old woman with metabolic acidosis, high anion gap, and delayed neurologic deterioration.

    PubMed

    Vakil, Abhay; Upadhyay, Hinesh; Sherani, Khalid; Cervellione, Kelly; Trepeta, Scott; Patel, Mahendra C

    2015-01-01

    A 44-year-old woman was brought to the ED from John F. Kennedy International Airport. The patient was returning with her son from a 3-month visit to Bangladesh. Her journey started with a 4-h flight from Dhaka, Bangladesh to Dubai, United Arab Emirates. She consumed 240 mL of whiskey during the flight. This was followed by a 14-h flight from Dubai to New York. According to the patient's son, she did not consume any alcohol during the second flight. The patient was in her usual state of health with normal mentation throughout her journey. Upon landing, she started complaining of shortness of breath. After disembarking, she was witnessed to have seizure-like activity with involuntary passage of urine, following which she collapsed. The patient was intubated by emergency medical services in the field. PMID:25560868

  20. Blueberries and Metabolic Syndrome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Metabolic Syndrome is a cluster of metabolic disorders that increase the risk of cardiovascular diseases. Type 2 diabetes, elevated blood pressure, and atherogenic dyslipidemia are among the metabolic alterations that predispose the individual to several adverse cardiovascular complications. The hea...

  1. Activation of GPR4 by Acidosis Increases Endothelial Cell Adhesion through the cAMP/Epac Pathway

    PubMed Central

    Leffler, Nancy R.; Asch, Adam S.; Witte, Owen N.; Yang, Li V.

    2011-01-01

    Endothelium-leukocyte interaction is critical for inflammatory responses. Whereas the tissue microenvironments are often acidic at inflammatory sites, the mechanisms by which cells respond to acidosis are not well understood. Using molecular, cellular and biochemical approaches, we demonstrate that activation of GPR4, a proton-sensing G protein-coupled receptor, by isocapnic acidosis increases the adhesiveness of human umbilical vein endothelial cells (HUVECs) that express GPR4 endogenously. Acidosis in combination with GPR4 overexpression further augments HUVEC adhesion with U937 monocytes. In contrast, overexpression of a G protein signaling-defective DRY motif mutant (R115A) of GPR4 does not elicit any increase of HUVEC adhesion, indicating the requirement of G protein signaling. Downregulation of GPR4 expression by RNA interference reduces the acidosis-induced HUVEC adhesion. To delineate downstream pathways, we show that inhibition of adenylate cyclase by inhibitors, 2′,5′-dideoxyadenosine (DDA) or SQ 22536, attenuates acidosis/GPR4-induced HUVEC adhesion. Consistently, treatment with a cAMP analog or a Gi signaling inhibitor increases HUVEC adhesiveness, suggesting a role of the Gs/cAMP signaling in this process. We further show that the cAMP downstream effector Epac is important for acidosis/GPR4-induced cell adhesion. Moreover, activation of GPR4 by acidosis increases the expression of vascular adhesion molecules E-selectin, VCAM-1 and ICAM-1, which are functionally involved in acidosis/GPR4-mediated HUVEC adhesion. Similarly, hypercapnic acidosis can also activate GPR4 to stimulate HUVEC adhesion molecule expression and adhesiveness. These results suggest that acidosis/GPR4 signaling regulates endothelial cell adhesion mainly through the Gs/cAMP/Epac pathway and may play a role in the inflammatory response of vascular endothelial cells. PMID:22110680

  2. Seasonal influence over serum and urine metabolic markers in submariners during prolonged patrols.

    PubMed

    Holy, Xavier; Bégot, Laurent; Renault, Sylvie; Butigieg, Xavier; André, Catherine; Bonneau, Dominique; Savourey, Gustave; Collombet, Jean-Marc

    2015-08-01

    Within the framework of earlier publications, we have consistently dedicated our investigations to eliciting the effects of both seasonal vitamin D deficiency and submarine-induced hypercapnia on serum parameters for acid-base balance and bone metabolism in submariners over a 2-month winter (WP) or summer (SP) patrols. The latest findings reported herein, contribute further evidence with regard to overall physiological regulations in the same submariner populations that underwent past scrutiny. Hence, urine and blood samples were collected in WP and SP submariners at control prepatrol time as well as on submarine patrol days 20, 41, and 58. Several urine and serum metabolic markers were quantified, namely, deoxypyridinoline (DPD), lactate, albumin, creatinine, nonesterified fatty acids (NEFA), and ionized sodium (Na(+)) or potassium (K(+)), with a view to assessing bone, muscle, liver, or kidney metabolisms. We evidenced bone metabolism alteration (urine DPD, calcium, and phosphorus) previously recorded in submarine crewmembers under prolonged patrols. We also highlighted transitory modifications in liver metabolism (serum albumin) occurring within the first 20 days of submersion. We further evidenced changes in submariners' renal physiology (serum creatinine) throughout the entire patrol time span. Measurements of ionic homeostasis (serum Na(+) and K(+)) displayed potential seasonal impact over active ionic pumps in submariners. Finally, there is some evidence that submersion provides beneficial conditions prone to fend off seasonal lactic acidosis (serum lactate) detected in WP submariners. PMID:26265754

  3. Seasonal influence over serum and urine metabolic markers in submariners during prolonged patrols

    PubMed Central

    Holy, Xavier; Bégot, Laurent; Renault, Sylvie; Butigieg, Xavier; André, Catherine; Bonneau, Dominique; Savourey, Gustave; Collombet, Jean-Marc

    2015-01-01

    Within the framework of earlier publications, we have consistently dedicated our investigations to eliciting the effects of both seasonal vitamin D deficiency and submarine-induced hypercapnia on serum parameters for acid–base balance and bone metabolism in submariners over a 2-month winter (WP) or summer (SP) patrols. The latest findings reported herein, contribute further evidence with regard to overall physiological regulations in the same submariner populations that underwent past scrutiny. Hence, urine and blood samples were collected in WP and SP submariners at control prepatrol time as well as on submarine patrol days 20, 41, and 58. Several urine and serum metabolic markers were quantified, namely, deoxypyridinoline (DPD), lactate, albumin, creatinine, nonesterified fatty acids (NEFA), and ionized sodium (Na+) or potassium (K+), with a view to assessing bone, muscle, liver, or kidney metabolisms. We evidenced bone metabolism alteration (urine DPD, calcium, and phosphorus) previously recorded in submarine crewmembers under prolonged patrols. We also highlighted transitory modifications in liver metabolism (serum albumin) occurring within the first 20 days of submersion. We further evidenced changes in submariners’ renal physiology (serum creatinine) throughout the entire patrol time span. Measurements of ionic homeostasis (serum Na+ and K+) displayed potential seasonal impact over active ionic pumps in submariners. Finally, there is some evidence that submersion provides beneficial conditions prone to fend off seasonal lactic acidosis (serum lactate) detected in WP submariners. PMID:26265754

  4. Marked mitochondrial DNA depletion associated with a novel SUCLG1 gene mutation resulting in lethal neonatal acidosis, multi-organ failure, and interrupted aortic arch.

    PubMed

    Rivera, Henry; Merinero, Begoña; Martinez-Pardo, Mercedes; Arroyo, Ignacio; Ruiz-Sala, Pedro; Bornstein, Belen; Serra-Suhe, Clara; Gallardo, Esther; Marti, Ramon; Moran, Maria J; Ugalde, Cristina; Perez-Jurado, Luis A; Andreu, Antoni L; Garesse, Rafael; Ugarte, Magdalena; Arenas, Joaquin; Martin, Miguel A

    2010-06-01

    The aim of this study was to identify the causative genetic lesion in two apparently unrelated newborns having lethal lactic acidosis, multi-organ failure and congenital malformations including interrupted aortic arch, who exhibited mild methylmalonic aciduria, combined mitochondrial respiratory chain deficiency, and marked muscle mitochondrial DNA depletion. A novel mutation in the SUCLG1 gene was identified. Phenotype severity in Succinate-CoA ligase dysfunction appears to be more correlated to the muscle mtDNA content than to the tissue distribution of the heterodimer subunits. Prominent impairment of mitochondrial respiratory chain may result in deep ravages in developmental tissues leading to multiple organ failure and malformations. PMID:20227526

  5. Experimental acute rumen acidosis in sheep: consequences on clinical, rumen, and gastrointestinal permeability conditions and blood chemistry.

    TOXLINE Toxicology Bibliographic Information

    Minuti A; Ahmed S; Trevisi E; Piccioli-Cappelli F; Bertoni G; Jahan N; Bani P

    2014-09-01

    Acute acidosis was induced in sheep, and gastrointestinal permeability was assessed by using lactulose as a permeability marker. Metabolism was evaluated by monitoring blood metabolites. Four rams (72.5 ± 4.6 kg BW) were used in a 2 × 2 changeover design experiment. The experimental period lasted 96 h from -24 to 72 h. After 24 h of fasting (from -24 to 0 h) for both controls and acidosis-induced rams (ACID), 0.5 kg of wheat flour was orally dosed at 0 and 12 h of the experimental period to ACID, while the basal diet (grass hay, ad libitum) was restored to control. At 24 h, a lactulose solution (30 g of lactulose in 200 mL of water) was orally administered. Blood samples were collected at -24, 0, 24, 48, and 72 h of the experimental periods for the analysis of metabolic profiles and during the 10 h after lactulose dosage to monitor lactulose changes in blood. In addition, rumen and fecal samples were collected at 24 h of the experimental period. The acidotic challenge markedly reduced (P < 0.01) rumen pH and VFA but increased rumen d- and l-lactic acid (P < 0.01). Concurrently, a decrease of fecal pH and VFA occurred in ACID (P < 0.01), together with an abrupt increase (P < 0.01) of lactate and fecal alkaline phosphatase. Blood lactulose was significantly increased in ACID peaking 2 h after lactulose dosage. Blood glucose, β-hydroxybutyrate, Ca, K, Mg, and alkaline phosphatase showed a significant reduction (P < 0.05) at 24 h, whereas urea and NEFA declined (P < 0.05) from 48 to 72 h. A strong inflammatory acute phase response with oxidative stress in ACID group was observed from 24 to 72 h; higher values of haptoglobin (P < 0.01) were measured from 24 to 72 h and of ceruloplasmin from 48 (P < 0.05) to 72 h (P < 0.01). Among the negative acute phase reactants, plasma albumin, cholesterol, paraoxonase, and Zn concentration also decreased (P < 0.05) in ACID at different time points between 24 and 72 h after acidotic challenge start. A rise (P < 0.05) of reactive oxygen metabolites and a drop of vitamin E (P < 0.01) between 24 and 72 h were indicative of oxidative stress in ACID. The perturbation of these blood metabolites suggests that acute acidosis was effectively induced by our model. The increase of lactulose in blood in ACID indicates that gastrointestinal permeability for the marker increased and the large increment after 2 h from dosage suggests that most of the passage occurred through the rumen or abomasal walls.

  6. Experimental acute rumen acidosis in sheep: consequences on clinical, rumen, and gastrointestinal permeability conditions and blood chemistry.

    PubMed

    Minuti, A; Ahmed, S; Trevisi, E; Piccioli-Cappelli, F; Bertoni, G; Jahan, N; Bani, P

    2014-09-01

    Acute acidosis was induced in sheep, and gastrointestinal permeability was assessed by using lactulose as a permeability marker. Metabolism was evaluated by monitoring blood metabolites. Four rams (72.5 ± 4.6 kg BW) were used in a 2 × 2 changeover design experiment. The experimental period lasted 96 h from -24 to 72 h. After 24 h of fasting (from -24 to 0 h) for both controls and acidosis-induced rams (ACID), 0.5 kg of wheat flour was orally dosed at 0 and 12 h of the experimental period to ACID, while the basal diet (grass hay, ad libitum) was restored to control. At 24 h, a lactulose solution (30 g of lactulose in 200 mL of water) was orally administered. Blood samples were collected at -24, 0, 24, 48, and 72 h of the experimental periods for the analysis of metabolic profiles and during the 10 h after lactulose dosage to monitor lactulose changes in blood. In addition, rumen and fecal samples were collected at 24 h of the experimental period. The acidotic challenge markedly reduced (P < 0.01) rumen pH and VFA but increased rumen d- and l-lactic acid (P < 0.01). Concurrently, a decrease of fecal pH and VFA occurred in ACID (P < 0.01), together with an abrupt increase (P < 0.01) of lactate and fecal alkaline phosphatase. Blood lactulose was significantly increased in ACID peaking 2 h after lactulose dosage. Blood glucose, β-hydroxybutyrate, Ca, K, Mg, and alkaline phosphatase showed a significant reduction (P < 0.05) at 24 h, whereas urea and NEFA declined (P < 0.05) from 48 to 72 h. A strong inflammatory acute phase response with oxidative stress in ACID group was observed from 24 to 72 h; higher values of haptoglobin (P < 0.01) were measured from 24 to 72 h and of ceruloplasmin from 48 (P < 0.05) to 72 h (P < 0.01). Among the negative acute phase reactants, plasma albumin, cholesterol, paraoxonase, and Zn concentration also decreased (P < 0.05) in ACID at different time points between 24 and 72 h after acidotic challenge start. A rise (P < 0.05) of reactive oxygen metabolites and a drop of vitamin E (P < 0.01) between 24 and 72 h were indicative of oxidative stress in ACID. The perturbation of these blood metabolites suggests that acute acidosis was effectively induced by our model. The increase of lactulose in blood in ACID indicates that gastrointestinal permeability for the marker increased and the large increment after 2 h from dosage suggests that most of the passage occurred through the rumen or abomasal walls. PMID:24987080

  7. Severe dermatitis, multiple allergies, and metabolic wasting syndrome caused by a novel mutation in the N-terminal plakin domain of desmoplakin

    PubMed Central

    McAleer, Maeve A.; Pohler, Elizabeth; Smith, Frances J.D.; Wilson, Neil J.; Cole, Christian; MacGowan, Stuart; Koetsier, Jennifer L.; Godsel, Lisa M.; Harmon, Robert M.; Gruber, Robert; Crumrine, Debra; Elias, Peter M.; McDermott, Michael; Butler, Karina; Broderick, Annemarie; Sarig, Ofer; Sprecher, Eli; Green, Kathleen J.; McLean, W.H. Irwin; Irvine, Alan D.

    2015-01-01

    Background Severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome is a recently recognized syndrome caused by mutations in the desmoglein 1 gene (DSG1). To date, only 3 families have been reported. Objective We studied a new case of SAM syndrome known to have no mutations in DSG1 to detail the clinical, histopathologic, immunofluorescent, and ultrastructural phenotype and to identify the underlying molecular mechanisms in this rare genodermatosis. Methods Histopathologic, electron microscopy, and immunofluorescent studies were performed. Whole-exome sequencing data were interrogated for mutations in desmosomal and other skin structural genes, followed by Sanger sequencing of candidate genes in the patient and his parents. Results No mutations were identified in DSG1; however, a novel de novo heterozygous missense c.1757A>C mutation in the desmoplakin gene (DSP) was identified in the patient, predicting the amino acid substitution p.His586Pro in the desmoplakin polypeptide. Conclusions SAM syndrome can be caused by mutations in both DSG1 and DSP. Knowledge of this genetic heterogeneity is important for both analysis of patients and genetic counseling of families. This condition and these observations reinforce the importance of heritable skin barrier defects, in this case desmosomal proteins, in the pathogenesis of atopic disease. PMID:26073755

  8. The plasticizer benzyl butyl phthalate (BBP) alters the ecdysone hormone pathway, the cellular response to stress, the energy metabolism, and several detoxication mechanisms in Chironomus riparius larvae.

    PubMed

    Herrero, Óscar; Planelló, Rosario; Morcillo, Gloria

    2015-06-01

    Butyl benzyl phthalate (BBP) has been extensively used worldwide as a plasticizer in the polyvinyl chloride (PVC) industry and the manufacturing of many other products, and its presence in the aquatic environment is expected for decades. In the present study, the toxicity of BBP was investigated in Chironomus riparius aquatic larvae. The effects of acute 24-h and 48-h exposures to a wide range of BBP doses were evaluated at the molecular level by analysing changes in genes related to the stress response, the endocrine system, the energy metabolism, and detoxication pathways, as well as in the enzyme activity of glutathione S-transferase. BBP caused a dose and time-dependent toxicity in most of the selected biomarkers. 24-h exposures to high doses affected larval survival and lead to a significant response of several heat-shock genes (hsp70, hsp40, and hsp27), and to a clear endocrine disrupting effect by upregulating the ecdysone receptor gene (EcR). Longer treatments with low doses triggered a general repression of transcription and GST activity. Furthermore, delayed toxicity studies were specially relevant, since they allowed us to detect unpredictable toxic effects, not immediately manifested after contact with the phthalate. This study provides novel and interesting results on the toxic effects of BBP in C. riparius and highlights the suitability of this organism for ecotoxicological risk assessment, especially in aquatic ecosystems. PMID:25725395

  9. Missense mutation T485S alters NBCe1-A electrogenicity causing proximal renal tubular acidosis.

    PubMed

    Zhu, Quansheng; Shao, Xuesi M; Kao, Liyo; Azimov, Rustam; Weinstein, Alan M; Newman, Debra; Liu, Weixin; Kurtz, Ira

    2013-08-15

    Mutations in SLC4A4, the gene encoding the electrogenic Na(+)-HCO3(-) cotransporter NBCe1, cause severe proximal renal tubular acidosis (pRTA), growth retardation, decreased IQ, and eye and teeth abnormalities. Among the known NBCe1 mutations, the disease-causing mechanism of the T485S (NBCe1-A numbering) mutation is intriguing because the substituted amino acid, serine, is structurally and chemically similar to threonine. In this study, we performed intracellular pH and whole cell patch-clamp measurements to investigate the base transport and electrogenic properties of NBCe1-A-T485S in mammalian HEK 293 cells. Our results demonstrated that Ser substitution of Thr485 decreased base transport by ~50%, and importantly, converted NBCe1-A from an electrogenic to an electroneutral transporter. Aqueous accessibility analysis using sulfhydryl reactive reagents indicated that Thr485 likely resides in an NBCe1-A ion interaction site. This critical location is also supported by the finding that G486R (a pRTA causing mutation) alters the position of Thr485 in NBCe1-A thereby impairing its transport function. By using NO3(-) as a surrogate ion for CO3(2-), our result indicated that NBCe1-A mediates electrogenic Na(+)-CO3(2-) cotransport when functioning with a 1:2 charge transport stoichiometry. In contrast, electroneutral NBCe1-T485S is unable to transport NO3(-), compatible with the hypothesis that it mediates Na(+)-HCO3(-) cotransport. In patients, NBCe1-A-T485S is predicted to transport Na(+)-HCO3(-) in the reverse direction from blood into proximal tubule cells thereby impairing transepithelial HCO3(-) absorption, possibly representing a new pathogenic mechanism for generating human pRTA. PMID:23636456

  10. Epimural Indicator Phylotypes of Transiently-Induced Subacute Ruminal Acidosis in Dairy Cattle

    PubMed Central

    Wetzels, Stefanie U.; Mann, Evelyne; Metzler-Zebeli, Barbara U.; Pourazad, Poulad; Qumar, Muhammad; Klevenhusen, Fenja; Pinior, Beate; Wagner, Martin; Zebeli, Qendrim; Schmitz-Esser, Stephan

    2016-01-01

    The impact of a long-term subacute rumen acidosis (SARA) on the bovine epimural bacterial microbiome (BEBM) and its consequences for rumen health is poorly understood. This study aimed to investigate shifts in the BEBM during a long-term transient SARA model consisting of two concentrate-diet-induced SARA challenges separated by a 1-week challenge break. Eight cows were fed forage and varying concentrate amounts throughout the experiment. In total, 32 rumen papilla biopsies were taken for DNA isolation (4 sampling time points per cow: at the baseline before concentrate was fed, after the first SARA challenge, after the challenge break, and after the second SARA challenge). Ruminal pH was continuously monitored. The microbiome was determined using Illumina MiSeq sequencing of the 16S rRNA gene (V345 region). In total 1,215,618 sequences were obtained and clustered into 6833 operational taxonomic units (OTUs). Campylobacter and Kingella were the most abundant OTUs (16.5 and 7.1%). According to ruminal pH dynamics, the second challenge was more severe than the first challenge. Species diversity estimates and evenness increased during the challenge break compared to all other sampling time points (P < 0.05). During both SARA challenges, Kingella- and Azoarcus-OTUs decreased (0.5 and 0.4 fold-change) and a dominant Ruminobacter-OTU increased during the challenge break (18.9 fold-change; P < 0.05). qPCR confirmed SARA-related shifts. During the challenge break noticeably more OTUs increased compared to other sampling time points. Our results show that the BEBM re-establishes the baseline conditions slower after a SARA challenge than ruminal pH. Key phylotypes that were reduced during both challenges may help to establish a bacterial fingerprint to facilitate understanding effects of SARA conditions on the BEBM and their consequences for the ruminant host. PMID:26973642

  11. Epimural Indicator Phylotypes of Transiently-Induced Subacute Ruminal Acidosis in Dairy Cattle.

    PubMed

    Wetzels, Stefanie U; Mann, Evelyne; Metzler-Zebeli, Barbara U; Pourazad, Poulad; Qumar, Muhammad; Klevenhusen, Fenja; Pinior, Beate; Wagner, Martin; Zebeli, Qendrim; Schmitz-Esser, Stephan

    2016-01-01

    The impact of a long-term subacute rumen acidosis (SARA) on the bovine epimural bacterial microbiome (BEBM) and its consequences for rumen health is poorly understood. This study aimed to investigate shifts in the BEBM during a long-term transient SARA model consisting of two concentrate-diet-induced SARA challenges separated by a 1-week challenge break. Eight cows were fed forage and varying concentrate amounts throughout the experiment. In total, 32 rumen papilla biopsies were taken for DNA isolation (4 sampling time points per cow: at the baseline before concentrate was fed, after the first SARA challenge, after the challenge break, and after the second SARA challenge). Ruminal pH was continuously monitored. The microbiome was determined using Illumina MiSeq sequencing of the 16S rRNA gene (V345 region). In total 1,215,618 sequences were obtained and clustered into 6833 operational taxonomic units (OTUs). Campylobacter and Kingella were the most abundant OTUs (16.5 and 7.1%). According to ruminal pH dynamics, the second challenge was more severe than the first challenge. Species diversity estimates and evenness increased during the challenge break compared to all other sampling time points (P < 0.05). During both SARA challenges, Kingella- and Azoarcus-OTUs decreased (0.5 and 0.4 fold-change) and a dominant Ruminobacter-OTU increased during the challenge break (18.9 fold-change; P < 0.05). qPCR confirmed SARA-related shifts. During the challenge break noticeably more OTUs increased compared to other sampling time points. Our results show that the BEBM re-establishes the baseline conditions slower after a SARA challenge than ruminal pH. Key phylotypes that were reduced during both challenges may help to establish a bacterial fingerprint to facilitate understanding effects of SARA conditions on the BEBM and their consequences for the ruminant host. PMID:26973642

  12. Carbenoxolone Treatment Ameliorated Metabolic Syndrome in WNIN/Ob Obese Rats, but Induced Severe Fat Loss and Glucose Intolerance in Lean Rats

    PubMed Central

    Prasad Sakamuri, Siva Sankara Vara; Sukapaka, Mahesh; Prathipati, Vijay Kumar; Nemani, Harishankar; Putcha, Uday Kumar; Pothana, Shailaja; Koppala, Swarupa Rani; Ponday, Lakshmi Raj Kumar; Acharya, Vani; Veetill, Giridharan Nappan; Ayyalasomayajula, Vajreswari

    2012-01-01

    Background 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates local glucocorticoid action in tissues by catalysing conversion of inactive glucocorticoids to active glucocorticoids. 11β-HSD1 inhibition ameliorates obesity and associated co-morbidities. Here, we tested the effect of 11β-HSD inhibitor, carbenoxolone (CBX) on obesity and associated comorbidities in obese rats of WNIN/Ob strain, a new animal model for genetic obesity. Methodology/Principal Findings Subcutaneous injection of CBX (50 mg/kg body weight) or volume-matched vehicle was given once daily for four weeks to three month-old WNIN/Ob lean and obese rats (n = 6 for each phenotype and for each treatment). Body composition, plasma lipids and hormones were assayed. Hepatic steatosis, adipose tissue morphology, inflammation and fibrosis were also studied. Insulin resistance and glucose intolerance were determined along with tissue glycogen content. Gene expressions were determined in liver and adipose tissue. CBX significantly inhibited 11β-HSD1 activity in liver and adipose tissue of WNIN/Ob lean and obese rats. CBX significantly decreased body fat percentage, hypertriglyceridemia, hypercholesterolemia, insulin resistance in obese rats. CBX ameliorated hepatic steatosis, adipocyte hypertrophy, adipose tissue inflammation and fibrosis in obese rats. Tissue glycogen content was significantly decreased by CBX in liver and adipose tissue of obese rats. Severe fat loss and glucose- intolerance were observed in lean rats after CBX treatment. Conclusions/Significance We conclude that 11β-HSD1 inhibition by CBX decreases obesity and associated co-morbidities in WNIN/Ob obese rats. Our study supports the hypothesis that inhibition of 11β-HSD1 is a key strategy to treat metabolic syndrome. Severe fat loss and glucose -intolerance by CBX treatment in lean rats suggest that chronic 11β-HSD1 inhibition may lead to insulin resistance in normal conditions. PMID:23284633

  13. Dental Aspect of Distal Tubular Renal Acidosis with Genu Valgum Secondary to Rickets: A Case Report

    PubMed Central

    Bahadure, Rakesh N.; Thosar, Nilima; Kriplani, Ritika; Baliga, Sudhindra; Fulzele, Punit

    2012-01-01

    Distal renal tubular acidosis is a disease that occurs when the kidneys do not remove acid properly into the urine, leaving the blood too acidic (called acidosis). Distal renal tubular acidosis (type I RTA) is caused by a defect in the kidney tubes that causes acid to build up in the bloodstream. It ultimately results rickets which include chronic skeletal pain, in skeletal deformities, skeletal fractures. Rickets is among the most frequent childhood diseases in many developing countries. Dental problems in rickets include delayed eruption of permanent teeth, premature fall of deciduous teeth, defects in structure of teeth, enamel defects in permanent teeth (hypoplastic), pulp defects, intraglobular dentine, and caries tooth. Herewith, reported a case of distal tubular renal acidosis with genu valgum secondary to rickets, with pain and extraoral swelling associated with right and left mandibular 1st permanent molars. Teeth were infected with pulp without being involved with caries. Radiographically cracks in enamel and dentin were observed. Pulp revascularization with 46 and root canal treatment was done for 36 with followup of 1 year. PMID:22567455

  14. Matriptase activation and shedding through PDGF-D-mediated extracellular acidosis.

    PubMed

    Najy, Abdo J; Dyson, Gregory; Jena, Bhanu P; Lin, Chen-Yong; Kim, Hyeong-Reh C

    2016-02-15

    Activation of ?-platelet-derived growth factor receptor (?-PDGFR) is associated with prostate cancer (PCa) progression and recurrence after prostatectomy. Analysis of the ?-PDGFR ligands in PCa revealed association between PDGF-D expression and Gleason score as well as tumor stage. During the course of studying the functional consequences of PDGF ligand-specific ?-PDGFR signaling in PCa, we discovered a novel function of PDGF-D for activation/shedding of the serine protease matriptase leading to cell invasion, migration, and tumorigenesis. The present study showed that PDGF-D, not PDGF-B, induces extracellular acidification, which correlates with increased matriptase activation. A cDNA microarray analysis revealed that PDGF-D/?-PDGFR signaling upregulates expression of the acidosis regulator carbonic anhydrase IX (CAIX), a classic target of the transcriptional factor hypoxia-inducible factor-1? (HIF-1?). Cellular fractionation displayed a strong HIF-1? nuclear localization in PDGF-D-expressing cells. Treatment of vector control or PDGF-B-expressing cells with the HIF-1? activator CoCl2 led to increased CAIX expression accompanied by extracellular acidosis and matriptase activation. Furthermore, the analysis of the CAFTD cell lines, variants of the BPH-1 transformation model, showed that increased PDGF-D expression is associated with enhanced HIF-1? activity, CAIX induction, cellular acidosis, and matriptase shedding. Importantly, shRNA-mediated knockdown of CAIX expression effectively reversed extracellular acidosis and matriptase activation in PDGF-D-transfected BPH-1 cells and in CAFTD variants that express endogenous PDGF-D at a high level. Taken together, these novel findings reveal a new paradigm in matriptase activation involving PDGF-D-specific signal transduction leading to extracellular acidosis. PMID:26157007

  15. Identification of Differentially Expressed Proteins in Liver in Response to Subacute Ruminal Acidosis (SARA) Induced by High-concentrate Diet

    PubMed Central

    Jiang, X. Y.; Ni, Y. D.; Zhang, S. K.; Zhang, Y. S.; Shen, X. Z.

    2014-01-01

    The aim of this study was to evaluate protein expression patterns of liver in response to subacute ruminal acidosis (SARA) induced by high-concentrate diet. Sixteen healthy mid-lactating goats were randomly divided into 2 groups and fed either a high-forage (HF) diet or a high-concentrate (HC) diet. The HC diet was expected to induce SARA. After ensuring the occurrence of SARA, liver samples were collected. Proteome analysis with differential in gel electrophoresis technology revealed that, 15 proteins were significantly modulated in liver in a comparison between HF and HC-fed goats. These proteins were found mainly associated with metabolism and energy transfer after identified by matrix-assisted laser desorption ionization/time of flight. The results indicated that glucose, lipid and protein catabolism could be enhanced when SARA occurred. It prompted that glucose, lipid and amine acid in the liver mainly participated in oxidation and energy supply when SARA occurred, which possibly consumed more precursors involved in milk protein and milk fat synthesis. These results suggest new candidate proteins that may contribute to a better understanding of the mechanisms that mediate liver adaptation to SARA. PMID:25083113

  16. Acidosis-induced coronary constriction in the rat heart: evidence for the activation of L-type calcium channels.

    PubMed

    Wilson, D A; Woodward, B

    1999-01-01

    Perfused rat hearts were used to study the effects of acidosis on coronary tone. When pH was decreased, over the range pH 7.4 to pH 6.2, by reducing perfusate bicarbonate levels, under constant flow conditions, there was a transient decrease in coronary perfusion pressure (CPP), followed by a sustained acidosis-dependent increase in CPP, which reversed when pH was returned to pH 7.4. This increase in CPP was seen at perfusion rates of 5, 10, and 20 ml/min(-1). When using constant pressure perfusion acidosis reduced coronary flow. In a HEPES-buffered bicarbonate-free solution, acidosis did not cause a transient fall in CPP but it did produce a sustained increase in CPP. Addition of ammonium chloride (10 mM) reduced CPP, while washout of ammonium chloride increased CPP. The acidosis-induced increase in CPP was not affected by indomethacin, nitro-L-arginine, the nonselective adenosine receptor antagonist, 8-phenyl theophylline, or the thromboxane receptor antagonist, ZD 1542. The acidosis-induced increase in CPP was independent of the myocardial depressant effects of acidosis, but was attenuated by three different L-type calcium channel blockers. These results demonstrate that the coronary circulation of the rat constricts in response to acidosis. Experiments performed with L-type calcium channel blockers, and the calcium channel activator BAY K8644, suggest that constriction occurs via activation of L-type calcium channels. This would not be expected on the basis of electrophysiological studies, which have shown an inhibition of L-type calcium channels by acidosis. PMID:10651181

  17. Benzothiadiazole and l-2-oxothiazolidine-4-carboxylic acid reduce the severity of Sharka symptoms in pea leaves: effect on antioxidative metabolism at the subcellular level.

