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Safe delivery of two parturient women in severe metabolic acidosis.
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
Shariffuddin, Ina Ismiarti; Rai, Vineya; Chan, Y K; Muniandy, Rajesh Kumar
Extreme ?-butyrolactone overdose with severe metabolic acidosis requiring hemodialysis.
?-Hydroxybutyrate (GHB) and its precursor ?-butyrolactone (GBL) are commonly abused drugs with a narrow therapeutic index. Therefore, overdoses occur readily with recreational use, and severe poisoning can occur after deliberate self-poisoning. We report the sequelae in a patient who ingested a massive dose of GBL, with suicidal intent. Severe metabolic acidosis and an asystolic cardiac arrest were successfully treated with standard resuscitation, supportive care, and continuous venovenous hemodiafiltration. Plasma GHB concentrations were the highest reported to date. The acidosis was attributed to rapid systemic absorption of GBL, followed by rapid metabolism to GHB. PMID:21435738
Roberts, Darren M; Smith, Myles W H; Gopalakrishnan, Manivannan; Whittaker, Geoffrey; Day, Richard O
... diabetes Hyperchloremic acidosis results from excessive loss of sodium bicarbonate from the body, as can happen with severe ... aimed at the underlying condition. In certain circumstances, sodium bicarbonate (baking soda) may be given to improve the ...
Starvation Ketoacidosis: A Cause of Severe Anion Gap Metabolic Acidosis in Pregnancy
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.
Venkatram, Sindhaghatta; Diaz-Fuentes, Gilda
Metabolic acidosis in maintenance dialysis patients: Clinical considerations
Metabolic acidosis in maintenance dialysis patients: Clinical considerations. Metabolic acidosis is a common consequence of advanced chronic renal failure (CRF) and maintenance dialysis (MD) therapies are not infrequently unable to completely correct the base deficit. In MD patients, severe metabolic acidosis is associated with an increased relative risk for death. The chronic metabolic acidosis of the severity commonly encountered in
RAJNISH MEHROTRA; Joel D. Kopple; MARSHA WOLFSON
Topiramate and metabolic acidosis.
Topiramate (TPM) is a novel antiepileptic medication (AED) with at least three mechanisms of action. A possible fourth mechanism, that of a carbonic anhydrase inhibitor, also may contribute to its antiepileptic properties. We report a patient with intractable epilepsy and normal renal function who developed a normal anion gap metabolic acidosis, which worsened during elective surgery for temporal lobectomy. We believe this side effect of TPM can become clinically significant during surgery, concomitant use of another carbonic anhydrase inhibitor, and potentially with the ketogenic diet. PMID:10368081
Wilner, A; Raymond, K; Pollard, R
Metabolic acidosis: pathophysiology, diagnosis and management.
Metabolic acidosis is characterized by a primary reduction in serum bicarbonate (HCO(3)(-)) concentration, a secondary decrease in the arterial partial pressure of carbon dioxide (PaCO(2)) of approximately 1 mmHg for every 1 mmol/l fall in serum HCO(3)(-) concentration, and a reduction in blood pH. Acute forms (lasting minutes to several days) and chronic forms (lasting weeks to years) of the disorder can occur, for which the underlying cause/s and resulting adverse effects may differ. Acute forms of metabolic acidosis most frequently result from the overproduction of organic acids such as ketoacids or lactic acid; by contrast, chronic metabolic acidosis often reflects bicarbonate wasting and/or impaired renal acidification. The calculation of the serum anion gap, calculated as [Na(+)] - ([HCO(3)(-)] + [Cl(-)]), aids diagnosis by classifying the disorders into categories of normal (hyperchloremic) anion gap or elevated anion gap. These categories can overlap, however. Adverse effects of acute metabolic acidosis primarily include decreased cardiac output, arterial dilatation with hypotension, altered oxygen delivery, decreased ATP production, predisposition to arrhythmias, and impairment of the immune response. The main adverse effects of chronic metabolic acidosis are increased muscle degradation and abnormal bone metabolism. Using base to treat acute metabolic acidosis is controversial because of a lack of definitive benefit and because of potential complications. By contrast, the administration of base for the treatment of chronic metabolic acidosis is associated with improved cellular function and few complications. PMID:20308999
Kraut, Jeffrey A; Madias, Nicolaos E
Chronic acetaminophen ingestion resulting in severe anion gap metabolic acidosis secondary to 5-oxoproline accumulation: an under diagnosed phenomenon
Anion gap metabolic acidosis is commonly caused by lactic acidosis, ketoacidosis, and ingestion of methanol, salicylates, ethylene glycol or accumulation of organic/inorganic acids. However, rare causes of metabolic acidosis from enzyme defects, such as disturbances in the ?-glutamyl cycle, are being reported in higher frequencies in the adult population. Such disturbances cause an accumulation of 5-oxoproline and ultimately an anion gap metabolic acidosis. These disturbances are often associated with acetaminophen in the setting of certain risk factors such as sepsis, malnutrition, liver disease, female gender, pregnancy or renal failure.
O'Brien, L. Morgan Nordstrom; Hooper, Michael; Flemmer, Mark; Marik, Paul Ellis
Metabolic acidosis: neo-considerations for general surgeons
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 more common, and surgeons treating patients with neobladders should recognise and treat metabolic acidosis with intravenous fluids and bicarbonate.
Martin, LCE; Abah, U; Bean, E; Gupta, S
Metabolic acidosis and fetal reserve.
Dr Bailey, Director of the National Institute of Neurological Diseases and Blindness, Bethesda, Maryland, introduced the 1956 symposium on 'Neurological and psychological deficits of asphyxia neonatorum' by saying. 'Medical research in regard to cerebral palsy and other neurological disabilities has been relatively neglected. For a truly comprehensive attack on this problem we must focus a sharper scientific search for greater knowledge of those adverse biological factors which operate in the perinatal period. The proper point of departure in such a search is through controlled animal observations, for which purpose monkeys are best suited' (Windle, 1958). Our understanding of the significance of asphyxia is built on the foundation of the laboratory research that has followed upon this initiative. Laboratory studies in fetal monkeys and fetal lambs have clearly demonstrated that the fetus can initially compensate for an asphyxial insult and protect the vital organs. However, if the hypoxaemia progresses to a severe metabolic acidosis and cardiovascular decompensation with hypotension, brain damage will occur. There is a growing body of clinical evidence that supports the contention that the human fetus responds in a similar manner. The varied nature of hypoxic and ischaemic insults has been well demonstrated in animal studies. Total anoxia and isolated cerebral ischaemia are uncommon events in the human fetus. The common insult, particularly during labour, is a degree of hypoxia present over a variable period of time. This is fortunate in that such insults are associated with a period of fetal compensation that may last several hours, during which time a diagnosis of a developing metabolic acidosis can be made. This is the clinician's window of opportunity, when a definitive diagnosis of an asphyxial insult can be made and if necessary intervention made before the threshold of decompensation has been reached. A consensus on the threshold of decompensation has yet to be achieved. However, there is a growing body of evidence that the threshold is in the range of an umbilical artery base deficit of 12-16 mmol/l. Since the aim of the obstetrician during labour is the prevention of asphyxial morbidity and mortality, the determination of this threshold is important to provide criteria for clinical action. A blood gas and acid-base assessment with the determination of a metabolic acidosis is the best measure of an asphyxial insult that may be of clinical significance. The definition of the threshold of metabolic acidosis requiring intervention will continue to be clarified with future clinical research. However, there are many factors that will influence the fetal response to an asphyxial insult, which may require that a range of threshold be acknowledged. The effect upon the fetus will be influenced by whether the asphyxial event is the first or the last of a series of asphyxial episodes, and the duration of the asphyxial episode. The characteristics of the fetus, i.e. maturity (pre-term versus term), and fetal growth small for gestational age (SGA) or appropriate for gestational age (AGA) may influence the fetal response to an asphyxial insult. Improved understanding of these issues will provide a better rationale for clinical management. PMID:8836481
Low, J A
Head CT in patient with metabolic acidosis
An unresponsive 30-year-old female with a history of anxiety and chronic alcohol abuse presented to an emergency department\\u000a with altered mental status and a severe metabolic acidosis. The patient was intubated for airway protection, and she empirically\\u000a received folic acid, bicarbonate, and 5% ethanol continuous infusion for suspected ingestion of toxic alcohol. Following transfer\\u000a to our institution, the patient was
Kavita M. Babu; C. D. Rosenbaum; Edward W. Boyer
Reported survival with severe mixed acidosis and hyperlactemia after toluene poisoning
Lactic acidosis is a recognized complication of the inhalant abuse such as toluene, especially in patients with renal insufficiency. We report a case of severe metabolic acidosis and hyperlactemia due to toluene sniffing. The favorable outcome, despite extremely poor clinical symptoms, signs, laboratory and radiological findings, was unexpected. Specific aspects of the clinical course are addressed. Toluene sniffing should be considered in evaluating sever metabolic acidosis. Favorable outcome could be achieved with early diagnosis and proper interventions.
Omar, Amr S.; Rahman, Masood ur; Abuhasna, Said
Hyperchloraemic metabolic acidosis following open cardiac surgery
Aims: To describe acid�base derangements in children following open cardiac surgery on cardiopulmonary bypass (CPB), using the Fencl�Stewart strong ion approach. Methods: Prospective observational study set in the paediatric intensive care unit (PICU) of a university children's hospital. Arterial blood gas parameters, serum electrolytes, strong ion difference, strong ion gap (SIG), and partitioned base excess (BE) were measured and calculated on admission to PICU. Results: A total of 97 children, median age 57 months (range 0.03�166), median weight 14 kg (range 2.1�50), were studied. Median CPB time was 80 minutes (range 17�232). Predicted mortality was 2% and there was a single non-survivor. These children showed mild metabolic acidosis (median standard bicarbonate 20.1 mmol/l, BE �5.1 mEq/l) characterised by hyperchloraemia (median corrected Cl 113 mmol/l), and hypoalbuminaemia (median albumin 30 g/l), but no significant excess unmeasured anions or cations (median SIG 0.7 mEq/l). The major determinants of the net BE were the chloride and albumin components (chloride effect �4.8 mEq/l, albumin effect +3.4 mEq/l). Metabolic acidosis occurred in 72 children (74%) but was not associated with increased morbidity. Hyperchloraemia was a causative factor in 53 children (74%) with metabolic acidosis. Three (4%) hyperchloraemic children required adrenaline for inotropic support, compared to eight children (28%) without hyperchloraemia. Hypoalbuminaemia was associated with longer duration of inotropic support and PICU stay. Conclusions: In these children with low mortality following open cardiac surgery, hypoalbuminaemia and hyperchloraemia were the predominant acid�base abnormalities. Hyperchloraemia was associated with reduced requirement for adrenaline therapy. It is suggested that hyperchloraemic metabolic acidosis is a benign phenomenon that should not prompt escalation of haemodynamic support. By contrast, hypoalbuminaemia, an alkalinising force, was associated with prolonged requirement for intensive care.
Hatherill, M; Salie, S; Waggie, Z; Lawrenson, J; Hewitson, J; Reynolds, L; Argent, A
A case of PDH-E1 alpha mosaicism in a male patient with severe metabolic lactic acidosis.
We have characterized a novel mutation in a male patient that affects the coding sequence of PDH-E1 alpha gene and changes arginine-141 to a leucine. This nucleotide substitution was found in about 75% of the studied DNA (fibroblasts, liver and muscle), a scenario that would indicate a case of E1 alpha mosaicism in a male patient. When the mutant E1 alpha protein was expressed in human skin fibroblasts with zero endogenous pyruvate dehydrogenase complex activity and E1 alpha protein expression, no significant restoration of activity was recorded, in contrast to the wild-type cDNA. even though both wild-type and mutant protein levels were comparable. We concluded that the R141L mutation is a severe one and that it must have occurred in one of the E1 alpha alleles during early embryogenesis. PMID:11757583
Seyda, A; Chun, K; Packman, S; Robinson, B H
Pyroglutamic acid-induced metabolic acidosis: a case report.
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
Luyasu, S; Wamelink, M M C; Galanti, L; Dive, A
Risks of chronic metabolic acidosis in patients with chronic kidney disease
Risks of chronic metabolic acidosis in patients with chronic kidney disease Metabolic acidosis is associated with chronic renal failure (CRF). Often, maintenance dialysis therapies are not able to reverse this condition. The major systemic consequences of chronic metabolic acidosis are increased protein catabolism, decreased protein synthesis, and a negative protein balance that improves after bicarbonate supplementation. Metabolic acidosis also induces
Joel D. Kopple; KAMYAR KALANTAR-ZADEH; RAJNISH MEHROTRA
�Cerebral� lactic acidosis: defects in pyruvate metabolism with profound brain damage and minimal systemic acidosis
Six patients are described with a combination of early onset of neurological symptoms, gross cerebral changes and elevated concentrations of pyruvate and lactate in cerebrospinal fluid. Although at least five of the six patients appear to have a generalised defect in pyruvate metabolism, reflected in deficient pyruvate dehydrogenase activity in cultured fibroblasts, systemic acidosis was not a problem clinically and
G. K. Brown; E. A. Haan; D. M. Kirby; R. D. Scholem; J. E. Wraith; J. G. Rogers; D. M. Danks
Metabolic acidosis inhibits soft tissue calcification in uremic rats.
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
Mendoza, F J; Lopez, I; Montes de Oca, A; Perez, J; Rodriguez, M; Aguilera-Tejero, E
Metabolic engineering of lactate dehydrogenase rescues mice from acidosis.
Acidosis causes millions of deaths each year and strategies for normalizing the blood pH in acidosis patients are greatly needed. The lactate dehydrogenase (LDH) pathway has great potential for treating acidosis due to its ability to convert protons and pyruvate into lactate and thereby raise blood pH, but has been challenging to develop into a therapy because there are no pharmaceutical-based approaches for engineering metabolic pathways in vivo. In this report we demonstrate that the metabolic flux of the LDH pathway can be engineered with the compound 5-amino-2-hydroxymethylphenyl boronic acid (ABA), which binds lactate and accelerates the consumption of protons by converting pyruvate to lactate and increasing the NAD(+)/NADH ratio. We demonstrate here that ABA can rescue mice from metformin induced acidosis, by binding lactate, and increasing the blood pH from 6.7 to 7.2 and the blood NAD(+)/NADH ratio by 5 fold. ABA is the first class of molecule that can metabolically engineer the LDH pathway and has the potential to have a significant impact on medicine, given the large number of patients that suffer from acidosis. PMID:24898534
Acharya, Abhinav P; Rafi, Mohammad; Woods, Elliot C; Gardner, Austin B; Murthy, Niren
Metabolic engineering of lactate dehydrogenase rescues mice from acidosis
Acidosis causes millions of deaths each year and strategies for normalizing the blood pH in acidosis patients are greatly needed. The lactate dehydrogenase (LDH) pathway has great potential for treating acidosis due to its ability to convert protons and pyruvate into lactate and thereby raise blood pH, but has been challenging to develop into a therapy because there are no pharmaceutical-based approaches for engineering metabolic pathways in vivo. In this report we demonstrate that the metabolic flux of the LDH pathway can be engineered with the compound 5-amino-2-hydroxymethylphenyl boronic acid (ABA), which binds lactate and accelerates the consumption of protons by converting pyruvate to lactate and increasing the NAD+/NADH ratio. We demonstrate here that ABA can rescue mice from metformin induced acidosis, by binding lactate, and increasing the blood pH from 6.7 to 7.2 and the blood NAD+/NADH ratio by 5 fold. ABA is the first class of molecule that can metabolically engineer the LDH pathway and has the potential to have a significant impact on medicine, given the large number of patients that suffer from acidosis.
Acharya, Abhinav P.; Rafi, Mohammad; Woods, Elliot C.; Gardner, Austin B.; Murthy, Niren
Metabolic Factors Influencing Myocardial Recovery from Acidosis (CiC3).
National Technical Information Service (NTIS)
The mechanisms involved in cardiac dysfunction during acidosis were explored in an isolated heart model. Metabolic acidosis was observed to cause marked functional and energy metabolic derangement consistent with a primary impairment of energy production....
J. I. Shapiro J. Doers R. F. Kucera M. McCormick N. Elkins
Haematopoietic indicators of fetal metabolic acidosis.
We aimed to study the haematopoietic response in normal and acidotic deliveries following vaginal and abdominal delivery and to compare this to the surrogate markers of perinatal acidosis. Blood gas analyses, complete blood pictures and erythropoietin assays were performed on umbilical or early neonatal blood samples. Placental sections were examined for the presence of nucleated red blood cells. Perinatal clinical risk factors and major neonatal outcomes were collected. The control population was 78 deliveries where the cord arterial pH was > 7.10. Controls born after labour were compared to those born prior to the onset of labour and to 14 acidotic infants born after labour. Nucleated red blood cells did not increase with labour in the control groups but were significantly higher (p < 0.05) in the acidotic group. Erythropoietin did not significantly change with either labour or acidosis. The predictive values from nucleated red blood cell counts were higher than those from low Apgar scores, atypical cardiotocograph traces, meconium-stained amniotic fluid, erythropoietin and the presence of nucleated red blood cells in placental sections. Nucleated red blood cell counts may be a useful surrogate marker of acidosis where blood gas analysis is unavailable. Further studies are required to examine the timing of the increase of erythropoiesis to help define the onset of the stimulus. PMID:11065035
Spencer, M K; Khong, T Y; Matthews, B L; MacLennan, A H
Attending rounds: patient with hypokalemia and metabolic acidosis.
Hypokalemic paralysis represents a medical emergency requiring both rapid diagnosis and treatment. In this Attending Rounds a patient with hypokalemia and metabolic acidosis is presented to emphasize the role of routine laboratory studies in the assessment of such patients so that a correct diagnosis can be made and appropriate treatment can be initiated promptly. PMID:21921151
Rastegar, Asghar
Comparison of sevelamer hydrochloride and sevelamer carbonate: risk of metabolic acidosis and clinical implications.
Hyperphosphatemia is highly prevalent in patients with chronic kidney disease (CKD), particularly in those with advanced or end-stage renal disease. Sevelamer hydrochloride is an ion-exchange resin that reduces serum phosphorus concentrations. The agent also produces favorable lipid profile effects and does not cause hypercalcemia. However, reported drawbacks of this agent are metabolic acidosis, high pill burden, and a relatively low affinity and selectivity for phosphate anions. Sevelamer carbonate is a new buffered formulation that does not increase the risk of metabolic acidosis. To determine the roles of these two agents in the treatment of hyperphosphatemia in patients with CKD, we performed a MEDLINE search (June 1995-June 2008) focusing on the mechanism of action of resin binding with phosphate and the development of metabolic acidosis. We also reviewed studies that evaluated the effects of sevelamer hydrochloride or sevelamer carbonate on serum bicarbonate concentrations. Several studies in patients with CKD and hyperphosphatemia who received hemodialysis or peritoneal dialysis found decreases in serum bicarbonate concentrations with the use of sevelamer hydrochloride, whereas sevelamer carbonate did not have this negative effect on bicarbonate concentrations. Both drugs appear to be equivalent in their abilities to lower serum phosphorus concentrations. However, as sevelamer carbonate does not decrease serum bicarbonate levels, it may be more appropriate for patients at risk for metabolic acidosis who require phosphate binders that do not contain calcium or aluminum. PMID:19397463
Pai, Ashwini B; Shepler, Brian M
Metabolic Acidosis in Maintenance Hemodialysis Patients: Clinical Impact and Intervention
Metabolic acidosis has been considered as one of the reverse epidemiologic factors for the morbidity and mortality in maintenance hemodialysis patients (MHP). Expectedly, in the recent large scale epidemiologic study (The Dialysis Outcome Practice Pattern Study, DOPPS), a mild to moderate degree of predialysis metabolic acidosis has shown better nutritional status and lower relative risk for mortality and hospitalization in MHP. Similarly, another recent study of the largest sample size of MHP of more than 55,000 revealed the lowest unadjusted mortality with mild to moderate degree of predialysis HCO3 levels (17 to 23 mEq/L). However, it was reversed after case-mix and multivariate adjustment, including the malnutrition-inflammation complex syndrome, so that predialysis HCO3 levels of more than 22 mEq/L had a lower death risk. On view of this up-to-date on-going controversy about the optimal acid-base status for MHP, this paper will review the historical and break-through data about the pros and cons of metabolic acidosis published in the clinical human studies of MHP, a special subgroup of chronic kidney disease patients. Based on these results, if possible, we would like to suggest the best practice guideline, particularly, for the optimal predialysis HCO3 level, dialysate HCO3 concentration, and dietary protein intake.
Han, Sang-Woong
In vivo unaltered muscle protein synthesis in experimental chronic metabolic acidosis
In vivo unaltered muscle protein synthesis in experimental chronic metabolic acidosis. Chronic metabolic acidosis (CMA) is a major cause of growth defect, implying disturbances of protein metabolism. Previously, in vivo studies performed in the fasting state showed enhanced whole body protein turnover, whereas in vitro studies showed unchanged muscle protein synthesis. The present study is the first to determine the
Sa�d Maniar; Denise Laouari; Mich�le Dechaux; V�ronique Motel; Jean-Pierre Yvert; Bruno Mathian; Claire Kleinknecht
Sulfatides are required for renal adaptation to chronic metabolic acidosis
Urinary ammonium excretion by the kidney is essential for renal excretion of sufficient amounts of protons and to maintain stable blood pH. Ammonium secretion by the collecting duct epithelia accounts for the majority of urinary ammonium; it is driven by an interstitium-to-lumen NH3 gradient due to the accumulation of ammonium in the medullary and papillary interstitium. Here, we demonstrate that sulfatides, highly charged anionic glycosphingolipids, are important for maintaining high papillary ammonium concentration and increased urinary acid elimination during metabolic acidosis. We disrupted sulfatide synthesis by a genetic approach along the entire renal tubule. Renal sulfatide-deficient mice had lower urinary pH accompanied by lower ammonium excretion. Upon acid diet, they showed impaired ammonuria, decreased ammonium accumulation in the papilla, and chronic hyperchloremic metabolic acidosis. Expression levels of ammoniagenic enzymes and Na+-K+/NH4+-2Cl? cotransporter 2 were higher, and transepithelial NH3 transport, examined by in vitro microperfusion of cortical and outer medullary collecting ducts, was unaffected in mutant mice. We therefore suggest that sulfatides act as counterions for interstitial ammonium facilitating its retention in the papilla. This study points to a seminal role of sulfatides in renal ammonium handling, urinary acidification, and acid�base homeostasis.
Stettner, Paula; Bourgeois, Soline; Marsching, Christian; Traykova-Brauch, Milena; Porubsky, Stefan; Nordstrom, Viola; Hopf, Carsten; Koesters, Robert; Sandhoff, Roger; Wiegandt, Herbert; Wagner, Carsten A.; Grone, Hermann-Josef; Jennemann, Richard
Effect of acute acidosis on protein and amino acid metabolism in rats
Background & aims: Metabolic acidosis is a common finding in critical illness. The aim of the present study was to evaluate acute acidosis as a signal that induces changes in protein metabolism.Methods: In the first study, Wistar rats were infused for 6h with HCl or saline resulting in blood pH7.30�0.03 and 7.46�0.02, respectively. The whole body protein metabolism was evaluated
R. �afr�nek; M. Hole?ek; J. Kadl???kov�; L. �prongl; C. Mi�lanov�; M. Kukan; J. Chl�dek
Lactate versus non-lactate metabolic acidosis: a retrospective outcome evaluation of critically ill patients
Introduction Acid�base abnormalities are common in the intensive care unit (ICU). Differences in outcome exist between respiratory and metabolic acidosis in similar pH ranges. Some forms of metabolic acidosis (for example, lactate) seem to have worse outcomes than others (for example, chloride). The relative incidence of each type of disorder is unknown. We therefore designed this study to determine the nature and clinical significance of metabolic acidosis in critically ill patients. Methods An observational, cohort study of critically ill patients was performed in a tertiary care hospital. Critically ill patients were selected on the clinical suspicion of the presence of lactic acidosis. The inpatient mortality of the entire group was 14%, with a length of stay in hospital of 12 days and a length of stay in the ICU of 5.8 days. Results We reviewed records of 9,799 patients admitted to the ICUs at our institution between 1 January 2001 and 30 June 2002. We selected a cohort in which clinicians caring for patients ordered a measurement of arterial lactate level. We excluded patients in which any necessary variable required to characterize an acid�base disorder was absent. A total of 851 patients (9% of ICU admissions) met our criteria. Of these, 548 patients (64%) had a metabolic acidosis (standard base excess < -2 mEq/l) and these patients had a 45% mortality, compared with 25% for those with no metabolic acidosis (p < 0.001). We then subclassified metabolic acidosis cases on the basis of the predominant anion present (lactate, chloride, or all other anions). The mortality rate was highest for lactic acidosis (56%); for strong ion gap (SIG) acidosis it was 39% and for hyperchloremic acidosis 29% (p < 0.001). A stepwise logistic regression model identified serum lactate, SIG, phosphate, and age as independent predictors of mortality. Conclusion In critically ill patients in which a measurement of lactate level was ordered, lactate and SIG were strong independent predictors of mortality when they were the major source of metabolic acidosis. Overall, patients with metabolic acidosis were nearly twice as likely to die as patients without metabolic acidosis.