    PubMed

    Clemente-Moreno, M J; Díaz-Vivancos, P; Barba-Espín, G; Hernández, J A

    2010-01-01

    The effect of treatment with benzothiadiazole (BTH) or l-2-oxothiazolidine-4-carboxylic acid (OTC), and their interaction with Plum pox virus (PPV) infection, on antioxidative metabolism of pea plants was studied at the subcellular level. PPV infection produced a 20% reduction in plant growth. Pre-treatment of pea plants with OTC or BTH afforded partial protection against PPV infection, measured as the percentage of leaves showing symptoms, but neither BTH nor OTC significantly reduced the virus content. PPV infection caused oxidative stress, as monitored by increases in lipid peroxidation and protein oxidation in soluble and chloroplastic fractions. In leaves of non-infected plants, OTC increased the content of reduced glutathione (GSH) and total glutathione; accordingly, an increase in the redox state of glutathione was observed. An increase in oxidized glutathione (GSSG) was found in symptomatic leaves from infected plants. A similar increase in GSSG was also observed in asymptomatic leaves from infected, untreated plants. However, no changes in GSSG occurred in asymptomatic leaves from infected plants treated with BTH and OTC and, accordingly, a higher redox state of GSH was recorded in those leaves, which could have had a role in the reduction of symptoms, as observed in asymptomatic leaves from infected plants treated with BTH or OTC. Treatment with BTH or OTC had some effect on antioxidant enzymes in soluble and chloroplastic fractions from infected pea leaves. An increase in antioxidative mechanisms, such as GSH-related enzymes (DHAR, GR and G6PDH), as well as APX and POX, at the subcellular level was observed, which could play a role in reducing the severity of cellular damage induced by Sharka in pea leaves. PMID:20653891

  18. Effects of the neurological wake-up test on clinical examination, intracranial pressure, brain metabolism and brain tissue oxygenation in severely brain-injured patients

    PubMed Central

    2012-01-01

    Introduction Daily interruption of sedation (IS) has been implemented in 30 to 40% of intensive care units worldwide and may improve outcome in medical intensive care patients. Little is known about the benefit of IS in acutely brain-injured patients. Methods This prospective observational study was performed in a neuroscience intensive care unit in a tertiary-care academic center. Twenty consecutive severely brain-injured patients with multimodal neuromonitoring were analyzed for levels of brain lactate, pyruvate and glucose, intracranial pressure (ICP), cerebral perfusion pressure (CPP) and brain tissue oxygen tension (PbtO2) during IS trials. Results Of the 82 trial days, 54 IS-trials were performed as interruption of sedation and analgesics were not considered safe on 28 days (34%). An increase in the FOUR Score (Full Outline of UnResponsiveness score) was observed in 50% of IS-trials by a median of three (two to four) points. Detection of a new neurologic deficit occurred in one trial (2%), and in one-third of IS-trials the trial had to be stopped due to an ICP-crisis (> 20 mmHg), agitation or systemic desaturation. In IS-trials that had to be aborted, a significant increase in ICP and decrease in PbtO2 (P < 0.05), including 67% with critical values of PbtO2 < 20 mmHg, a tendency to brain metabolic distress (P < 0.07) was observed. Conclusions Interruption of sedation revealed new relevant clinical information in only one trial and a large number of trials could not be performed or had to be stopped due to safety issues. Weighing pros and cons of IS-trials in patients with acute brain injury seems important as related side effects may overcome the clinical benefit. PMID:23186037

  19. Carotid body, insulin, and metabolic diseases: unraveling the links.

    PubMed

    Conde, Sílvia V; Sacramento, Joana F; Guarino, Maria P; Gonzalez, Constancio; Obeso, Ana; Diogo, Lucilia N; Monteiro, Emilia C; Ribeiro, Maria J

    2014-01-01

    The carotid bodies (CB) are peripheral chemoreceptors that sense changes in arterial blood O2, CO2, and pH levels. Hypoxia, hypercapnia, and acidosis activate the CB, which respond by increasing the action potential frequency in their sensory nerve, the carotid sinus nerve (CSN). CSN activity is integrated in the brain stem to induce a panoply of cardiorespiratory reflexes aimed, primarily, to normalize the altered blood gases, via hyperventilation, and to regulate blood pressure and cardiac performance, via sympathetic nervous system (SNS) activation. Besides its role in the cardiorespiratory control the CB has been proposed as a metabolic sensor implicated in the control of energy homeostasis and, more recently, in the regulation of whole body insulin sensitivity. Hypercaloric diets cause CB overactivation in rats, which seems to be at the origin of the development of insulin resistance and hypertension, core features of metabolic syndrome and type 2 diabetes. Consistent with this notion, CB sensory denervation prevents metabolic and hemodynamic alterations in hypercaloric feed animal. Obstructive sleep apnea (OSA) is another chronic disorder characterized by increased CB activity and intimately related with several metabolic and cardiovascular abnormalities. In this manuscript we review in a concise manner the putative pathways linking CB chemoreceptors deregulation with the pathogenesis of insulin resistance and arterial hypertension. Also, the link between chronic intermittent hypoxia (CIH) and insulin resistance is discussed. Then, a final section is devoted to debate strategies to reduce CB activity and its use for prevention and therapeutics of metabolic diseases with an emphasis on new exciting research in the modulation of bioelectronic signals, likely to be central in the future. PMID:25400585

  20. Carotid body, insulin, and metabolic diseases: unraveling the links

    PubMed Central

    Conde, Sílvia V.; Sacramento, Joana F.; Guarino, Maria P.; Gonzalez, Constancio; Obeso, Ana; Diogo, Lucilia N.; Monteiro, Emilia C.; Ribeiro, Maria J.

    2014-01-01

    The carotid bodies (CB) are peripheral chemoreceptors that sense changes in arterial blood O2, CO2, and pH levels. Hypoxia, hypercapnia, and acidosis activate the CB, which respond by increasing the action potential frequency in their sensory nerve, the carotid sinus nerve (CSN). CSN activity is integrated in the brain stem to induce a panoply of cardiorespiratory reflexes aimed, primarily, to normalize the altered blood gases, via hyperventilation, and to regulate blood pressure and cardiac performance, via sympathetic nervous system (SNS) activation. Besides its role in the cardiorespiratory control the CB has been proposed as a metabolic sensor implicated in the control of energy homeostasis and, more recently, in the regulation of whole body insulin sensitivity. Hypercaloric diets cause CB overactivation in rats, which seems to be at the origin of the development of insulin resistance and hypertension, core features of metabolic syndrome and type 2 diabetes. Consistent with this notion, CB sensory denervation prevents metabolic and hemodynamic alterations in hypercaloric feed animal. Obstructive sleep apnea (OSA) is another chronic disorder characterized by increased CB activity and intimately related with several metabolic and cardiovascular abnormalities. In this manuscript we review in a concise manner the putative pathways linking CB chemoreceptors deregulation with the pathogenesis of insulin resistance and arterial hypertension. Also, the link between chronic intermittent hypoxia (CIH) and insulin resistance is discussed. Then, a final section is devoted to debate strategies to reduce CB activity and its use for prevention and therapeutics of metabolic diseases with an emphasis on new exciting research in the modulation of bioelectronic signals, likely to be central in the future. PMID:25400585

  1. Improvement in lacrimal and salivary secretions after alkali therapy in Sjøgren's syndrome with renal tubular acidosis.

    PubMed Central

    Flynn, C T; Negus, T W; McHardy, J; Rainford, D J

    1976-01-01

    A patient with Sjøgren's syndrome developed renal tubular acidosis which led to systemic acidosis and potassium depletion. Treatment with Shohl's solution and potassium supplements was followed by subjective improvement in tear flow, salivary flow, and by disappearance of bronchitic symptoms. Detailed objective assessments were then made during the next year, twice on treatment and twice without. These confirmed the subjective impression of improvement. PMID:970999

  2. Rumen microbial and fermentation characteristics are affected differently by bacterial probiotic supplementation during induced lactic and subacute acidosis in sheep

    PubMed Central

    2012-01-01

    Background Ruminal disbiosis induced by feeding is the cause of ruminal acidosis, a digestive disorder prevalent in high-producing ruminants. Because probiotic microorganisms can modulate the gastrointestinal microbiota, propionibacteria- and lactobacilli-based probiotics were tested for their effectiveness in preventing different forms of acidosis. Results Lactic acidosis, butyric and propionic subacute ruminal acidosis (SARA) were induced by feed chalenges in three groups of four wethers intraruminally dosed with wheat, corn or beet pulp. In each group, wethers were either not supplemented (C) or supplemented with Propionibacterium P63 alone (P) or combined with L. plantarum (Lp + P) or L. rhamnosus (Lr + P). Compared with C, all the probiotics stimulated lactobacilli proliferation, which reached up to 25% of total bacteria during wheat-induced lactic acidosis. This induced a large increase in lactate concentration, which decreased ruminal pH. During the corn-induced butyric SARA, Lp + P decreased Prevotella spp. proportion with a concomitant decrease in microbial amylase activity and total volatile fatty acids concentration, and an increase in xylanase activity and pH. Relative to the beet pulp-induced propionic SARA, P and Lr + P improved ruminal pH without affecting the microbial or fermentation characteristics. Regardless of acidosis type, denaturing gradient gel electrophoresis revealed that probiotic supplementations modified the bacterial community structure. Conclusion This work showed that the effectiveness of the bacterial probiotics tested depended on the acidosis type. Although these probiotics were ineffective in lactic acidosis because of a deeply disturbed rumen microbiota, some of the probiotics tested may be useful to minimize the occurrence of butyric and propionic SARA in sheep. However, their modes of action need to be further investigated. PMID:22812531

  3. Primary hyperparathyroidism and proximal renal tubular acidosis: Report of two cases

    PubMed Central

    Siddiqui, Abdullah A.; Wilson, Douglas R.

    1972-01-01

    Two cases of primary hyperparathyroidism due to single parathyroid adenomas presented with the additional feature of hyperchloremic acidosis. The defect in urinary acidification responsible was not of the distal or gradient-limited type since both patients could lower urine pH adequately. However, there was a defect of bicarbonate reabsorption, an abnormality referred to as the proximal or rate-limited type of renal tubular acidosis. It is suggested that this defect represents an exaggeration of the physiological effect of parathormone on bicarbonate reabsorption and may be responsible for the frequent finding of hyperchloremia in association with primary hyperparathyroidism as well as for the urinary bicarbonate-wasting associated with a variety of causes of secondary hyperparathyroidism. PMID:5012229

  4. A triad of linezolid toxicity: hypoglycemia, lactic acidosis, and acute pancreatitis

    PubMed Central

    Johnson, P. Connor; Phillips, Kristy M.; O'Donnell, Walter J.

    2015-01-01

    We present a case of suspected linezolid toxicity in a 34-year-old man with sickle cell disease and line-related vancomycin-resistant enterococcal bacteremia and tricuspid valve endocarditis. The patient developed sudden-onset hypoglycemia, lactic acidosis, and acute pancreatitis 11 days after initiation of linezolid. All adverse effects quickly resolved with drug cessation. The pathophysiology underlying this triad of linezolid toxicity is unclear, but may be related to mitochondrial dysfunction. PMID:26424943

  5. Subacute Ruminal Acidosis and Evaluation of Blood Gas Analysis in Dairy Cow

    PubMed Central

    Gianesella, Matteo; Morgante, Massimo; Cannizzo, Chiara; Stefani, Annalisa; Dalvit, Paolo; Messina, Vanessa; Giudice, Elisabetta

    2010-01-01

    Subacute Ruminal Acidosis (SARA) corresponds to an imbalance between lactate-producing bacteria and lactate-using bacteria, which results in a change in ruminal pH associated with a prevalent consumption of rapidly fermentable carbohydrates. In our study, 216 primiparus and multiparus dairy cows were selected from 20 Italian intensive dairy herds and were divided into three groups based on the risk of SARA. All the dairy cows had high average milk production. After blood sampling, a complete blood gas analysis was performed. One-way ANOVA was performed to compare the three groups. O2 Cont, PCO2, blood pH, O2Hb, urinary pH, and rumen pH were significantly lower in cows with rumen pH < 5.5. These results indicate that blood gas analysis is a valuable tool to diagnose acidosis in dairy cows because it provides good assessment of acidosis while being less invasive than rumen pH analysis. PMID:20953375

  6. Subacute ruminal acidosis and evaluation of blood gas analysis in dairy cow.

    PubMed

    Gianesella, Matteo; Morgante, Massimo; Cannizzo, Chiara; Stefani, Annalisa; Dalvit, Paolo; Messina, Vanessa; Giudice, Elisabetta

    2010-01-01

    Subacute Ruminal Acidosis (SARA) corresponds to an imbalance between lactate-producing bacteria and lactate-using bacteria, which results in a change in ruminal pH associated with a prevalent consumption of rapidly fermentable carbohydrates. In our study, 216 primiparus and multiparus dairy cows were selected from 20 Italian intensive dairy herds and were divided into three groups based on the risk of SARA. All the dairy cows had high average milk production. After blood sampling, a complete blood gas analysis was performed. One-way ANOVA was performed to compare the three groups. O(2) Cont, PCO(2), blood pH, O(2)Hb, urinary pH, and rumen pH were significantly lower in cows with rumen pH < 5.5. These results indicate that blood gas analysis is a valuable tool to diagnose acidosis in dairy cows because it provides good assessment of acidosis while being less invasive than rumen pH analysis. PMID:20953375

  7. Chronic acidosis in the tumour microenvironment selects for overexpression of LAMP2 in the plasma membrane

    PubMed Central

    Damaghi, Mehdi; Tafreshi, Narges K.; Lloyd, Mark C.; Sprung, Robert; Estrella, Veronica; Wojtkowiak, Jonathan W.; Morse, David L.; Koomen, John M.; Bui, Marilyn M.; Gatenby, Robert A; Gillies, Robert J

    2015-01-01

    Early cancers are avascular and hence, profoundly acidic. Pre-malignant cells must adapt to acidosis to thrive in this hostile microenvironment. Here, we investigate MCF-7 cells that are adapted to grow in acidic conditions using SILAC proteomics and we reveal a significant upregulation of lysosomal proteins. Prominent among these is LAMP2 that functions to protect lysosomal membranes from acid proteolysis. LAMP2 upregulation by acidosis is confirmed both in vitro and in vivo. Furthermore, we show that the depletion of LAMP2 is sufficient to increase acidosis-mediated toxicity. In breast cancer patient samples, there is a high correlation of LAMP2 mRNA and protein expression with progression. We also observe that LAMP2 is located at the plasma membrane in clinical samples and this redistribution is acid-induced in vitro. Our findings suggest a potential adaptive mechanism, wherein cells chronically exposed to an acidic environment translocate lysosomal proteins to their surface, thus protecting the plasmalemma from acid-induced hydrolysis. PMID:26658462

  8. Mind the gap: a case of severe methanol intoxication.

    PubMed

    Nazir, Salik; Melnick, Stephen; Ansari, Shabana; Kanneh, Haitham T

    2016-01-01

    We report a case of a 37-year-old woman with non-insulin-dependent diabetes on sitagliptin, an alcohol abuser who was brought unresponsive to the emergency department of our hospital. On arrival, the patient was intubated and mechanically ventilated due to a low Glasgow Coma score of 3/15. Initial laboratory testing identified profound high anion gap metabolic acidosis. Owing to the dubious circumstances and the depth of acidosis, methanol and ethylene glycol intoxication was suspected. Further evaluation revealed a significantly increased serum osmolal gap. Pending volatile compound screen, fomepizole was started and urgent haemodialysis undertaken. Subsequent brain MRI identified changes in putamen of bilateral basal ganglia, suggestive of methanol intoxication. The patient was later found to have an initial methanol level of 237 mg/dL. She was successfully extubated on day 2 of hospitalisation, with residual cognitive and visual deficits. PMID:26917798

  9. Experimental feed induction of ruminal lactic, propionic, or butyric acidosis in sheep.

    PubMed

    Lettat, A; Nozière, P; Silberberg, M; Morgavi, D P; Berger, C; Martin, C

    2010-09-01

    A study was conducted to determine the feasibility to induce rumen acidosis with propionate, butyrate, or lactate as the major fermentation end products. Three rumen-cannulated Texel wethers were used in a 3 x 3 Latin square design. Each period consisted of 11 d of adaptation where wethers were daily fed at 90% of ad libitum intake a hay and wheat-based concentrate diet (4:1 ratio on a DM basis) in 2 equal portions followed by 3 d of acidosis induction. During the challenge, the morning feeding was replaced by an intraruminal supply of wheat (readily fermentable starch), corn (slowly fermentable starch), or beet pulp (easily digestible fiber), dosed at 1.2% of BW. Ruminal liquid samples were taken daily 1 h before (-1) and 1, 3, 5, and 6 h after intraruminal feed supply to measure pH, VFA, and lactic acid concentration. The differences between treatments accentuated throughout the 3-d challenge, being maximal and significant on d 3. Indeed, 6 h after the third day of the challenge, mean ruminal pH was less for wheat (4.85) than for corn (5.61; P = 0.008) and beet pulp (6.09; P = 0.001), and total VFA tended to be less for wheat (48.7 mM) than for corn and beet pulp (84.7 mM on average; P = 0.08). At the same time, the proportion of acetate was greater for wheat than for corn (75.5 and 62.2%, respectively; P = 0.005) but did not differ from beet pulp challenge (69.0%). The proportion of propionate was greatest for beet pulp compared with corn and wheat (21.0, 17.3, and 12.1%, respectively; P = 0.03), whereas the butyrate proportion was greatest for corn, intermediate for wheat, and least for beet pulp (16.3, 10.8, and 8.3%, respectively; P = 0.05). Lactate concentration was greatest for wheat (45.5 mM) compared with corn and beet pulp (8.3 mM on average; P = 0.01). Under our experimental conditions, ruminal lactic acidosis was successfully induced by wheat, whereas butyric and propionic subacute ruminal acidosis were respectively provoked by corn and beet pulp. We developed an original model that promoted differentiated fermentation pathways in the rumen of sheep. It will be used to study the ruminal microbiome changes involved in different acidosis situations. PMID:20495125

  10. Grain-based versus alfalfa-based subacute ruminal acidosis induction experiments: Similarities and differences between changes in milk fatty acids.

    PubMed

    Colman, E; Khafipour, E; Vlaeminck, B; De Baets, B; Plaizier, J C; Fievez, V

    2013-07-01

    Subacute ruminal acidosis (SARA) is one of the most important metabolic disorders, traditionally characterized by low rumen pH, which might be induced by an increase in the dietary proportion of grains as well as by a reduction of structural fiber. Both approaches were used in earlier published experiments in which SARA was induced by replacing part of the ration by a grain mixture or alfalfa hay by alfalfa pellets. The main differences between both experiments were the presence of blood lipopolysaccharide and Escherichia coli and associated effects on the rumen microbial population in the rumen of grain-based induced SARA animals as well as a great amount of quickly fermentable carbohydrates in the grain-based SARA induction experiment. Both induction approaches changed rumen pH although the pH decrease was more substantial in the alfalfa-based SARA induction protocol. The goal of the current analysis was to assess whether both acidosis induction approaches provoked similar shifts in the milk fatty acid (FA) profile. Similar changes of the odd- and branched-chain FA and the C18 biohydrogenation intermediates were observed in the alfalfa-based SARA induction experiment and the grain-based SARA induction experiment, although they were more pronounced in the former. The proportion of trans-10 C18:1 in the last week of the alfalfa-based induction experiment was 6 times higher than the proportion measured during the control week. The main difference between both induction experiments under similar rumen pH changes was the decreasing sum of iso FA during the grain-based SARA induction experiment whereas the sum of iso FA remained stable during the alfalfa-based SARA induction experiment. The cellulolytic bacterial community seemed to be negatively affected by either the presence of E. coli and the associated lipopolysaccharide accumulation in the rumen or by the amount of starch and quickly fermentable carbohydrates in the diet. In general, changes in the milk FA profile were related to changes in rumen pH. Nevertheless, feed characteristics (low in structural fiber vs. high in starch) also affected the milk FA profile and, as such, both effects should be taken into account when subacute acidosis occurs. PMID:23628250

  11. The progression from a lower to a higher invasive stage of bladder cancer is associated with severe alterations in glucose and pyruvate metabolism

    SciTech Connect

    Conde, Vanessa R.; Oliveira, Pedro F.; Ramalhosa, Elsa; Pereira, José A.; Alves, Marco G.; Silva, Branca M.

    2015-07-01

    Cancer cells present a particular metabolic behavior. We hypothesized that the progression of bladder cancer could be accompanied by changes in cells glycolytic profile. We studied two human bladder cancer cells, RT4 and TCCSUP, in which the latter represents a more invasive stage. The levels of glucose, pyruvate, alanine and lactate in the extracellular media were measured by Proton Nuclear Magnetic Resonance. The protein expression levels of glucose transporters 1 (GLUT1) and 3 (GLUT3), monocarboxylate transporter 4 (MCT4), phosphofructokinase-1 (PFK1), glutamic-pyruvate transaminase (GPT) and lactate dehydrogenase (LDH) were determined. Our data showed that glucose consumption and GLUT3 levels were similar in both cell lines, but TCCSUP cells displayed lower levels of GLUT1 and PFK expression. An increase in pyruvate consumption, concordant with the higher levels of lactate and alanine production, was also detected in TCCSUP cells. Moreover, TCCSUP cells presented lower protein expression levels of GPT and LDH. These results illustrate that bladder cancer progression is associated with alterations in cells glycolytic profile, namely the switch from glucose to pyruvate consumption in the more aggressive stage. This may be useful to develop new therapies and to identify biomarkers for cancer progression. - Highlights: • Metabolic phenotype of less and high invasive bladder cancer cells was studied. • Bladder cancer progression involves alterations in cells glycolytic profile. • More invasive bladder cancer cells switch from glucose to pyruvate consumption. • Our results may help to identify metabolic biomarkers of bladder cancer progression.

  12. Severe malaria in children: A descriptive report from Kinshasa, the Democratic Republic of Congo.

    PubMed

    Kunuanunua, Thomas S; Nsibu, Célestin N; Bodi, Joseph M; Tshibola, Thérèse K; Makusi Bura, Mimy; Magoga, Kumbundu; Ekila, Mathilde B; Situakibanza, Hypolite T; Aloni, Michel N

    2015-08-01

    The decline of susceptibility of Plasmodium falciparum to chloroquine and sulfadoxine-pyrimethamine resulted in the change of drug policy. This policy has probably changed the facies of the severe form of malaria. A prospective study was conducted in Kinshasa, the Democratic Republic of Congo. Data on children aged ≤13 years, diagnosed with severe malaria were analyzed. In total, 378 children were included with an overall median age of 8 years (age range: 1-13 years). Dark urine was seen in 25.1% of cases. Metabolic acidosis (85.2%), hypoglycemia (62.2%) and hemoglobin ≤5 g/dl (39.1%) were the common laboratories features. Severe malaria anemia, cerebral malaria and Blackwater fever (BWF) were found in 39.1, 30.1 and 25.4%, respectively. Mortality rate was 4%. BWF emerges as a frequent form of severe malaria in our midst. Availing artemisin-based combination treatments in the health care system is a priority to reduce the incidence of BWF in our environment. PMID:25957436

  13. Mutations in GTPBP3 Cause a Mitochondrial Translation Defect Associated with Hypertrophic Cardiomyopathy, Lactic Acidosis, and Encephalopathy

    PubMed Central

    Kopajtich, Robert; Nicholls, Thomas J.; Rorbach, Joanna; Metodiev, Metodi D.; Freisinger, Peter; Mandel, Hanna; Vanlander, Arnaud; Ghezzi, Daniele; Carrozzo, Rosalba; Taylor, Robert W.; Marquard, Klaus; Murayama, Kei; Wieland, Thomas; Schwarzmayr, Thomas; Mayr, Johannes A.; Pearce, Sarah F.; Powell, Christopher A.; Saada, Ann; Ohtake, Akira; Invernizzi, Federica; Lamantea, Eleonora; Sommerville, Ewen W.; Pyle, Angela; Chinnery, Patrick F.; Crushell, Ellen; Okazaki, Yasushi; Kohda, Masakazu; Kishita, Yoshihito; Tokuzawa, Yoshimi; Assouline, Zahra; Rio, Marlène; Feillet, François; Mousson de Camaret, Bénédict; Chretien, Dominique; Munnich, Arnold; Menten, Björn; Sante, Tom; Smet, Joél; Régal, Luc; Lorber, Abraham; Khoury, Asaad; Zeviani, Massimo; Strom, Tim M.; Meitinger, Thomas; Bertini, Enrico S.; Van Coster, Rudy; Klopstock, Thomas; Rötig, Agnès; Haack, Tobias B.; Minczuk, Michal; Prokisch, Holger

    2014-01-01

    Respiratory chain deficiencies exhibit a wide variety of clinical phenotypes resulting from defective mitochondrial energy production through oxidative phosphorylation. These defects can be caused by either mutations in the mtDNA or mutations in nuclear genes coding for mitochondrial proteins. The underlying pathomechanisms can affect numerous pathways involved in mitochondrial physiology. By whole-exome and candidate gene sequencing, we identified 11 individuals from 9 families carrying compound heterozygous or homozygous mutations in GTPBP3, encoding the mitochondrial GTP-binding protein 3. Affected individuals from eight out of nine families presented with combined respiratory chain complex deficiencies in skeletal muscle. Mutations in GTPBP3 are associated with a severe mitochondrial translation defect, consistent with the predicted function of the protein in catalyzing the formation of 5-taurinomethyluridine (τm5U) in the anticodon wobble position of five mitochondrial tRNAs. All case subjects presented with lactic acidosis and nine developed hypertrophic cardiomyopathy. In contrast to individuals with mutations in MTO1, the protein product of which is predicted to participate in the generation of the same modification, most individuals with GTPBP3 mutations developed neurological symptoms and MRI involvement of thalamus, putamen, and brainstem resembling Leigh syndrome. Our study of a mitochondrial translation disorder points toward the importance of posttranscriptional modification of mitochondrial tRNAs for proper mitochondrial function. PMID:25434004

  14. Individual animal variability in ruminal bacterial communities and ruminal acidosis in primiparous Holstein cows during the periparturient period.

    PubMed

    Mohammed, R; Stevenson, D M; Weimer, P J; Penner, G B; Beauchemin, K A

    2012-11-01

    The purpose of this study was to investigate variability among individual cows in their severity of ruminal acidosis (RA) pre- and postpartum, and determine whether this variability was related to differences in their ruminal bacterial community composition (BCC). Variability in the severity of RA among individual cows was characterized based on ruminal fermentation variables. Effects of prepartum dietary treatment on the severity of RA were also examined. Fourteen Holstein heifers paired by expected calving date and BCS were allotted to 1 of 2 prepartum dietary treatments: low-concentrate or high-concentrate diets. All cows received the same lactation diet postpartum. Microbial DNA extracted from 58 ruminal digesta samples in total collected prepartum (d -50, -31, and -14; 27 samples) and postpartum (d +14 and +52; 31 samples) and amplified by PCR were subjected to automated ribosomal intergenic spacer analysis. Changes in ruminal variables over time [pH, volatile fatty acids (VFA), and acidosis indicators, including duration and area under the rumen pH curve below 5.8, 5.5, and 5.2, measured on d -54, -35, -14, -3, +3, +17, +37, and +58] were analyzed using principal components analysis. Based on the shift (defined as the distance of the mean loadings) between the prepartum and postpartum period for each cow, the 14 cows were classified into 3 groups: least acidotic (n=5), most acidotic (n=5), and intermediate (n=4). Cows in the most acidotic group had greater severity of RA (measured as duration of total RA, mild RA, moderate RA, and acute RA; area under the pH curve for total RA, mild RA, and moderate RA) postpartum than prepartum, and this difference between periods was greater than for the least acidotic cows. Similarly, the RA index (total area of pH <5.8 normalized to intake) showed an interaction between severity of RA and period. The variation in the severity of RA was independent of intake, total VFA concentration, and individual VFA proportions. Production variables (milk yield, fat percentage, fat yield, fat-corrected milk, and efficiency of milk production) were not influenced by the severity of RA. Ruminal BCC was not influenced by dietary treatment or period. However, some cows experienced greater shift in BCC than other cows across the periods. Based on the magnitude of the shift in BCC (distance between mean ordination values across the periods for each cow), cows were grouped into 3 BCC profile categories: stable (5 cows with lesser shift), unstable (5 cows with greater shift), and intermediate (4 cows with average shift). Cows demonstrating a greater shift in BCC were not necessarily those in the most acidotic group and vice versa. The shift in ruminal fermentation variables (principal components analysis rankings) and the shift in BCC (automated ribosomal intergenic spacer analysis rankings) between pre- and postpartum were not related (n=14; R(2)=0.00). It was concluded that not all cows are equally susceptible to RA and postpartum shifts in BCC appear to be independent of the differences in the severity of RA postpartum. PMID:22981585

  15. Protective effects of high dietary potassium: nutritional and metabolic aspects.

    PubMed

    Demigné, Christian; Sabboh, Houda; Rémésy, Christian; Meneton, Pierre

    2004-11-01

    Potassium (K+) requirements have been largely overlooked because severe deficiencies are uncommon due to the ubiquity of this element in foods. However, a transition toward modern ("Westernized") diets has led to a substantial decline of K+ intake compared with traditional food habits, and a large fraction of the population might now have suboptimal K+ intake. A high K+ intake was demonstrated to have protective effects against several pathologic states affecting the cardiovascular system, kidneys, and bones. Additionally, fruits and vegetables contain K/organic anion salts (malate, citrate), which exert alkalinizing effects, through KHCO(3)(-) generation, which serves to neutralize fixed acidity in urine. Low-grade metabolic acidosis, when not properly controlled, may exacerbate various catabolic processes (bone Ca++ mobilization, proteolysis), especially in the elderly. Fruits and vegetables are therefore receiving great attention in a strategy to increase the nutritional value of meals while reducing energy density and intake. The need to ensure a 2.5- to 3.5-g daily K+ supply from fruits and vegetables represents a strong rationale for the "5-10 servings per day" recommendations. PMID:15514249

  16. Dynamic scenario of metabolic pathway adaptation in tumors and therapeutic approach

    PubMed Central

    Peppicelli, Silvia; Bianchini, Francesca; Calorini, Lido

    2015-01-01

    Cancer cells need to regulate their metabolic program to fuel several activities, including unlimited proliferation, resistance to cell death, invasion and metastasis. The aim of this work is to revise this complex scenario. Starting from proliferating cancer cells located in well-oxygenated regions, they may express the so-called “Warburg effect” or aerobic glycolysis, meaning that although a plenty of oxygen is available, cancer cells choose glycolysis, the sole pathway that allows a biomass formation and DNA duplication, needed for cell division. Although oxygen does not represent the primary font of energy, diffusion rate reduces oxygen tension and the emerging hypoxia promotes “anaerobic glycolysis” through the hypoxia inducible factor-1α-dependent up-regulation. The acquired hypoxic phenotype is endowed with high resistance to cell death and high migration capacities, although these cells are less proliferating. Cells using aerobic or anaerobic glycolysis survive only in case they extrude acidic metabolites acidifying the extracellular space. Acidosis drives cancer cells from glycolysis to OxPhos, and OxPhos transforms the available alternative substrates into energy used to fuel migration and distant organ colonization. Thus, metabolic adaptations sustain different energy-requiring ability of cancer cells, but render them responsive to perturbations by anti-metabolic agents, such as inhibitors of glycolysis and/or OxPhos. PMID:25897425

  17. A case of severe hyperammonemia and unconsciousness following sodium valproate intoxication.

    PubMed

    Lee, W L; Yang, C C; Deng, J F; Chen, Y F; Lin, H D; Wang, P H

    1998-12-01

    Although valproic acid has gradually gained its popularity in the treatment of various seizure disorders, overdose of valproate is not common. An 18-y-old man with a history of epilepsy controlled by sodium valproate and clonazepam attempted suicide with an ingestion of 45 g sodium valproate. He presented to our service with drowsiness and irritability. Extremely high serum ammonia (623 ug/dL) and elevated serum valproate concentration (575 ug/mL) were found on admission. Several metabolic abnormalities, including hypernatremia, hypocalcemia and metabolic acidosis, as well as, increased serum transaminase levels were also recorded. With supportive measures, he became clear 24 h later and was discharged 6 d after ingestion. Serial follow-up of his serum valproate and ammonia levels disclosed a close relationship between these 2 measurables. After acute overdose of valproic acid, patients usually present with mild and generally reversible depression of the central nervous system. However, impairment of liver function, hyperammonemia, fluid-electrolyte disturbances, coma, seizures, hypotension and even death may occur following valproate overdose. Symptomatic and supportive measures are the mainstay in the treatment of valproic acid overdose. With prompt diagnosis and early institution of treatment, a complete recovery should be anticipated. PMID:9830696

  18. Intermediary metabolism.

    PubMed Central

    Braeckman, Bart P; Houthoofd, Koen; Vanfleteren, Jacques R

    2009-01-01

    Caenorhabditis elegans has orthologs for most of the key enzymes involved in eukaryotic intermediary metabolism, suggesting that the major metabolic pathways are probably present in this species. We discuss how metabolic patterns and activity change as the worm traverses development and ages, or responds to unfavorable external factors, such as temperature extremes or shortages in food or oxygen. Dauer diapause is marked by an enhanced resistance to oxidative stress and a shift toward microaerobic and anaplerotic metabolic pathways and hypometabolism, as indicated by the increased importance of the malate dismutation and glyoxylate pathways and the repression of citric acid cycle activity. These alterations promote prolonged survival of the dauer larva; some of these changes also accompany the extended lifespan of insulin/IGF-1 and several mitochondrial mutants. We also present a brief overview of the nutritional requirements, energy storage and waste products generated by C. elegans. PMID:19248207

  19. NADPH Oxidase-2: Linking Glucose, Acidosis, and Excitotoxicity in Stroke

    PubMed Central

    Brennan-Minnella, Angela M.; Won, Seok Joon

    2015-01-01

    Abstract Significance: Neuronal superoxide production contributes to cell death in both glutamate excitotoxicity and brain ischemia (stroke). NADPH oxidase-2 (NOX2) is the major source of neuronal superoxide production in these settings, and regulation of NOX2 activity can thereby influence outcome in stroke. Recent Advances: Reduced NOX2 activity can rescue cells from oxidative stress and cell death that otherwise occur in excitotoxicity and ischemia. NOX2 activity is regulated by several factors previously shown to affect outcome in stroke, including glucose availability, intracellular pH, protein kinase ζ/δ, casein kinase 2, phosphoinositide-3-kinase, Rac1/2, and phospholipase A2. The newly identified functions of these factors as regulators of NOX2 activity suggest alternative mechanisms for their effects on ischemic brain injury. Critical Issues: Key aspects of these regulatory influences remain unresolved, including the mechanisms by which rac1 and phospholipase activities are coupled to N-methyl-D-aspartate (NMDA) receptors, and whether superoxide production by NOX2 triggers subsequent superoxide production by mitochondria. Future Directions: It will be important to establish whether interventions targeting the signaling pathways linking NMDA receptors to NOX2 in brain ischemia can provide a greater neuroprotective efficacy or a longer time window to treatment than provided by NMDA receptor blockade alone. It will likewise be important to determine whether dissociating superoxide production from the other signaling events initiated by NMDA receptors can mitigate the deleterious effects of NMDA receptor blockade. Antioxid. Redox Signal. 22, 161–174. PMID:24628477

  20. Ras triggers acidosis-induced activation of the extracellular-signal-regulated kinase pathway in cardiac myocytes

    PubMed Central

    Haworth, Robert S.; Dashnyam, Semjidmaa; Avkiran, Metin

    2006-01-01

    In cardiac myocytes, sustained (3 min) intracellular acidosis activates the ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway and, through this pathway, increases sarcolemmal NHE (Na+/H+ exchanger) activity [Haworth, McCann, Snabaitis, Roberts and Avkiran (2003) J. Biol. Chem. 278, 31676–31684]. In the present study, we aimed to determine the time-dependence, pH-dependence and upstream signalling mechanisms of acidosis-induced ERK1/2 activation in ARVM (adult rat ventricular myocytes). Cultured ARVM were subjected to intracellular acidosis for up to 20 min by exposure to NH4Cl, followed by washout with a bicarbonate-free Tyrode solution containing the NHE1 inhibitor cariporide. After the desired duration of intracellular acidosis, the phosphorylation status of ERK1/2 and its downstream effector p90RSK (90 kDa ribosomal S6 kinase) were determined by Western blotting. This revealed a time-dependent transient phosphorylation of both ERK1/2 and p90RSK by intracellular acidosis (intracellular pH ∼6.6), with maximum activation occurring at 3 min and a return to basal levels by 20 min. When the degree of intracellular acidosis was varied from ∼6.8 to ∼6.5, maximum ERK1/2 phosphorylation was observed at an intracellular pH of 6.64. Inhibition of MEK1/2 [MAPK (mitogen-activated protein kinase)/ERK kinase 1/2) by pre-treatment of ARVM with U0126 or adenoviral expression of dominant-negative D208A-MEK1 protein prevented the phosphorylation of ERK1/2 by sustained intracellular acidosis, as did inhibition of Raf-1 with GW 5074 or ZM 336372. Interference with Ras signalling by the adenoviral expression of dominant-negative N17-Ras protein or with FPT III (farnesyl protein transferase inhibitor III) also prevented acidosis-induced ERK1/2 phosphorylation, whereas inhibiting G-protein signalling [by adenoviral expression of RGS4 or Lsc, the RGS domain of p115 RhoGEF (guanine nucleotide-exchange factor)] or protein kinase C (with bisindolylmaleimide I) had no effect. Our data show that, in ARVM, sustained intracellular acidosis activates ERK1/2 through proximal activation of the classical Ras/Raf/MEK pathway. PMID:16831126

  1. Ruminal microbial and fermentative changes associated with experimentally induced subacute acidosis in steers.

    PubMed

    Goad, D W; Goad, C L; Nagaraja, T G

    1998-01-01

    We used six ruminally cannulated steers in a two-period crossover design to study ruminal fermentative and microbial changes associated with induced subacute acidosis. Steers were adapted to either an 80% alfalfa hay (hay-adapted)- or corn grain (grain-adapted)-based concentrate diet. After feed was withheld for 24 h, steers were overfed with an all-grain diet at 3.5 x NEm daily for 3 d. Ruminal contents and jugular blood samples were collected before withholding feed and at 0 and 12 h daily for 3 d during the overfeeding period. Ruminal samples were analyzed for pH, lactate, VFA concentrations, and counts of total anaerobic, amylolytic, lactic acid-producing and -fermenting bacteria, and ciliated protozoa. Blood samples were analyzed to assess acid-base status. Ruminal pH declined to a range of 5.5 to 5.0 with increased VFA concentrations, but normal lactate concentrations (<5 mM) were indicative of subacute acidosis. Total viable and amylolytic bacterial counts were higher (P < .05) in grain-adapted than hay-adapted steers. Anaerobic lactobacilli counts increased over time (P < .01) in both groups and were generally higher in grain-adapted than hay-adapted steers. Lactate-utilizing bacteria were initially greater in grain-adapted than hay-adapted steers and increased over time in both groups following grain challenge. Total ciliates were initially higher (P < .05) in grain-adapted than hay-adapted steers and decreased after 48 h in both groups. Blood acid-base changes were minimal. Bacterial changes associated with subacute acidosis resemble those reported during adaptation to grain feeding, and the decline in ciliated protozoa may be the only microbial indicator of a potentially acidotic condition in the rumen. PMID:9464904

  2. Acidosis dilates brain parenchymal arterioles by conversion of calcium waves to sparks to activate BK channels

    PubMed Central

    Dabertrand, Fabrice; Nelson, Mark T.; Brayden, Joseph E.

    2012-01-01

    Rationale Acidosis is a powerful vasodilator signal in the brain circulation. However, the mechanisms by which this response occurs are not well understood, particularly in the cerebral microcirculation. One important mechanism to dilate cerebral (pial) arteries is by activation of large-conductance, calcium-sensitive potassium (BKCa) channels by local Ca2+ signals (Ca2+ sparks) through ryanodine receptors (RyRs). However, the role of this pathway in the brain microcirculation is not known. Objective The objectives of this study were to determine the mechanism by which acidosis dilates brain parenchymal arterioles (PAs) and to elucidate the roles of RyRs and BKCa channels in this response. Methods and Results Internal diameter and vascular smooth muscle cell (VSMC) Ca2+ signals were measured in isolated pressurized murine PAs, using imaging techniques. In physiological pH (7.4), VSMCs exhibited primarily RyR-dependent Ca2+ waves. Reducing external pH from 7.4 to 7.0 in both normocapnic and hypercapnic conditions decreased Ca2+ wave activity, and dramatically increased Ca2+ spark activity. Acidic pH caused a dilation of PAs which was inhibited by about 60% by BKCa channel or RyR blockers, in a non-additive manner. Similarly, dilator responses to acidosis were reduced by nearly 60% in arterioles from BKCa channel knockout mice. Dilations induced by acidic pH were unaltered by inhibitors of KATP channels or nitric oxide synthase. Conclusions These results support the novel concept that acidification, by converting Ca2+ waves to sparks, leads to the activation of BKCa channels to induce dilation of cerebral parenchymal arterioles. PMID:22095728

  3. Metabolic Surgery Profoundly Influences Gut Microbial-Host Metabolic Crosstalk

    PubMed Central

    Li, Jia V.; Ashrafian, Hutan; Bueter, Marco; Kinross, James; Sands, Caroline; le Roux, Carel W; Bloom, Stephen R.; Darzi, Ara; Athanasiou, Thanos; Marchesi, Julian R.; Nicholson, Jeremy K.; Holmes, Elaine

    2013-01-01

    Background and Aims Bariatric surgery is increasingly performed worldwide to treat morbid obesity and is also known as metabolic surgery to reflect its beneficial metabolic effects especially with respect to improvement in type 2 diabetes. Understanding surgical weight loss mechanisms and metabolic modulation is required to enhance patient benefits and operative outcomes. Methods We apply a parallel and statistically integrated metagenomic and metabonomic approach to characterize Roux-en-Y gastric bypass (RYGB) effects in a rat model. Results We show substantial shifts of the main gut phyla towards higher levels of Proteobacteria (52-fold) specifically Enterobacter hormaechei. We also find low levels of Firmicutes (4.5-fold) and Bacteroidetes (2-fold) in comparison to sham-operated rats. Faecal extraction studies reveal a decrease in faecal bile acids and a shift from protein degradation to putrefaction through decreased faecal tyrosine with concomitant increases in faecal putrescine and diamnoethane. We find decreased urinary amines and cresols and demonstrate indices of modulated energy metabolism post-RYGB including decreased urinary succinate, 2-oxoglutarate, citrate and fumarate. These changes could also indicate renal tubular acidosis, which associates with increased flux of mitochondrial tricarboxylic acid cycle intermediates. A surgically-induced effect on the gut-brain-liver metabolic axis is inferred by increased neurotropic compounds; faecal γ-aminobutyric acid (GABA) and glutamate. Conclusion This profound co-dependence of mammalian and microbial metabolism, which is systematically altered following RYGB surgery, suggests that RYGB exerts local and global metabolic activities. The effect of RYGB surgery on the host metabolic-microbial crosstalk augments our understanding of the metabolic phenotype of bariatric procedures and can facilitate enhanced treatments for obesity-related diseases. PMID:21572120

  4. QTL for several metabolic traits map to loci controlling growth and body composition in an F2 intercross between high- and low-growth chicken lines.

    PubMed

    Nadaf, Javad; Pitel, Frédérique; Gilbert, Hélène; Duclos, Michel J; Vignoles, Florence; Beaumont, Catherine; Vignal, Alain; Porter, Tom E; Cogburn, Larry A; Aggrey, Samuel E; Simon, Jean; Le Bihan-Duval, Elisabeth

    2009-08-01

    Quantitative trait loci (QTL) for metabolic and body composition traits were mapped at 7 and 9 wk, respectively, in an F(2) intercross between high-growth and low-growth chicken lines. These lines also diverged for abdominal fat percentage (AFP) and plasma insulin-like growth factor-I (IGF-I), insulin, and glucose levels. Genotypings were performed with 129 microsatellite markers covering 21 chromosomes. A total of 21 QTL with genomewide level of significance were detected by single-trait analyses for body weight (BW), breast muscle weight (BMW) and percentage (BMP), AF weight (AFW) and percentage (AFP), shank length (ShL) and diameter (ShD), fasting plasma glucose level (Gluc), and body temperature (T(b)). Other suggestive QTL were identified for these parameters and for plasma IGF-I and nonesterified fatty acid levels. QTL controlling adiposity and Gluc were colocalized on GGA3 and GGA5 and QTL for BW, ShL and ShD, adiposity, and T(b) on GGA4. Multitrait analyses revealed two QTL controlling Gluc and AFP on GGA5 and Gluc and T(b) on GGA26. Significant effects of the reciprocal cross were observed on BW, ShD, BMW, and Gluc, which may result from mtDNA and/or maternal effects. Most QTL regions for Gluc and adiposity harbor genes for which alleles have been associated with increased susceptibility to diabetes and/or obesity in humans. Identification of genes responsible for these metabolic QTL will increase our understanding of the constitutive "hyperglycemia" found in chickens. Furthermore, a comparative approach could provide new information on the genetic causes of diabetes and obesity in humans. PMID:19531576

  5. Hashimoto thyroiditis, distal renal tubular acidosis, pernicious anaemia and encephalopathy: a rare combination of auto-immune disorders in a 12-year-old girl.

    PubMed

    Suzuki, N; Mitamura, R; Ohmi, H; Itoh, Y; Yano, K; Okuno, A; Tateno, M; Itoh, T

    1994-02-01

    A case of a 12-year-old girl with a multiple auto-immune disorder is reported. She showed Hashimoto thyroiditis which subsequently developed to hashitoxicosis and distal renal tubular acidosis at 5 years of age, pernicious anaemia at the age of 9 and severe encephalopathy at the age of 12. Laboratory studies revealed very high titres of anti-microsomal and anti-thyroglobulin antibodies and positive gastric parietal cell antibody. As to the encephalopathy, positive oligoclonal IgG bands and high values of IgG index and IgG synthesis ratio in CSF were observed with aggravation of her neurological symptoms. High-dose steroid therapy was effective toward the encephalopathy. Paediatricians should pay careful attention to patients with Hashimoto thyroiditis for association with other autoimmune disorders. PMID:8157029

  6. An autopsy case of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with intestinal bleeding in chronic renal failure.

    PubMed

    Mima, Akira; Shiota, Fumihiko; Matsubara, Takeshi; Iehara, Noriyuki; Akagi, Taro; Abe, Hideharu; Nagai, Kojiro; Matsuura, Motokazu; Murakami, Taichi; Kishi, Seiji; Araoka, Toshikazu; Kishi, Fumi; Kondo, Naoki; Shigeta, Reiko; Yoshikawa, Kazuhiro; Kita, Toru; Doi, Toshio; Fukatsu, Atsushi

    2011-01-01

    A 50-year-old man who underwent hemodialysis (HD) at local outpatient HD center due to end-stage renal disease (ESRD) was transferred to our hospital because of pneumonia. He had severe emaciation and past history of congestive heart failure. Presenting symptoms almost consistently involved difficulty in hearing and recurrent attacks of migraine-like headaches. He was diagnosed with dilated cardiomyopathy, showing diastolic mechanical dyssynchrony by tissue Doppler echocardiography. On the day of death, he had hematemesis and hemorrhagic shock. Autopsy revealed perforation of duodenum, and genetic analysis using mitochondrial DNA from cardiac muscle and iliopsoas muscle revealed a 3243A > G mutation in the mitochondrial tRNA(Leu(UUR)) gene, which is related to mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Multiple organ failure due to the mutation of mitochondrial DNA with gastrointestinal bleeding is not a common. PMID:21631236

  7. Exploring the mechanism of endothelial involvement in acidosis-induced vasodilatation of aortic tissues from normal and diabetic rats.

    PubMed

    Yeo, Jian Loong; Tan, Boris Teng Chuan; Achike, Francis I

    2010-09-10

    Acidosis modulates physiologic and pathophysiologic processes but the mechanism of acidotic vasodilatation remains unclear. We therefore explored this in aortic rings from normal and streptozotocin-induced diabetic Sprague-Dawley rats. Phenylephrine (PE)-induced contraction in endothelium-intact and -denuded rings were recorded under normal and acidotic pH with or without drug probes. Acidosis exerted a relaxant effect in endothelium-intact and -denuded euglycaemic and diabetic tissues. l-NAME or methylene blue partially inhibited acidotic relaxation in these endothelium-intact but not the -denuded tissues, with greater inhibition in the diabetic tissues, indicating that acidosis induces relaxation by endothelium-dependent and -independent mechanisms, the former being EDNO-cGMP mediated. Indomethacin had no effect on the tissues, indicating that cyclooxygenase products are neither involved in acidosis-induced vasodilatation nor in the modulation of phenylephrine-contraction. In euglycaemic tissues under normal pH, no K(+) channel blocker altered phenylephrine-contraction, but all (except glibenclamide) enhanced diabetic tissue contraction, indicating that normally, these channels (K(ir), K(V), BK(Ca), K(ATP)) do not modulate phenylephrine-contraction, but they (except K(ATP)) are expressed in diabetes where they attenuate phenylephine-induced contraction and modulate acidosis. Only the K(ir) channel modulates acidotic relaxation in euglycaemic tissues. Only tetraethylammonium and iberiotoxin enhanced phenylephrine-induced contraction in endothelium-denuded diabetic tissues indicating that BK(Ca) attenuates phenylephrine-contraction and that acidotic relaxation in this condition is modulated by a tetraethylammonium-sensitive mechanism. In conclusion, acidosis causes vasodilatation in normal and diabetic tissues via endothelium-dependent and -independent mechanisms differentially modulated by a combination of a NO-cGMP process and K(+) channels, some of which are dormant in the normal state but activated in diabetes mellitus. PMID:20553918

  8. Planned reoperation for severe trauma.

    PubMed Central

    Hirshberg, A; Mattox, K L

    1995-01-01

    OBJECTIVE: The authors review the physiologic basis, indications, techniques, and results of the planned reoperation approach to severe trauma. SUMMARY BACKGROUND DATA: Multivisceral trauma and exsanguinating hemorrhage lead to hypothermia, coagulopathy, and acidosis. Formal resections and reconstructions in these unstable patients often result in irreversible physiologic insult. A new surgical strategy addresses these physiologic concerns by staged control and repair of the injuries. METHOD: The authors review the literature. RESULTS: Indications for planned reoperation include avoidance of irreversible physiologic insult and inability to obtain direct hemostasis or formal abdominal closure. The three phases of the strategy include initial control, stabilization, and delayed reconstruction. Various techniques are used to obtain rapid temporary control of bleeding and hollow visceral spillage. Hypothermia, coagulopathy, and the abdominal compartment syndrome are major postoperative concerns. Definitive repair of the injuries is undertaken after stabilization. CONCLUSION: Planned reoperation offers a simple and effective alternative to the traditional surgical management of complex or multiple injuries in critically wounded patients. PMID:7618965

  9. [Higher Brain Dysfunction in Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS)].

    PubMed

    Ichikawa, Hiroo

    2016-02-01

    Stroke-like episodes are one of the cardinal features of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and occur in 84-99% of the patients. The affected areas detected on neuroimaging do not have classical vascular distribution, and involve predominantly the temporal, parietal and occipital lobes. Thus, the neurological symptoms including higher brain dysfunction correlate with this topographical distribution. In association with the occipital lobe involvement, the most frequent symptom is cortical blindness. Other symptoms have been occasionally reported in case reports: visual agnosia, prosopagnosia, cortical deafness, auditory agnosia, topographical disorientation, various types of aphasia, hemispatial neglect, and so on. On the other hand, cognitive decline associated with more diffuse brain impairment rather than with focal stroke-like lesions has been postulated. This condition is also known as mitochondrial dementia. Domains of cognitive dysfunction include abstract reasoning, verbal memory, visual memory, language (naming and fluency), executive or constructive functions, attention, and visuospatial function. Cognitive functions and intellectual abilities may decline from initially minimal cognitive impairment to dementia. To date, the neuropsychological and neurologic impairment has been reported to be associated with cerebral lactic acidosis as estimated by ventricular spectroscopic lactate levels. PMID:26873235

  10. D-Lactic Acidosis: An Underrecognized Complication of Short Bowel Syndrome

    PubMed Central

    Kowlgi, N. Gurukripa; Chhabra, Lovely

    2015-01-01

    D-lactic acidosis or D-lactate encephalopathy is a rare condition that occurs primarily in individuals who have a history of short bowel syndrome. The unabsorbed carbohydrates act as a substrate for colonic bacteria to form D-lactic acid among other organic acids. The acidic pH generated as a result of D-lactate production further propagates production of D-lactic acid, hence giving rise to a vicious cycle. D-lactic acid accumulation in the blood can cause neurologic symptoms such as delirium, ataxia, and slurred speech. Diagnosis is made by a combination of clinical and laboratory data including special assays for D-lactate. Treatment includes correcting the acidosis and decreasing substrate for D-lactate such as carbohydrates in meals. In addition, antibiotics can be used to clear colonic flora. Although newer techniques for diagnosis and treatment are being developed, clinical diagnosis still holds paramount importance, as there can be many confounders in the diagnosis as will be discussed subsequently. PMID:25977687

  11. Impact of subacute ruminal acidosis (SARA) adaptation on rumen microbiota in dairy cattle using pyrosequencing.

    PubMed

    Mao, S Y; Zhang, R Y; Wang, D S; Zhu, W Y

    2013-12-01

    The objective of this study was to evaluate the changes in bacterial populations in the rumen of dairy cattle following adaptation to subacute ruminal acidosis (SARA) using 16S rRNA gene pyrosequencing. Rumen contents were collected from four cattle adapted to either a 40% (control diet, COD) or 70% (SARA induction diet, SAID) concentrate feeds. DNA was extracted from each of the samples. Bacterial 16S rRNA genes of ruminal DNA extracts were PCR amplified with 2 bar coded primer sets and sequenced by 454 pyrosequencing. At a high taxonomic level, the percentage of Proteobacteria and Bacteroidetes were reduced by SAID feeding, whereas Firmicutes and Actinobacteria were more abundant in the SAID than in the COD group. At the genus level, as compared with the COD group, the abundances of Prevotella, Treponema, Anaeroplasma, Papillibacter, Acinetobacter and unclassified populations including unclassified Lentisphaerae, and unclassified bacteria were lower (P < 0.05), while the percentages of Ruminococcus, Atopobium, unclassified Clostridiales and Bifidobacterium were increased (P < 0.05) in the SAID group. Feeding of SAID reduced (P < 0.001) the diversity of the rumen microbial community. Taken together, our findings provide a comprehensive picture of current knowledge of the community structure of the rumen bacterial ecosystem during SARA, and enhance our understanding about the ruminal microbial ecology that may be useful in the prevention of ruminal acidosis. PMID:23994204

  12. The progression from a lower to a higher invasive stage of bladder cancer is associated with severe alterations in glucose and pyruvate metabolism.

    PubMed

    Conde, Vanessa R; Oliveira, Pedro F; Nunes, Ana R; Rocha, Cátia S; Ramalhosa, Elsa; Pereira, José A; Alves, Marco G; Silva, Branca M

    2015-07-01

    Cancer cells present a particular metabolic behavior. We hypothesized that the progression of bladder cancer could be accompanied by changes in cells glycolytic profile. We studied two human bladder cancer cells, RT4 and TCCSUP, in which the latter represents a more invasive stage. The levels of glucose, pyruvate, alanine and lactate in the extracellular media were measured by Proton Nuclear Magnetic Resonance. The protein expression levels of glucose transporters 1 (GLUT1) and 3 (GLUT3), monocarboxylate transporter 4 (MCT4), phosphofructokinase-1 (PFK1), glutamic-pyruvate transaminase (GPT) and lactate dehydrogenase (LDH) were determined. Our data showed that glucose consumption and GLUT3 levels were similar in both cell lines, but TCCSUP cells displayed lower levels of GLUT1 and PFK expression. An increase in pyruvate consumption, concordant with the higher levels of lactate and alanine production, was also detected in TCCSUP cells. Moreover, TCCSUP cells presented lower protein expression levels of GPT and LDH. These results illustrate that bladder cancer progression is associated with alterations in cells glycolytic profile, namely the switch from glucose to pyruvate consumption in the more aggressive stage. This may be useful to develop new therapies and to identify biomarkers for cancer progression. PMID:25907297

  13. The effects of cinacalcet treatment on bone mineral metabolism, anemia parameters, left ventricular mass index and parathyroid gland volume in hemodialysis patients with severe secondary hyperparathyroidism.

    PubMed

    Torun, Dilek; Yildiz, Ismail; Micozkadioglu, Hasan; Nursal, Gul Nihal; Yigit, Fatma; Ozelsancak, Ruya

    2016-01-01

    The aim of this study was to investigate the effects of cinacalcet therapy on anemia parameters, bone mineral metabolism, left ventricular mass index (LVMI) and parathyroid gland volume in hemodialysis (HD) patients with secondary hyperparathyroidism. Twenty-five HD patients (M/F: 11/14, mean age: 45.2±17.9 years, mean HD duration: 96.4±32.7 months) were included in this prospective pilot study. The indication to start calcimimetic therapy was persistent serum levels of parathyroid hormone (PTH)>1000 pg/mL, refractory to intravenous (i.v.) vitamin D and phosphate-binding therapy. The initial and one-year results of adjusted serum calcium (Ca+2), phosphate (P), Ca×P product, PTH, hemoglobin (Hb) and ferritin levels, transferrin saturation index (TSAT), median weekly erythropoietin (EPO) dose, LVMI, and parathyroid volume by parathyroid ultrasonography were determined. There were no differences between pre- and post-treatment levels of serum Ca+2 (P=0.853), P (P=0.447), Ca×P product (P=0.587), PTH (P=0.273), ferritin (P=0.153) and TSAT (P=0.104). After 1 year of calcimimetic therapy, the Hb levels were significantly higher than the initial levels (P=0.048). The weekly dose of EPO decreased with no statistical significance. The dose of cinacalcet was increased from 32.4±12.0 to 60.0±24.4 mg/day (P=0.01). There were no differences between the pre- and post-treatment results regarding weekly vitamin D dose, parenteral iron dose, LVMI and parathyroid volume. The results of our study suggest that cinacalcet therapy might have an additional benefit in the control anemia in HD patients. PMID:26787561

  14. Human H+ATPase a4 subunit mutations causing renal tubular acidosis reveal a role for interaction with phosphofructokinase-1

    PubMed Central

    Su, Ya; Blake-Palmer, Katherine G.; Sorrell, Sara; Javid, Babak; Bowers, Katherine; Zhou, Aiwu; Chang, Simon H.; Qamar, Seema; Karet, Fiona E.

    2008-01-01

    The vacuolar-type ATPase (H+ATPase) is a ubiquitously expressed multisubunit pump whose regulation is poorly understood. Its membrane-integral a-subunit is involved in proton translocation and in humans has four forms, a1–a4. This study investigated two naturally occurring point mutations in a4's COOH terminus that cause recessive distal renal tubular acidosis (dRTA), R807Q and G820R. Both lie within a domain that binds the glycolytic enzyme phosphofructokinase-1 (PFK-1). We recreated these disease mutations in yeast to investigate effects on protein expression, H+ATPase assembly, targeting and activity, and performed in vitro PFK-1 binding and activity studies of mammalian proteins. Mammalian studies revealed complete loss of binding between the COOH terminus of a4 containing the G-to-R mutant and PFK-1, without affecting PFK-1's catalytic activity. In yeast expression studies, protein levels, H+ATPase assembly, and targeting of this mutant were all preserved. However, severe (78%) loss of proton transport but less decrease in ATPase activity (36%) were observed in mutant vacuoles, suggesting a requirement for the a-subunit/PFK-1 binding to couple these two functions. This role for PFK in H+ATPase function was supported by similar functional losses and uncoupling ratio between the two proton pump domains observed in vacuoles from a PFK-null strain, which was also unable to grow at alkaline pH. In contrast, the R-to-Q mutation dramatically reduced a-subunit production, abolishing H+ATPase function completely. Thus in the context of dRTA, stability and function of the metabolon composed of H+ATPase and glycolytic components can be compromised by either loss of required PFK-1 binding (G820R) or loss of pump protein (R807Q). PMID:18632794

  15. Impact of hard vs. soft wheat and monensin level on rumen acidosis in feedlot heifers.

    PubMed

    Yang, W Z; Xu, L; Zhao, Y L; Chen, L Y; McAllister, T A

    2014-11-01

    Many feedlot finishing diets include wheat when the relative wheat prices are low. This study was conducted to examine the responses in ruminal pH and fermentation as well as site and extent of digestion from substituting soft or hard wheat for barley grain and to determine whether an elevated monensin concentration might decrease indicators of ruminal acidosis in feedlot heifers. Five ruminally cannulated beef heifers were used in a 5 × 5 Latin square with 2 × 2 + 1 factorial arrangement. Treatments included barley (10% barley silage, 86% barley, 4% supplement, with 28 mg monensin/kg DM) and diets where barley was substituted by either soft or hard wheat with either 28 or 44 mg monensin/kg diet DM. Intake of DM was not affected by grain source, whereas increasing monensin with wheat diets reduced (P < 0.02) DMI. Mean ruminal pH was lower (P < 0.04) and durations of pH < 5.8 and pH < 5.5 greater (P < 0.03) for wheat than for barley diets. However, ruminal pH was not affected by wheat type or monensin level. Total VFA concentrations were greater (P < 0.03) for wheat than barley diets with no effect of wheat type. The molar proportion of propionate was greater (P < 0.04), whereas butyrate (P < 0.01) and ratio of acetate to propionate tended to be lower (P < 0.09), with the high as compared to low level of monensin. Replacing barley with wheat in finishing diets did not affect the duodenal flow or the digestibility of OM, likely as a result of greater (P < 0.01) NDF digestion from barley offsetting the increased (P < 0.03) supply of digested starch from wheat. Feeding soft vs. hard wheat delivered a greater (P < 0.03) duodenal supply of OM and nonammonia N with no differences in total tract nutrient digestion. The increased monensin concentration decreased the flow of OM (P < 0.01), total N (P < 0.05), and microbial protein (P < 0.05) to the small intestine due to decreased DMI. These results indicated that hard and soft wheat exhibited digestive characteristics similar to barley, but ruminal pH measurements indicate that compared with barley, wheat increased the risk of ruminal acidosis. Although an increased level of monensin had limited impact on ruminal indicators of acidosis, an increase in propionate would be expected to improve efficiency of feed use by heifers fed wheat-based finishing diets. PMID:25253812

  16. Individual animal variability in ruminal bacterial communities and ruminal acidosis in primiparous Holstein cows during the periparturient period

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The purpose of this study was to investigate variability among individual cows for their susceptibility to ruminal acidosis (RA) pre- and postpartum, and determine whether this variability was related to differences in their ruminal bacterial community composition (BCC). Variability in susceptibilit...