Gunnerson, Kyle J; Saul, Melissa; He, Shui; Kellum, John A
Metabolic acidosis mimicking diabetic ketoacidosis after use of calorie-free mineral water.
A previously healthy boy was admitted with fever, tachycardia, dyspnea, and was vomiting. A blood test showed a severe metabolic acidosis with pH 7.08 and an anion gap of 36 mmol/L. His urine had an odor of acetone. The serum glucose was 5.6 mmol/L, and no glucosuria was found. Diabetic ketoacidosis could therefore be eliminated. Lactate level was normal. Tests for the most common metabolic diseases were negative. Because of herpes stomatitis, the boy had lost appetite and only been drinking Diet Coke and water the last days. Diet Coke or Coca-Cola Light is sweetened with a blend containing cyclamates, aspartame, and acesulfame potassium, all free of calories. The etiology of the metabolic acidosis appeared to be a catabolic situation exaggerated by fasting with no intake of calories. The elevated anion gap was due to a severe starvation ketoacidosis, mimicking a diabetic ketoacidosis. Pediatricians should recommend carbohydrate/calorie-containing fluids for rehydration of children with acute fever, diarrhea, or illness. PMID:22457081
Dahl, Gry T; Woldseth, Berit; Lindemann, Rolf
Metabolic Acidosis Treatment as Part of a Strategy to Curb Inflammation
Abnormalities in systemic acid-base balance may induce significant changes in the immune response, and they may play a significant role in the development or maintenance of immune dysfunction. Different forms of acidosis (metabolic and respiratory) and even different types of metabolic acidosis (hyperchloremic and lactic) may produce different effects on immune function. If alkalization has, or not, some effect on inflammation control is still a matter of speculation. Studies concerning these subjects are limited justifying this paper.
de Nadai, Tales Rubens; de Nadai, Mariane Nunes; Albuquerque, Agnes Afrodite Sumarelli; de Carvalho, Marco Tulio Menezes; Celotto, Andrea Carla; Evora, Paulo Roberto Barbosa
Outcome of severe lactic acidosis associated with metformin accumulation
Introduction��Metformin associated lactic acidosis (MALA) may complicate metformin therapy, particularly if metformin accumulates due to\\u000a renal dysfunction. Profound lactic acidosis (LA) generally predicts poor outcome. We aimed to determine if MALA differs in\\u000a outcome from LA of other origin (LAOO).\\u000a \\u000a \\u000a \\u000a \\u000a Methods��We conducted a retrospective analysis of all patients admitted with LA to our medical ICU of a tertiary referral center
Sigrun Friesecke; Peter Abel; Markus Roser; Stephan B Felix; Soeren Runge
A novel homozygous YARS2 mutation causes severe myopathy, lactic acidosis, and sideroblastic anemia 2.
Mitochondrial diseases are associated with defects of adenosine triphosphate production and energy supply to organs as a result of dysfunctions of the mitochondrial respiratory chain. Biallelic mutations in the YARS2 gene encoding mitochondrial tyrosyl-tRNA synthetase cause myopathy, lactic acidosis, and sideroblastic anemia 2 (MLASA2), a type of mitochondrial disease. Here, we report a consanguineous Turkish family with two siblings showing severe metabolic decompensation including recurrent hypoglycemia, lactic acidosis, and transfusion-dependent anemia. Using whole-exome sequencing of the proband and his parents, we identified a novel YARS2 mutation (c.1303A>G, p.Ser435Gly) that was homozygous in the patient and heterozygous in his parents. This mutation is located at the ribosomal protein S4-like domain of the gene, while other reported YARS2 mutations are all within the catalytic domain. Interestingly, the proband showed more severe symptoms and an earlier onset than previously reported patients, suggesting the functional importance of the S4-like domain in tyrosyl-tRNA synthetase. PMID:24430573
Nakajima, Junya; Eminoglu, Tuba F; Vatansever, Goksel; Nakashima, Mitsuko; Tsurusaki, Yoshinori; Saitsu, Hirotomo; Kawashima, Hisashi; Matsumoto, Naomichi; Miyake, Noriko
Population Kinetics, Efficacy, and Safety of Dichloroacetate for Lactic Acidosis Due to Severe Malaria in Children
The authors conducted a randomized, double-blind, placebo-controlled trial of intravenous dichloroacetate (DCA) for the purpose of treating lactic acidosis in 124 West African children with severe Plasmodium falciparum malaria. Lactic acidosis independently predicts mortality in severe malaria, and DCA stimulates the oxidative removal of lactate in vivo. A single infusion of 50 mg\\/kg DCA was well tolerated. When administered at
Tsiri Agbenyega; Tim Planche; George Bedu-Addo; Daniel Ansong; Alex Owusu-Ofori; Venkatesh A. Bhattaram; Nelamangala V. Nagaraja; Albert L. Shroads; George N. Henderson; Alan D. Hutson; Hartmut Derendorf; Sanjeev Krishna; Peter W. Stacpoole
Acute and chronic metabolic acidosis interferes with aquaporin-2 translocation in the rat kidney collecting ducts
Renal aquaporin-2 (AQP2) expression plays a key role in urine concentration. However, it is not known whether metabolic acidosis affects urine-concentrating ability through AQP2 expression in the kidney and urine. We examined urinary excretion and renal expression of AQP2 in control and acidosis rats, using RT-competitive PCR, immunoblot and immunocytochemistry. Urinary excretion of AQP2 is decreased by 92% even with
Tomohiko Mouri; Takeaki Inoue; Hiroshi Nonoguchi; Yushi Nakayama; Hiroki Miyazaki; Takanobu Matsuzaki; Hideyuki Saito; Takeshi Nakanishi; Yukimasa Kohda; Kimio Tomita
Conventional or physicochemical approach in intensive care unit patients with metabolic acidosis
Introduction Metabolic acidosis is the most frequent acid�base disorder in the intensive care unit. The optimal analysis of the underlying mechanisms is unknown. Aim To compare the conventional approach with the physicochemical approach in quantifying complicated metabolic acidosis in patients in the intensive care unit Patients and methods We included 50 consecutive patients with a metabolic acidosis (standard base excess ? -5). We measured sodium, potassium, calcium, magnesium, chloride, lactate, creatinine, urea, phosphate, albumin, pH, and arterial carbon dioxide and oxygen tensions in every patient. We then calculated HCO3-, the base excess, the anion gap, the albumin-corrected anion gap, the apparent strong ion difference, the effective strong ion difference and the strong ion gap. Results Most patients had multiple underlying mechanisms explaining the metabolic acidosis. Unmeasured strong anions were present in 98%, hyperchloremia was present in 80% and elevated lactate levels were present in 62% of patients. Calculation of the anion gap was not useful for the detection of hyperlactatemia. There was an excellent relation between the strong ion gap and the albumin-corrected and lactate-corrected anion gap (r2 = 0.934), with a bias of 1.86 and a precision of 0.96. Conclusion Multiple underlying mechanisms are present in most intensive care unit patients with a metabolic acidosis. These mechanisms are reliably determined by measuring the lactate-corrected and albumin-corrected anion gap. Calculation of the more time-consuming strong ion gap according to Stewart is therefore unnecessary.
Moviat, MAM; van Haren, FMP; van der Hoeven, JG
Bone Mineral Changes in Acute Metabolic Acidosis due to Acute Gastroenteritis
We studied bone mineral metabolism changes complicated by acute gastroenteritis in a clinical acute metabolic acidosis milieu where we observed hypercalcemia, hypercalciuria, and elevated urinary hydroxyproline excretion. Serum magnesium and plasma osteocalcin, alkaline phosphatase, and IGF-1 levels were decreased. No significant changes in serum inorganic phosphate and plasma PTH, calcitonin, or 25-hydroxy vitamin D3 levels were detected. All abnormalities disappeared
Dincer Yildizdas; A. Kemal Topaloglu; Neslihan O. Mungan; Bilgin Yuksel; Guler Ozer
Infusion of sodium bicarbonate in experimentally induced metabolic acidosis does not provoke cerebrospinal fluid (CSF) acidosis in calves
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.
Abeysekara, Saman; Zello, Gordon A.; Lohmann, Katharina L.; Alcorn, Jane; Hamilton, Don L.; Naylor, Jonathan M.
Identification of neonatal near miss by systematic screening for metabolic acidosis at birth
Aims: To evaluate the relevance of systematic screening for neonatal metabolic acidosis at birth as part of perinatal audit. Methods: For every baby, born in Ziekenhuis Oost Limburg, Genk Belgium between 1/1/2010 and 31/12/2010, cord blood was analysed to diagnose metabolic acidosis, defined as arterial or venous pH ? 7.05 or 7.17 respectively, in association with base excess of ? -10?mmol/L. Three observers identified indicators for suboptimal peripartal care with likely contribution to metabolic acidosis. In a multidisciplinary consensus meeting, these indicators were classified into 5 categories : (a) fetal monitoring error (b) labour management error, (c) instrumental vaginal delivery for fetal distress within 2?h of second stage, (d) non-obstetric medical complications, (e) preterm births or accidental cases at term. Results: In a total of 2117 neonates, there were 11 intra-uterine, 1 intrapartum and 3 early neonatal deaths, bringing early perinatal mortality rate at 7.1�. Metabolic acidosis was identified in 23 (1.1%) babies, of which 21 (91.3%) left hospital in good clinical condition. Two babies (0.9�), born in category c, had chronic neurologic symptoms. Discussion: Systematic screening for neonatal metabolic acidosis caused a 2.5-fold increase of case identifications eligible for perinatal audit and opened perspectives towards rationalised improvement of perinatal care, in addition to the information obtained from cases of perinatal mortality. Next to indicators of perinatal mortality, perinatal audit programs should include neonatal metabolic acidosis as an extra parameter for quality assessment of perinatal care. Conclusion: Adding cases of near-miss neonatal morbidity to perinatal mortalities in perinatal audit programs increases opportunities for improvement of perinatal care.
Bonnaerens, A.; Thaens, A.; Mesens, T.; Van Holsbeke, C.; de Jonge, E. T. M.; Gyselaers, W.
Ionized alkaline water: new strategy for management of metabolic acidosis in experimental animals.