  17. When should MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis?

    PubMed

    Lorenzoni, Paulo Jos; Werneck, Lineu Cesar; Kay, Cludia Suemi Kamoi; Silvado, Carlos Eduardo Soares; Scola, Rosana Herminia

    2015-11-01

    Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a rare mitochondrial disorder. Diagnostic criteria for MELAS include typical manifestations of the disease: stroke-like episodes, encephalopathy, evidence of mitochondrial dysfunction (laboratorial or histological) and known mitochondrial DNA gene mutations. Clinical features of MELAS are not necessarily uniform in the early stages of the disease, and correlations between clinical manifestations and physiopathology have not been fully elucidated. It is estimated that point mutations in the tRNALeu(UUR) gene of the DNAmt, mainly A3243G, are responsible for more of 80% of MELAS cases. Morphological changes seen upon muscle biopsy in MELAS include a substantive proportion of ragged red fibers (RRF) and the presence of vessels with a strong reaction for succinate dehydrogenase. In this review, we discuss mainly diagnostic criterion, clinical and laboratory manifestations, brain images, histology and molecular findings as well as some differential diagnoses and current treatments. PMID:26517220

  18. P-leader multifractal analysis and sparse SVM for intrapartum fetal acidosis detection.

    PubMed

    Leonarduzzi, R; Spilka, J; Frecon, J; Wendt, H; Pustelnik, N; Jaffard, S; Abry, P; Doret, M

    2015-08-01

    Interpretation and analysis of intrapartum fetal heart rate, enabling early detection of fetal acidosis, remains a challenging signal processing task. Among the many strategies that were used to tackle this problem, scale-invariance and multifractal analysis stand out. Recently, a new and promising variant of multifractal analysis, based on p-leaders, has been proposed. In this contribution, we use sparse support vector machines applied to p-leader multifractal features with a double aim: Assessment of the features actually contributing to classification; Assessment of the contribution of non linear features (as opposed to linear ones) to classification performance. We observe and interpret that the classification rate improves when small values of the tunable parameter p are used. PMID:26736671

  19. Effect of pump prime on acidosis, strong-ion-difference and unmeasured ions during cardiopulmonary bypass.

    PubMed

    Liskaser, F; Story, D A; Hayhoe, M; Poustie, S J; Bailey, M J; Bellomo, R

    2009-09-01

    We tested the hypothesis that a cardiopulmonary bypass prime with lactate would be associated with less acidosis than a prime with only chloride anions because of differences in the measured strong-ion-difference. We randomised 20 patients to a 1500 ml bypass prime with either a chloride-only solution (Ringer's Injection; anions: chloride 152 mmol/l) or a lactated solution (Hartmann's solution; anions: chloride 109 mmol/l, lactate 29 mmol/l). Arterial blood was sampled before bypass and then two, five, 15 and 30 minutes after initiating bypass. We used repeated measures analysis of variance to compare groups. In both groups, the base-excess and measured strong-ion-difference decreased markedly from baseline after two minutes of bypass. The chloride-only group had greater acidosis with lower base-excess and pH (P < 0.05), greatest after five minutes of bypass (C5). Contrary to our hypothesis, however, the difference between the groups was not due to a difference in the measured strong-ion-difference, P = 0.88. At C5 when the difference in standard base-excess between the groups was greatest, 1.9 mmol/l (95% confidence interval: 0.1 to 3.6 mmol/l, P < 0.05), the difference in the measured strong-ion-difference was only 0.2 mmol/l (95% confidence interval: -2.4 to 2.7 mmol/l, P > 0.05). There was, however a difference in the net-unmeasured-ions (strong-ion-gap). We conclude that acid-base changes with cardiopulmonary bypass may differ with the prime but that the early differences between chloride-only and lactated primes appear not to be due to differences in the measured strong-ion-difference. We suggest future studies examine other possible mechanisms including unmeasured ions. PMID:19775041

  20. Prevalence and consequences of subacute ruminal acidosis in German dairy herds

    PubMed Central

    2013-01-01

    Background The prevalence and the clinical consequences of subacute ruminal acidosis (SARA) in dairy cows are still poorly understood. In order to evaluate the prevalence of SARA, 26 German dairy farms were included in a field study. In each herd, between 11 and 14 lactating dairy cows were examined for their ruminal pH using rumenocentesis. Milk production data and farm management characteristics were recorded. Each farm was scored for lameness prevalence among lactating animals, and body condition score was recorded three times four to five weeks apart in all animals examined. Farms were grouped on basis of ruminal pH and compared for lameness, body condition, milk production parameters and style of management. Animals were grouped on basis of their measured ruminal pH and compared accordingly for milk production parameters and body condition score. Results Of 315 cows examined, 63 individuals (20%) exhibited a ruminal pH of ≤ 5.5 at time of rumenocentesis. Of 26 farms examined, eleven farms had three or more of their cows experiencing a ruminal pH of ≤ 5.5 and were classified as likely experiencing subacute ruminal acidosis. These farms tended to be bigger than the others and offered less lying space to the lactating cows. There was no clear tendency regarding lameness. Among individual cows, animals with a low ruminal pH of ≤ 5.5 were found to be in significantly poorer body condition than animals with higher pH values (p < 0,05). Conclusions The study shows 11 out of 26 of herds likely experiencing SARA. Bigger herds tend to be at a higher risk for SARA, while individuals with low ruminal pH tend to be lower in body condition. The study points to the importance of management in preventing SARA. PMID:23805878

  1. 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. PMID:24256552

  2. Deficiency of dihydrolipoyl dehydrogenase (a component of the pyruvate and alpha-ketoglutarate dehydrogenase complexes): a cause of congenital chronic lactic acidosis in infancy.

    PubMed

    Robinson, B H; Taylor, J; Sherwood, W G

    1977-12-01

    A male child died at 7 months of age with progressive neurologic deterioration and persistent metabolic acidosis. Investigations during life showed this child to have elevated blood pyruvate, lactate, and alpha-ketoglutarate as well as elevation of branched chain amino acids and occasional hypoglycemia. Cofactor therapy using either thiamine-HCl (2 g/kg/24 hr) or thiamine tetrahydrofurfuryl disulfide had no measurable effect on the clinical or biochemical status of the patient. Tissue taken postmortem showed normal levels of key gluconeogenic enzymes but a deficiency in the activity of pyruvate dehydrogenase in all tissues tested (liver, brain, kidney, skeletal muscle, and heart). Examination of the individual activities of pyruvate dehydrogenase complex showed pyruvate decarboxylase (E1) to be normal in liver and other tissues. Dihydrolipoyl dehydrogenase (E3), on the other hand, was deficient in all tissues tested. alpha-Ketoglutarate dehydrogenase complex, which depends of E3 for its total activity, was also deficient in all tissues tested. The absence of this enzyme id discussed in relation to the clinical and biochemical status of the patient. PMID:413089

  3. Correlation analysis of hypothalamic mRNA levels of appetite regulatory neuropeptides and several metabolic parameters in 28-day-old layer chickens.

    PubMed

    Honda, Kazuhisa; Saneyasu, Takaoki; Aoki, Koji; Shimatani, Tomohiko; Yamaguchi, Takuya; Kamisoyama, Hiroshi

    2015-05-01

    Various lines of evidence suggest that appetite-related neuropeptides in the hypothalamus are regulated by adiposity signals such as leptin and insulin in mammals. In the present study, we examined age-dependent changes in the weight of abdominal fat and hypothalamic mRNA levels of neuropeptide Y (NPY, an orexigenic neuropeptide) and proopiomelanocortin (POMC, a precursor of anorexigenic neuropeptides) in growing chickens at 7, 14, 21 and 28 days of age. Hypothalamic NPY mRNA levels were significantly (P < 0.05) decreased after 14 days of age, whereas hypothalamic POMC mRNA levels were significantly (P < 0.05) increased at 28 days of age. The percentage of abdominal fat was significantly increased after 14 days of age in chickens. We next examined the correlation of hypothalamic NPY and POMC mRNA levels and several parameters at 28 days of age. There were no significant correlations between hypothalamic mRNA levels of NPY or POMC and the percentage of abdominal fat. These findings suggest that the gene expressions of NPY and POMC do not depend on adiposity in chickens, at least in 28-day-old layer chickens. PMID:25441031

  4. Metabolic alkalosis transition in renal proximal tubule cells facilitates an increase in CYP27B1, while blunting responsiveness to PTH

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Parathyroid hormone (PTH) is the central activator of renal proximal 1-alpha-hydroxylase (CYP27B1), the enzyme responsible for synthesis of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Past studies have documented a disruption of CYP27B1 activity in chronic metabolic acidosis in vivo, while simulated ac...

  5. The central role of chloride in the metabolic acid-base changes in canine parvoviral enteritis.

    PubMed

    Burchell, Richard K; Schoeman, Johan P; Leisewitz, Andrew L

    2014-04-01

    The acid-base disturbances in canine parvoviral (CPV) enteritis are not well described. In addition, the mechanisms causing these perturbations have not been fully elucidated. The purpose of the present study was to assess acid-base changes in puppies suffering from CPV enteritis, using a modified strong ion model (SIM). The hypothesis of the study was that severe acid-base disturbances would be present and that the SIM would provide insights into pathological mechanisms, which have not been fully appreciated by the Henderson-Hasselbalch model. The study analysed retrospective data, obtained from 42 puppies with confirmed CPV enteritis and 10 healthy control dogs. The CPV-enteritis group had been allocated a clinical score, to allow classification of the data according to clinical severity. The effects of changes in free water, chloride, l-lactate, albumin and phosphate were calculated, using a modification of the base excess algorithm. When the data were summated for each patient, and correlated to each individual component, the most important contributor to the metabolic acid-base changes, according to the SIM, was chloride (P<0.001). Severely-affected animals tended to demonstrate hypochloraemic alkalosis, whereas mildly-affected puppies had a hyperchloraemic acidosis (P=0.007). In conclusion, the acid-base disturbances in CPV enteritis are multifactorial and complex, with the SIM providing information in terms of the origin of these changes. PMID:24613416

  6. Rumen epithelial adaptation to ruminal acidosis in lactating cattle involves the coordinated expression of insulin-like growth factor-binding proteins and a cholesterolgenic enzyme.

    PubMed

    Steele, M A; Dionissopoulos, L; AlZahal, O; Doelman, J; McBride, B W

    2012-01-01

    The objective of this study was to characterize the mRNA expression of metabolic and proliferative genes in the rumen epithelium during ruminal acidosis. To meet our objectives, 16 rumen-fistulated, lactating Holstein dairy cattle (618±35 kg of body weight, 221±32 d in milk) were used in a randomized complete block design. All cattle were fed a high-forage diet (HF; 88.9% of dry matter) for 5 wk before the experiment. After the baseline week (wk 0), half of the cattle were randomly assigned and transitioned to a high-concentrate diet (HC; 62.2% of dry matter) which was fed for 3 wk (wk 1, 2, and 3). For the last 48 h of each week, continuous ruminal pH, short-chain fatty acids, and plasma β-hydroxybutyrate were assessed, followed by a rumen papillae biopsy. Milk production was higher in HC cattle compared with HF during wk 1, 2, and 3 (17.4±0.5 vs. 23.4±0.9 kg/d, respectively); however, the mean ruminal pH was decreased (5.75±0.03 vs. 6.30±0.02). The HC cattle spent more time below pH 5.6 (594±54 vs. 3±3 min/d) and displayed greater concentrations of ruminal butyrate (15.8±0.9 vs. 10.2±0.4 mmol) and plasma β-hydroxybutyrate (1,036±63 vs. 778±20 μM) compared with the HF cattle. The mRNA expression of genes involved in ketogenesis (HMGCS2 and PPARA) and short-chain fatty acid transport (MCT1) was unchanged by treatment. However, a downregulation in HMGCS1 (0.72±0.09), one of the cholesterol biosynthesis genes, was observed in HC cattle during wk 1 of the grain challenge. In addition, the relative mRNA expression value of insulin-like growth factor-binding protein 3 was lower (0.78±0.06), whereas insulin-like growth factor-binding protein 5 was higher (1.79±0.15) in HC compared with HF cattle. These results suggest that grain-induced ruminal acidosis alters the mRNA expression of IGF-binding proteins and a cholesterolgenic enzyme in the rumen epithelium of lactating dairy cattle. PMID:22192211

  7. Comprehensive review on lactate metabolism in human health.

    PubMed

    Adeva-Andany, M; López-Ojén, M; Funcasta-Calderón, R; Ameneiros-Rodríguez, E; Donapetry-García, C; Vila-Altesor, M; Rodríguez-Seijas, J

    2014-07-01

    Metabolic pathways involved in lactate metabolism are important to understand the physiological response to exercise and the pathogenesis of prevalent diseases such as diabetes and cancer. Monocarboxylate transporters are being investigated as potential targets for diagnosis and therapy of these and other disorders. Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. Pyruvate may be either oxidized to carbon dioxide producing energy or transformed into glucose. Pyruvate oxidation requires oxygen supply and the cooperation of pyruvate dehydrogenase, the tricarboxylic acid cycle, and the mitochondrial respiratory chain. Enzymes of the gluconeogenesis pathway sequentially convert pyruvate into glucose. Congenital or acquired deficiency on gluconeogenesis or pyruvate oxidation, including tissue hypoxia, may induce lactate accumulation. Both obese individuals and patients with diabetes show elevated plasma lactate concentration compared to healthy subjects, but there is no conclusive evidence of hyperlactatemia causing insulin resistance. Available evidence suggests an association between defective mitochondrial oxidative capacity in the pancreatic β-cells and diminished insulin secretion that may trigger the development of diabetes in patients already affected with insulin resistance. Several mutations in the mitochondrial DNA are associated with diabetes mellitus, although the pathogenesis remains unsettled. Mitochondrial DNA mutations have been detected in a number of human cancers. d-lactate is a lactate enantiomer normally formed during glycolysis. Excess d-lactate is generated in diabetes, particularly during diabetic ketoacidosis. d-lactic acidosis is typically associated with small bowel resection. PMID:24929216

  8. Clinical spectrum and treatment outcome of severe malaria caused by Plasmodium vivax in 18 children from northern India

    PubMed Central

    Gehlawat, Virender Kumar; Arya, Vandana; Kaushik, Jaya Shankar; Gathwala, Geeta

    2013-01-01

    Objective The study was intended to document the clinical profile and treatment outcome of severe malaria caused by Plasmodium vivax (P.vivax) in children hospitalized in a tertiary care centre of northern India. Methods This prospective observational study was performed among children admitted with severe malaria at a tertiary care referral hospital of northern India from January 2012 to December 2012. Information was recorded pertaining to clinical symptoms at presentation, examination findings, biochemical and hematological investigation, and treatment outcome. Presence of malarial parasite on thick and thin smears and/or positive parasite lactate dehydrogenase (p-LDH) based rapid malaria antigen test was considered diagnostic of ‘malaria’. Based on the etiology, children were categorized into three groups: P.vivax, Plasmodium falciparum (P. falciparum) and mixed infection. Children diagnosed with ‘severe malaria’ (World Health Organization, 2000), were started on intravenous artesunate followed by artemether-lumefantrine combination. Results Thirty-five children with a diagnosis of severe malaria were enrolled [18 (51.4%) P. vivax, nine (25.7%) mixed infection, eight (22.8%) P. falciparum]. Clinical features of severe vivax malaria (n = 18) were abnormal sensorium [9 (50%)], multiple seizures [8 (44.4%)], jaundice [5 (27.8%)], severe anaemia [5 (27.8%)], and shock [3 (16.7%)]. Two children [2/18 (11.1%)] infected with P. vivax had died of cerebral malaria, acute respiratory distress syndrome, shock, and metabolic acidosis. The clinical presentation and outcome of severe vivax malaria was found to be similar to severe malaria caused by P. falciparum and mixed infection, except for higher chances of severe anaemia among the children infected with P. falciparum (P = 0.04). Conclusion The present study highlights P. vivax as an increasingly recognized causative agent for severe malaria in children from Rohtak, with similar clinical presentation and outcome to that caused by P. falciparum. PMID:23816514

  9. [Severe felodipine and theophylline poisoning successfully treated by 4-aminopyridine: a case report].

    PubMed

    Magdalan, Jan; Kochman, Krystyna; Smolarek, Ma?gorzata; Przew?ocki, Michal; Anto?czyk, Andrzej

    2003-01-01

    The case of a 51-year-old man who ingested 100 mg of felodipine (Plendil, 20 tablets 5 mg) and 9 g of theophylline (Theospirex retard, 30 tablets 300 mg) is presented. The patient developed severe hypotension, tachycardia, circulatory insufficiency and paralytic ileus. No ECG effects were observed. Although felodipine led to a reduction in the bioability of theophylline, the serum theophylline concentration 15 h after the admission was 92 mg/L (the therapeutic concentration of theophylline 10-20 mg/L). The protracted hypotension did not respond to vasopressor and calcium therapy. The addition of 4-aminopyridine (4-AP) infusion resulted in fast receding of poisoning symptoms: increase of blood pressure, receding of circulatory insufficiency and metabolic acidosis, and return of peristalsis. This case suggests the usefulness of 4-AP in the treatment of poisoning by dihydropyridine derivatives. However, confirmation of the effectiveness of this substance for pharmacotherapy of dihydrophyridine derivatives poisoning requires further clinical research. The influence of 4-AP on calcium channels is indirect. It blocks potassium channels K1 in cytoplasm side which makes potassium stay inside the cell leading to depolarisation and opening of voltage-dependent calcium channels. PMID:14569900

  10. Role of interleukin 1 and tumor necrosis factor on energy metabolism in rabbits

    SciTech Connect

    Tredget, E.E.; Yu, Y.M.; Zhong, S.; Burini, R.; Okusawa, S.; Gelfand, J.A.; Dinarello, C.A.; Young, V.R.; Burke, J.F.

    1988-12-01

    A study of the combined effects of intravenous infusion of the recombinant cytokines beta-interleukin 1 (IL-1) and alpha-tumor necrosis factor (TNF) on energy substrate metabolism in awake, conditioned, adult rabbits was performed. After a 2-h basal or control period, 48-h fasted rabbits were administered TNF and IL-1 as a bolus (5 micrograms/kg) followed by a continuous intravenous infusion (25 ng.kg-1.min-1) for 3 h. Significant increases in plasma lactate (P less than 0.01), glucose (P less than 0.01), and triglycerides (P less than 0.05) occurred during the combined infusion of IL-1 and TNF, whereas neither cytokine alone had no effect. There was a 33% increase in the rate of glucose appearance (P less than 0.05), but glucose clearance was not altered compared with the control period. Glucose oxidation increased during the combined cytokine infusion period and glucose recycling increased by 600% (P less than 0.002). Lactic acidosis and decreased oxygen consumption, as a result of the cytokine infusions, indicated development of anaerobic glycolytic metabolism. A reduction in the activity state of hepatic mitochondrial pyruvate dehydrogenase (65 vs. 82% in control animals, P less than 0.05) was consistent with the observed increase in anaerobic glycolysis. Thus the combined infusion of IL-1 and TNF in rabbits produces metabolic manifestations seen in severe injury and sepsis in human patients and, as such, may account for the profound alterations of energy metabolism seen in these conditions.

  11. Role of arginine vasopressin and angiotensin II in cardiovascular responses to combined acute hypoxemia and hypercapnic acidosis in conscious dogs.

    PubMed Central

    Rose, C E; Godine, R L; Rose, K Y; Anderson, R J; Carey, R M

    1984-01-01

    The physiological relationship of increased circulating angiotensin II and vasopressin to circulatory changes during combined hypoxemia and hypercapnic acidosis is unclear. To evaluate the role(s) of angiotensin II and vasopressin, seven unanesthetized female mongrel dogs with controlled sodium intake (80 meq/24 h X 4 d) were studied during 40 min of combined acute hypoxemia and hypercapnic acidosis (PaO2, 36 +/- 1 mmHg; PaCO2, 55 +/- 2 mmHg; pH = 7.16 +/- 0.04) under the following conditions: (a) intact state with infusion of vehicles alone; (b) beta-adrenergic blockade with infusion of d,l-propranolol (1.0 mg/kg bolus, 0.5 mg/kg per h); of the vasopressin pressor antagonist d-(CH2)5Tyr(methyl)arginine-vasopressin (10 micrograms/kg); and (d) simultaneous vasopressin pressor and angiotensin II inhibition with the additional infusion of 1-sarcosine, 8-alanine angiotensin II (2.0 micrograms/kg per min). The rise in mean arterial pressure during the combined blood-gas derangement with vehicles appeared to be related to increased cardiac output, since total peripheral resistance fell. Beta-adrenergic blockade abolished the fall in total peripheral resistance and diminished the rise in cardiac output during combined hypoxemia and hypercapnic acidosis, but the systemic pressor response was unchanged. In addition, the rise in mean arterial pressure during the combined blood-gas derangement was unaltered with vasopressin pressor antagonism alone. In contrast, the simultaneous administration of the vasopressin pressor and angiotensin II inhibitors during combined hypoxemia and hypercapnic acidosis resulted in the abrogation of the overall systemic pressor response despite increased cardiac output, owing to a more pronounced fall in total peripheral resistance. Circulating catecholamines were increased during the combined blood-gas derangement with vasopressin pressor and angiotensin II blockade, suggesting that the abolition of the systemic pressor response in the last 30 min of combined hypoxemia and hypercapnic acidosis was not related to diminished activity of the sympathetic nervous system. These studies show that vasopressin and angiotensin II are major contributors to the systemic pressor response during combined acute hypoxemia and hypercapnic acidosis. PMID:6547729

  12. Metabolic alkalosis.

    PubMed

    Khanna, A; Kurtzman, N A

    2001-04-01

    Metabolic alkalosis is a primary pathophysiologic event characterized by the gain of bicarbonate or the loss of nonvolatile acid from extracellular fluid. The kidney preserves normal acid-base balance by two mechanisms: bicarbonate reclamation, mainly in the proximal tubule, and bicarbonate generation, predominantly in the distal nephron. Bicarbonate reclamation is mediated mainly by a Na(+)-H(+) antiporter and to a smaller extent by the H(+)-ATPase (adenosine triphosphate-ase). The principal factors affecting HCO3(-) reabsorption include effective arterial blood volume, glomerular filtration rate, chloride, and potassium. Bicarbonate regeneration is primarily affected by distal Na(+) delivery and reabsorption, aldosterone, arterial pH, and arterial partial pressure of carbon dioxide. To generate metabolic alkalosis, either a gain of base or a loss of acid must occur. The loss of acid may be via the gastrointestinal tract or via the kidney. Excess base may be gained by oral or parenteral HCO3(-) administration or by lactate, acetate, or citrate administration. Factors that help maintain metabolic alkalosis include decreased glomerular filtration rate, volume contraction, hypokalemia, hypochloremia, and aldosterone excess. Clinical states associated with metabolic alkalosis are vomiting, mineralocorticoid excess, the adrenogenital syndrome, licorice ingestion, diuretic administration, and Bartter's and Gitelman's syndromes. The effects of metabolic alkalosis on the body are variable and include effects on the central nervous system, myocardium, skeletal muscle, and liver. Treatment of this disorder is simple, once the pathophysiology of the cause is delineated. Therapy consists of reversing the contributory factors that are promoting the alkalosis and, in severe cases, administration of carbonic anhydrase inhibitors, acid infusion, and low bicarbonate dialysis. PMID:11262555

  13. Molecular Connections between Cancer Cell Metabolism and the Tumor Microenvironment

    PubMed Central

    Justus, Calvin R.; Sanderlin, Edward J.; Yang, Li V.

    2015-01-01

    Cancer cells preferentially utilize glycolysis, instead of oxidative phosphorylation, for metabolism even in the presence of oxygen. This phenomenon of aerobic glycolysis, referred to as the “Warburg effect”, commonly exists in a variety of tumors. Recent studies further demonstrate that both genetic factors such as oncogenes and tumor suppressors and microenvironmental factors such as spatial hypoxia and acidosis can regulate the glycolytic metabolism of cancer cells. Reciprocally, altered cancer cell metabolism can modulate the tumor microenvironment which plays important roles in cancer cell somatic evolution, metastasis, and therapeutic response. In this article, we review the progression of current understandings on the molecular interaction between cancer cell metabolism and the tumor microenvironment. In addition, we discuss the implications of these interactions in cancer therapy and chemoprevention. PMID:25988385

  14. Effect of induction of subacute ruminal acidosis on milk fat profile and rumen parameters.

    PubMed

    Colman, E; Fokkink, W B; Craninx, M; Newbold, J R; De Baets, B; Fievez, V

    2010-10-01

    High-concentrate diets can lead to subacute ruminal acidosis and are known to result in changes of the ruminal fermentation pattern and mammary secretion of fatty acids. The objective of this paper is to describe modifications in milk fatty acid proportions, particularly odd- and branched-chain fatty acids and rumen biohydrogenation intermediates, associated with rumen parameters during a 6-wk subacute ruminal acidosis induction protocol with 12 ruminally fistulated multiparous cows. The protocol involved a weekly gradual replacement of a standard dairy concentrate with a wheat-based concentrate (610 g of wheat/kg of concentrate) during the first 5 wk and an increase in the total amount of concentrate in wk 6. Before the end of induction wk 6, cows were switched to a control diet because 7 cows showed signs of sickness. The pH was measured continuously by an indwelling pH probe. Milk and rumen samples were taken on d 2 and 7 of each week. Data were analyzed using a linear mixed model and by principal component analysis. A pH decrease occurred after the first concentrate switch but rumen parameters returned to the original values and remained stable until wk 5. In wk 5 and 6, rumen pH values were indicative of increasing acidotic conditions. After switching to the control diet in wk 6, rumen pH values rapidly achieved normal values. Odd- and branched-chain fatty acids and C18:1 trans-10 increased with increasing amount of concentrate in the diet, whereas C18:1 trans-11 decreased. Four fatty acids [C18:1 trans-10, C15:0 and C17:0+C17:1 cis-9 (negative loadings), and iso C14:0 (positive loading)] largely correlated with the first principal component (PC1), with cows spread along the PC1 axis. The first 4 wk of the induction experiment showed variation across the second principal component (PC2) only, with high loadings of anteiso C13:0 (negative loading) and C18:2 cis-9,trans-11 and C18:1 trans-11 (positive loadings). Weeks 5 and 6 deviated from PC2 and tended toward the negative PC1 axis. A discriminant analysis using a stepwise approach indicated the main fatty acids discriminating between the control and acidotic samples as iso C13:0, iso C16:0, and C18:2 cis-9,trans-11 rather than milk fat content or C18:1 trans-10, which have been used before as indicators of acidosis. This shows that specific milk fatty acids have potential in discriminating acidotic cases. PMID:20855010

  15. Responses of glomus cells to hypoxia and acidosis are uncoupled, reciprocal and linked to ASIC3 expression: selectivity of chemosensory transduction

    PubMed Central

    Lu, Yongjun; Whiteis, Carol A; Sluka, Kathleen A; Chapleau, Mark W; Abboud, Franois M

    2013-01-01

    Carotid body glomus cells are the primary sites of chemotransduction of hypoxaemia and acidosis in peripheral arterial chemoreceptors. They exhibit pronounced morphological heterogeneity. A quantitative assessment of their functional capacity to differentiate between these two major chemical signals has remained undefined. We tested the hypothesis that there is a differential sensory transduction of hypoxia and acidosis at the level of glomus cells. We measured cytoplasmic Ca2+ concentration in individual glomus cells, isolated in clusters from rat carotid bodies, in response to hypoxia ( mmHg) and to acidosis at pH 6.8. More than two-thirds (68%) were sensitive to both hypoxia and acidosis, 19% were exclusively sensitive to hypoxia and 13% exclusively sensitive to acidosis. Those sensitive to both revealed significant preferential sensitivity to either hypoxia or to acidosis. This uncoupling and reciprocity was recapitulated in a mouse model by altering the expression of the acid-sensing ion channel 3 (ASIC3) which we had identified earlier in glomus cells. Increased expression of ASIC3 in transgenic mice increased pH sensitivity while reducing cyanide sensitivity. Conversely, deletion of ASIC3 in the knockout mouse reduced pH sensitivity while the relative sensitivity to cyanide or to hypoxia was increased. In this work, we quantify functional differences among glomus cells and show reciprocal sensitivity to acidosis and hypoxia in most glomus cells. We speculate that this selective chemotransduction of glomus cells by either stimulus may result in the activation of different afferents that are preferentially more sensitive to either hypoxia or acidosis, and thus may evoke different and more specific autonomic adjustments to either stimulus. PMID:23165770

  16. Sigmoid volvulus in a patient with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): a rare occurrence.

    PubMed

    Hallac, Alexander; Keshava, Hari B; Morris-Stiff, Gareth; Ibrahim, Samuel

    2016-01-01

    Mitochondrial diseases are rare and devastating, with a wide spectrum of clinical presentations and systemic symptoms. The majority of the published literature focuses on the neuromuscular manifestations and genetic components of this mitochondrial cytopathy, however, cardiac, renal, endocrine and gastrointestinal manifestations may also be present. The authors report a case detailing a 56-year-old woman's final hospitalisation from the gastrointestinal sequelae of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) (Co Q10 deficiency variant). She presented with abdominal pain and distension associated with lactic acidosis, and was shown on imaging to have a colon perforation. This resulted in emergent surgery at which a necrotic colon secondary to a sigmoid colon was identified. Following four subsequent operations, and the development of multiorgan failure, care was eventually withdrawn. Practitioners of patients with MELAS should be cognisant of the rare but devastating gastrointestinal consequences of mitochondrial diseases. PMID:26935953

  17. Cellular metabolism and disease: what do metabolic outliers teach us?

    PubMed Central

    DeBerardinis, Ralph J.; Thompson, Craig B.

    2012-01-01

    An understanding of metabolic pathways based solely on biochemistry textbooks would underestimate the pervasive role of metabolism in essentially every aspect of biology. It is evident from recent work that many human diseases involve abnormal metabolic states – often genetically programmed – that perturb normal physiology and lead to severe tissue dysfunction. Understanding these metabolic outliers is now a crucial frontier in disease-oriented research. This review discusses the broad impact of metabolism in cellular function, how modern concepts of metabolism can inform our understanding of common diseases like cancer, and considers the prospects of developing new metabolic approaches to disease treatment. PMID:22424225

  18. Protective effects of polyethylene oxide on the vascular and organ function of rats with severe hemorrhagic shock.

    PubMed

    Li, Qiang; Huang, Tao; Dong, Zhen

    2015-08-01

    This study examined the effects of polyethylene oxide (PEO) on the survival rate, hemodynamics, blood gas indexes, lactic acid levels, microcirculation, and inflammatory cytokine levels in rats subjected to severe hemorrhagic shock. The shocked rats were resuscitated with either Ringer's lactate solution or 20 ppm of PEO in Ringer's lactate solution for 1 h. It was found that infusion of PEO effectively improved the survival, metabolic acidosis, oxygen delivery, hyperlactacidemia, tissue perfusion, and inflammatory responses of rats subjected to hemorrhagic shock. In addition, we found, for the first time, that PEO showed protective effects on hepatic and renal injury, as evidenced by the significant decreases in the elevated levels of alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and creatinine caused by shock induction after infusion of PEO (p < 0.05, 60 min post-resuscitation by comparison with pre-resuscitation). All of these findings indicate that PEO exhibits strong therapeutic effects under conditions of severe hemorrhagic shock,which also provides theoretical and experimental bases for the clinical use of PEO. PMID:26047259

  19. 17?-Estradiol Enhances ASIC Activity in Primary Sensory Neurons to Produce Sex Difference in Acidosis-Induced Nociception.

    PubMed

    Qu, Zu-Wei; Liu, Ting-Ting; Ren, Cuixia; Gan, Xiong; Qiu, Chun-Yu; Ren, Ping; Rao, Zhiguo; Hu, Wang-Ping

    2015-12-01

    Sex differences have been reported in a number of pain conditions. Women are more sensitive to most types of painful stimuli than men, and estrogen plays a key role in the sex differences in pain perception. However, it is unclear whether there is a sex difference in acidosis-evoked pain. We report here that both male and female rats exhibit nociceptive behaviors in response to acetic acid, with females being more sensitive than males. Local application of exogenous 17?-estradiol (E2) exacerbated acidosis-evoked nociceptive response in male rats. E2 and estrogen receptor (ER)-? agonist 1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole, but not ER? agonist 2,3-bis(4-hydroxyphenyl)-propionitrile, replacement also reversed attenuation of the acetic acid-induced nociceptive response in ovariectomized females. Moreover, E2 can exert a rapid potentiating effect on the functional activity of acid-sensing ion channels (ASICs), which mediated the acidosis-induced events. E2 dose dependently increased the amplitude of ASIC currents with a 42.8 1.6 nM of EC50. E2 shifted the concentration-response curve for proton upward with a 50.1% 6.2% increase of the maximal current response to proton. E2 potentiated ASIC currents via an ER? and ERK1/2 signaling pathway. E2 also altered acidosis-evoked membrane excitability of dorsal root ganglia neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acidic stimuli. E2 potentiation of the functional activity of ASICs revealed a peripheral mechanism underlying this sex difference in acetic acid-induced nociception. PMID:26441237

  20. ACIDOSIS IS A KEY REGULATIOR OF OSTEOBLAST ECTO-NUCLEOTIDASE PYROPHOSPHATASE/PHOSPHODIESTERASE 1 (NPP1) EXPRESSION AND ACTIVITY

    PubMed Central

    Orriss, Isabel R; Key, Michelle L; Hajjawi, Mark OR; Millán, José Luis; Arnett, Timothy R

    2015-01-01

    Previous work has shown that acidosis prevents bone nodule formation by osteoblasts in vitro by inhibiting mineralisation of the collagenous matrix. The ratio of phosphate (Pi) to pyrophosphate (PPi) in the bone microenvironment is a fundamental regulator of bone mineralisation. Both Pi and PPi, a potent inhibitor of mineralisation, are generated from extracellular nucleotides by the actions of ecto-nucleotidases. This study investigated the expression and activity of ecto-nucleotidases by osteoblasts under normal and acid conditions. We found that osteoblasts express mRNA for a number of ecto-nucleotidases including NTPdase 1–6 (ecto-nucleoside triphosphate diphosphohydrolase) and NPP1-3 (ecto-nucleotide pyrophosphatase/phosphodiesterase). The rank order of mRNA expression in differentiating rat osteoblasts (day 7) was Enpp1 > NTPdase 4 > NTPdase 6 > NTPdase 5 > alkaline phosphatase > ecto-5-nucleotidase > Enpp3 > NTPdase 1 > NTPdase 3 > Enpp2 > NTPdase 2. Acidosis (pH 6.9) upregulated NPP1 mRNA (2.8-fold) and protein expression at all stages of osteoblast differentiation compared to physiological pH (pH 7.4); expression of other ecto-nucleotidases was unaffected. Furthermore, total NPP activity was increased up to 53% in osteoblasts cultured in acid conditions (p<0.001). Release of ATP, one of the key substrates for NPP1, from osteoblasts, was unaffected by acidosis. Further studies showed that mineralised bone formation by osteoblasts cultured from NPP1 knockout mice was increased compared with wildtypes (2.5-fold, p<0.001) and was partially resistant to the inhibitory effect of acidosis. These results indicate that increased NPP1 expression and activity might contribute to the decreased mineralisation observed when osteoblasts are exposed to acid conditions. PMID:26033523

  1. Hypercapnia causes cellular oxidation and nitrosation in addition to acidosis: implications for CO2 chemoreceptor function and dysfunction

    PubMed Central

    2010-01-01

    Cellular mechanisms of CO2 chemoreception are discussed and debated in terms of the stimuli produced during hypercapnic acidosis and their molecular targets: protons generated by the hydration of CO2 and dissociation of carbonic acid, which target membrane-bound proteins and lipids in brain stem neurons. The CO2 hydration reaction, however, is not the only reaction that CO2 undergoes that generates molecules capable of modifying proteins and lipids. Molecular CO2 also reacts with peroxynitrite (ONOO−), a reactive nitrogen species (RNS), which is produced from nitric oxide (•NO) and superoxide (•O2−). The CO2/ONOO− reaction, in turn, produces additional nitrosative and oxidative reactive intermediates. Furthermore, protons facilitate additional redox reactions that generate other reactive oxygen species (ROS). ROS/RNS generated by these redox reactions may act as additional stimuli of CO2 chemoreceptors since neurons in chemosensitive areas produce both •NO and •O2− and, therefore, ONOO−. Perturbing •NO, •O2−, and ONOO− activities in chemosensitive areas modulates cardiorespiration. Moreover, neurons in at least one chemosensitive area, the solitary complex, are stimulated by cellular oxidation. Together, these data raise the following two questions: 1) do pH and ROS/RNS work in tandem to stimulate CO2 chemoreceptors during hypercapnic acidosis; and 2) does nitrosative stress and oxidative stress contribute to CO2 chemoreceptor dysfunction? To begin considering these two issues and their implications for central chemoreception, this minireview has the following three goals: 1) summarize the nitrosative and oxidative reactions that occur during hypercapnic acidosis and isocapnic acidosis; 2) review the evidence that redox signaling occurs in chemosensitive areas; and 3) review the evidence that neurons in the solitary complex are stimulated by cellular oxidation. PMID:20150563

  2. Acidosis Decreases c-Myc Oncogene Expression in Human Lymphoma Cells: A Role for the Proton-Sensing G Protein-Coupled Receptor TDAG8

    PubMed Central

    Li, Zhigang; Dong, Lixue; Dean, Eric; Yang, Li V.

    2013-01-01

    Acidosis is a biochemical hallmark of the tumor microenvironment. Here, we report that acute acidosis decreases c-Myc oncogene expression in U937 human lymphoma cells. The level of c-Myc transcripts, but not mRNA or protein stability, contributes to c-Myc protein reduction under acidosis. The pH-sensing receptor TDAG8 (GPR65) is involved in acidosis-induced c-Myc downregulation. TDAG8 is expressed in U937 lymphoma cells, and the overexpression or knockdown of TDAG8 further decreases or partially rescues c-Myc expression, respectively. Acidic pH alone is insufficient to reduce c-Myc expression, as it does not decrease c-Myc in H1299 lung cancer cells expressing very low levels of pH-sensing G protein-coupled receptors (GPCRs). Instead, c-Myc is slightly increased by acidosis in H1299 cells, but this increase is completely inhibited by ectopic overexpression of TDAG8. Interestingly, TDAG8 expression is decreased by more than 50% in human lymphoma samples in comparison to non-tumorous lymph nodes and spleens, suggesting a potential tumor suppressor function of TDAG8 in lymphoma. Collectively, our results identify a novel mechanism of c-Myc regulation by acidosis in the tumor microenvironment and indicate that modulation of TDAG8 and related pH-sensing receptor pathways may be exploited as a new approach to inhibit Myc expression. PMID:24152439

  3. Acidosis decreases c-Myc oncogene expression in human lymphoma cells: a role for the proton-sensing G protein-coupled receptor TDAG8.

    PubMed

    Li, Zhigang; Dong, Lixue; Dean, Eric; Yang, Li V

    2013-01-01

    Acidosis is a biochemical hallmark of the tumor microenvironment. Here, we report that acute acidosis decreases c-Myc oncogene expression in U937 human lymphoma cells. The level of c-Myc transcripts, but not mRNA or protein stability, contributes to c-Myc protein reduction under acidosis. The pH-sensing receptor TDAG8 (GPR65) is involved in acidosis-induced c-Myc downregulation. TDAG8 is expressed in U937 lymphoma cells, and the overexpression or knockdown of TDAG8 further decreases or partially rescues c-Myc expression, respectively. Acidic pH alone is insufficient to reduce c-Myc expression, as it does not decrease c-Myc in H1299 lung cancer cells expressing very low levels of pH-sensing G protein-coupled receptors (GPCRs). Instead, c-Myc is slightly increased by acidosis in H1299 cells, but this increase is completely inhibited by ectopic overexpression of TDAG8. Interestingly, TDAG8 expression is decreased by more than 50% in human lymphoma samples in comparison to non-tumorous lymph nodes and spleens, suggesting a potential tumor suppressor function of TDAG8 in lymphoma. Collectively, our results identify a novel mechanism of c-Myc regulation by acidosis in the tumor microenvironment and indicate that modulation of TDAG8 and related pH-sensing receptor pathways may be exploited as a new approach to inhibit Myc expression. PMID:24152439

  4. Ischemia/Reperfusion-Induced CHOP Expression Promotes Apoptosis and Impairs Renal Function Recovery: The Role of Acidosis and GPR4

    PubMed Central

    Xu, Longmei; Zhang, Ming; Fu, Yaowen; Xia, Qiang

    2014-01-01

    Endoplasmic reticulum (ER) stress-induced apoptosis is implicated in a wide range of diseases, including ischemia/reperfusion injury (IRI). As a common feature of ER stress, the role of CCAT/enhancer-binding protein homologous protein (CHOP) in renal IRI has not been thoroughly investigated. We found that IR led to renal CHOP expression, accompanied by apoptosis induction. Renal IRI was markedly alleviated in CHOP?/? mice. Observations from bone marrow chimeras showed that this was based on CHOP inactivation in renal parenchymal cells rather than inflammatory cells. In vivo and in vitro studies demonstrated that IRI induced CHOP expression in both endothelial and epithelial cells, which was responsible for apoptosis induction. These results were reinforced by the observation that CHOP knockout led to improvement of the postischemic microcirculatory recovery. In vitro studies revealed hypoxia-induced acidosis to be a major inducer of CHOP in endothelial cells, and neutralizing acidosis not only diminished CHOP protein, but also reduced apoptosis. Finally, knockdown of a proton-sensing G protein-coupled receptor GPR4 markedly reduced CHOP expression and endothelial cell apoptosis after hypoxia exposure. These results highlight the importance of hypoxia-acidosis in ER stress signaling regulation in ischemic kidneys and suggest that GPR4 inhibitors or agents targeting CHOP expression may be promising in the treatment of renal IRI. PMID:25343248

  5. 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

  6. Carnosine inhibits carbonic anhydrase IX-mediated extracellular acidosis and suppresses growth of HeLa tumor xenografts

    PubMed Central

    2014-01-01

    Background Carbonic anhydrase IX (CA IX) is a transmembrane enzyme that is present in many types of solid tumors. Expression of CA IX is driven predominantly by the hypoxia-inducible factor (HIF) pathway and helps to maintain intracellular pH homeostasis under hypoxic conditions, resulting in acidification of the tumor microenvironment. Carnosine (β-alanyl-L-histidine) is an anti-tumorigenic agent that inhibits the proliferation of cancer cells. In this study, we investigated the role of CA IX in carnosine-mediated antitumor activity and whether the underlying mechanism involves transcriptional and translational modulation of HIF-1α and CA IX and/or altered CA IX function. Methods The effect of carnosine was studied using two-dimensional cell monolayers of several cell lines with endogenous CA IX expression as well as Madin Darby canine kidney transfectants, three-dimensional HeLa spheroids, and an in vivo model of HeLa xenografts in nude mice. mRNA and protein expression and protein localization were analyzed by real-time PCR, western blot analysis, and immunofluorescence staining, respectively. Cell viability was measured by a flow cytometric assay. Expression of HIF-1α and CA IX in tumors was assessed by immunohistochemical staining. Real-time measurement of pH was performed using a sensor dish reader. Binding of CA IX to specific antibodies and metabolon partners was investigated by competitive ELISA and proximity ligation assays, respectively. Results Carnosine increased the expression levels of HIF-1α and HIF targets and increased the extracellular pH, suggesting an inhibitory effect on CA IX-mediated acidosis. Moreover, carnosine significantly inhibited the growth of three-dimensional spheroids and tumor xenografts compared with untreated controls. Competitive ELISA showed that carnosine disrupted binding between CA IX and antibodies specific for its catalytic domain. This finding was supported by reduced formation of the functional metabolon of CA IX and anion exchanger 2 in the presence of carnosine. Conclusions Our results indicate that interaction of carnosine with CA IX leads to conformational changes of CA IX and impaired formation of its metabolon, which in turn disrupts CA IX function. These findings suggest that carnosine could be a promising anticancer drug through its ability to attenuate the activity of CA IX. PMID:24886661

  7. A reliable, practical, and economical protocol for inducing diarrhea and severe dehydration in the neonatal calf.

    PubMed Central

    Walker, P G; Constable, P D; Morin, D E; Drackley, J K; Foreman, J H; Thurmon, J C

    1998-01-01

    Fifteen healthy, colostrum-fed, male dairy calves, aged 2 to 7 d were used in a study to develop a diarrhea protocol for neonatal calves that is reliable, practical, and economical. After instrumentation and recording baseline data, diarrhea and dehydration were induced by administering milk replacer [16.5 mL/kg of body weight (BW), PO], sucrose (2 g/kg in a 20% aqueous solution, p.o.), spironolactone and hydrochlorothiazide (1 mg/kg, PO) every 8 h, and furosemide (2 mg/kg, i.m., q6h). Calves were administered sucrose and diuretic agents for 48 h to induce diarrhea and severe dehydration. Clinical changes after 48 h were severe watery diarrhea, severe depression, and marked dehydration (mean, 14% BW loss). Cardiac output, stroke volume, mean central venous pressure, plasma volume, thiocyanate space, blood pH and bicarbonate concentration, base excess, serum chloride concentration, and fetlock temperature were decreased. Plasma lactate concentration, hematocrit, and serum potassium, creatinine, phosphorus, total protein and albumin concentrations were increased. This non-infectious calf diarrhea protocol has a 100% response rate, while providing a consistent and predictable hypovolemic state with diarrhea that reflects most of the clinicopathologic changes observed in osmotic/maldigestive diarrhea caused by infection with rotavirus, coronavirus or cryptosporidia. Limitations of the protocol, when compared to infectious diarrhea models, include failure to induce a severe metabolic acidosis, absence of hyponatremia, renal instead of enteric loss of chloride, renal as well as enteric loss of free water, absence of profound clinical depression and suspected differences in the morphologic and functional effect on intestinal epithelium. Despite these differences, the sucrose/diuretic protocol should be useful in the initial screening of new treatment modalities for calf diarrhea. To confirm their efficacy, the most effective treatment methods should then be examined in calves with naturally-acquired diarrhea. PMID:9684050

  8. Rare mutation in the SLC26A3 transporter causes life-long diarrhoea with metabolic alkalosis.

    PubMed

    Abou Ziki, Maen D; Verjee, Mohamud A

    2015-01-01

    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. PMID:25568271

  9. Ruminal temperature may aid in the detection of subacute ruminal acidosis.

    PubMed

    AlZahal, O; Kebreab, E; France, J; Froetschel, M; McBride, B W

    2008-01-01

    The objective of this study was to investigate the relationship between ruminal pH and ruminal temperature and to develop a predictive equation that can aid in the diagnosis of subacute ruminal acidosis (SARA). Six rumen-fistulated lactating Holstein dairy cows (639 +/- 51 kg body weight) were used in the study. Cows were randomly allocated to 1 of 2 dietary treatments: control (% of dry matter, 40% corn silage, 27% mixed haylage, 7% alfalfa hay, 18% protein supplement, 4% ground corn, and 4% wheat bran) or SARA total mixed ration (% of dry matter, 31% corn silage, 20% mixed haylage, 5% alfalfa hay, 15% protein supplement, 19% ground wheat, and 10% ground barley) and were fed daily at 0700 and 1300 h. The experiment consisted of 1 wk of adaptation followed by 1 wk of treatment. Ruminal pH and ruminal temperature were simultaneously and continuously recorded every minute for 4 d per week using the same indwelling electrode. Subacute-acidotic cows spent more time (min/d) below ruminal pH 5.6 and a greater time above 39.2 degrees C than control cows. Ruminal pH nadir had a negative relationship with its corresponding ruminal temperature (R2 = 0.77). Therefore, ruminal temperature may have potential to predict ruminal pH and thus aid in the diagnosis of SARA. PMID:18096941

  10. Early respiratory acidosis is a new risk factor for pneumonia after lung resection.

    PubMed

    Planquette, Benjamin; Le Pimpec-Barthes, Françoise; Trinquart, Ludovic; Meyer, Guy; Riquet, Marc; Sanchez, Olivier

    2012-03-01

    Postoperative pneumonia (POP) is a life-threatening complication of lung resection (LR). Its risk factors, bacteriological profile and outcome are not well known. The aims of this study were to describe the outcome and causal bacteria and to identify risk factors for POP. We reviewed all cases admitted to intensive care after LR. Clinical parameters, operative and postoperative data were recorded. POP was suspected on the basis of fever, radiographic infiltrate, and either leucocytosis or purulent sputum. The diagnosis was confirmed by culture of a respiratory sample. Risk factors for POP were identified by univariate and multivariate analysis. We included 159 patients in this study. POP was diagnosed in 23 patients (14.4%) and was associated with a higher hospital mortality rate (30% versus 5%, P = 0.0007) and a longer hospital stay. Members of the Enterobacteriaceae and Pseudomonas species were the most frequently identified pathogens. Early respiratory acidosis (ERA; OR, 2.94; 95% CI, 1.1-8.1), blood transfusion (OR, 3.8; 95% CI, 1.1-13.1), bilobectomy (OR, 7.26; 95% CI, 1.2-43.1) and smoking history (OR, 1.84; 95% CI, 1.1-3) were identified as independent risk factors. ERA may be a risk factor for POP and could serve as a target for therapeutic interventions. PMID:22184462

  11. Pathophysiological evaluation of subacute ruminal acidosis (SARA) by continuous ruminal pH monitoring.

    PubMed

    Sato, Shigeru

    2016-02-01

    Evaluation of the radio-transmission pH-measurement system for monitoring the ruminal pH and subacute ruminal acidosis (SARA) in cattle is described. This is done in order to reveal the possible application of this system for detection and pathophysiological research of SARA by continuous ruminal pH measurement. The possibility of using this system for assessment of the ruminal pH in SARA cattle, and the presence of negative correlation between the ruminal pH and ruminal temperature in heathy and SARA cattle were determined. In addition, the 16S rRNA gene pyrosequencing analysis showed that the ruminal microbial community was simpler in SARA cattle, and the bacterial numbers in SARA cattle were lower than those in healthy hay-fed cattle. Concentrate feeding might have reduced the diversity of the ruminal microbial community. Changes in the ruminal microbial community of SARA cattle might be related to the changes in ruminal pH followed by the decrease in the number of some bacteria. Continuous monitoring of the ruminal pH using the radio-transmission pH-measurement system would be applied for detection and prevention of SARA in the field and pathophysiological research of SARA, including ruminal zymology and bacteriology, which have been determined previously by sampling of the ruminal fluid and measuring of ruminal pH. PMID:26279060

  12. Extracellular Spermine Exacerbates Ischemic Neuronal Injury through Sensitization of ASIC1a Channels to Extracellular Acidosis

    PubMed Central

    Duan, Bo; Wang, Yi-Zhi; Yang, Tao; Chu, Xiang-Ping; Yu, Ye; Huang, Yu; Cao, Hui; Hansen, Jillian; Simon, Roger P.; Zhu, Michael X.; Xiong, Zhi-Gang; Xu, Tian-Le

    2011-01-01

    Ischemic brain injury is a major problem associated with stroke. It has been increasingly recognized that acid-sensing ion channels (ASICs) contribute significantly to ischemic neuronal damage, but the underlying mechanism has remained elusive. Here, we show that extracellular spermine, one of the endogenous polyamines, exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis. Pharmacological blockade of ASIC1a or deletion of the ASIC1 gene greatly reduces the enhancing effect of spermine in ischemic neuronal damage both in cultures of dissociated neurons and in a mouse model of focal ischemia. Mechanistically, spermine profoundly reduces desensitization of ASIC1a by slowing down desensitization in the open state, shifting steady-state desensitization to more acidic pH, and accelerating recovery between repeated periods of acid stimulation. Spermine-mediated potentiation of ASIC1a activity is occluded by PcTX1 (psalmotoxin 1), a specific ASIC1a inhibitor binding to its extracellular domain. Functionally, the enhanced channel activity is accompanied by increased acid-induced neuronal membrane depolarization and cytoplasmic Ca2+ overload, which may partially explain the exacerbated neuronal damage caused by spermine. More importantly, blocking endogenous spermine synthesis significantly attenuates ischemic brain injury mediated by ASIC1a but not that by NMDA receptors. Thus, extracellular spermine contributes significantly to ischemic neuronal injury through enhancing ASIC1a activity. Our data suggest new neuroprotective strategies for stroke patients via inhibition of polyamine synthesis and subsequent spermine–ASIC interaction. PMID:21307247

  13. Metabolic neuropathies

    MedlinePlus

    Neuropathy - metabolic ... can be caused by many different things. Metabolic neuropathy may be caused by: A problem with the ... one of the most common causes of metabolic neuropathies. People who are at the highest risk of ...

  14. Sustained metabolic scope.

    PubMed Central

    Peterson, C C; Nagy, K A; Diamond, J

    1990-01-01

    Sustained metabolic rates (SusMR) are time-averaged metabolic rates that are measured in free-ranging animals maintaining constant body mass over periods long enough that metabolism is fueled by food intake rather than by transient depletion of energy reserves. Many authors have suggested that SusMR of various wild animal species are only a few times resting (basal or standard) metabolic rates (RMR). We test this conclusion by analyzing all 37 species (humans, 31 other endothermic vertebrates, and 5 ectothermic vertebrates) for which SusMR and RMR had both been measured. For all species, the ratio of SusMR to RMR, which we term sustained metabolic scope, is less than 7; most values fall between 1.5 and 5. Some of these values, such as those for Tour de France cyclists and breeding birds, are surely close to sustainable metabolic ceilings for the species studied. That is, metabolic rates higher than 7 times RMR apparently cannot be sustained indefinitely. These observations pose several questions: whether the proximate physiological causes of metabolic ceilings reside in the digestive tract's ability to process food or in each tissue's metabolic capacity; whether ceiling values are independent of the mode of energy expenditure; whether ceilings are set by single limiting physiological capacities or by coadjusted clusters of capacities (symmorphosis); what the ultimate evolutionary causes of metabolic ceilings are; and how metabolic ceilings may limit animals' reproductive effort, foraging behavior, and geographic distribution. PMID:2315323

  15. Targeting the Metabolic Microenvironment of Tumors

    PubMed Central

    Bailey, Kate M.; Wojtkowiak, Jonathan W.; Hashim, Arig Ibrahim; Gillies, Robert J.

    2013-01-01

    The observation of aerobic glycolysis by tumor cells in 1924 by Otto Warburg, and subsequent innovation of imaging glucose uptake by tumors in patients with PET-CT has incited a renewed interest in the altered metabolism of tumors. As tumors grow in situ, a fraction of it is further away from their blood supply, leading to decreased oxygen concentrations (hypoxia), which induces the hypoxia response pathways of HIF1α, mTOR and UPR. In normal tissues, these responses mitigate hypoxic stress and induce neo-angiogenesis. In tumors, these pathways are dysregulated and lead to decreased perfusion and exacerbation of hypoxia as a result of immature and chaotic blood vessels. Hypoxia selects for a glycolytic phenotype and resultant acidification of the tumor microenvironment, facilitated by upregulation of proton transporters. Acidification selects for enhanced metastatic potential and reduced drug efficacy through ion trapping. In this review, we provide a comprehensive summary of pre-clinical and clinical drugs under development for targeting aerobic glycolysis, acidosis, hypoxia and hypoxia-response pathways. Hypoxia and acidosis can be manipulated, providing further therapeutic benefit for cancers that feature these common phenotypes. PMID:22959024

  16. The effects of active dried and killed dried yeast on subacute ruminal acidosis, ruminal fermentation, and nutrient digestibility in beef heifers.

    PubMed

    Vyas, D; Uwizeye, A; Mohammed, R; Yang, W Z; Walker, N D; Beauchemin, K A

    2014-02-01

    The study addressed the importance of yeast (Saccharomyces cerevisiae) viability for reducing the incidence of subacute ruminal acidosis (SARA) and improving total tract nutrient digestibility in beef heifers. Six ruminally cannulated beef heifers (680 ± 50 kg BW) were used in a replicated 3 × 3 Latin square design and were fed a diet consisting of 40% barley silage, 10% chopped grass hay, and 50% barley grain-based concentrate (DM basis). Treatments were 1) no yeast (Control), 2) active dried yeast (ADY; 4 g providing 10(10) cfu/g; AB Vista, Marlborough, UK), and 3) killed dried yeast (KDY; 4 g autoclaved ADY). The treatments were directly dosed via the ruminal cannula daily at the time of feeding. The periods consisted of 2 wk of adaptation (d 1 to 14) and 7 d of measurements (d 15 to 21). Ruminal pH was continuously measured (d 15 to 21) using an indwelling system. Ruminal contents were sampled on d 15 and 17 at 0, 3, 6, 9, and 12 h after feeding. Total tract nutrient digestibility was measured using an external marker (YbCl3) from d 15 to 19. No treatment difference was observed for DMI (P = 0.86). Yeast supplementation (ADY and KDY) tended to increase total tract digestibility of starch (P = 0.07) whereas no effects were observed on digestibility of other nutrients. Both ADY and KDY elevated minimum (P < 0.01) and mean ruminal pH (P = 0.02) whereas no effects were observed on maximum pH (P = 0.12). Irrespective of its viability, yeast supplementation was effective in reducing time that ruminal pH was below 5.8 (P < 0.01) and 5.6 (P < 0.01). No treatment differences were observed for the ruminal VFA profile and lactate concentration. No treatment differences were observed on the relative population size of Streptococcus bovis, Fibrobacter succinogenes, and Megasphaera elsdenii (P > 0.10); however, the proportion of Ruminococcus flavefaciens in solid fraction of digesta was greater with KDY (P = 0.05). The study demonstrates the positive effects of yeast, irrespective of its viability, in reducing the severity of SARA. However, further studies are required to evaluate the importance of yeast viability for other dietary conditions, particularly when the risk of acidosis is high. PMID:24398831

  17. Glucose metabolism derangements in adults with the MELAS m.3243A>G mutation.

    PubMed

    El-Hattab, Ayman W; Emrick, Lisa T; Hsu, Jean W; Chanprasert, Sirisak; Jahoor, Farook; Scaglia, Fernando; Craigen, William J

    2014-09-01

    The m.3243A>G mutation in the mitochondrial gene MT-TL1 leads to a wide clinical spectrum ranging from asymptomatic carriers to MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) at the severe end. Diabetes mellitus (DM) occurs in mitochondrial diseases, with the m.3243A>G mutation being the most common mutation associated with mitochondrial DM. The pathogenesis of mitochondrial DM remains largely unknown, with previous studies suggesting that impaired insulin secretion is the major factor. In this study we used stable isotope infusion techniques to assess glucose metabolism in vivo and under physiological conditions in 5 diabetic and 11 non-diabetic adults with the m.3243A>G mutation and 10 healthy adult controls. Our results revealed increased glucose production due to increased gluconeogenesis in both diabetic and non-diabetic subjects with the m.3243A>G mutation. In addition, diabetic subjects demonstrated insulin resistance and relative insulin deficiency, resulting in an inability to increase glucose oxidation which can explain the development of DM in these subjects. Non-diabetic subjects showed normal insulin sensitivity; and therefore, they were able to increase their glucose oxidation rate. The ability to increase glucose utilization can act as a compensatory mechanism that explains why these subjects do not have DM despite the higher rate of glucose production. These results suggest that increased gluconeogenesis is not enough to cause DM and the occurrence of combined insulin resistance and relative insulin deficiency are needed to develop DM in individuals with the m.3243A>G mutation. Therefore, multiple defects in insulin and glucose metabolism are required for DM to occur in individuals with mitochondrial diseases. The results of this study uncover previously undocumented alterations in glucose metabolism in individuals with the m.3243A>G mutation that contribute significantly to our understanding of the pathogenesis of mitochondrial DM and can have significant implications for its management. PMID:25086207

  18. Effect of cellular acidosis on cell volume in S2 segments of renal proximal tubules.

    PubMed

    Sullivan, L P; Wallace, D P; Clancy, R L; Grantham, J J

    1990-04-01

    The presence of pH-sensitive transport mechanisms in the basolateral membrane of proximal tubular cells suggests that cell volume and its regulation may be sensitive to changes in cell pH. We have measured the response of cell pH and cell volume to changes in the acid-base composition of solutions bathing isolated, lumen-collapsed, proximal S2 tubular segments taken from the rabbit kidney. Cell pH was determined by measurement of the fluorescence emission of 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein. Cell volume was calculated from measurements of tubular diameter. An increase in CO2 from 5 to 15% reduced cell pH 0.30 units and raised cell bicarbonate concentration ([HCO3]) 10 mM. Cell volume rose to 108.6% of control in 4 min. A decrease in bath [HCO3] from 25 to 5 mM reduced cell pH 0.41 units and cell [HCO3] by 15 mM. Cell volume gradually increased to 105.7% at 8 min. The rate of the regulatory volume decrease after cell swelling on exposure to a 160 mosM solution was determined in the presence of 5 and 15% CO2. The latter reduced the maximum fractional rate of recovery of volume from 0.18 to 0.11 min-1 but did not affect the extent of regulation. We conclude that acidosis causes cell swelling and reduces the rate of volume regulation in response to hypotonic media. PMID:2109935

  19. Preepithelial mucus-HCO-3 layer protects against intracellular acidosis in acid-exposed gastric mucosa.

    PubMed

    Kiviluoto, T; Ahonen, M; Bäck, N; Häppölä, O; Mustonen, H; Paimela, H; Kivilaakso, E

    1993-01-01

    The role of the preepithelial mucus-HCO-3 layer in protection against intracellular acidosis was investigated in isolated Necturus gastric antral mucosa exposed to luminal acid by simultaneous measurement of intracellular pH (pH(i)) and extracellular surface pH (pHs) in surface epithelium with microelectrode technique. Acidification of the luminal perfusate to pH 2.5 acidified pH(i) in surface epithelial cells from 7.33 +/- 0.02 to 7.20 +/- 0.04, whereas pHs fell from 6.75 +/- 0.21 to 5.20 +/- 0.25 (P < 0.01; n = 9), followed by a steady state for at least 2 h. Inhibition of epithelial HCO-3 secretion and transport by removal of serosal HCO-3 and CO2 (HEPES and O2 substitution) during acid exposure provoked a progressive acidification of pHs from 5.60 +/- 0.41 to 2.74 +/- 0.14 in 30 min (P < 0.01; n = 9), which was accompanied, after a 5- to 10-min delay, by acidification of pH(i) from 7.21 +/- 0.03 to 5.68 +/- 0.26 (P < 0.01). Digestion of the surface mucus gel by pepsin (5% wt/vol) at pH 2.5 caused a slow acidification of pHs from 5.22 +/- 0.59 to 3.60 +/- 0.46 within 2 h. This was followed by a more rapid acidification to 2.53 +/- 0.38 (P < 0.01; n = 7), with concomitant acidification of pH(i) from 7.19 +/- 0.05 to 6.03 +/- 0.33 (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8430804