Metabolic acidosis can occur as a result of either the accumulation of endogenous acids or loss of bicarbonate from the gastrointestinal tract or the kidney, which represent common causes of metabolic acidosis. The appropriate treatment of acute metabolic acidosis has been very controversial. Ionized alkaline water was not evaluated in such groups of patients in spite of its safety and reported benefits. So, we aimed to assess its efficacy in the management of metabolic acidosis in animal models. Two models of metabolic acidosis were created in dogs and rats. The first model of renal failure was induced by ligation of both ureters; and the second model was induced by urinary diversion to gut (gastrointestinal bicarbonate loss model). Both models were subjected to ionized alkaline water (orally and by hemodialysis). Dogs with renal failure were assigned to two groups according to the type of dialysate utilized during hemodialysis sessions, the first was utilizing alkaline water and the second was utilizing conventional water. Another two groups of animals with urinary diversion were arranged to receive oral alkaline water and tap water. In renal failure animal models, acid-base parameters improved significantly after hemodialysis with ionized alkaline water compared with the conventional water treated with reverse osmosis (RO). Similar results were observed in urinary diversion models as there was significant improvement of both the partial pressure of carbon dioxide and serum bicarbonate (P = 0.007 and 0.001 respectively) after utilizing alkaline water orally. Alkaline ionized water can be considered as a major safe strategy in the management of metabolic acidosis secondary to renal failure or dialysis or urinary diversion. Human studies are indicated in the near future to confirm this issue in humans. PMID:19527469
Abol-Enein, Hassan; Gheith, Osama A; Barakat, Nashwa; Nour, Eman; Sharaf, Abd-Elhameed
Grocery store baking soda. A source of sodium bicarbonate in the management of chronic metabolic acidosis.
Oral sodium bicarbonate is used to treat metabolic acidosis in patients with renal tubular acidosis. Since infants and young children are unable to swallow tablets, those affected must ingest sodium bicarbonate in a powder or liquid form. Pharmacy-weighed sodium bicarbonate is expensive and inconvenient to obtain; some pharmacists are reluctant to provide it. We determined that the sodium bicarbonate contained in 8-oz boxes of Arm and Hammer Baking Soda was sufficiently constant in weight that, dissolved in water to a given volume, it yielded a quantitatively acceptable therapeutic solution of sodium bicarbonate at a cost of approximately 3 percent of that of pharmacy-weighed sodium bicarbonate. Grocery store baking soda can be a safe, economical, and convenient source of sodium bicarbonate for the treatment of chronic metabolic acidosis in infants and young children. PMID:6319065
Booth, B E; Gates, J; Morris, R C
Mild metabolic acidosis impairs the ?-adrenergic response in isolated human failing myocardium
Introduction Pronounced extracellular acidosis reduces both cardiac contractility and the ?-adrenergic response. In the past, this was shown in some studies using animal models. However, few data exist regarding how the human end-stage failing myocardium, in which compensatory mechanisms are exhausted, reacts to acute mild metabolic acidosis. The aim of this study was to investigate the effect of mild metabolic acidosis on contractility and the ?-adrenergic response of isolated trabeculae from human end-stage failing hearts. Methods Intact isometrically twitching trabeculae isolated from patients with end-stage heart failure were exposed to mild metabolic acidosis (pH 7.20). Trabeculae were stimulated at increasing frequencies and finally exposed to increasing concentrations of isoproterenol (0 to 1 � 10-6 M). Results A mild metabolic acidosis caused a depression in twitch-force amplitude of 26% (12.1 � 1.9 to 9.0 � 1.5 mN/mm2; n = 12; P < 0.01) as compared with pH 7.40. Force-frequency relation measurements yielded no further significant differences of twitch force. At the maximal isoproterenol concentration, the force amplitude was comparable in each of the two groups (pH 7.40 versus pH 7.20). However, the half-maximal effective concentration (EC50) was significantly increased in the acidosis group, with an EC50 of 5.834 � 10-8 M (confidence interval (CI), 3.48 � 10-8 to 9.779 � 10-8; n = 9), compared with the control group, which had an EC50 of 1.056 � 10-8 M (CI, 2.626 � 10-9 to 4.243 � 10-8; n = 10; P < 0.05), indicating an impaired ?-adrenergic force response. Conclusions Our data show that mild metabolic acidosis reduces cardiac contractility and significantly impairs the ?-adrenergic force response in human failing myocardium. Thus, our results could contribute to the still-controversial discussion about the therapy regimen of acidosis in patients with critical heart failure.
Response of the mitochondrial proteome of rat renal proximal convoluted tubules to chronic metabolic acidosis
Metabolic acidosis is a common clinical condition that is caused by a decrease in blood pH and bicarbonate concentration. Increased extraction and mitochondrial catabolism of plasma glutamine within the renal proximal convoluted tubule generates ammonium and bicarbonate ions that facilitate the excretion of acid and partially restore acid-base balance. Previous studies identified only a few mitochondrial proteins, including two key enzymes of glutamine metabolism, which are increased during chronic acidosis. A workflow was developed to characterize the mitochondrial proteome of the proximal convoluted tubule. Based upon the increase in specific activity of cytochrome c oxidase, the isolated mitochondria were enriched eightfold. Two-dimensional liquid chromatography coupled with mass spectrometry was utilized to compare mitochondrial-enriched samples from control and chronic acidotic rats. Proteomic analysis identified 901 proteins in the control and acidotic samples. Further analysis identified 37 peptides that contain an N-?-acetyl-lysine; of these, 22 are novel sites. Spectral counting analysis revealed 33 proteins that are significantly altered in abundance in response to chronic metabolic acidosis. Western blot analysis was performed to validate the calculated changes in abundance. Thus the current study represents the first comprehensive analysis of the mitochondrial proteome of the rat renal proximal convoluted tubule and its response to metabolic acidosis.
Freund, Dana M.; Prenni, Jessica E.
Sevelamer hydrochloride dose-dependent increase in prevalence of severe acidosis in hemodialysis patients: analysis of nationwide statistical survey in Japan.
Metabolic acidosis has a negative impact on prognosis of dialysis patients. The aim of this study was to determine the prevalence of severe metabolic acidosis in dialysis patients treated with sevelamer hydrochloride. In 2004, a nationwide survey (101,516 dialysis patients) was conducted by the Japanese Society for Dialysis Therapy. We analyzed 32,686 dialysis patients whose bicarbonate levels were measured in the survey. Sevelamer hydrochloride was prescribed to 9231 dialysis patients while 23,455 dialysis patients were not prescribed sevelamer hydrochloride. In the present study, we defined severe acidosis as bicarbonate <15.8 mmol/L. The mean serum bicarbonate level correlated significantly and negatively with the daily dose of sevelamer hydrochloride (R(2)?= 0.806, P < 0.0001). Logistic regression analysis indicated that the percentage of patients with severe acidosis increased significantly with increased dose of sevelamer hydrochloride (R(2) = 0.885, P < 0.00001). The estimated doses of sevelamer hydrochloride associated with severe acidosis in 10% and 15% of patients were 3.5 g/day (95% confidence interval [95%CI], 2.8-4.4) and 7.7 g/day (95%CI = 5.9-10.9), respectively. Severe acidosis was noted in 4.5% of patients who were not treated with sevelamer hydrochloride and in 16.1% of patients treated with sevelamer hydrochloride at ? 5.25 g/day (P < 0.0001). The results call for careful monitoring of serum bicarbonate level in hemodialysis patients treated with sevelamer hydrochloride. PMID:24499082
Oka, Yoshinari; Miyazaki, Masashi; Matsuda, Hiroaki; Takatsu, Shigeko; Katsube, Ryouichi; Mori, Toshiko; Takehara, Kiyoto; Umeda, Yuzo; Uno, Futoshi
Grocery Store Baking SodaA Source of Sodium Bicarbonate in the Management of Chronic Metabolic Acidosis
Oral sodium bicarbonate is used to treat metabolic acidosis in patients with renal tubular acidosis. Since infants and young children are unable to swallow tablets, those affected must ingest sodium bicarbonate in a powder or liquid form. Pharmacy-weighed sodium bicarbonate is expensive and inconvenient to obtain; some pharmacists are reluctant to provide it. We determined that the sodium bicarbonate contained
Beverley E. Booth; Jay Gates; R. Curtis Morris
Branched-chain amino acid metabolism in rat muscle: abnormal regulation in acidosis
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.
May, R.C.; Hara, Y.; Kelly, R.A.; Block, K.P.; Buse, M.G.; Mitch, W.E.
Effects of tight versus non tight control of metabolic acidosis on early renal function after kidney transplantation
Background Recently, several studies have been conducted to determine the optimal strategy for intra-operative fluid replacement therapy in renal transplantation surgery. Since infusion of sodium bicarbonate as a buffer seems to be safer than other buffer compounds (lactate, gluconate, acetate)that indirectly convert into it within the liver, We hypothesized tight control of metabolic acidosis by infusion of sodium bicarbonate may improve early post-operative renal function in renal transplant recipients. Methods 120 patients were randomly divided into two equal groups. In group A, bicarbonate was infused intra-operatively according to Base Excess (BE) measurements to achieve the normal values of BE (?5 to +5?mEq/L). In group B, infusion of bicarbonate was allowed only in case of severe metabolic acidosis (BE????15?mEq/L or bicarbonate???10?mEq/L or PH???7.15). Minute ventilation was adjusted to keep PaCO2 within the normal range. Primary end-point was sampling of serum creatinine level in first, second, third and seventh post-operative days for statistical comparison between groups. Secondary objectives were comparison of cumulative urine volumes in the first 24?h of post-operative period and serum BUN levels which were obtained in first, second, third and seventh post-operative days. Results In group A, all of consecutive serum creatinine levels were significantly lower in comparison with group B. With regard to secondary outcomes, no significant difference between groups was observed. Conclusion Intra-operative tight control of metabolic acidosis by infusion of Sodium Bicarbonate in renal transplant recipients may improve early post-operative renal function.
Changes in bone sodium and carbonate in metabolic acidosis and alkalosis in the dog
Metabolic acidosis and alkalosis were produced in adult dogs over 5- to 10-day periods. Midtibial cortical bone was analyzed for calcium, sodium, phosphorus, and carbonate. In acidosis bone CO3/Ca decreased 9.5% and bone Na/Ca decreased 6.3%. In alkalosis bone CO3/Ca increased 3.1% and bone Na/Ca increased 3.0%. Previous attempts to account for changes in net acid balance by summation of extra- and intracellular acid-base changes have uniformly resulted in about 40-60% of acid gained or lost being �unaccounted for.� If it is assumed that changes in tibial cortex reflect changes in the entire skeletal system, changes in bone CO3= are sufficiently large to account for the �unaccounted for� acid change without postulating changes in cellular metabolic acid production.
Burnell, James M.
Multiplexed Microneedle-based Biosensor Array for Characterization of Metabolic Acidosis
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-hour period.
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.
Plasma amino acid profile and expression of the ubiquitin-mediated proteolytic pathway in lambs with induced metabolic acidosis.
Metabolic acidosis is a condition often induced by ruminal acidosis. Identification of the specific proteolytic pathways affected by metabolic acidosis and characterization of AA concentration changes induced by metabolic acidosis in ruminants has yet to be confirmed. The objective of this study was to examine the effect of nutritionally induced metabolic acidosis on lamb plasma AA and tissue variables, including mRNA and protein expression of components of the ubiquitin-mediated proteolytic pathway. Lambs (n = 10) were divided evenly into treatment groups receiving alfalfa pellets supplemented with 1) a control canola meal supplement, or 2) HCl-treated canola meal supplement for a 10-d treatment period. On d 11, lambs were slaughtered and liver, muscle, and kidney samples were collected to determine mRNA expression of components of the ubiquitin-mediated proteolytic pathway and ubiquitin protein expression. Plasma concentrations of serine (P = 0.06), glycine (P = 0.002), and glutamine (P = 0.04) were greater in acidotic lambs compared with control animals, indicating that protein catabolism may be occurring. However, no alteration (P > 0.1) in messenger RNA expression of the proteasome subunit C8, ubiquitin-conjugating enzyme E2, or ubiquitin or in ubiquitin protein expression were observed. These results suggest that ubiquitin-mediated proteolysis is not the primary pathway of protein degradation in lambs afflicted with metabolic acidosis. PMID:18539839
Greenwood, S L; Odongo, N E; AlZahal, O; Swanson, K C; Shoveller, A K; Matthews, J C; McBride, B W
Experimentally-Induced Metabolic Acidosis Does not Alter Aortic Fatty Streak Formation in High-Cholesterol Fed Rabbits
Objective(s) Cardiovascular disease causes a major clinical problem in patients with end stage renal disease. Since metabolic acidosis is very common in patients with end stage renal disease, we aimed to investigate the effect of experimentally-induced metabolic acidosis on serum lipid profile and aortic fatty streak (FS) formation in normal and high-cholesterol fed rabbits. Materials and Methods Twenty-four male rabbits were divided into four groups (n=6 each): (1) normal diet (ND): (2) hypercholesterolemic diet (HCD) (1%): (3) ND plus acidemic diet: (4) HCD plus acidemic diet. Metabolic acidosis was induced by adding 0.75% NH4Cl in drinking water. After 4 weeks, blood samples were taken and thoracic aortae were dissected for histological examinations. Results Results showed that in the animals who received NH4Cl, metabolic acidosis was successfully induced. Serum total cholesterol and low density lipoprotein (LDL) concentrations in HCD groups were significantly higher than ND groups (P<0.05) and acidosis did not significantly change serum lipid levels neither in ND nor in HCD animals (P>0.05). Histological examination of aortae showed higher mean average grades of pathological evaluation in HCD than ND groups (2.1�0.16 vs. 0�0; P<0.05). Acidosis did not further increase FS formation in HCD groups (P >0.05). Conclusion In this model of experimentally-induced metabolic acidosis, acidosis could not increase FS formation in HCD animals and it seems that it does not interfere in progression of atherosclerosis process.