  20. Progress in Diagnosing Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episodes

    PubMed Central

    Wang, Ying-Xin; Le, Wei-Dong

    2015-01-01

    Objective: Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a progressive, multisystem affected mitochondrial disease associated with a number of disease-related defective genes. MELAS has unpredictable presentations and clinical course, and it can be commonly misdiagnosed as encephalitis, cerebral infarction, or brain neoplasms. This review aimed to update the diagnosis progress in MELAS, which may provide better understanding of the disease nature and help make the right diagnosis as well. Data Sources: The data used in this review came from published peer review articles from October 1984 to October 2014, which were obtained from PubMed. The search term is “MELAS”. Study Selection: Information selected from those reported studies is mainly based on the progress on clinical features, blood biochemistry, neuroimaging, muscle biopsy, and genetics in diagnosing MELAS. Results: MELAS has a wide heterogeneity in genetics and clinical manifestations. The relationship between mutations and phenotypes remains unclear. Advanced serial functional magnetic resonance imaging (MRI) can provide directional information on this disease. Muscle biopsy has meaningful value in diagnosing MELAS, which shows the presence of ragged red fibers and mosaic appearance of cytochrome oxidase negative fibers. Genetic studies have reported that approximately 80% of MELAS cases are caused by the mutation m.3243A>G of the mitochondrial transfer RNA (Leu (UUR)) gene (MT-TL1). Conclusions: MELAS involves multiple systems with variable clinical symptoms and recurrent episodes. The prognosis of MELAS patients depends on timely diagnosis. Therefore, overall diagnosis of MELAS should be based on the maternal inheritance family history, clinical manifestation, and findings from serial MRI, muscle biopsy, and genetics. PMID:26112726

  1. Population structure of rumen Escherichia coli associated with subacute ruminal acidosis (SARA) in dairy cattle.

    PubMed

    Khafipour, E; Plaizier, J C; Aikman, P C; Krause, D O

    2011-01-01

    Previous studies indicated that only subacute ruminal acidosis (SARA), induced by feeding a high-grain diet, is associated with an inflammatory response and increased abundance of Escherichia coli in the rumen. We hypothesized that ruminal E. coli in grain pellet-induced SARA carried virulence factors that potentially contribute to the immune activation during SARA. One hundred twenty-nine E. coli isolates were cultured from the rumens of 8 cows (4 animals per treatment) in which SARA had been nutritionally induced by feeding a high-grain diet (GPI-SARA) or a diet containing alfalfa pellets (API-SARA). The population structure of the E. coli was evaluated with the ABD genotyping system and repetitive sequence-based (rep)-PCR fingerprinting. Twenty-five virulence factors were evaluated with PCR. Escherichia coli numbers were higher in the GPI-SARA treatment than in the API-SARA treatment. The genetic structure of the E. coli was significantly different between SARA challenge models. Isolates from GPI-control (46%), API-control (70%), and API-SARA (53%) were closely related and fell into one cluster, whereas isolates from GPI-SARA (54%) grouped separately. The ABD typing indicated a shift from an A-type E. coli population to a B1-type population only due to GPI-SARA. Of the 25 virulence factors tested, curli fiber genes were highly associated with GPI. Curli fibers were first identified in E. coli mastitis isolates and are potent virulence factors that induce a range of immune responses. Results suggest that under low rumen pH conditions induced by a grain diet, there is a burst in the number of E. coli with virulence genes that can take advantage of these rumen conditions to trigger an inflammatory response. PMID:21183045

  2. Subacute ruminal acidosis and total mixed ration preference in lactating dairy cows.

    PubMed

    Maulfair, D D; McIntyre, K K; Heinrichs, A J

    2013-10-01

    Subacute ruminal acidosis (SARA) is a condition where the pH of the rumen becomes abnormally acidic because of increased and altered production of volatile fatty acids. The objective of this experiment was to determine how a SARA challenge affects total mixed ration selection in dairy cows. In this study, 8 multiparous, lactating, ruminally cannulated Holstein cows were given a choice between a long-forage-particle-size diet with slow-fermenting starch (LC) and a short-forage-particle-size diet with fast-fermenting starch in a crossover design. Cows were allowed to adapt to this feeding scheme and were then subjected to a rumen challenge to induce a bout of SARA. The rumen challenge successfully decreased rumen pH and altered rumen volatile fatty acid profiles. Daily average rumen pH decreased from 6.02 to 5.77, and average minimum rumen pH decreased from 5.59 to 5.28. In addition, following the rumen challenge, concentrations of acetate, butyrate, and valerate, and acetate-to-propionate ratio increased. In response to the rumen challenge, intake of LC increased from the baseline level of 18.1% of total daily dry matter intake to 38.3% for that day. During the first recovery day after the rumen challenge, LC intake moderated to 28.0% of total daily dry matter intake. On the second recovery day, LC intake returned to baseline levels at 18.6%. These results indicate that cows are able to alter their diet preference for higher physically effective fiber and slower starch fermentability during a bout of SARA and that they can effectively fully recover from this type of SARA within 72 h when appropriate diets are available. PMID:23932130

  3. Bovine rumen epithelium undergoes rapid structural adaptations during grain-induced subacute ruminal acidosis.

    PubMed

    Steele, Michael A; Croom, Jim; Kahler, Melissa; AlZahal, Ousama; Hook, Sarah E; Plaizier, Kees; McBride, Brian W

    2011-06-01

    Alterations in rumen epithelial structure and function during grain-induced subacute ruminal acidosis (SARA) are largely undescribed. In this study, four mature nonlactating dairy cattle were transitioned from a high-forage diet (HF; 0% grain) to a high-grain diet (HG; 65% grain). After feeding the HG diet for 3 wk, the cattle were transitioned back to the original HF diet, which was fed for an additional 3 wk. Continuous ruminal pH was measured on a weekly basis, and rumen papillae were biopsied during the baseline and at the first and final week of each diet. The mean, minimum, and maximum daily ruminal pH were depressed (P < 0.01) in the HG period compared with the HF period. During the HG period, SARA was diagnosed only during week 1, indicating ruminal adaptation to the HG diet. Microscopic examination of the papillae revealed a reduction (P < 0.01) in the stratum basale, spinosum, and granulosum layers, as well as total depth of the epithelium during the HG period. The highest (P < 0.05) papillae lesion scores were noted during week 1 when SARA occurred. Biopsied papillae exhibited a decline in cellular junctions, extensive sloughing of the stratum corneum, and the appearance of undifferentiated cells near the stratum corneum. Differential mRNA expression of candidate genes, including desmoglein 1 and IGF binding proteins 3, 5, and 6, was detected between diets using qRT-PCR. These results suggest that the structural integrity of the rumen epithelium is compromised during grain feeding and is associated with the differential expression of genes involved in epithelial growth and structure. PMID:21451145

  4. Severe Weather

    ERIC Educational Resources Information Center

    Forde, Evan B.

    2004-01-01

    Educating the public about safety issues related to severe weather is part of the National Oceanic and Atmospheric Administration's (NOAA) mission. This article deals with a poster entitled, "Severe Weather," that has been created by NOAA to help educate the public about hazardous weather conditions. The four types of severe weather highlighted in

  5. Severe Weather

    ERIC Educational Resources Information Center

    Forde, Evan B.

    2004-01-01

    Educating the public about safety issues related to severe weather is part of the National Oceanic and Atmospheric Administration's (NOAA) mission. This month's insert, Severe Weather, has been created by NOAA to help educate the public about hazardous weather conditions. The four types of severe weather highlighted in this poster are hurricanes,

  6. Sever's Disease

    MedlinePlus

    ... any problems linked with Sever's disease? No long-term problems have been linked with Sever's disease. However, call your doctor if your child's heel pain does not get better with treatment, gets worse or if you notice changes in skin color or swelling. Prevention Can Sever's disease be prevented? ...

  7. Severe Weather

    ERIC Educational Resources Information Center

    Forde, Evan B.

    2004-01-01

    Educating the public about safety issues related to severe weather is part of the National Oceanic and Atmospheric Administration's (NOAA) mission. This article deals with a poster entitled, "Severe Weather," that has been created by NOAA to help educate the public about hazardous weather conditions. The four types of severe weather highlighted in…

  8. Severe Weather

    ERIC Educational Resources Information Center

    Forde, Evan B.

    2004-01-01

    Educating the public about safety issues related to severe weather is part of the National Oceanic and Atmospheric Administration's (NOAA) mission. This month's insert, Severe Weather, has been created by NOAA to help educate the public about hazardous weather conditions. The four types of severe weather highlighted in this poster are hurricanes,…

  9. Metabolism at Evolutionary Optimal States

    PubMed Central

    Rabbers, Iraes; van Heerden, Johan H.; Nordholt, Niclas; Bachmann, Herwig; Teusink, Bas; Bruggeman, Frank J.

    2015-01-01

    Metabolism is generally required for cellular maintenance and for the generation of offspring under conditions that support growth. The rates, yields (efficiencies), adaptation time and robustness of metabolism are therefore key determinants of cellular fitness. For biotechnological applications and our understanding of the evolution of metabolism, it is necessary to figure out how the functional system properties of metabolism can be optimized, via adjustments of the kinetics and expression of enzymes, and by rewiring metabolism. The trade-offs that can occur during such optimizations then indicate fundamental limits to evolutionary innovations and bioengineering. In this paper, we review several theoretical and experimental findings about mechanisms for metabolic optimization. PMID:26042723

  10. Metabolic disturbances and renal stone promotion on treatment with topiramate: a systematic review

    PubMed Central

    Dell'Orto, Valentina G; Belotti, Eva A; Goeggel-Simonetti, Barbara; Simonetti, Giacomo D; Ramelli, Gian Paolo; Bianchetti, Mario G; Lava, Sebastiano A G

    2014-01-01

    Aims The use of topiramate, which is prescribed for the management of epilepsy, for migraine headache prophylaxis and as a weight-loss agent, has been associated with the development of metabolic acidosis, hypokalaemia and renal stone disease. We systematically reviewed all the literature. Methods The systematic review of the literature was realized using the principles underlying the UK Economic and Social Research Council guidance on the conduct of narrative synthesis and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Results Fourty-seven reports published between 1996 and 2013 were retained for the final analysis. Five case–control studies and six longitudinal studies addressed the effect of topiramate on acid–base and potassium balance. A significant tendency towards mild-to-moderate hyperchloraemic metabolic acidosis (with bicarbonate ≤21.0 mmol l−1 in approximately every third case) and mild hypokalaemia (with potassium ≤3.5 mmol l−1 in 10% of the cases) was noted on treatment with topiramate, which was similar in children and adults. A single study observed that topiramate causes mild hyperuricaemia in male adults. A tendency towards hypocitraturia, a recognized promoter of renal stone formation, was noted in all patients on topiramate. Conclusions Increasing evidence supports the use of topiramate. Topiramate is generally well tolerated, and serious adverse events are rare. Nonetheless, the present systematic review of the literature indicates that its use is linked with the development of acidosis, hypokalaemia, hyperuricaemia and hypocitraturia. PMID:24219102

  11. 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

  12. 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

    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

  13. Beta-alanine supplementation reduces acidosis but not oxygen uptake response during high-intensity cycling exercise.

    PubMed

    Baguet, Audrey; Koppo, Katrien; Pottier, Andries; Derave, Wim

    2010-02-01

    The oral ingestion of beta-alanine, the rate-limiting precursor in carnosine synthesis, has been shown to elevate the muscle carnosine content. Carnosine is thought to act as a physiologically relevant pH buffer during exercise but direct evidence is lacking. Acidosis has been hypothesised to influence oxygen uptake kinetics during high-intensity exercise. The present study aimed to investigate whether oral beta-alanine supplementation could reduce acidosis during high-intensity cycling and thereby affect oxygen uptake kinetics. 14 male physical education students participated in this placebo-controlled, double-blind study. Subjects were supplemented orally for 4 weeks with 4.8 g/day placebo or beta-alanine. Before and after supplementation, subjects performed a 6-min cycling exercise bout at an intensity of 50% of the difference between ventilatory threshold (VT) and VO(2peak). Capillary blood samples were taken for determination of pH, lactate, bicarbonate and base excess, and pulmonary oxygen uptake kinetics were determined with a bi-exponential model fitted to the averaged breath-by-breath data of three repetitions. Exercise-induced acidosis was significantly reduced following beta-alanine supplementation compared to placebo, without affecting blood lactate and bicarbonate concentrations. The time delay of the fast component (Td(1)) of the oxygen uptake kinetics was significantly reduced following beta-alanine supplementation compared to placebo, although this did not reduce oxygen deficit. The parameters of the slow component did not differ between groups. These results indicate that chronic beta-alanine supplementation, which presumably increased muscle carnosine content, can attenuate the fall in blood pH during high-intensity exercise. This may contribute to the ergogenic effect of the supplement found in some exercise modes. PMID:19841932

  14. Inhibition of the oxygen sensor PHD2 in the liver improves survival in lactic acidosis by activating the Cori cycle

    PubMed Central

    Suhara, Tomohiro; Hishiki, Takako; Kasahara, Masataka; Hayakawa, Noriyo; Oyaizu, Tomoko; Nakanishi, Tsuyoshi; Kubo, Akiko; Morisaki, Hiroshi; Kaelin, William G.; Suematsu, Makoto; Minamishima, Yoji Andrew

    2015-01-01

    Loss of prolyl hydroxylase 2 (PHD2) activates the hypoxia-inducible factor-dependent hypoxic response, including anaerobic glycolysis, which causes large amounts of lactate to be released from cells into the circulation. We found that Phd2-null mouse embryonic fibroblasts (MEFs) produced more lactate than wild-type MEFs, as expected, whereas systemic inactivation of PHD2 in mice did not cause hyperlacticacidemia. This unexpected observation led us to hypothesize that the hypoxic response activated in the liver enhances the Cori cycle, a lactate–glucose carbon recycling system between muscle and liver, and thereby decreases circulating lactate. Consistent with this hypothesis, blood lactate levels measured after a treadmill or lactate tolerance test were significantly lower in Phd2-liver-specific knockout (Phd2-LKO) mice than in control mice. An in vivo 13C-labeled lactate incorporation assay revealed that the livers of Phd2-LKO mice produce significantly more glucose derived from 13C-labeled lactate than control mice, suggesting that blockade of PHD2 in the liver ameliorates lactic acidosis by activating gluconeogenesis from lactate. Phd2-LKO mice were resistant to lactic acidosis induced by injection of a lethal dose of lactate, displaying a significant elongation of survival. Moreover, oral administration of a PHD inhibitor improved survival in an endotoxin shock mice model. These data suggest that PHD2 is a potentially novel drug target for the treatment of lactic acidosis, which is a serious and often fatal complication observed in some critically ill patients. PMID:26324945

  15. Inhibition of the oxygen sensor PHD2 in the liver improves survival in lactic acidosis by activating the Cori cycle.

    PubMed

    Suhara, Tomohiro; Hishiki, Takako; Kasahara, Masataka; Hayakawa, Noriyo; Oyaizu, Tomoko; Nakanishi, Tsuyoshi; Kubo, Akiko; Morisaki, Hiroshi; Kaelin, William G; Suematsu, Makoto; Minamishima, Yoji Andrew

    2015-09-15

    Loss of prolyl hydroxylase 2 (PHD2) activates the hypoxia-inducible factor-dependent hypoxic response, including anaerobic glycolysis, which causes large amounts of lactate to be released from cells into the circulation. We found that Phd2-null mouse embryonic fibroblasts (MEFs) produced more lactate than wild-type MEFs, as expected, whereas systemic inactivation of PHD2 in mice did not cause hyperlacticacidemia. This unexpected observation led us to hypothesize that the hypoxic response activated in the liver enhances the Cori cycle, a lactate-glucose carbon recycling system between muscle and liver, and thereby decreases circulating lactate. Consistent with this hypothesis, blood lactate levels measured after a treadmill or lactate tolerance test were significantly lower in Phd2-liver-specific knockout (Phd2-LKO) mice than in control mice. An in vivo (13)C-labeled lactate incorporation assay revealed that the livers of Phd2-LKO mice produce significantly more glucose derived from (13)C-labeled lactate than control mice, suggesting that blockade of PHD2 in the liver ameliorates lactic acidosis by activating gluconeogenesis from lactate. Phd2-LKO mice were resistant to lactic acidosis induced by injection of a lethal dose of lactate, displaying a significant elongation of survival. Moreover, oral administration of a PHD inhibitor improved survival in an endotoxin shock mice model. These data suggest that PHD2 is a potentially novel drug target for the treatment of lactic acidosis, which is a serious and often fatal complication observed in some critically ill patients. PMID:26324945

  16. Features and Prognosis of Severe Malaria Caused by Plasmodium falciparum, Plasmodium vivax and Mixed Plasmodium Species in Papua New Guinean Children

    PubMed Central

    Manning, Laurens; Laman, Moses; Law, Irwin; Bona, Cathy; Aipit, Susan; Teine, David; Warrell, Jonathan; Rosanas-Urgell, Anna; Lin, Enmoore; Kiniboro, Benson; Vince, John; Hwaiwhanje, Ilomo; Karunajeewa, Harin; Michon, Pascal; Siba, Peter

    2011-01-01

    Background Mortality from severe pediatric falciparum malaria appears low in Oceania but Plasmodium vivax is increasingly recognized as a cause of complications and death. The features and prognosis of mixed Plasmodium species infections are poorly characterized. Detailed prospective studies that include accurate malaria diagnosis and detection of co-morbidities are lacking. Methods and Findings We followed 340 Papua New Guinean (PNG) children with PCR-confirmed severe malaria (77.1% P. falciparum, 7.9% P. vivax, 14.7% P. falciparum/vivax) hospitalized over a 3-year period. Bacterial cultures were performed to identify co-incident sepsis. Clinical management was under national guidelines. Of 262 children with severe falciparum malaria, 30.9%, 24.8% and 23.2% had impaired consciousness, severe anemia, and metabolic acidosis/hyperlactatemia, respectively. Two (0.8%) presented with hypoglycemia, seven (2.7%) were discharged with neurologic impairment, and one child died (0.4%). The 27 severe vivax malaria cases presented with similar phenotypic features to the falciparum malaria cases but respiratory distress was five times more common (P = 0.001); one child died (3.7%). The 50 children with P. falciparum/vivax infections shared phenotypic features of mono-species infections, but were more likely to present in deep coma and had the highest mortality (8.0%; P = 0.003 vs falciparum malaria). Overall, bacterial cultures were positive in only two non-fatal cases. 83.6% of the children had alpha-thalassemia trait and seven with coma/impaired consciousness had South Asian ovalocytosis (SAO). Conclusions The low mortality from severe falciparum malaria in PNG children may reflect protective genetic factors other than alpha-thalassemia trait/SAO, good nutrition, and/or infrequent co-incident sepsis. Severe vivax malaria had similar features but severe P. falciparum/vivax infections were associated with the most severe phenotype and worst prognosis. PMID:22216212

  17. Epithelial capacity for apical uptake of short chain fatty acids is a key determinant for intraruminal pH and the susceptibility to subacute ruminal acidosis in sheep.

    PubMed

    Penner, Gregory B; Aschenbach, Jörg R; Gäbel, Gotthold; Rackwitz, Reiko; Oba, Masahito

    2009-09-01

    Subacute ruminal acidosis (SARA) is a common digestive disorder occurring in ruminants, with considerable variation in the severity of SARA observed among animals fed the same diet. Our aim in this study was to determine whether differences in the capacity of the ruminal epithelium for the apical uptake of acetate and butyrate (determined in Ussing chambers after slaughter) explains differences observed for the severity of a preceding episode of SARA in vivo. Adult sheep with an indwelling small ruminant ruminal pH measurement system (SRS) were randomly assigned to either a SARA induction treatment (oral drench containing 5 g glucose/kg body weight; n = 17) or a sham treatment (SHAM; n = 7; 12 mL water/kg body weight). Sheep receiving the glucose drench were further classified as nonresponders (NR; n = 7) or responders (RES; n = 7) according to their ruminal pH profile for the 3 h following the oral drench. Mean ruminal pH for the 3 h following the drench differed among groups (P < 0.001), with it being highest for SHAM (6.67 +/- 0.08), intermediate for NR (5.97 +/- 0.05), and lowest for RES (5.57 +/- 0.08) sheep. The apical uptake of acetate and butyrate did not differ between SHAM and RES sheep. However, NR sheep had greater in vitro apical uptake of acetate and butyrate and a higher plasma beta-hydroxybutyrate concentration than RES sheep, suggesting greater absorptive capacity for NR. Differences between NR and RES were attributed to greater bicarbonate-independent, nitrate-sensitive uptake of acetate (P = 0.007), a tendency for greater bicarbonate-dependent uptake of acetate (P = 0.071), and greater bicarbonate-independent uptake of butyrate (P = 0.022). These data indicate that differences in the rates and pathways for the uptake of acetate and butyrate explain a large proportion of the individual variation observed for the severity of SARA. PMID:19640964

  18. Clinical Features and Outcome in Children with Severe Plasmodium falciparum Malaria: A Meta-Analysis

    PubMed Central

    Manning, Laurens; Laman, Moses; Davis, Wendy A.; Davis, Timothy M. E.

    2014-01-01

    Background Although global malaria mortality is declining, estimates may not reflect better inpatient management of severe malaria (SM) where reported case fatality rates (CFRs) vary from 1–25%. Methods A meta-analysis of prospective studies of SM was conducted to examine i) whether hypothesized differences between clinical features and outcome in Melanesian compared with African or Asian children really exist, and ii) to explore temporal changes in overall and complication-specific CFRs. The proportions of different SM complications and, overall and complication-specific CFRs were incorporated into the meta-analysis. Adjustments were made for study-level covariates including geographic region, SM definition, artemisinin treatment, median age of participants and time period. Findings Sixty-five studies were included. Substantial heterogeneity (I2>80%) was demonstrated for most outcomes. SM definition contributed to between-study heterogeneity in proportions of cerebral malaria (CM), metabolic acidosis (MA), severe anemia and overall CFR, whilst geographic region was a significant moderator in for CM and hypoglycemia (HG) rates. Compared with their African counterparts, Melanesian children had lower rates of HG (10% [CI95 7–13%] versus 1% [0–3%], P<0.05), lower overall CFR (2% [0–4%] versus 7% [6–9%], P<0.05) and lower CM-specific CFR (8% [0–17%] versus 19% [16–21%], P<0.05). There was no temporal trend for overall CFR and CM-specific CFR but declining HG- and MA- specific CFRs were observed. Interpretation These data highlight that recent estimates of declining global malaria mortality are not replicated by improved outcomes for children hospitalized with SM. Significant geographic differences in the complication rates and subsequent CFRs exist and provide the first robust confirmation of lower CFRs in Melanesian children, perhaps due to less frequent HG. PMID:24516538

  19. Adult nephron-specific MR-deficient mice develop a severe renal PHA-1 phenotype.

    PubMed

    Canonica, Jérémie; Sergi, Chloé; Maillard, Marc; Klusonova, Petra; Odermatt, Alex; Koesters, Robert; Loffing-Cueni, Dominique; Loffing, Johannes; Rossier, Bernard; Frateschi, Simona; Hummler, Edith

    2016-05-01

    Aldosterone is the main mineralocorticoid hormone controlling sodium balance, fluid homeostasis, and blood pressure by regulating sodium reabsorption in the aldosterone-sensitive distal nephron (ASDN). Germline loss-of-function mutations of the mineralocorticoid receptor (MR) in humans and in mice lead to the "renal" form of type 1 pseudohypoaldosteronism (PHA-1), a case of aldosterone resistance characterized by salt wasting, dehydration, failure to thrive, hyperkalemia, and metabolic acidosis. To investigate the importance of MR in adult epithelial cells, we generated nephron-specific MR knockout mice (MR(Pax8/LC1)) using a doxycycline-inducible system. Under standard diet, MR(Pax8/LC1) mice exhibit inability to gain weight and significant weight loss compared to control mice. Interestingly, despite failure to thrive, MR(Pax8/LC1) mice survive but develop a severe PHA-1 phenotype with higher urinary Na(+) levels, decreased plasma Na(+), hyperkalemia, and higher levels of plasma aldosterone. This phenotype further worsens and becomes lethal under a sodium-deficient diet. Na(+)/Cl(-) co-transporter (NCC) protein expression and its phosphorylated form are downregulated in the MR(Pax8/LC1) knockouts, as well as the αENaC protein expression level, whereas the expression of glucocorticoid receptor (GR) is increased. A diet rich in Na(+) and low in K(+) does not restore plasma aldosterone to control levels but is sufficient to restore body weight, plasma, and urinary electrolytes. In conclusion, MR deletion along the nephron fully recapitulates the features of severe human PHA-1. ENaC protein expression is dependent on MR activity. Suppression of NCC under hyperkalemia predominates in a hypovolemic state. PMID:26762397

  20. Induction of Subacute Ruminal Acidosis Affects the Ruminal Microbiome and Epithelium

    PubMed Central

    McCann, Joshua C.; Luan, Shaoyu; Cardoso, Felipe C.; Derakhshani, Hooman; Khafipour, Ehsan; Loor, Juan J.

    2016-01-01

    Subacute ruminal acidosis (SARA) negatively impacts the dairy industry by decreasing dry matter intake, milk production, profitability, and increasing culling rate and death loss. Six ruminally cannulated, lactating Holstein cows were used in a replicated incomplete Latin square design to determine the effects of SARA induction on the ruminal microbiome and epithelium. Experimental periods were 10 days with days 1–3 for ad libitum intake of control diet, followed by 50% feed restriction on day 4, and ad libitum access on day 5 to the basal diet or the basal diet with an additional 10% of a 50:50 wheat/barley pellet. Based on subsequent ruminal pH, cows were grouped (SARA grouping; SG) as Non-SARA or SARA based on time <5.6 pH (0 and 3.4 h, respectively). Ruminal samples were collected on days 1 and 6 of each period prior to feeding and separated into liquid and solid fractions. Microbial DNA was extracted for bacterial analysis using 16S rRNA gene paired-end sequencing on the MiSeq Illumina platform and quantitative PCR (qPCR). Ruminal epithelium biopsies were taken on days 1 and 6 before feeding. Quantitative RT-PCR was used to determine gene expression in rumen epithelium. Bray–Curtis similarity indicated samples within the liquid fraction separated by day and coincided with an increased relative abundance of genera Prevotella, Ruminococcus, Streptococcus, and Lactobacillus on day 6 (P < 0.06). Although Firmicutes was the predominant phyla in the solid fraction, a SG × day interaction (P < 0.01) indicated a decrease on day 6 for SARA cows. In contrast, phylum Bacteroidetes increased on day 6 (P < 0.01) for SARA cows driven by greater genera Prevotella and YRC22 (P < 0.01). Streptococcus bovis and Succinivibrio dextrinosolvens populations tended to increase on day 6 but were not affected by SG. In ruminal epithelium, CLDN1 and CLDN4 expression increased on day 6 (P < 0.03) 24 h after SARA induction and a tendency for a SG × day interaction (P < 0.10) was observed for CLDN4. Overall, results indicate more rapid adaptation to an induced bout of SARA in the solid fraction ruminal microbiome compared with ruminal epithelium.

  1. Progressive infantile neurodegeneration caused by 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency: a novel inborn error of branched-chain fatty acid and isoleucine metabolism.

    PubMed

    Zschocke, J; Ruiter, J P; Brand, J; Lindner, M; Hoffmann, G F; Wanders, R J; Mayatepek, E

    2000-12-01

    We report a novel inborn error of metabolism identified in a child with an unusual neurodegenerative disease. The male patient was born at term and recovered well from a postnatal episode of metabolic decompensation and lactic acidosis. Psychomotor development in the first year of life was only moderately delayed. After 14 mo of age, there was progressive loss of mental and motor skills; at 2 years of age, he was severely retarded with marked restlessness, choreoathetoid movements, absence of directed hand movements, marked hypotonia and little reaction to external stimuli. Notable laboratory findings included marked elevations of urinary 2-methyl-3-hydroxybutyrate and tiglylglycine without elevation of 2-methylacetoacetate, mild elevations of lactate in CSF and blood, and a slightly abnormal acylcarnitine profile. These abnormalities became more apparent after isoleucine challenge. Enzyme studies showed absent activity of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) in the mitochondrial oxidation of 2-methyl branched-chain fatty acids and isoleucine. Under dietary isoleucine restriction, neurologic symptoms stabilized over the next 7 months. PMID:11102558

  2. Cytochrome P450-mediated warfarin metabolic ability is not a critical determinant of warfarin sensitivity in avian species: In vitro assays in several birds and in vivo assays in chicken.

    PubMed

    Watanabe, Kensuke P; Kawata, Minami; Ikenaka, Yoshinori; Nakayama, Shouta M M; Ishii, Chihiro; Darwish, Wageh Sobhi; Saengtienchai, Aksorn; Mizukawa, Hazuki; Ishizuka, Mayumi

    2015-10-01

    Coumarin-derivative anticoagulant rodenticides used for rodent control are posing a serious risk to wild bird populations. For warfarin, a classic coumarin derivative, chickens have a high median lethal dose (LD50), whereas mammalian species generally have much lower LD50. Large interspecies differences in sensitivity to warfarin are to be expected. The authors previously reported substantial differences in warfarin metabolism among avian species; however, the actual in vivo pharmacokinetics have yet to be elucidated, even in the chicken. In the present study, the authors sought to provide an in-depth characterization of warfarin metabolism in birds using in vivo and in vitro approaches. A kinetic analysis of warfarin metabolism was performed using liver microsomes of 4 avian species, and the metabolic abilities of the chicken and crow were much higher in comparison with those of the mallard and ostrich. Analysis of in vivo metabolites from chickens showed that excretions predominantly consisted of 4'-hydroxywarfarin, which was consistent with the in vitro results. Pharmacokinetic analysis suggested that chickens have an unexpectedly long half-life despite showing high metabolic ability in vitro. The results suggest that the half-life of warfarin in other bird species could be longer than that in the chicken and that warfarin metabolism may not be a critical determinant of species differences with respect to warfarin sensitivity. PMID:25959534

  3. Tissue kallikrein protects cortical neurons against in vitro ischemia-acidosis/reperfusion-induced injury through the ERK1/2 pathway.