Khazaei, Majid; Nematbakhsh, Mehdi
Background Large animals treated with immunosuppressive drugs for preclinical experiments of transplantation have increased risks of infection, which can be compounded by the induction of diabetes in these animals if islet transplantation is planned. Methods We report our experience with severe sepsis in two young cynomolgus monkeys and five pigs that were subjected to diabetes induction, immunosuppressive therapy +/? islet allotransplantation. Results In two monkeys and five pigs, infection was associated with a syndrome of profound hypoglycemia accompanied by severe acidosis, which was resistant to treatment. We do not believe this syndrome has been reported previously by others. Conclusions Despite treatment, this syndrome complicated the interpretation of blood glucose readings as a measure of islet graft function, and resulted in death or the need for euthanasia in all 7 animals. We tentatively suggest that the syndrome may be related to the presence of microorganisms that metabolize glucose and produce lactate.
Zhou, Hao; van der Windt, Dirk J.; Dons, Eefje M.; Rigatti, Lora H.; Echeverri, Gabriel J.; Bottino, Rita; Wijkstrom, Martin; Wagner, Robert; Cooper, David K.C.
Refractory metabolic acidosis in patients with sepsis following hemiarthroplasty for femoral neck fracture: a causative role for paracetamol and flucloxacillin?
The authors report two cases of pyroglutamic acidosis as a result of paracetamol and flucloxacillin therapy in patients with prosthesis infection following hemiarthroplasty for neck of femur fractures. Pyroglutamic acidosis is an important and often unrecognised cause of refractory metabolic acidosis that disproportionately affects older women, and can be caused by drugs such as paracetamol and flucloxacillin in the setting of sepsis, renal failure and malnutrition. Although relatively rare, the widespread use of these drugs in orthopaedic patients confirms the importance of this disorder. PMID:22689665
Amer, Halima; Dockery, Frances; Barrett, Nicholas; George, Marc; Witek, Karolina; Stanton, Jeremy; Back, Diane
Roux-en-Y gastric bypass surgery reduces bone mineral density and induces metabolic acidosis in rats.
Roux-en-Y gastric bypass (RYGB) surgery leads to bone loss in humans, which may be caused by vitamin D and calcium malabsorption and subsequent secondary hyperparathyroidism. However, because these conditions occur frequently in obese people, it is unclear whether they are the primary causes of bone loss after RYGB. To determine the contribution of calcium and vitamin D malabsorption to bone loss in a rat RYGB model, adult male Wistar rats were randomized for RYGB surgery, sham-operation-ad libitum fed, or sham-operation-body weight-matched. Bone mineral density, calcium and phosphorus balance, acid-base status, and markers of bone turnover were assessed at different time points for 14 wk after surgery. Bone mineral density decreased for several weeks after RYGB. Intestinal calcium absorption was reduced early after surgery, but plasma calcium and parathyroid hormone levels were normal. 25-hydroxyvitamin D levels decreased, while levels of active 1,25-dihydroxyvitamin D increased after surgery. RYGB rats displayed metabolic acidosis due to increased plasma lactate levels and increased urinary calcium loss throughout the study. These results suggest that initial calcium malabsorption may play a key role in bone loss early after RYGB in rats, but other factors, including chronic metabolic acidosis, contribute to insufficient bone restoration after normalization of intestinal calcium absorption. Secondary hyperparathyroidism is not involved in postoperative bone loss. Upregulated vitamin D activation may compensate for any vitamin D malabsorption. PMID:24026074
Abegg, Kathrin; Gehring, Nicole; Wagner, Carsten A; Liesegang, Annette; Schiesser, Marc; Bueter, Marco; Lutz, Thomas A
Adaptations in urea ammonium excretion in metabolic acidosis in the rat: a reinterpretation.
1. The effects of oral hydrochloric acid, ammonium chloride, sodium bicarbonate and ammonium bicarbonate on urea and ammonium excretion in rats on a constant diet were studied. 2. Hydrochloric acid acidosis significantly reduced urea excretion in the rat, with an equimolar increase in NH+4 excretion and no change in their sum. In ammonium chloride acidosis, most of the additional nitrogen intake is excreted as NH+4 and a small percentage as urea. The converse holds true after administration of ammonium bicarbonate. The physiological significance of this is discussed. 3. The shift in nitrogen excretion from urea to NH+4 in acidosis is interpreted on the basis of bicarbonate production and utilization. Urea formation utilizes HCO-3. For amino acid sources, this utilization is offset by the metabolism of the carbon skeleton, which gives rise to HCO-3. When waste nitrogen is excreted as NH+4, no bicarbonate is utilized and the new HCO-3, generated by the carbon skeleton, hels to maintain hydrogen ion homeostasis. PMID:1056282
Oliver, J; Bourke, E
Metabolic acidosis stimulates muscle protein degradation by activating the adenosine triphosphate-dependent pathway involving ubiquitin and proteasomes.
Metabolic acidosis often leads to loss of body protein due mainly to accelerated protein breakdown in muscle. To identify which proteolytic pathway is activated, we measured protein degradation in incubated epitrochlearis muscles from acidotic (NH4Cl-treated) and pair-fed rats under conditions that block different proteolytic systems. Inhibiting lysosomal and calcium-activated proteases did not reduce the acidosis-induced increase in muscle proteolysis. However, when ATP production was also blocked, proteolysis fell to the same low level in muscles of acidotic and control rats. Acidosis, therefore, stimulates selectively an ATP-dependent, nonlysosomal, proteolytic process. We also examined whether the activated pathway involves ubiquitin and proteasomes (multicatalytic proteinases). Acidosis was associated with a 2.5- to 4-fold increase in ubiquitin mRNA in muscle. There was no increase in muscle heat shock protein 70 mRNA or in kidney ubiquitin mRNA, suggesting specificity of the response. Ubiquitin mRNA in muscle returned to control levels within 24 h after cessation of acidosis. mRNA for subunits of the proteasome (C2 and C3) in muscle were also increased 4-fold and 2.5-fold, respectively, with acidosis; mRNA for cathepsin B did not change. These results are consistent with, but do not prove that acidosis stimulates muscle proteolysis by activating the ATP-ubiquitin-proteasome-dependent, proteolytic pathway. Images
Mitch, W E; Medina, R; Grieber, S; May, R C; England, B K; Price, S R; Bailey, J L; Goldberg, A L
Multiplexed microneedle-based biosensor array for characterization of metabolic acidosis.
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
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
Liquid chromatographic-mass spectrometric method for simultaneous determination of small organic acids potentially contributing to acidosis in severe malaria.
Acidosis is an important cause of mortality in severe falciparum malaria. Lactic acid is a major contributor to metabolic acidosis, but accounts for only one-quarter of the strong anion gap. Other unidentified organic acids have an independent strong prognostic significance for a fatal outcome. In this study, a simultaneous bio-analytical method for qualitative and quantitative assessment in plasma and urine of eight small organic acids potentially contributing to acidosis in severe malaria was developed and validated. High-throughput strong anion exchange solid-phase extraction in a 96-well plate format was used for sample preparation. Hydrophilic interaction liquid chromatography (HILIC) coupled to negative mass spectroscopy was utilized for separation and detection. Eight possible small organic acids; l-lactic acid (LA), ?-hydroxybutyric acid (aHBA), ?-hydroxybutyric acid (bHBA), p-hydroxyphenyllactic acid (pHPLA), malonic acid (MA), methylmalonic acid (MMA), ethylmalonic acid (EMA) and ?-ketoglutaric acid (aKGA) were analyzed simultaneously using a ZIC-HILIC column with an isocratic elution containing acetonitrile and ammonium acetate buffer. This method was validated according to U.S. Food and Drug Administration guidelines with additional validation procedures for endogenous substances. Accuracy for all eight acids ranged from 93.1% to 104.0%, and the within-day and between-day precisions (i.e. relative standard deviations) were lower than 5.5% at all tested concentrations. The calibration ranges were: 2.5-2500?g/mL for LA, 0.125-125?g/mL for aHBA, 7.5-375?g/mL for bHBA, 0.1-100?g/mL for pHPLA, 1-1000?g/mL for MA, 0.25-250?g/mL for MMA, 0.25-100?g/mL for EMA, and 30-1500?g/mL for aKGA. Clinical applicability was demonstrated by analyzing plasma and urine samples from five patients with severe falciparum malaria; five acids had increased concentrations in plasma (range LA=177-1169?g/mL, aHBA=4.70-38.4?g/mL, bHBA=7.70-38.0?g/mL, pHPLA=0.900-4.30?g/mL and aKGA=30.2-32.0) and seven in urine samples (range LA=11.2-513?g/mL, aHBA=1.50-69.5?g/mL, bHBA=8.10-111?g/mL, pHPLA=4.30-27.7?g/mL, MMA=0.300-13.3?g/mL, EMA=0.300-48.1?g/mL and aKGA=30.4-107?g/mL). In conclusion, a novel bioanalytical method was developed and validated which allows for simultaneous quantification of eight small organic acids in plasma and urine. This new method may be a useful tool for the assessment of acidosis in patients with severe malaria, and other conditions complicated by acidosis. PMID:24200840
Sriboonvorakul, Natthida; Leepipatpiboon, Natchanun; Dondorp, Arjen M; Pouplin, Thomas; White, Nicholas J; Tarning, Joel; Lindegardh, Niklas
Alteration in surface ion composition of cultured bone during metabolic, but not respiratory, acidosis.
Acidosis produced by a fall in [HCO3-] (metabolic acidosis, Met) produces greater Ca efflux from cultured bone than that produced by a rise in PCO2 (respiratory acidosis, Resp). To compare the effects of Met and Resp on bone surface ion composition we measured the surface abundance of 40Ca, 23Na, and 39K in cultured bone with a scanning ion microprobe utilizing secondary-ion mass spectrometry. Neonatal mouse calvariae were incubated for 24 h in medium simulating either Met (pH = 7.193 +/- 0.034, [HCO3-] = 15.1 +/- 1.4 meq/l), Resp (pH = 7.153 +/- 0.014, PCO2 = 85.4 +/- 1.2 mmHg) or normal physiological (Ctl; pH = 7.484 +/- 0.009, [HCO3-] = 29.7 +/- 0.7, PCO2 = 39.6 +/- 0.3) conditions. The surface of Ctl at 2-nm depth is rich in Na and K relative to Ca (Na/Ca = 25.6, K/Ca = 12.0, ratios of counts/s of secondary ions). Compared with Ctl, Met produced a sharp fall in both Na/Ca (6.5, P less than 0.01) and K/Ca (4.6, P less than 0.01), whereas Resp did not alter Na/Ca (23.8) or K/Ca (15.0). Ca efflux was greater in Met (873 +/- 54 nmol.bone-1.24 h-1) than in Resp (546 +/- 71 nmol.bone-1.24 h-1, P less than 0.01), which was greater than that in Ctl (315 +/- 49 nmol.bone-1.24 h-1, P less than 0.01 vs. Met and vs. Resp).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1858906
Chabala, J M; Levi-Setti, R; Bushinsky, D A
Renal response to metabolic acidosis: Role of mRNA stabilization
The renal response to metabolic acidosis is mediated, in part, by increased expression of the genes encoding key enzymes of glutamine catabolism and various ion transporters that contribute to the increased synthesis and excretion of ammonium ions and the net production and release of bicarbonate ions. The resulting adaptations facilitate the excretion of acid and partially restore systemic acid-base balance. Much of this response may be mediated by selective stabilization of the mRNAs that encode the responsive proteins. For example, the glutaminase mRNA contains a direct repeat of 8-nt AU-sequences that function as a pH-response element (pH-RE). This element is both necessary and sufficient to impart a pH-responsive stabilization to chimeric mRNAs. The pH-RE also binds multiple RNA binding proteins, including ?-crystallin, AUF1 and HuR. The onset of acidosis initiates an ER-stress response that leads to the formation of cytoplasmic stress granules. ?-crystallin is transiently recruited to the stress granules and concurrently, HuR is translocated from the nucleus to the cytoplasm. Based upon the cumulative data, a mechanism for the stabilization of selective mRNAs is proposed. This hypothesis suggests multiple experiments that should better define how cells in the kidney sense very slight changes in intracellular pH and mediate this essential adaptive response.