    PubMed

    Liu, Ling; Zhang, Renliang; Liu, Kui; Zhou, Houguang; Yang, Xuelian; Liu, Xinfeng; Tang, Min; Su, Jinjin; Dong, Qiang

    2009-10-01

    Human tissue kallikrein (hTK) gene transfer has been shown to protect neurons against cerebral ischemia/reperfusion (I/R) injury, and exogenous tissue kallikrein (TK) administration can enhance neurogenesis and angiogenesis following focal cortical infarction. Previous studies have reported that acidosis is a common feature of ischemia and plays a critical role in brain injury. However, little is known about the role of TK in ischemia-acidosis-induced injury, which is partially caused by the activation of acid-sensing ion channels (ASICs). Here we report that pretreatment of cultured cortical neurons with TK reduced cell death induced by either acidosis or oxygen and glucose deprivation-acidosis/reoxygenation (OGD-A/R). Immunocytochemical staining revealed that TK largely prevented OGD-A/R-induced neuronal morphological changes. We also observed that TK treatment protected cultured neurons from acidosis and OGD-A/R insults. TK exerted the neuroprotective effects by reducing production of reactive oxygen species (ROS), stabilizing the mitochondrial membrane potential (MMP) and inhibiting caspase-3 activation, and thereby attenuating oxidative stress and apoptosis. In addition, we found that activation of the extracellular signal-regulated kinase1/2 (ERK1/2) signaling cascade but not the PI3K/Akt signaling pathway was required for the survival-promoting effect of TK on neurons exposed to OGD-A/R. Moreover, blockade of ASICs had effects similar to TK administration, suggesting direct or indirect involvement of ASICs in TK protection. In conclusion, TK has antioxidant characteristics and is capable of alleviating ischemia-acidosis/reperfusion-induced injury, inhibiting apoptosis and promoting cell survival in vitro through activating the ERK1/2 signaling pathways. Therefore, TK represents a promising therapeutic strategy for ischemic stroke. PMID:19576887

  4. Effects of hypoxia, glucose deprivation and acidosis on phosphatidylcholine synthesis in HL-1 cardiomyocytes. CTP:phosphocholine cytidylyltransferase activity correlates with sarcolemmal disruption

    PubMed Central

    Sarri, Elisabet; Garcia-Dorado, David; Abellan, Arancha; Soler-Soler, Jordi

    2005-01-01

    A decrease in [3H]Cho (choline) incorporation in to PtdCho (phos-phatidylcholine) preceded the onset of LDH (lactate dehydrogenase) release in HL-1 cardiomyocytes submitted to simulated ischaemia. This observation led us to examine the role of PtdCho synthesis in sarcolemmal disruption in HL-1 cardiomyocytes. To address this objective we analysed the individual effects of hypoxia, glucose deprivation and acidosis, three prominent components of ischaemia, on the different steps of the Kennedy pathway for the synthesis of PtdCho. Pulse and pulse-chase experiments with [3H]Cho, performed in whole HL-1 cells submitted to hypoxia or normoxia, in the presence or absence of glucose at different pHs indicated first, that CK (choline kinase) was inhibited by hypoxia and acidosis, whereas glucose deprivation exacerbated the inhibition caused by hypoxia. Second, the rate-limiting reaction in PtdCho synthesis, catalysed by CCT (CTP:phosphocholine cytidylyltransferase), was inhibited by hypoxia and glucose deprivation, but unexpectedly activated by acidosis. In cellfree system assays, acidosis inhibited both CK and CCT. In experiments performed in whole cells, the effect of acidosis was likely to be direct on CK, but indirect or intact-cell-dependent on CCT. Since hypoxia and glucose deprivation favoured membrane disruption, but acidosis prevented it, we hypothesized that the modulation of CCT could be an important determinant of cell survival. Supporting this hypothesis, we show that CCT activity in whole-cell experiments clearly correlated with LDH release, but not with ATP concentration. Altogether our results suggest a significant role for CCT activity in sarcolemmal disruption during ischaemia. PMID:16236026

  5. A single mild episode of subacute ruminal acidosis does not affect ruminal barrier function in the short term.

    PubMed

    Penner, G B; Oba, M; Gäbel, G; Aschenbach, J R

    2010-10-01

    Twenty-four German Merino sheep (72.3±10.1 kg of body weight) were fed an all-hay diet and assigned to either the subacute ruminal acidosis (SARA) treatment (n=17) or sham treatment (n=7). The SARA sheep were orally dosed with a 2.2 M glucose solution to supply 5 g of glucose/kg of body weight, whereas sham sheep received an equal volume of water. Ruminal pH was measured for 48 h before and 3 h after the oral dose. Sheep were then killed and ruminal epithelia from the ventral sac were mounted in Ussing chambers. The serosal-to-mucosal flux rate of partially (3)H-labeled mannitol (J(mannitol-SM)), an indicator of barrier function, was measured while epithelia were exposed to 3 sequential in vitro measurement periods lasting 1 h each. The measurement periods consisted of baseline, challenge, and recovery periods and were interspersed by 30-min periods for treatment equilibration. Baseline conditions were pH 6.1 (mucosal solution) and pH 7.4 (serosal solution) with a bilateral osmolarity of 293 mOsm/L. During the challenge period, the mucosal side of the epithelia was exposed to either an acidotic challenge (pH 5.2, osmolarity 293 mOsm/L) or an osmotic challenge (pH 6.1, osmolarity 450 mOsm/L); a third group served as control (pH 6.1, osmolarity 293 mOsm/L). The mucosal buffer solution was replaced for the recovery period. In vivo, sheep on the SARA treatment had lower mean (5.77 vs. 6.67) and nadir (5.48 vs. 6.47) ruminal pH for the 3h following the oral drench compared with sham sheep, indicating the successful induction of SARA with the oral glucose dose. Despite the marked reduction in pH in vivo, induction of SARA had no detectable effects on the baseline measurements of J(mannitol-SM), tissue conductance (G(t)), and short-circuit current (I(sc)) in vitro. However, reducing mucosal pH to 5.2 in vitro had negative effects on epithelial barrier function in the recovery period, including increased J(mannitol-SM), increased G(t), and decreased I(sc). The osmotic challenge increased J(mannitol-SM) and G(t) and decreased I(sc) during the challenge period, which was reversible in the recovery period except for slight reduction in I(sc). Interactions between the in vitro treatment and measurement period were detected for J(mannitol-SM), G(t), and I(sc). These data indicate that a mild episode of SARA (nadir pH, 5.48; duration ruminal pH <5.8, 111 min relative to the 180-min measurement period) does not affect ruminal epithelial barrier function immediately after the episode but that a rapid and more severe acidification (pH 5.2) in vitro increases epithelial permeability following the insult. PMID:20855017

  6. Severe Sarcoidosis.

    PubMed

    Kouranos, Vasileios; Jacob, Joe; Wells, Athol U

    2015-12-01

    In sarcoidosis, reduction in mortality and the prevention of disability due to major organ involvement are treatment goals. Thus, it is important to recognize severe disease and identify patients at higher risk of progression to severe disease. In this article, fibrotic lung disease and cardiac sarcoidosis are reviewed as the major contributors to sarcoidosis mortality and morbidity. In the absence of a standardized definition of severe pulmonary disease, a multidisciplinary approach to clinical staging is suggested, based on symptoms, pulmonary function tests, and imaging findings at presentation, integrated with the duration of disease and longitudinal disease behavior during early follow-up. PMID:26593144

  7. Evolution of Metabolism

    NASA Astrophysics Data System (ADS)

    Nealson, K. H.; Rye, R.

    2003-12-01

    This chapter is devoted to the discussion of the evolution of metabolism, with a particular focus towards redox metabolism and the utilization of redox energy by life. We will deal with various aspects of metabolism that involve direct interaction with, and the extraction of energy from, the environment (catabolic metabolism) and will talk briefly of the reactions that affect mineral formation and dissolution. However, we will de-emphasize the aspects related to the formation of complex molecules and organisms. To some, it will be refreshingly brief; to others, somewhat superficial. This is unavoidable, as our knowledge of the details of the evolution of metabolism is at best slim. However, by piecing together aspects of the properties and history of the Earth and coupling these with what we know of today's metabolism, it is possible to at least frame several different hypotheses that, with time, should be possible to test and modify so that the next writing of this chapter might contain some intellectual entrees and not just the appetizers. Any discussion of metabolic evolution must occur in concert with a consideration of the Earth - the understanding of the forces that drove the co-evolution of life and Earth can be achieved only by considering them together. This theme will pervade this chapter, and any real understanding of the evolution of metabolism must be inexorably coupled to, and consistent with, the geological record of the Earth.The first aspect of evolution concerns the metabolic participants as we know them now (i.e., a definition of metabolic diversity), and the second concerns the sequence of events that have led to this remarkable metabolic diversity. The first part is fairly straightforward: a discussion of the domains of life, and the metabolic achievements that are expressed in the various domains, and relating metabolism to biogeochemical processes whenever possible. The second part is much more problematic. While it is possible to make up nearly any story regarding the evolution of metabolism (and nearly all have been attempted!), the starting point of life is not known (great debates still rage as to the nature and origin of the first living systems), and it is not a trivial matter to specify the sequence and timing of metabolic innovations. As will be discussed below, genetic and genomic data have revealed that genetic exchange between organisms has been so pervasive that it has essentially uncoupled the evolution of taxonomic groups from the evolution of metabolic processes, thus, obscuring the evolutionary trail with blurred signals. Given these challenges, it may be prudent at this time to admit what we do not know, and lay out the challenges for the coming years.

  8. Cryoamputation as a temporizing measure in severe burn injury.

    PubMed

    Pennington, J Daniel; Wall, Anji E; Schlesinger, Joseph J; Higdon, Kent K; Weavind, Liza

    2014-01-01

    Cryoamputation, or physiologic amputation, is a well-described procedure typically used to amputate gangrenous lower extremities. In such cases the patient is too unstable for transport to the operating room, so cryoamputation using dry ice or other refrigerant allows for immediate bedside intervention and later operative amputation when the patient is more stable. In this study the authors describe the use of cryoamputation to stabilize a burn patient with a nonviable upper extremity considered to be contributing significantly to his metabolic acidosis. This experience suggests that cryoamputation may be a reasonable technique to consider when a burn patient presents with a nonviable extremity but is too unstable for immediate operative amputation. PMID:24978024

  9. Dysregulated metabolism contributes to oncogenesis.

    PubMed

    Hirschey, Matthew D; DeBerardinis, Ralph J; Diehl, Anna Mae E; Drew, Janice E; Frezza, Christian; Green, Michelle F; Jones, Lee W; Ko, Young H; Le, Anne; Lea, Michael A; Locasale, Jason W; Longo, Valter D; Lyssiotis, Costas A; McDonnell, Eoin; Mehrmohamadi, Mahya; Michelotti, Gregory; Muralidhar, Vinayak; Murphy, Michael P; Pedersen, Peter L; Poore, Brad; Raffaghello, Lizzia; Rathmell, Jeffrey C; Sivanand, Sharanya; Vander Heiden, Matthew G; Wellen, Kathryn E

    2015-12-01

    Cancer is a disease characterized by unrestrained cellular proliferation. In order to sustain growth, cancer cells undergo a complex metabolic rearrangement characterized by changes in metabolic pathways involved in energy production and biosynthetic processes. The relevance of the metabolic transformation of cancer cells has been recently included in the updated version of the review "Hallmarks of Cancer", where dysregulation of cellular metabolism was included as an emerging hallmark. While several lines of evidence suggest that metabolic rewiring is orchestrated by the concerted action of oncogenes and tumor suppressor genes, in some circumstances altered metabolism can play a primary role in oncogenesis. Recently, mutations of cytosolic and mitochondrial enzymes involved in key metabolic pathways have been associated with hereditary and sporadic forms of cancer. Together, these results demonstrate that aberrant metabolism, once seen just as an epiphenomenon of oncogenic reprogramming, plays a key role in oncogenesis with the power to control both genetic and epigenetic events in cells. In this review, we discuss the relationship between metabolism and cancer, as part of a larger effort to identify a broad-spectrum of therapeutic approaches. We focus on major alterations in nutrient metabolism and the emerging link between metabolism and epigenetics. Finally, we discuss potential strategies to manipulate metabolism in cancer and tradeoffs that should be considered. More research on the suite of metabolic alterations in cancer holds the potential to discover novel approaches to treat it. PMID:26454069

  10. Psoriasis and Metabolic Syndrome

    PubMed Central

    Malkic Salihbegovic, Eldina; Hadzigrahic, Nermina; Cickusic, Amra Jakubovic

    2015-01-01

    Introduction: Psoriasis is a chronic skin ailment which can be connected with an increased occurrence of other illnesses, including the metabolic syndrome. Examinees and methods: A prospective study has been conducted which included 70 patients affected by psoriasis, both genders, older than 18 years. Average age being 47,14 (SD=±15,41) years, from that there were 36 men or 51,43 and 34 women or 48,57%. The average duration of psoriasis was 15,52 (SD= ±12,54) years. For purposes of diagnosing the metabolic syndrome, the criteria of National Cholesterol Education Program Adult Treatment Panel III, (NCEP ATP III) were used. For purposes of detecting the severity and spread of psoriasis, Psoriasis Area and Severity Index (PASI) was used. Results: The incidence of metabolic syndrome in patients with psoriasis was 38,57%. Average values of PASI score were 16,65. The increase in values of PASI score and metabolic syndrome were statistically highly connected. (r=0,3, p=0,0001). Conclusion: Psoriasis is connected with metabolic syndrome, there is a positive correlation between the severity of psoriasis and frequency of metabolic syndrome. PMID:26005254

  11. Subacute ruminal acidosis challenge changed in situ degradability of feedstuffs in dairy goats.

    PubMed

    Li, Fei; Cao, Yangchun; Liu, Nannan; Yang, Xinjian; Yao, Junhu; Yan, Dabing

    2014-01-01

    This study investigated the effects of wheat-induced subacute ruminal acidosis (SARA) on rumen bacterial populations and in situ degradabilities of NDF, starch, and crude protein of feeds. Four multiparous dairy goats (BW=60±3.3kg) fitted with ruminal cannulas were assigned to a 2×2 crossover design (28-d treatment periods separated by a 7-d washout interval). The treatment diets consisted of 2 levels of cracked wheat: 0 (control, corn based concentrate) and 35% (diet-induced SARA, wheat-based concentrate), with a constant forage- (45% alfalfa hay and 5% corn silage of DM) to-concentrate (50% of DM) ratio. Results indicate that diets with a 35% wheat decreased ruminal pH (6.21 vs. 5.98) and increased the duration (1.13 vs. 4.72h/d) and area (0.12 vs. 0.78 pH × h/d) of ruminal pH below 5.6 and induced SARA. The SARA increased ruminal total volatile fatty acid concentration, from 105.0 to 123.8mM, and decreased the acetate molar proportion (62.8 vs. 56.6mol/100mol) and the acetate-to-propionate ratio (3.5 vs. 2.8). Compared with the control group, SARA decreases the relative abundance of Fibrobacter succinogenes (-59.3%) and Ruminococcus flavefaciens (-68.4%), whereas it increased Succinimonas amylolytica (198.1%) and Ruminobacter amylophilus (125.2%). The SARA decreased 24- and 48-h dry matter (DM) and neutral detergent fiber (NDF) degradabilities of corn silage. The 48-h degradabilities of DM (51.0 vs. 48.2%) and NDF (40.3 vs. 36.0%) in alfalfa hay were not affected by SARA, but the SARA tended to reduce the 24-h DM (49.6 vs. 46.3%) and NDF (37.8 vs. 33.2%) degradabilities. The effective ruminal degradabilities of DM and NDF in alfalfa hay and corn silage were reduced during SARA. In situ degradability parameters of DM and starch of wheat were not affected by SARA, but starch degradability of corn (9.5 vs. 13.3%/h) increased. The SARA reduced in situ 12-h degradabilities of DM and crude protein of soybean meal and extruded soybean without affecting the degradabilities of the other protein supplements (corn gluten meal, cottonseed meal, corn dried distillers grains with solubles, rapeseed meal, and wheat germ meal). These results indicated that the cracked wheat-induced SARA reduced the degradation of NDF in roughages and that of protein in soybean meal (-19.8%) and extruded soy (-18.9%) and increased the starch degradability in corn, due to the increased amylolytic bacteria and decreased cellulolytic bacteria counts in the rumen. PMID:24913652

  12. Active dry Saccharomyces cerevisiae can alleviate the effect of subacute ruminal acidosis in lactating dairy cows.

    PubMed

    AlZahal, O; Dionissopoulos, L; Laarman, A H; Walker, N; McBride, B W

    2014-12-01

    The objective of the study was to determine the effect of active dry Saccharomyces cerevisiae (ADSC) supplementation on dry matter intake, milk yield, milk components, ruminal pH, and microbial community during a dietary regimen that leads to subacute ruminal acidosis (SARA). Sixteen multiparous, rumen-cannulated lactating Holstein cows were randomly assigned to 1 of 2 dietary treatments that included ADSC (Biomate; AB Vista, Marlborough, UK; 8 × 10(10) cfu/head per day) or control. During wk 1 to 6, all cows received a high-forage (HF) diet (77:23, forage:concentrate). Cows were then abruptly switched during wk 7 to a high-grain (HG) diet (49:51, forage:concentrate) and remained on the HG until the end of wk 10. Feed intake and milk yields were recorded daily. Ruminal pH was recorded continuously using an indwelling system for 1 to 2 d per week during the pre-experimental phase, and wk 6, 7, and 10. Ruminal digesta samples were collected at the end of the experiment and analyzed for relative change in microbial communities using real-time quantitative PCR. Cows were considered to have SARA if the duration below pH 5.6 was ≥300 min/d. Ruminal pH during wk 6 (HF plateau) was not different across treatments (15 ± 46 min/d at pH <5.6). The dietary regimen successfully induced SARA during wk 7 (transition from HF to HG diet), and ruminal pH (551 ± 46 min/d at pH <5.6) was not different across treatments. However, cows receiving ADSC had an improved ruminal pH (122 ± 57 vs. 321 ± 53 min/d at pH <5.6) during wk 10 (HG plateau) compared with control. Additionally, cows receiving ADSC had a better dry matter intake (23.3 ± 0.66 vs. 21.6 ± 0.61 kg/d) and 4% fat-corrected milk yield (29.6 ± 1.2 vs. 26.5 ± 1.2 kg/d) than control cows during the HG phase (wk 8 to 10). During HG feeding, cows receiving ADSC had greater total volatile fatty acid and propionate concentrations (175 ± 7.5 vs. 154 ± 7.5 and 117 ± 6.1 vs. 94 ± 5.7 mM for ADSC and control, respectively) and lower acetate:propionate ratio (0.26 ± 0.5 vs. 0.36 ± 0.05 for ADSC and control, respectively). Microbial analyses conducted on samples collected during wk 10 showed that cows supplemented with S. cerevisiae had a 9-fold, 2-fold, 6-fold, 1.3-fold, and 8-fold increase in S. cerevisiae, Fibrobacter succinogenes, Anaerovibrio lipolytica, Ruminococcus albus, and anaerobic fungi, respectively, which suggested an increase in cellulolytic microbes within the rumen. Cows supplemented with ADSC had 2.2-fold reduction in Prevotella albensis, which is a gram-negative bacterium predominant during SARA. Prevotella spp. are suggested to be an important source of lipopolysaccharide responsible for inflammation within the rumen. Cows supplemented with ADSC had a 2.3-fold increase in Streptococcus bovis and a 12-fold reduction in Megasphaera elsdenii. The reduction in M. elsdenii may reflect lower concentration of lactic acid within the rumen for ADSC cows. In conclusion, ADSC supplementation to dairy cows was demonstrated to alleviate the condition of SARA caused by abrupt dietary changes from HF to HG, and can potentially improve rumen function, as indicated by greater numbers of cellulolytic microorganisms within the rumen. PMID:25282426

  13. Early Onset of Diabetes Mellitus Accelerates Cognitive Decline in Japanese Patients with Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes.

    PubMed

    Murakami, Takaaki; Shinoto, Yuya; Yonemitsu, Shin; Muro, Seiji; Oki, Shogo; Koga, Yasutoshi; Goto, Yu-Ichi; Kaneda, Daita

    2016-01-01

    Approximately 80% of patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) carry the A3243G mutation in the mitochondrial tRNALeu (UUR) gene. Conversely, this mutation has also been identified as one of the most prevalent genetic abnormalities in patients with diabetes mellitus. Mitochondrial diabetes mellitus complicated with MELAS is relatively common, and 12.5% of patients with the A3243G mutation develop MELAS after being diagnosed with diabetes mellitus. However, the clinical impact of diabetes mellitus in MELAS patients remains unclear. Therefore, we retrospectively studied 14 Japanese MELAS patients with the A3243G mutation: three men and eleven women, with the mean age of 48.0 (± 15.4) years. Eight patients had been diagnosed with diabetes mellitus prior to the diagnosis of mitochondrial disease, and all of them were treated with insulin. The other six included four patients with concurrent diagnosis of diabetes and mitochondrial disease, one patient diagnosed with diabetes after the diagnosis of mitochondrial disease, and one patient without developing diabetes currently. We thus compared the patients' characteristics between those with and without early onset of diabetes mellitus. Cognitive decline (75.0% vs. 0%; p = 0.03) and poor glycemic control with severe hypoglycemic events (75.0% vs. 16.7%; p = 0.05) were more common in MELAS patients with a prior diagnosis of diabetes than in those without the prior diagnosis of diabetes. Our data suggest that the latent progress of cognitive decline is accelerated because of early onset of diabetes mellitus in MELAS patients. PMID:27063563

  14. The Effects of Lung Protective Ventilation or Hypercapnic Acidosis on Gas Exchange and Lung Injury in Surfactant Deficient Rabbits

    PubMed Central

    Hummler, Helmut D.; Banke, Katharina; Wolfson, Marla R.; Buonocore, Giuseppe; Ebsen, Michael; Bernhard, Wolfgang; Tsikas, Dimitrios; Fuchs, Hans

    2016-01-01

    Background Permissive hypercapnia has been shown to reduce lung injury in subjects with surfactant deficiency. Experimental studies suggest that hypercapnic acidosis by itself rather than decreased tidal volume may be a key protective factor. Objectives To study the differential effects of a lung protective ventilatory strategy or hypercapnic acidosis on gas exchange, hemodynamics and lung injury in an animal model of surfactant deficiency. Methods 30 anesthetized, surfactant-depleted rabbits were mechanically ventilated (FiO2 = 0.8, PEEP = 7cmH2O) and randomized into three groups: Normoventilation-Normocapnia (NN)-group: tidal volume (Vt) = 7.5 ml/kg, target PaCO2 = 40 mmHg; Normoventilation-Hypercapnia (NH)-group: Vt = 7.5 ml/kg, target PaCO2 = 80 mmHg by increasing FiCO2; and a Hypoventilation-Hypercapnia (HH)-group: Vt = 4.5 ml/kg, target PaCO2 = 80 mmHg. Plasma lactate and interleukin (IL)-8 were measured every 2 h. Animals were sacrificed after 6 h to perform bronchoalveolar lavage (BAL), to measure lung wet-to-dry weight, lung tissue IL-8, and to obtain lung histology. Results PaO2 was significantly higher in the HH-group compared to the NN-group (p<0.05), with values of the NH-group between the HH- and NN-groups. Other markers of lung injury (wet-dry-weight, BAL-Protein, histology-score, plasma-IL-8 and lung tissue IL-8) resulted in significantly lower values for the HH-group compared to the NN-group and trends for the NH-group towards lower values compared to the NN-group. Lactate was significantly lower in both hypercapnia groups compared to the NN-group. Conclusion Whereas hypercapnic acidosis may have some beneficial effects, a significant effect on lung injury and systemic inflammatory response is dependent upon a lower tidal volume rather than resultant arterial CO2 tensions and pH alone. PMID:26840779

  15. Ibuprofen-Induced Hypokalemia and Distal Renal Tubular Acidosis: A Patient's Perceptions of Over-the-Counter Medications and Their Adverse Effects

    PubMed Central

    Salter, Mark D.

    2013-01-01

    We highlight a case of distal renal tubular acidosis secondary to ibuprofen and codeine use. Of particular interest in this case are the patient's perception of over-the-counter (OTC) medication use, her own OTC use prior to admission, and her knowledge of adverse reactions or side effects of these medications prior to taking them. PMID:24829833

  16. Metabolic myopathies

    NASA Technical Reports Server (NTRS)

    Martin, A.; Haller, R. G.; Barohn, R.; Blomqvist, C. G. (Principal Investigator)

    1994-01-01

    Metabolic myopathies are disorders of muscle energy production that result in skeletal muscle dysfunction. Cardiac and systemic metabolic dysfunction may coexist. Symptoms are often intermittent and provoked by exercise or changes in supply of lipid and carbohydrate fuels. Specific disorders of lipid and carbohydrate metabolism in muscle are reviewed. Evaluation often requires provocative exercise testing. These tests may include ischemic forearm exercise, aerobic cycle exercise, and 31P magnetic resonance spectroscopy with exercise.

  17. [Severe Asthma].

    PubMed

    Hagmeyer, Lars; Randerath, Winfried J

    2015-10-01

    The European Respiratory Society and the American Thoracic Society recently published the international ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. It is aim of the guideline to establish standardized diagnostic criteria and to develop evidence based diagnostic and therapeutic strategies. In the diagnostic approach verifying the diagnosis of asthma and identifying comorbidities and contributing factors are very important. In the therapeutic guidance of asthma patients steroid insensitivity and overdosage of betamimetic inhaler therapy are typical challenges. Novel therapeutic strategies open the perspective to personalized therapy in asthma. PMID:26445257

  18. Metabolic ecology.

    PubMed

    Humphries, Murray M; McCann, Kevin S

    2014-01-01

    Ecological theory that is grounded in metabolic currencies and constraints offers the potential to link ecological outcomes to biophysical processes across multiple scales of organization. The metabolic theory of ecology (MTE) has emphasized the potential for metabolism to serve as a unified theory of ecology, while focusing primarily on the size and temperature dependence of whole-organism metabolic rates. Generalizing metabolic ecology requires extending beyond prediction and application of standardized metabolic rates to theory focused on how energy moves through ecological systems. A bibliometric and network analysis of recent metabolic ecology literature reveals a research network characterized by major clusters focused on MTE, foraging theory, bioenergetics, trophic status, and generalized patterns and predictions. This generalized research network, which we refer to as metabolic ecology, can be considered to include the scaling, temperature and stoichiometric models forming the core of MTE, as well as bioenergetic equations, foraging theory, life-history allocation models, consumer-resource equations, food web theory and energy-based macroecology models that are frequently employed in ecological literature. We conclude with six points we believe to be important to the advancement and integration of metabolic ecology, including nomination of a second fundamental equation, complementary to the first fundamental equation offered by the MTE. PMID:24028511

  19. Effects of feeding buffering mineral mixture on subacute rumen acidosis and some production traits in dairy cows.

    PubMed

    Petrujkić, Branko; Samanc, Horea; Adamović, Milan; Stojić, Velibor; Petrujkić, Tihomir; Grdović, Svetlana; Sefer, Dragan; Marković, Radmila

    2010-11-01

    This trial was designed in order to evaluate the incidence of subacute rumen acidosis (SARA) during early lactation and to investigate the possibilities for its prevention by use of a buffering mineral mixture. On the beginning of the trial it was found that the pH value of rumen fluid in 4 animals was lower than normal (pH < 6.0) and that 20% of animals have had SARA. The control and the experimental group of cows were fed the same meal with exception of concentrated feed which in the experimental group contained the mineral mix with buffering activity in amount of 1%. Continuous addition of buffering mineral mixture in the amount of 1% in concentrated feed for early lactation cows successfully prevents SARA formation and leads to increased milk production, as well as increased milk fat and protein content. PMID:21180257

  20. Reduced Tc-99m DMSA uptake in a patient with renal tubular acidosis: effect of acid-base imbalance.

    PubMed

    Caglar, Meltem; Topaloğlu, Rezan

    2002-11-01

    Tc-99m dimercaptosuccinic acid (DMSA) is used as a renal cortical imaging agent to detect parenchymal abnormalities especially in children. Kidney uptake of DMSA provides an index for evaluation of a functional tubular mass, which depends on the renal blood flow and proximal tubular cell membrane transport function. We here report a boy with renal tubular acidosis, which has noticeably reduced uptake on his Tc-99m DMSA scintigraphy, despite a totally normal Tc-99m MAG-3 study. The case reported here clearly demonstrates a situation in which renal uptake of DMSA may be dissociated from a functional renal mass and the importance of acid-base balance which alters Tc-99m DMSA uptake. PMID:12508844

  1. Mucosal necrosis of the small intestine in myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome.

    PubMed

    Fukuyama, Keita; Ishikawa, Yasuhide; Ogino, Tetsuro; Inoue, Hidenobu; Yamaoka, Ryoya; Hirose, Tetsuro; Nishihira, Tomohiko

    2012-11-01

    This report presents a case of massive mucosal necrosis of the small intestine in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), which particularly affects the brain, nervous system and muscles. A 45-year-old Japanese female, with an established diagnosis of MELAS, presented with vomiting. Computed tomography showed portomesenteric venous gas and pneumatosis intestinalis. She underwent a resection of the small intestine. A microscopic study showed necrosis of the mucosa and vacuolar degeneration of smooth muscle cells in the arterial wall. Immunohistochemistry showed anti-mitochondrial antibody to be highly expressed in the crypts adjacent the necrotic mucosa. The microscopic and immunohistochemical findings suggested the presence of a large number of abnormal mitochondria in MELAS to be closely linked to mucosal necrosis of the small intestine. PMID:23139618

  2. Coagulopathy after severe pediatric trauma: A review

    PubMed Central

    Russell, Robert T.; Lisco, Steven J.; Kerby, Jeffrey D.; Pittet, Jean-François

    2014-01-01

    Trauma remains the leading cause of morbidity and mortality in the United States among children from the age 1 year to 21 years old. The most common cause of lethality in pediatric trauma is traumatic brain injury (TBI). Early coagulopathy has been commonly observed after severe trauma and is usually associated with severe hemorrhage and/or traumatic brain injury. In contrast to adult patients, massive bleeding is less common after pediatric trauma. The classical drivers of trauma-induced coagulopathy (TIC) include hypothermia, acidosis, hemodilution and consumption of coagulation factors secondary to local activation of the coagulation system following severe traumatic injury. Furthermore, there is also recent evidence for a distinct mechanism of TIC that involves the activation of the anticoagulant protein C pathway. Whether this new mechanism of posttraumatic coagulopathy plays a role in children is still unknown. The goal of this review is to summarize the current knowledge on the incidence and potential mechanisms of coagulopathy after pediatric trauma and the role of rapid diagnostic tests for early identification of coagulopathy. Finally, we discuss different options for treating coagulopathy after severe pediatric trauma. PMID:24569507

  3. Oxygen-deficient metabolism and corneal edema

    PubMed Central

    Leung, B.K.; Bonanno, J.A.; Radke, C.J.

    2014-01-01

    Wear of low-oxygen-transmissible soft contact lenses swells the cornea significantly, even during open eye. Although oxygen-deficient corneal edema is well-documented, a self-consistent quantitative prediction based on the underlying metabolic reactions is not available. We present a biochemical description of the human cornea that quantifies hypoxic swelling through the coupled transport of water, salt, and respiratory metabolites. Aerobic and anaerobic consumption of glucose, as well as acidosis and pH buffering, are incorporated in a seven-layer corneal model (anterior chamber, endothelium, stroma, epithelium, postlens tear film, contact lens, and prelens tear film). Corneal swelling is predicted from coupled transport of water, dissolved salts, and especially metabolites, along with membrane-transport resistances at the endothelium and epithelium. At the endothelium, the Na+/K+ - ATPase electrogenic channel actively transports bicarbonate ion from the stroma into the anterior chamber. As captured by the Kedem–Katchalsky membrane-transport formalism, the active bicarbonate-ion flux provides the driving force for corneal fluid pump-out needed to match the leak-in tendency of the stroma. Increased lactate-ion production during hypoxia osmotically lowers the pump-out rate requiring the stroma to swell to higher water content. Concentration profiles are predicted for glucose, water, oxygen, carbon dioxide, and hydronium, lactate, bicarbonate, sodium, and chloride ions, along with electrostatic potential and pressure profiles. Although the active bicarbonate-ion pump at the endothelium drives bicarbonate into the aqueous humor, we find a net flux of bicarbonate ion into the cornea that safeguards against acidosis. For the first time, we predict corneal swelling upon soft-contact-lens wear from fundamental biophysico-chemical principles. We also successfully predict that hypertonic tear alleviates contact-lens-induced edema. PMID:21820076

  4. Effects of grain, fructose, and histidine on ruminal pH and fermentation products during an induced subacute acidosis protocol.