Ibrahim, Hend; Lee, Yeon J.; Curthoys, Norman P.
Influence of mild metabolic acidosis on cardiac contractility and isoprenaline response in isolated ovine myocardium.
The postoperative course after major surgical procedures such as cardiothoracic operations is often accompanied by acute metabolic abnormalities due to large volume and temperature shifts. In general, those intervention-induced trauma might cause the use of catecholamines to stabilize hemodynamics. Within the cardiac community, there are still controversial discussions about standardized medical therapy to treat postoperative acidosis, for example, buffering versus nonbuffering for improving catecholaminergic response of myocardial contractility. The aim of this study was to investigate the influence of mild (and thus clinically relevant) acidosis on myocardial contractility and catecholamine response in explanted trabeculae of ovine hearts. Intact trabeculae (n = 24) were isolated from the right ventricle of healthy sheep hearts. Two different groups (group 1: pH = 7.40, n = 9 and group 2: pH = 7.20, n = 13) were investigated, and force amplitudes were measured at frequencies between 30 and 180 beats per minute and increasing catecholamine concentrations (isoprenaline 0-3 � 10(-6) mM). Force-frequency relation experiments in the presence of a physiological and/or mild acidotic pH solution showed no significant differences. Mean force amplitudes normalized to the lowest frequency showing no significant differences in force development between 0.5 and 3 Hz (n = 9 vs. 13, P = n.s.) (0.5 Hz absolute values 3.1 � 2.6 for pH = 7.40 vs. 3.8 � 2.6 mN/mm(2) for pH = 7.20, P = n.s.). Moreover, there was no significant difference in relaxation kinetics between the two groups. Furthermore, the experiments showed similar catecholamine responses in both groups. Force amplitudes normalized to baseline and maximum force showed no significant differences in force development between baseline and maximum isoprenaline concentrations (n = 6 vs. 9, P = n.s.) (baseline absolute values 4.3 � 4.0 for pH = 7.40 vs. 3.9 � 1.2 mN/mm(2) for pH = 7.20, P = n.s.). Additionally, relaxation kinetics did not show differences after catecholamine stimulation. The presented experiments revealed no significant negative inotropic effects on isometrically contracting ovine trabeculae with mild metabolic acidosis (pH = 7.2) compared with physiological pH (7.4). Additionally, similar catecholamine responses were seen in both groups. Further investigations (e.g., in vivo and/or in failing hearts with reduced compensatory reserves) will be necessary to examine optimal medical treatment for metabolic abnormalities after cardiac surgery. PMID:22097981
Schotola, Hanna; Sossalla, Samuel; Rajab, Taufiek K; Toischer, Karl; Quintel, Michael; Bauer, Martin; Schmitto, Jan D
Neuronal expression of sodium/bicarbonate cotransporter NBCn1 (SLC4A7) and its response to chronic metabolic acidosis
The sodium-bicarbonate cotransporter NBCn1 (SLC4A7) is an acid-base transporter that normally moves Na+ and HCO3? into the cell. This membrane protein is sensitive to cellular and systemic pH changes. We examined NBCn1 expression and localization in the brain and its response to chronic metabolic acidosis. Two new NBCn1 antibodies were generated by immunizing a rabbit and a guinea pig. The antibodies stained neurons in a variety of rat brain regions, including hippocampal pyramidal neurons, dentate gyrus granular neurons, posterior cortical neurons, and cerebellar Purkinje neurons. Choroid plexus epithelia were also stained. Double immunofluorescence labeling showed that NBCn1 and the postsynaptic density protein PSD-95 were found in the same hippocampal CA3 neurons and partially colocalized in dendrites. PSD-95 was pulled down from rat brain lysates with the GST/NBCn1 fusion protein and was also coimmunoprecipitated with NBCn1. Chronic metabolic acidosis was induced by feeding rats with normal chow or 0.4 M HCl-containing chow for 7 days. Real-time PCR and immunoblot showed upregulation of NBCn1 mRNA and protein in the hippocampus of acidotic rats. NBCn1 immunostaining was enhanced in CA3 neurons, posterior cortical neurons, and cerebellar granular cells. Intraperitoneal administration of N-methyl-d-aspartate caused neuronal death determined by caspase-3 activity, and this effect was more severe in acidotic rats. Administering N-methyl-d-aspartate also inhibited NBCn1 upregulation in acidotic rats. We conclude that NBCn1 in neurons is upregulated by chronic acid loads, and this upregulation is associated with glutamate excitotoxicity.
Park, Hae Jeong; Rajbhandari, Ira; Yang, Han Soo; Lee, Soojung; Cucoranu, Delia; Cooper, Deborah S.; Klein, Janet D.; Sands, Jeff M.
Severe metabolic alkalosis and recurrent acute on chronic kidney injury in a patient with Crohn's disease
BACKGROUND: Diarrhea is common in patients with Crohn's disease and may be accompanied by acid base disorders, most commonly metabolic acidosis due to intestinal loss of bicarbonate. CASE PRESENTATION: Here, we present a case of severe metabolic alkalosis in a young patient suffering from M. Crohn. The patient had undergone multiple resections of the intestine and suffered from chronic kidney
Johannes Jacobi; Susanne Schnellhardt; Mirian Opgenoorth; Kerstin U Amann; Axel K�ttner; Axel Schmid; Kai-Uwe Eckardt; Karl F Hilgers
Metabolic determinants of the onset of acidosis in exercising human muscle: a 31P-MRS study.
Onset of intracellular acidosis during muscular exercise has been generally attributed to activation or hyperactivation of nonoxidative ATP production but has not been analyzed quantitatively in terms of H(+) balance, i.e., production and removal mechanisms. To address this issue, we have analyzed the relation of intracellular acidosis to H(+) balance during exercise bouts in seven healthy subjects. Each subject performed a 6-min ramp rhythmic exercise (finger flexions) at low frequency (LF, 0.47 Hz), leading to slight acidosis, and at high frequency (HF, 0.85 Hz), inducing a larger acidosis. Metabolic changes were recorded using (31)P-magnetic resonance spectroscopy. Onset of intracellular acidosis was statistically identified after 3 and 4 min of exercise for HF and LF protocols, respectively. A detailed investigation of H(+) balance indicated that, for both protocols, nonoxidative ATP production preceded a change in pH. For HF and LF protocols, H(+) consumption through the creatine kinase equilibrium was constant in the face of increasing H(+) generation and efflux. For both protocols, changes in pH were not recorded as long as sources and sinks for H(+) approximately balanced. In contrast, a significant acidosis occurred after 4 min of LF exercise and 3 min of HF exercise, whereas the rise in H(+) generation exceeded the rise in H(+) efflux at a nearly constant H(+) uptake associated with phosphocreatine breakdown. We have clearly demonstrated that intracellular acidosis in exercising muscle does not occur exclusively as a result of nonoxidative ATP production but, rather, reflects changes in overall H(+) balance. PMID:12433845
Roussel, M; Mattei, J P; Le Fur, Y; Ghattas, B; Cozzone, P J; Bendahan, D
Noninvasive measurement of tissue carbon dioxide tension using a fiberoptic conjunctival sensor: effects of respiratory and metabolic alkalosis and acidosis.
To evaluate potential clinical applications of a newly developed, noninvasive fiberoptic conjunctival carbon dioxide (PcjCO2) sensor designed to measure continuously tissue PCO2 in a vascular bed supplied by the internal carotid artery, we studied the effects of graded respiratory and metabolic alkalosis and acidosis on PcjCO2 in a hemodynamically stable canine model. Respiratory changes were induced by varying the frequency of ventilation and metabolic changes were induced by incremental infusions of sodium bicarbonate and hydrochloric acid. Continuous measurement of end-tidal carbon dioxide tension (PETCO2) was also performed. During respiratory alkalosis and acidosis, PcjCO2 values correlated well with PaCO2 (r = 0.96, n = 106); linear regression analysis of PcjCO2 vs. PaCO2 produced a slope of 1.01 and a y-intercept of 3.94 over a PaCO2 range of 12 to 76 torr. The mean PcjCO2-PaCO2 gradient was 4 +/- 3 (SD) torr. PETCO2 values also correlated well with PaCO2 (r = 0.91), as well as with PcjCO2 values (r = 0.91). Both PcjCO2 and PETCO2 showed a much weaker correlation with PaCO2 during metabolic alkalosis and acidosis, partly because the variation in PaCO2 was less. Moreover, the PcjCO2-PaCO2 gradient increased during the metabolic portion of the study up to a mean of 10 +/- 8 (SD) torr during metabolic acidosis, implying a build-up and/or lack of washout of CO2 from the conjunctival tissues, despite the normal physiologic range of PaCO2 values. We conclude that in a hemodynamically stable canine model, PcjCO2 and PETCO2 values correlate well with PaCO2 during pure respiratory alkalosis and acidosis; the correlation weakens significantly, however, with metabolic alterations in tissue CO2 levels. PMID:3125006
Kram, H B; Fink, S; Tsang, M; Markle, D; Appel, P L; Shoemaker, W C
Targeted mutation of SLC4A5 induces arterial hypertension and renal metabolic acidosis.
The human SLC4A5 gene has been identified as a hypertension susceptibility gene based on the association of single nucleotide polymorphisms with blood pressure (BP) levels and hypertension status. The biochemical basis of this association is unknown particularly since no single gene variant was linked to hypertension in humans. SLC4A5 (NBCe2, NBC4) is expressed in the collecting duct of the kidney and acts as an electrogenic ion-transporter that transports sodium and bicarbonate with a 1:2 or 1:3 stoichiometry allowing bicarbonate reabsorption with relatively minor concurrent sodium uptake. We have mutated the Slc4a5 gene in mice, which caused a persistent increase in systolic and diastolic BP. Slc4a5 mutant mice also displayed a compensated metabolic acidosis and hyporeninemic hypoaldosteronism. Analysis of kidney physiology revealed elevated fluid intake and urine excretion and increased glomerular filtration rate. Transcriptome analysis uncovers possible compensatory mechanisms induced by SLC4A5 mutation, including upregulation of SLC4A7 and pendrin as well as molecular mechanisms associated with hypertension. Induction of metabolic alkalosis eliminated the BP difference between wild-type and Slc4a5 mutant mice. We conclude that the impairment of the function of SLC4A5 favors development of a hypertensive state. We reason that the loss of sodium-sparing bicarbonate reabsorption by SLC4A5 initiates a regulatory cascade consisting of compensatory bicarbonate reabsorption via other sodium-bicarbonate transporters (e.g. SLC4A7) at the expense of an increased sodium uptake. This will ultimately raise BP and cause hypoaldosteronism, thus providing a mechanistic explanation for the linkage of the SLC4A5 locus to hypertension in humans. PMID:22082831
Gr�ger, Nicole; Vitzthum, Helga; Fr�hlich, Henning; Kr�ger, Marcus; Ehmke, Heimo; Braun, Thomas; Boettger, Thomas
Consequences and therapy of the metabolic acidosis of chronic kidney disease
Metabolic acidosis is common in patients with chronic kidney disease (CKD), particularly once the glomerular filtration rate (GFR) falls below 25�ml/min/1.73�m2. It is usually mild to moderate in magnitude with the serum bicarbonate concentration ([HCO3?]) ranging from 12 to 23�mEq/l. Even so, it can have substantial adverse effects, including development or exacerbation of bone disease, growth retardation in children, increased muscle degradation with muscle wasting, reduced albumin synthesis with a predisposition to hypoalbuminemia, resistance to the effects of insulin with impaired glucose tolerance, acceleration of the progression of CKD, stimulation of inflammation, and augmentation of ?2-microglobulin production. Also, its presence is associated with increased mortality. The administration of base to patients prior to or after initiation of dialysis leads to improvement in many of these adverse effects. The present recommendation by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) is to raise serum [HCO3?] to ?22�mEq/l, whereas Caring for Australians with Renal Impairment (CARI) recommends raising serum [HCO3?] to >22�mEq/l. Base administration can potentially contribute to volume overload and exacerbation of hypertension as well as to metastatic calcium precipitation in tissues. However, sodium retention is less when given as sodium bicarbonate and sodium chloride intake is concomitantly restricted. Results from various studies suggest that enhanced metastatic calcification is unlikely with the pH values achieved during conservative base administration, but the clinician should be careful not to raise serum [HCO3?] to values outside the normal range.
Kraut, Jeffrey A.
Graft failure of autologous peripheral blood stem cell transplantation due to acute metabolic acidosis associated with total parenteral nutrition in a patient with relapsed breast cancer.
A 32-year-old female had been diagnosed as having relapsed breast cancer and liver metastasis. She underwent high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT) with 5.8 x 10(6)/kg CD34+ cells. She was supported by total parenteral nutrition (TPN) without vitamins throughout these therapies. Hematopoietic recovery was not observed by day 28 after PBSCT, necessitating a second PBSCT on day 29 using the back-up material of 4.4 x 10(6)/kg CD34+ cells. On the next day, she suddenly developed severe metabolic acidosis, heart failure and deep coma. After immediate infusion of thiamine, heart failure and coma rapidly improved. The neutrophil count reached 0.5 x 10(9)/l on day 9 and the platelet count 50 x 10(9)/l on day 15 after the second PBSCT. This is a rare graft failure due to acute metabolic acidosis or thiamine deficiency associated with TPN. PMID:10692681
Sawada, M; Tsurumi, H; Hara, T; Goto, H; Yamada, T; Oyama, M; Moriwaki, H
Severe lactic acidosis and multiorgan failure due to thiamine deficiency during total parenteral nutrition.
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
Ramsi, Musaab; Mowbray, Claire; Hartman, Gary; Pageler, Natalie
Contribution of individual superficial nephron segments to ammonium handling in chronic metabolic acidosis in the rat. Evidence for ammonia disequilibrium in the renal cortex.
Ammonia entry along surface nephron segments of rats was studied with micropuncture techniques under control and chronic metabolic acidosis conditions. Tubule fluid was collected successively from sites at the end and beginning of the distal tubule and at the end of the proximal tubule of the same nephron. During chronic metabolic acidosis, ammonium excretion doubled. As anticipated, the ammonium concentration (TFNH+4) was significantly higher in proximal tubule fluid during acidosis, and ammonium delivery to end proximal sites increased from 19.4 +/- 2.3 to 34.0 +/- 3.2 pmol/min (P less than 0.001). Although chronic acidosis did not affect TFNH+4 at the beginning of the distal tubule, ammonium delivery to the end of the distal tubule increased from 5.72 +/- 0.97 to 9.88 +/- 0.97 pmol/min. In both control and acidotic groups ammonium delivery was lower (P less than 0.001) to end distal sites than to end proximal sites, indicating net loss in the intervening segment. This loss was greater during chronic metabolic acidosis (23.9 +/- 3.3 vs. 13.6 +/- 2.0 pmol/min in controls, P less than 0.025). In both groups net entry of ammonia, in similar amounts, occurred along the distal tubule (P less than 0.05). In situ pH averaged 6.80 +/- 0.05 at end proximal tubule sites and fell to 6.54 +/- 0.08 at the beginning of the distal tubule (P less than 0.005). Chronic metabolic acidosis did not affect these measurements. The calculated free ammonia at the end of the proximal tubule rose from 9.3 +/- 2.2 to 21 +/- 9 microM (P less than 0.005) during chronic metabolic acidosis, and was also higher at beginning distal sites during acidosis (8.8 +/- 2.4 vs. 2.7 +/- 0.7 microM in controls, P less than 0.05). In both groups ammonia values for the beginning distal tubule fluid were lower than for end proximal tubule fluid. Thus, loss of ammonium in the loop segment is enhanced by chronic metabolic acidosis. Distal entry of ammonia is markedly less than along the proximal tubule and does not change in chronic metabolic acidosis, and ammonia permeabilities for the proximal and distal segments of surface nephrons seem different.
Simon, E; Martin, D; Buerkert, J
Sympathetic activation in exercise is not dependent on muscle acidosis. Direct evidence from studies in metabolic myopathies
NASA Technical Reports Server (NTRS)
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.
Vissing, J.; Vissing, S. F.; MacLean, D. A.; Saltin, B.; Quistorff, B.; Haller, R. G.; Blomqvist, C. G. (Principal Investigator)
Sympathetic activation in exercise is not dependent on muscle acidosis. Direct evidence from studies in metabolic myopathies.
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.
Vissing, J; Vissing, S F; MacLean, D A; Saltin, B; Quistorff, B; Haller, R G
Lactic acidosis is when lactic acid builds ups in the bloodstream faster than it can be removed. Lactic acid ... The most common cause of lactic acidosis is intense exercise. ... as: AIDS Cancer Kidney failure Respiratory failure Sepsis A ...
Incidence, prevalence, severity, and risk factors for ruminal acidosis in feedlot steers during backgrounding, diet transition, and finishing.
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
Castillo-Lopez, E; Wiese, B I; Hendrick, S; McKinnon, J J; McAllister, T A; Beauchemin, K A; Penner, G B
A Comparison of Treating Metabolic Acidosis in CKD Stage 4 Hypertensive Kidney Disease with Fruits and Vegetables or Sodium Bicarbonate
Summary Background and objectives Current guidelines recommend Na+-based alkali for CKD with metabolic acidosis and plasma total CO2 (PTCO2) < 22 mM. Because diets in industrialized societies are typically acid-producing, we compared base-producing fruits and vegetables with oral NaHCO3 (HCO3) regarding the primary outcome of follow-up estimated GFR (eGFR) and secondary outcomes of improved metabolic acidosis and reduced urine indices of kidney injury. Design, setting, participants, & measurements Individuals with stage 4 (eGFR, 15�29 ml/min per 1.73 m2) CKD due to hypertensive nephropathy, had a PTCO2 level < 22 mM, and were receiving angiotensin-converting enzyme inhibition were randomly assigned to 1 year of daily oral NaHCO3 at 1.0 mEq/kg per day (n=35) or fruits and vegetables dosed to reduce dietary acid by half (n=36). Results Plasma cystatin C�calculated eGFR did not differ at baseline and 1 year between groups. One-year PTCO2 was higher than baseline in the HCO3 group (21.2�1.3 versus 19.5�1.5 mM; P<0.01) and the fruits and vegetables group (19.9�1.7 versus 19.3�1.9 mM; P<0.01), consistent with improved metabolic acidosis, and was higher in the HCO3 than the fruits and vegetable group (P<0.001). One-year urine indices of kidney injury were lower than baseline in both groups. Plasma [K+] did not increase in either group. Conclusions One year of fruits and vegetables or NaHCO3 in individuals with stage 4 CKD yielded eGFR that was not different, was associated with higher-than-baseline PTCO2, and was associated with lower-than-baseline urine indices of kidney injury. The data indicate that fruits and vegetables improve metabolic acidosis and reduce kidney injury in stage 4 CKD without producing hyperkalemia.
Goraya, Nimrit; Simoni, Jan; Jo, Chan-Hee
Severe Lactic Acidosis in a Patient with B-Cell Lymphoma: A Case Report and Review of the Literature
Lactic acidosis is commonly observed in clinical situations such as shock and sepsis, as a result of tissue hypoperfusion and hypoxia. Lymphoma and leukemia are among other clinical situations where lactic acidosis has been reported. We present a case of a 59-year-old female with lactic acidosis who was found to have aggressive B-cell lymphoma. There have been 29 cases of lymphoma induced lactic acidosis reported thus far; however all reported cases have abnormal vital signs or concomitant medical conditions that may lead to lactic acidosis. The pathogenesis of malignancy-induced lactic acidosis is not well understood; however associated factors include increased glycolysis, increased lactate production by cancer cells, and decreased hepatic clearance of lactate. When it occurs, lactic acidosis is a poor prognostic sign in these patients. Prompt diagnosis and treatment of underlying lymphoma or leukemia remains the only way to achieve complete resolution of lactic acidosis in these patients.
Chan, Farn Huei; Carl, Daniel; Lyckholm, Laurel J.
Atypical distal renal tubular acidosis confirmed by mutation analysis.
In autosomal dominant distal renal tubular acidosis type I (dRTA) impaired hydrogen ion secretion is associated with metabolic acidosis, hyperchloremic hypokalemia, hypercalciuria, nephrocalcinosis, and/or nephrolithiasis. A retardation of growth is commonly observed. In this report we present a family with autosomal dominant dRTA with an atypical and discordant clinical picture. The father presented with severe nephrocalcinosis, nephrolithiasis, and isosthenuria but metabolic acidosis was absent. His 6-year-old daughter, however, suffered from metabolic acidosis, hypokalemia, and hypercalciuria. In addition, sonography revealed multiple bilateral renal cysts but no nephrocalcinosis. Mutation analysis of the AE1 gene coding for the renal Cl-/HCO3(-)-exchanger AE1 displayed a heterozygous Arg589Cys exchange in both patients but not in the healthy family members. This point mutation is frequently associated with autosomal dominant dRTA. Diagnosis of autosomal dominant dRTA is supported in this family by results of AE1 mutation analysis. PMID:11149111
Weber, S; Soergel, M; Jeck, N; Konrad, M
Effect of experimentally induced metabolic acidosis on aortic endothelial permeability and serum nitric oxide concentration in normal and high-cholesterol fed rabbits
Introduction Metabolic acidosis is present in end stage renal disease. There is a link between enhanced endothelial permeability and accelerated atherosclerosis. In this study, we investigated the effect of experimentally induced metabolic acidosis on aortic endothelial permeability and serum nitric oxide (NO) concentration in normal and high-cholesterol fed rabbits. Material and methods Twenty-four male rabbits were divided into four groups: normal, hypercholesterolemic, acidemic, and hypercholesterolemic plus acidemic. Acidosis and hypercholesterolemia were induced by drinking water containing ammonium chloride (NH4Cl), and cholesterol-rich animal chow (1%), respectively. After 6 weeks, blood samples were taken and endothelial permeability was measured using the Evans blue dye injection method. Results Hypercholesterolemic animals had higher aortic endothelial permeability compared with normal groups (16.18 �0.91 �g EB/g tissue vs. 12.89 �0.66 �g EB/g tissue, p < 0.05). Acidosis significantly increased endothelial permeability in the normal group (17.10 �0.56 �g/g tissue vs. 12.89 � 0.66 �g/g tissue; p < 0.05) but did not further increase endothelial permeability in hypercholesterolemic animals (16.18 �0.91 �g EB/g tissue vs. 17.29 �0.46 �g EB/g tissue; p > 0.05). Serum total cholesterol, low density lipoprotein (LDL) and NO concentrations in hypercholesterolemic animals were significantly higher than the normal group and acidosis could not change them either in the normal or in the high-cholesterol diet group. Conclusions Alterations of serum lipids and NO are not the main mechanism for accelerated atherosclerosis during metabolic acidosis. Acidosis increases aortic endothelial permeability at least in a normal diet which may be a possible mechanism for progression of atherosclerosis processes in end-stage renal disease.