    PubMed

    Golder, H M; Celi, P; Rabiee, A R; Heuer, C; Bramley, E; Miller, D W; King, R; Lean, I J

    2012-04-01

    The effects of grain, fructose, and histidine on ruminal pH and fermentation products were studied in dairy cattle during an induced subacute acidosis protocol. Thirty Holstein heifers were randomly allocated to 5 treatment groups: (1) control (no grain); (2) grain [fed at a crushed triticale dry matter intake (DMI) of 1.2% of body weight (BW)]; (3) grain (0.8% of BW DMI)+fructose (0.4% of BW DMI); (4) grain (1.2% of BW DMI)+histidine (6 g/head); and (5) grain (0.8% of BW DMI)+fructose (0.4% of BW DMI)+histidine (6 g/head) in a partial factorial arrangement. Heifers were fed 1 kg of grain daily with ad libitum access to ryegrass silage and alfalfa hay for 10 d. Feed was withheld for 14 h before challenge day, on which heifers were fed 200 g of alfalfa hay and then the treatment diets immediately thereafter. Rumen samples were collected 5 min after diet ingestion, 60 min later, and at 3 subsequent 50-min intervals. Grain decreased ruminal pH and increased ammonia, total volatile fatty acid (VFA), acetate, butyrate, propionate, and valerate concentrations compared with controls. The addition of grain had no effect on ruminal D- and L-lactate concentrations. Fructose markedly decreased ruminal pH and markedly increased D- and L-lactate concentrations. Fructose increased total VFA and butyrate and decreased valerate concentrations. Although histidine did not have a marked effect on ruminal fermentation, increased concentrations of histamine were observed following feeding. This study demonstrates that the substitution of some grain for fructose can lower ruminal pH and increase VFA and lactate concentrations, warranting further investigation into the role of sugars on the risk of acidosis in dairy cattle. PMID:22459843

  5. [Severe asthma].

    PubMed

    González, Claudio D

    2016-01-01

    The objectives of this work were to investigate the frequency of severe asthma (SA) according to WHO definition and to compare SA patients' characteristics with those of non-severe asthma (NSA); secondly, to investigate the level of control reached throughout a period of regular treatment. Between 1-1-2005 and 12-31-2014, 471 medical records from patients with bronchial asthma assisted in Buenos Aires City were analyzed. SA frequency was 40.1% (189/471), being significantly higher among patients from the public health system (47.7%, 108/226 vs. 33%, 81/245, p = 0.001). SA patients were older than NSA ones (51.3 ± 17.4 vs. 42.6 ± 17.1 years, p = 0.000), presented longer time since onset of the disease (median 30 vs. 20 years, p = 0.000), lower educational levels (secondary level or higher 41.7% vs. 58.1%, p = 0.000), lower frequency of rhinitis (47% vs. 60.6%, p = 0.004), more severe levels of airway obstruction (FEV% 50.2 ± 13.7 vs. 77.7 ± 12.4, p = 0.000), more frequent antecedents of Near Fatal Asthma (11.1% vs. 2.8%, p = 0.000), higher levels of serum IgE (median of 410 vs. 279 UI/l, p = 0.01) and higher demand of systemic steroids requirements and hospitalizations (68.7% vs. 50.7%, p = 0.000 and 37.5% vs. 15.9%, p = 0.000, respectively). A 30.6% of SA patients (58/189) reached a follow-up period of 12 months, 13 (22.5%) of whom reached the controlled asthma level. The frequency of SA found seems to be considerable. Multicenter studies to investigate the levels of control reached by SA patients with access to proper treatment are recommended. PMID:26826988

  6. Niche metabolism in parasitic protozoa

    PubMed Central

    Ginger, Michael L

    2005-01-01

    Complete or partial genome sequences have recently become available for several medically and evolutionarily important parasitic protozoa. Through the application of bioinformatics complete metabolic repertoires for these parasites can be predicted. For experimentally intractable parasites insight provided by metabolic maps generated in silico has been startling. At its more extreme end, such bioinformatics reckoning facilitated the discovery in some parasites of mitochondria remodelled beyond previous recognition, and the identification of a non-photosynthetic chloroplast relic in malarial parasites. However, for experimentally tractable parasites, mapping of the general metabolic terrain is only a first step in understanding how the parasite modulates its streamlined, yet still often puzzlingly complex, metabolism in order to complete life cycles within host, vector, or environment. This review provides a comparative overview and discussion of metabolic strategies used by several different parasitic protozoa in order to subvert and survive host defences, and illustrates how genomic data contribute to the elucidation of parasite metabolism. PMID:16553311

  7. Resuscitative goals and new strategies in severe trauma patient resuscitation.

    PubMed

    Egea-Guerrero, J J; Freire-Aragón, M D; Serrano-Lázaro, A; Quintana-Díaz, M

    2014-11-01

    Traumatic injuries represent a major health problem all over the world. In recent years we have witnessed profound changes in the paradigm of severe trauma patient resuscitation, new concepts regarding acute coagulopathy in trauma have been proposed, and there has been an expansion of specific commercial products related to hemostasis, among other aspects. New strategies in severe trauma management include the early identification of those injuries that are life threatening and require surgical hemostasis, tolerance of moderate hypotension, rational intravascular volume replacement, prevention of hypothermia, correction of acidosis, optimization of oxygen carriers, and identification of those factors required by the patient (fresh frozen plasma, platelets, tranexamic acid, fibrinogen, cryoprecipitates and prothrombin complex). However, despite such advances, further evidence is required to improve survival rates in severe trauma patients. PMID:25241268

  8. [Side effects of nalidixic acid in a patient with severe renal failure. Clinical study and proposal of a pharmacokinetic model].

    PubMed

    Mobbs, J P; Balant, L; Revillard, C; Favre, H

    1977-03-01

    Side effects due to ingestion of nalidixic acid in a 46 year old patient with phenacetine-induced interstitial nephritis and severe renal failure are reported. This observation underlines the point that, besides the direct neurotoxic effect of nalidixic acid, disturbance of the acid-basic equilibrium could be seen in patients with renal failure in particular. A hypothetical pharmacokinetic model suggests that two metabolites of nalidixic acid could provide enough hydrogen ion to induce acidosis in cases of renal failure. PMID:847456

  9. NBCe1 expression is required for normal renal ammonia metabolism.

    PubMed

    Handlogten, Mary E; Osis, Gunars; Lee, Hyun-Wook; Romero, Michael F; Verlander, Jill W; Weiner, I David

    2015-10-01

    The mechanisms regulating proximal tubule ammonia metabolism are incompletely understood. The present study addressed the role of the proximal tubule basolateral electrogenic Na(+)-coupled bicarbonate cotransporter (NBCe1; Slc4a4) in renal ammonia metabolism. We used mice with heterozygous and homozygous NBCe1 gene deletion and compared these mice with their wild-type littermates. Because homozygous NBCe1 gene deletion causes 100% mortality before day 25, we studied mice at day 8 (1 day). Both heterozygous and homozygous gene deletion caused a gene dose-related decrease in serum bicarbonate. The ability to lower urinary pH was intact, and even accentuated, with NBCe1 deletion. However, in contrast to the well-known effect of metabolic acidosis to increase urinary ammonia excretion, NBCe1 deletion caused a gene dose-related decrease in ammonia excretion. There was no identifiable change in proximal tubule structure by light microscopy. Examination of proteins involved in renal ammonia metabolism showed decreased expression of phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase, key enzymes in proximal tubule ammonia generation, and increased expression of glutamine synthetase, which recycles intrarenal ammonia and regenerates glutamine. Expression of key proteins involved in ammonia transport outside of the proximal tubule (rhesus B glycoprotein and rhesus C glycoprotein) was not significantly changed by NBCe1 deletion. We conclude from these findings that NBCe1 expression is necessary for normal proximal tubule ammonia metabolism. PMID:26224717

  10. Gut Microbiota and Metabolic Disorders

    PubMed Central

    Hur, Kyu Yeon

    2015-01-01

    Gut microbiota plays critical physiological roles in the energy extraction and in the control of local or systemic immunity. Gut microbiota and its disturbance also appear to be involved in the pathogenesis of diverse diseases including metabolic disorders, gastrointestinal diseases, cancer, etc. In the metabolic point of view, gut microbiota can modulate lipid accumulation, lipopolysaccharide content and the production of short-chain fatty acids that affect food intake, inflammatory tone, or insulin signaling. Several strategies have been developed to change gut microbiota such as prebiotics, probiotics, certain antidiabetic drugs or fecal microbiota transplantation, which have diverse effects on body metabolism and on the development of metabolic disorders. PMID:26124989

  11. Simultaneous Hypoxia and Low Extracellular pH Suppress Overall Metabolic Rate and Protein Synthesis In Vitro

    PubMed Central

    Sørensen, Brita Singers; Busk, Morten; Overgaard, Jens; Horsman, Michael R.; Alsner, Jan

    2015-01-01

    Background The tumor microenvironment is characterized by regions of hypoxia and acidosis which are linked to poor prognosis. This occurs due to an aberrant vasculature as well as high rates of glycolysis and lactate production in tumor cells even in the presence of oxygen (the Warburg effect), which weakens the spatial linkage between hypoxia and acidosis. Methods Five different human squamous cell carcinoma cell lines (SiHa, FaDuDD, UTSCC5, UTSCC14 and UTSCC15) were treated with hypoxia, acidosis (pH 6.3), or a combination, and gene expression analyzed using microarray. SiHa and FaDuDD were chosen for further characterization of cell energetics and protein synthesis. Total cellular ATP turnover and relative glycolytic dependency was determined by simultaneous measurements of oxygen consumption and lactate synthesis rates and total protein synthesis was determined by autoradiographic quantification of the incorporation of 35S-labelled methionine and cysteine into protein. Results Microarray analysis allowed differentiation between genes induced at low oxygen only at normal extracellular pH (pHe), genes induced at low oxygen at both normal and low pHe, and genes induced at low pHe independent of oxygen concentration. Several genes were found to be upregulated by acidosis independent of oxygenation. Acidosis resulted in a more wide-scale change in gene expression profiles than hypoxia including upregulation of genes involved in the translation process, for example Eukaryotic translation initiation factor 4A, isoform 2 (EIF4A2), and Ribosomal protein L37 (RPL37). Acidosis suppressed overall ATP turnover and protein synthesis by 50%. Protein synthesis, but not total ATP production, was also suppressed under hypoxic conditions. A dramatic decrease in ATP turnover (SiHa) and protein synthesis (both cell lines) was observed when hypoxia and low pHe were combined. Conclusions We demonstrate here that the influence of hypoxia and acidosis causes different responses, both in gene expression and in de novo protein synthesis, depending on whether the two factors induced alone or overlapping, and as such it is important for in vivo studies to take this into account. PMID:26274822

  12. Metabolic Syndrome

    MedlinePlus

    ... cause of metabolic syndrome. The cause might be insulin resistance. Insulin is a hormone your body produces to help ... into energy for your body. If you are insulin resistant, too much sugar builds up in your ...

  13. Metabolic Syndrome

    MedlinePlus

    ... lifestyle is a lifelong commitment. Successfully controlling metabolic syndrome requires long-term effort and teamwork with your health care providers. Rate This ... US National Institutes of Health Department of Health and ...

  14. Metabolic Syndrome

    MedlinePlus

    ... others, too. Checking for metabolic syndrome mostly involves stuff your doctor would be doing anyway, like taking ... lungs. It can be hard to take this stuff seriously when your thirties and forties seem like ...

  15. Metabolic Myopathies

    MedlinePlus

    ... muscles. Metabolic refers to chemical reactions that provide energy, nutrients and substances necessary for health and growth. ... occur when muscle cells don’t get enough energy. Without enough energy, the muscle lacks enough fuel ...

  16. Effects of partial mixed rations and supplement amounts on milk production and composition, ruminal fermentation, bacterial communities, and ruminal acidosis.

    PubMed

    Golder, H M; Denman, S E; McSweeney, C; Wales, W J; Auldist, M J; Wright, M M; Marett, L C; Greenwood, J S; Hannah, M C; Celi, P; Bramley, E; Lean, I J

    2014-09-01

    Late-lactation Holstein cows (n=144) that were offered 15kg dry matter (DM)/cow per day of perennial ryegrass to graze were randomized into 24 groups of 6. Each group contained a fistulated cow and groups were allocated to 1 of 3 feeding strategies: (1) control (10 groups): cows were fed crushed wheat grain twice daily in the milking parlor and ryegrass silage at pasture; (2) partial mixed ration (PMR; 10 groups): PMR that was isoenergetic to the control diet and fed twice daily on a feed pad; (3) PMR+canola (4 groups): a proportion of wheat in the PMR was replaced with canola meal to produce more estimated metabolizable protein than other groups. Supplements were fed to the control and PMR cows at 8, 10, 12, 14, or 16kg of DM/d, and to the PMR+canola cows at 14 or 16kg of DM/d. The PMR-fed cows had a lower incidence of ruminal acidosis compared with controls, and ruminal acidosis increased linearly and quadratically with supplement fed. Yield of milk fat was highest in the PMR+canola cows fed 14 or 16kg of total supplement DM/d, followed by the PMR-fed cows, and was lowest in controls fed at these amounts; a similar trend was observed for milk fat percentage. Milk protein yield was higher in the PMR+canola cows fed 14 or 16kg of total supplement DM/d. Milk yield and milk protein percentage were not affected by feeding strategy. Milk, energy-corrected milk, and milk protein yields increased linearly with supplement fed, whereas milk fat percentage decreased. Ruminal butyrate and d-lactate concentrations, acetate-to-propionate ratio, (acetate + butyrate)/propionate, and pH increased in PMR-fed cows compared with controls for all supplement amounts, whereas propionate and valerate concentrations decreased. Ruminal acetate, butyrate, and ammonia concentrations, acetate-to-propionate ratio, (acetate + butyrate)/propionate, and pH linearly decreased with amounts of supplement fed. Ruminal propionate concentration linearly increased and valerate concentration linearly and quadratically increased with supplement feeding amount. The Bacteroidetes and Firmicutes were the dominant bacterial phyla identified. The Prevotellaceae, Ruminococcaceae, and Lachnospiraceae were the dominant bacterial families, regardless of feeding group, and were influenced by feeding strategy, supplement feeding amount, or both. The Veillonellaceae family decreased in relative abundance in PMR-fed cows compared with controls, and the Streptococcaeae and Lactobacillaceae families were present in only minor relative abundances, regardless of feeding group. Despite large among- and within-group variation in bacterial community composition, distinct bacterial communities occurred among feeding strategies, supplement amounts, and sample times and were associated with ruminal fermentation measures. Control cows fed 16kg of DM of total supplement per day had the most distinct ruminal bacterial community composition. Bacterial community composition was most significantly associated with supplement feeding amount and ammonia, butyrate, valerate, and propionate concentrations. Feeding supplements in a PMR reduced the incidence of ruminal acidosis and altered ruminal bacterial communities, regardless of supplement feeding amount, but did not result in increased milk measures compared with isoenergetic control diets component-fed to late-lactation cows. PMID:24997657

  17. Metabolic Control of Autophagy

    PubMed Central

    Galluzzi, Lorenzo; Pietrocola, Federico; Levine, Beth; Kroemer, Guido

    2015-01-01

    Macroautophagy (herein referred to as autophagy) is an evolutionarily conserved mechanism of adaptation to adverse microenvironmental conditions, including limited nutrient supplies. Several sensors interacting with the autophagic machinery have evolved to detect fluctuations in key metabolic parameters. The signal transduction cascades operating downstream of these sensors are highly interconnected to control a spatially and chronologically coordinated autophagic response that maintains the health and function of individual cells while preserving organismal homeostasis. Here, we discuss the physiological regulation of autophagy by metabolic circuitries, as well as alterations of such control in disease. PMID:25480292

  18. Metabolic control of autophagy.

    PubMed

    Galluzzi, Lorenzo; Pietrocola, Federico; Levine, Beth; Kroemer, Guido

    2014-12-01

    Macroautophagy (herein referred to as autophagy) is an evolutionarily conserved mechanism of adaptation to adverse microenvironmental conditions, including limited nutrient supplies. Several sensors interacting with the autophagic machinery have evolved to detect fluctuations in key metabolic parameters. The signal transduction cascades operating downstream of these sensors are highly interconnected to control a spatially and chronologically coordinated autophagic response that maintains the health and function of individual cells while preserving organismal homeostasis. Here, we discuss the physiological regulation of autophagy by metabolic circuitries, as well as alterations of such control in disease. PMID:25480292

  19. Hypokalemia-Induced Rhabdomyolysis as a result of Distal Renal Tubular Acidosis in a Pregnant Woman: A Case Report and Literature Review

    PubMed Central

    Srisuttayasathien, Manasawee

    2015-01-01

    Rhabdomyolysis in pregnancy is a rare occurrence. The manifestation of distal renal tubular acidosis (RTA) for the first time during adulthood is uncommon. According to a review of the literature, pregnancy may predispose individuals to rhabdomyolysis due to hypokalemia. A reduction in interstitial potassium ions could decrease muscular blood flow and lead to muscle injury. This report describes the case of a pregnant woman with rhabdomyolysis induced by hypokalemia resulting from distal RTA. The patient subsequently delivered a healthy newborn. PMID:26788388

  20. Muscle carnosine metabolism and beta-alanine supplementation in relation to exercise and training.

    PubMed

    Derave, Wim; Everaert, Inge; Beeckman, Sam; Baguet, Audrey

    2010-03-01

    Carnosine is a dipeptide with a high concentration in mammalian skeletal muscle. It is synthesized by carnosine synthase from the amino acids L-histidine and beta-alanine, of which the latter is the rate-limiting precursor, and degraded by carnosinase. Recent studies have shown that the chronic oral ingestion of beta-alanine can substantially elevate (up to 80%) the carnosine content of human skeletal muscle. Interestingly, muscle carnosine loading leads to improved performance in high-intensity exercise in both untrained and trained individuals. Although carnosine is not involved in the classic adenosine triphosphate-generating metabolic pathways, this suggests an important role of the dipeptide in the homeostasis of contracting muscle cells, especially during high rates of anaerobic energy delivery. Carnosine may attenuate acidosis by acting as a pH buffer, but improved contractile performance may also be obtained by improved excitation-contraction coupling and defence against reactive oxygen species. High carnosine concentrations are found in individuals with a high proportion of fast-twitch fibres, because these fibres are enriched with the dipeptide. Muscle carnosine content is lower in women, declines with age and is probably lower in vegetarians, whose diets are deprived of beta-alanine. Sprint-trained athletes display markedly high muscular carnosine, but the acute effect of several weeks of training on muscle carnosine is limited. High carnosine levels in elite sprinters are therefore either an important genetically determined talent selection criterion or a result of slow adaptation to years of training. beta-Alanine is rapidly developing as a popular ergogenic nutritional supplement for athletes worldwide, and the currently available scientific literature suggests that its use is evidence based. However, many aspects of the supplement, such as the potential side effects and the mechanism of action, require additional and thorough investigation by the sports science community. PMID:20199122

  1. Computational Approaches for Understanding Energy Metabolism

    PubMed Central

    Shestov, Alexander A; Barker, Brandon; Gu, Zhenglong; Locasale, Jason W

    2013-01-01

    There has been a surge of interest in understanding the regulation of metabolic networks involved in disease in recent years. Quantitative models are increasingly being used to i nterrogate the metabolic pathways that are contained within this complex disease biology. At the core of this effort is the mathematical modeling of central carbon metabolism involving glycolysis and the citric acid cycle (referred to as energy metabolism). Here we discuss several approaches used to quantitatively model metabolic pathways relating to energy metabolism and discuss their formalisms, successes, and limitations. PMID:23897661

  2. Imaging metabolic syndrome

    PubMed Central

    Han, Weiping; Chuang, Kai-Hsiang; Chang, Young-Tae; Olivo, Malini; Velan, S Sendhil; Bhakoo, Kishore; Townsend, David; Radda, George K

    2010-01-01

    Metabolic syndrome is a fast growing public health burden for almost all the developed countries and many developing nations. Despite intense efforts from both biomedical and clinical scientists, many fundamental questions regarding its aetiology and development remain unclear, partly due to the lack of suitable imaging technologies to visualize lipid composition and distribution, insulin secretion, β-cell mass and functions in vivo. Such technologies would not only impact on our understanding of the complexity of metabolic disorders such as obesity and diabetes, but also aid in their diagnosis, drug development and assessment of treatment efficacy. In this article we discuss and propose several strategies for visualization of physiological and pathological changes that affect pancreas and adipose tissue as a result of the development of metabolic diseases. PMID:20533426

  3. Acidosis Mediates the Switching of Gs-PKA and Gi-PKCε Dependence in Prolonged Hyperalgesia Induced by Inflammation

    PubMed Central

    Huang, Wei-Yu; Dai, Shih-Ping; Chang, Yan-Ching; Sun, Wei-Hsin

    2015-01-01

    Chronic inflammatory pain, when not effectively treated, is a costly health problem and has a harmful effect on all aspects of health-related quality of life. Previous studies suggested that in male Sprague Dawley rats, prostaglandin E2 (PGE2)-induced short-term hyperalgesia depends on protein kinase A (PKA) activity, whereas long-lasting hyperalgesia induced by PGE2 with carrageenan pre-injection, requires protein kinase Cε (PKCε). However, the mechanism underlying the kinase switch with short- to long-term hyperalgesia remains unclear. In this study, we used the inflammatory agents carrageenan or complete Freund’s adjuvant (CFA) to induce long-term hyperalgesia, and examined PKA and PKCε dependence and switching time. Hyperalgesia induced by both agents depended on PKA/PKCε and Gs/Gi-proteins, and the switching time from PKA to PKCε and from Gs to Gi was about 3 to 4 h after inflammation induction. Among the single inflammatory mediators tested, PGE2 and 5-HT induced transient hyperalgesia, which depended on PKA and PKCε, respectively. Only acidic solution-induced hyperalgesia required Gs-PKA and Gi-PKCε, and the switch time for kinase dependency matched inflammatory hyperalgesia, in approximately 2 to 4 h. Thus, acidosis in inflamed tissues may be a decisive factor to regulate switching of PKA and PKCε dependence via proton-sensing G-protein–coupled receptors. PMID:25933021

  4. Structure, Function, and Regulation of the SLC4 NBCe1 Transporter and its Role in Causing Proximal Renal Tubular Acidosis

    PubMed Central

    Kurtz, Ira; Zhu, Quansheng

    2014-01-01

    Purpose of review There has been significant progress in our understanding of the structural and functional properties and regulation of NBCe1, a membrane transporter that plays a key role in renal acid-base physiology. NBCe1-A mediates basolateral electrogenic sodium-base transport in the proximal tubule and is critically required for transepithelial bicarbonate absorption. Mutations in NBCe1 cause autosomal recessive proximal renal tubular acidosis (pRTA). The review summarizes recent advances in this area. Recent findings A topological model of NBCe1 has been established that provides a foundation for future structure-functional studies of the transporter. Critical residues and regions have been identified in NBCe1 that play key roles in its structure, function (substrate transport, electrogenicity) and regulation. The mechanisms of how NBC1 mutations cause pRTA have also recently been elucidated. Summary Given the important role of proximal tubule transepithelial bicarbonate absorption in systemic acid-base balance, a clear understanding of the structure-functional properties of the NBCe1-A is a prerequisite for elucidating the mechanisms of defective transepithelial bicarbonate transport in pRTA. PMID:23917030

  5. Proximal renal tubular acidosis mediated by mutations in NBCe1-A: unraveling the transporter's structure-functional properties

    PubMed Central

    Kurtz, Ira; Zhu, Quansheng

    2013-01-01

    NBCe1 belongs to the SLC4 family of base transporting membrane proteins that plays a significant role in renal, extrarenal, and systemic acid-base homeostasis. Recent progress has been made in characterizing the structure-function properties of NBCe1 (encoded by the SLC4A4 gene), and those factors that regulate its function. In the kidney, the NBCe1-A variant that is expressed on the basolateral membrane of proximal tubule is the key transporter responsible for overall transepithelial bicarbonate absorption in this nephron segment. NBCe1 mutations impair transepithelial bicarbonate absorption causing the syndrome of proximal renal tubular acidosis (pRTA). Studies of naturally occurring NBCe1 mutant proteins in heterologous expression systems have been very helpful in elucidation the structure-functional properties of the transporter. NBCe1 mutations are now known to cause pRTA by various mechanisms including the alteration of the transporter function (substrate ion interaction, electrogenicity), abnormal processing to the plasma membrane, and a perturbation in its structural properties. The elucidation of how NBCe1 mutations cause pRTA in addition to the recent studies which have provided further insight into the topology of the transporter have played an important role in uncovering its critically important structural-function properties. PMID:24391589

  6. Metabolic analyzer

    NASA Technical Reports Server (NTRS)

    Lem, J. D.

    1977-01-01

    The metabolic analyzer was designed to support experiment M171. It operates on the so-called open circuit method to measure a subject's metabolic activity in terms of oxygen consumed, carbon dioxide produced, minute volume, respiratory exchange ratio, and tidal volume or vital capacity. The system operates in either of two modes. (1) In Mode I, inhaled respiratory volumes are actually measured by a piston spirometer. (2) In Mode II, inhaled volumes are calculated from the exhaled volume and the measured inhaled and exhaled nitrogen concentrations. This second mode was the prime mode for Skylab. Following is a brief description of the various subsystems and their operation.

  7. Lysophosphatidylinositol Signalling and Metabolic Diseases

    PubMed Central

    Arifin, Syamsul A.; Falasca, Marco

    2016-01-01

    Metabolism is a chemical process used by cells to transform food-derived nutrients, such as proteins, carbohydrates and fats, into chemical and thermal energy. Whenever an alteration of this process occurs, the chemical balance within the cells is impaired and this can affect their growth and response to the environment, leading to the development of a metabolic disease. Metabolic syndrome, a cluster of several metabolic risk factors such as abdominal obesity, insulin resistance, high cholesterol and high blood pressure, and atherogenic dyslipidaemia, is increasingly common in modern society. Metabolic syndrome, as well as other diseases, such as diabetes, obesity, hyperlipidaemia and hypertension, are associated with abnormal lipid metabolism. Cellular lipids are the major component of cell membranes; they represent also a valuable source of energy and therefore play a crucial role for both cellular and physiological energy homeostasis. In this review, we will focus on the physiological and pathophysiological roles of the lysophospholipid mediator lysophosphatidylinositol (LPI) and its receptor G-protein coupled receptor 55 (GPR55) in metabolic diseases. LPI is a bioactive lipid generated by phospholipase A (PLA) family of lipases which is believed to play an important role in several diseases. Indeed LPI can affect various functions such as cell growth, differentiation and motility in a number of cell-types. Recently published data suggest that LPI plays an important role in different physiological and pathological contexts, including a role in metabolism and glucose homeostasis. PMID:26784247

  8. Lysophosphatidylinositol Signalling and Metabolic Diseases.

    PubMed

    Arifin, Syamsul A; Falasca, Marco

    2016-01-01

    Metabolism is a chemical process used by cells to transform food-derived nutrients, such as proteins, carbohydrates and fats, into chemical and thermal energy. Whenever an alteration of this process occurs, the chemical balance within the cells is impaired and this can affect their growth and response to the environment, leading to the development of a metabolic disease. Metabolic syndrome, a cluster of several metabolic risk factors such as abdominal obesity, insulin resistance, high cholesterol and high blood pressure, and atherogenic dyslipidaemia, is increasingly common in modern society. Metabolic syndrome, as well as other diseases, such as diabetes, obesity, hyperlipidaemia and hypertension, are associated with abnormal lipid metabolism. Cellular lipids are the major component of cell membranes; they represent also a valuable source of energy and therefore play a crucial role for both cellular and physiological energy homeostasis. In this review, we will focus on the physiological and pathophysiological roles of the lysophospholipid mediator lysophosphatidylinositol (LPI) and its receptor G-protein coupled receptor 55 (GPR55) in metabolic diseases. LPI is a bioactive lipid generated by phospholipase A (PLA) family of lipases which is believed to play an important role in several diseases. Indeed LPI can affect various functions such as cell growth, differentiation and motility in a number of cell-types. Recently published data suggest that LPI plays an important role in different physiological and pathological contexts, including a role in metabolism and glucose homeostasis. PMID:26784247

  9. Metabolic and energy correlates of intracellular pH in progressive fatigue of squid (L. brevis) mantle muscle.

    PubMed

    Pörtner, H O; Finke, E; Lee, P G

    1996-11-01

    Squid (Lolliguncula brevis) were exercised at increasing swimming speeds to allow us to analyze the correlated changes in intracellular metabolic, acid-base, and energy status of the mantle musculature. Beyond a critical swimming velocity of 1.5 mantle lengths/s, an intracellular acidosis developed that was caused by an initial base loss from the cells, the onset of respiratory acidification, and, predominantly, octopine formation. The acidosis was correlated with decreasing levels of phospho-L-arginine and, thus, supported ATP buffering at the expense of the phosphagen. Monohydrogenphosphate, the actual substrate of glycogen phosphorylase accumulated, enabling glycogen degradation, despite progressive acidosis. In addition to octopine, succinate, and glycerophosphate accumulation, the onset of acidosis characterizes the critical velocity and indicates the transition to a non-steady-state time-limited situation. Accordingly, swimming above the critical velocity caused cellular energy levels (in vivo Gibbs free energy change of ATP hydrolysis) to fall. A minimal value was reached at about -45 kJ/mol. Model calculations demonstrate that changes in free Mg2+ levels only minimally affect ATP free energy, but minimum levels are relevant in maintaining functional concentrations of Mg(2+)-complexed adenylates. Model calculations also reveal that phosphagen breakdown enabled L. brevis to reach swimming speeds about three times higher than the critical velocity. Comparison of two offshore squid species (Loligo pealei and Illex illecebrosus) with the estuarine squid L.brevis indicates that the latter uses a strategy to delay the exploitation of high-energy phosphates and protect energy levels at higher than the minimum levels (-42 kJ/mol) characterizing fatigue in the other species. A more economical use of anaerobic resources and an early reduction in performance may enable L. brevis to tolerate more extreme environmental conditions in shallow estuarine waters and even hypoxic environments and to prevent a fatal depletion of energy stores. PMID:8945980

  10. Metabolic Syndrome

    MedlinePlus

    ... Web version Metabolic Syndrome Overview What is insulin resistance? Your body changes most of the food you eat into glucose (a form of sugar). Insulin is a hormone produced by the pancreas that allows ... as insulin resistance. If you have insulin resistance, your body will ...

  11. Metabolic cardiomyopathies

    PubMed Central

    Guertl, Barbara; Noehammer, Christa; Hoefler, Gerald

    2000-01-01

    The energy needed by cardiac muscle to maintain proper function is supplied by adenosine Ariphosphate primarily (ATP) production through breakdown of fatty acids. Metabolic cardiomyopathies can