Nematbakhsh, Mehdi
Veno-venous extracorporeal CO2 removal for the treatment of severe respiratory acidosis: pathophysiological and technical considerations
Introduction While non-invasive ventilation aimed at avoiding intubation has become the modality of choice to treat mild to moderate acute respiratory acidosis, many severely acidotic patients (pH <7.20) still need intubation. Extracorporeal veno-venous CO2 removal (ECCO2R) could prove to be an alternative. The present animal study tested in a systematic fashion technical requirements for successful ECCO2R in terms of cannula size, blood and sweep gas flow. Methods ECCO2R with a 0.98�m2 surface oxygenator was performed in six acidotic (pH <7.20) pigs using either a 14.5 French (Fr) or a 19Fr catheter, with sweep gas flow rates of 8 and 16�L/minute, respectively. During each experiment the blood flow was incrementally increased to a maximum of 400�mL/minute (14.5Fr catheter) and 1000�mL/minute (19Fr catheter). Results Amelioration of severe respiratory acidosis was only feasible when blood flow rates of 750 to 1000�mL/minute (19Fr catheter) were used. Maximal CO2-elimination was 146.1?�?22.6�mL/minute, while pH increased from 7.13?�?0.08 to 7.41?�?0.07 (blood flow of 1000�mL/minute; sweep gas flow 16�L/minute). Accordingly, a sweep gas flow of 8�L/minute resulted in a maximal CO2-elimination rate of 138.0?�?16.9�mL/minute. The 14.5Fr catheter allowed a maximum CO2 elimination rate of 77.9�mL/minute, which did not result in the normalization of pH. Conclusions Veno-venous ECCO2R may serve as a treatment option for severe respiratory acidosis. In this porcine model, ECCO2R was most effective when using blood flow rates ranging between 750 and 1000�mL/minute, while an increase in sweep gas flow from 8 to 16�L/minute had less impact on ECCO2R in this setting.
Renal tubular acidosis (RTAs) are a group of metabolic disorders characterized by metabolic acidosis with normal plasma anion gap. There are three main forms of RTA: a proximal RTA called type II and a distal RTA (type I and IV). The RTA type II is a consequence of the inability of the proximal tubule to reabsorb bicarbonate. The distal RTA is associated with the inability to excrete the daily acid load and may be associated with hyperkalaemia (type IV) or hypokalemia (type I). The most common etiology of RTA type IV is the hypoaldosteronism. The RTAs can be complicated by nephrocalcinosis and obstructive nephrolithiasis. Alkalinization is the cornerstone of treatment. PMID:24070792
Seidowsky, A; Moulonguet-Doleris, L; Hanslik, T; Yattara, H; Ayari, H; Rouveix, E; Massy, Z A; Prinseau, J
The progestin etonogestrel enhances the respiratory response to metabolic acidosis in newborn rats. Evidence for a mechanism involving supramedullary structures.
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
Loiseau, Camille; Osinski, Diane; Joubert, Fanny; Straus, Christian; Similowski, Thomas; Bodineau, Laurence
Metabolic acidosis stimulates H+ secretion in the rabbit outer medullary collecting duct (inner stripe) of the kidney.
The outer medullary collecting duct (OMCD) absorbs HCO3- at high rates, but it is not clear if it responds to metabolic acidosis to increase H+ secretion. We measured net HCO3- transport in isolated perfused OMCDs taken from deep in the inner stripes of kidneys from control and acidotic (NH4Cl-fed for 3 d) rabbits. We used specific inhibitors to characterize the mechanisms of HCO3- transport: 10 microM Sch 28080 or luminal K+ removal to inhibit P-type H+,K+-ATPase activity, and 5-10 nM bafilomycin A1 or 1-10 nM concanamycin A to inhibit H+-ATPase activity. The results were comparable using either of each pair of inhibitors, and allowed us to show in control rabbits that 65% of net HCO3- absorption depended on H+-ATPase (H flux), and 35% depended on H+,K+-ATPase (H,K flux). Tubules from acidotic rabbits showed higher rates of HCO3- absorption (16.8+/-0.3 vs. 12.8+/-0.2 pmol/min per mm, P < 0.01). There was no difference in the H,K flux (5.9+/-0.2 vs. 5.8+/-0.2 pmol/min per mm), whereas there was a 61% higher H flux in segments from acidotic rabbits (11.3+/-0.2 vs. 7.0+/-0.2 pmol/min per mm, P < 0.01). Transport was then measured in other OMCDs before and after incubation for 1 h at pH 6.8, followed by 2 h at pH 7.4 (in vitro metabolic acidosis). Acid incubation in vitro stimulated HCO3- absorption (12.3+/-0.3 to 16.2+/-0.3 pmol/min per mm, P < 0.01), while incubation at pH 7.4 for 3 h did not change basal rate (11.8+/-0.4 to 11.7+/-0.4 pmol/min per mm). After acid incubation the H,K flux did not change, (4.7+/-0.4 to 4.6+/-0.4 pmol/min per mm), however, there was a 60% increase in H flux (6.6+/-0.3 to 10.8+/-0.3 pmol/min per mm, P < 0.01). In OMCDs from acidotic animals, and in OMCDs incubated in acid in vitro, there was a higher basal rate and a further increase in HCO3- absorption (16.7+/-0.4 to 21.3+/-0.3 pmol/min per mm, P < 0.01) because of increased H flux (11.5+/-0.3 to 15.7+/-0.2 pmol/min per mm, P < 0.01) without any change in H,K flux (5.4+/-0.3 to 5.6+/-0.3 pmol/min per mm). These data indicate that HCO3- absorption (H+ secretion) in OMCD is stimulated by metabolic acidosis in vivo and in vitro by an increase in H+-ATPase-sensitive HCO3- absorption. The mechanism of adaptation may involve increased synthesis and exocytosis to the apical membrane of proton pumps. This adaptation helps maintain homeostasis during metabolic acidosis.
Tsuruoka, S; Schwartz, G J
Severe Encephalopathy, Lactic Acidosis, Vegetative Instability and Neuropathy with 5-Fluorouracil Treatment - Pyrimidine Degradation Defect or Beriberi?
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.
Rosen, A.; van Kuilenburg, A.; Assmann, B.; Kuhlen, M.; Borkhardt, A.
Excess Casein in the Diet Is Not the Unique Cause of Low-Grade Metabolic Acidosis: Role of a Deficit in Potassium Citrate in a Rat Model
This study examined the effects of a dietary model of protein excess and K anion salt deficit on the occurrence of metabolic acidosis in rat. Rats were adapted to diets containing either 13 or 26% casein, together with mineral imbalance, through lowering K\\/increasing sodium\\/omitting alkalinizing anions. For each protein level, a group of rats was supplemented with K citrate. Dietary
Houda Sabboh; Catherine Besson; Jean-Claude Tressol; Christian R�m�sy; Christian Demign�
Switching hemodialysis patients from sevelamer hydrochloride to bixalomer: a single-center, non-randomized analysis of efficacy and effects on gastrointestinal symptoms and metabolic acidosis
Background Bixalomer (BXL) was developed to improve gastrointestinal symptoms and reduce constipation, relative to sevelamer hydrochloride, in hemodialysis patients. We prospectively evaluated the safety and effectiveness of switching maintenance dialysis patients from sevelamer hydrochloride to BXL. Methods Twenty-eight patients were switched from sevelamer hydrochloride to BXL (1:1 dose) from July to October 2012, whereas 84 randomly selected patients not treated with sevelamer hydrochloride were enrolled as a control group. The primary endpoint was improvement of gastrointestinal symptoms; secondary endpoints included improvement in metabolic acidosis, changes in blood biochemistry, and safety 12�weeks after the switch. We also surveyed patient satisfaction with switching to BXL 12�weeks after the switch. Results Before switching, symptoms of epigastric fullness were significantly worse in the switch than in the control group. Twelve weeks after the switch, reflux, epigastric fullness, and constipation had improved significantly in the switch group. Other factors, including stomach ache, diarrhea, and form of stool, did not change significantly. Blood gas analysis showed that metabolic acidosis was significantly improved by switching. Four patients (14%) experienced grade 1 adverse events, all of which improved immediately after stopping BXL. Major adverse events were diarrhea and abdominal discomfort. Mean satisfaction score was 3.1?�?0.7, with 64% of patients reporting they were �neither satisfied nor dissatisfied� after switching. Conclusions A switch from sevelamer hydrochloride to BXL improved symptoms of reflux, epigastric fullness, constipation, and metabolic acidosis in hemodialysis patients. Trial registration The study was registered as Clinical trial: (UMIN000011150).
Acidosis activates complement system in vitro.
We investigated the in vitro effect of different forms of acidosis (pH 7.0) on the formation of anaphylatoxins C3a and C5a. Metabolic acidosis due to addition of hydrochloric acid (10 micromol/ml blood) or lactic acid (5.5 micromol/ml) to heparin blood (N=12) caused significant activation of C3a and C5a compared to control (both p=0.002). Respiratory acidosis activated C3a (p=0.007) and C5a (p=0.003) compared to normocapnic controls. Making blood samples with lactic acidosis hypocapnic resulted in a median pH of 7.37. In this respiratory compensated metabolic acidosis, C3a and C5a were not increased. These experiments show that acidosis itself and not lactate trigger for activation of complement components C3 and C5.
Emeis, M; Sonntag, J; Willam, C; Strauss, E; Walka, M M; Obladen, M
Effect of Sodium Bicarbonate Administration on Mortality in Patients with Lactic Acidosis: A Retrospective Analysis
Background Lactic acidosis is a common cause of high anion gap metabolic acidosis. Sodium bicarbonate may be considered for an arterial pH <7.15 but paradoxically depresses cardiac performance and exacerbates acidosis by enhancing lactate production. This study aimed to evaluate the cause and mortality rate of lactic acidosis and to investigate the effect of factors, including sodium bicarbonate use, on death. Methods We conducted a single center analysis from May 2011 through April 2012. We retrospectively analyzed 103 patients with lactic acidosis among 207 patients with metabolic acidosis. We used SOFA and APACHE II as severity scores to estimate illness severity. Multivariate logistic regression analysis and Cox regression analysis models were used to identify factors that affect mortality. Results Of the 103 patients with a mean age of 66.1�11.4 years, eighty-three patients (80.6%) died from sepsis (61.4%), hepatic failure, cardiogenic shock and other causes. The percentage of sodium bicarbonate administration (p?=?0.006), catecholamine use, ventilator care and male gender were higher in the non-survival group than the survival group. The non-survival group had significantly higher initial and follow-up lactic acid levels, lower initial albumin, higher SOFA scores and APACHE II scores than the survival group. The mortality rate was significantly higher in patients who received sodium bicarbonate. Sodium bicarbonate administration (p?=?0.016) was associated with higher mortality. Independent factors that affected mortality were SOFA score (Exp (B)?=?1.72, 95% CI?=?1.12�2.63, p?=?0.013) and sodium bicarbonate administration (Exp (B)?=?6.27, 95% CI?=?1.10�35.78, p?=?0.039). Conclusions Lactic acidosis, which has a high mortality rate, should be evaluated in patients with metabolic acidosis. In addition, sodium bicarbonate should be prescribed with caution in the case of lactic acidosis because sodium bicarbonate administration may affect mortality.
Kim, Hyun Jeong; Son, Young Ki; An, Won Suk
A quantitative analysis of the acidosis of cardiac arrest: a prospective observational study
Introduction Metabolic acidosis is common in patients with cardiac arrest and is conventionally considered to be essentially due to hyperlactatemia. However, hyperlactatemia alone fails to explain the cause of metabolic acidosis. Recently, the Stewart�Figge methodology has been found to be useful in explaining and quantifying acid�base changes in various clinical situations. This novel quantitative methodology might also provide useful insight into the factors responsible for the acidosis of cardiac arrest. We proposed that hyperlactatemia is not the sole cause of cardiac arrest acidosis and that other factors participate significantly in its development. Methods One hundred and five patients with out-of-hospital cardiac arrest and 28 patients with minor injuries (comparison group) who were admitted to the Emergency Department of a tertiary hospital in Tokyo were prospectively included in this study. Serum sodium, potassium, ionized calcium, magnesium, chloride, lactate, albumin, phosphate and blood gases were measured as soon as feasible upon arrival to the emergency department and were later analyzed using the Stewart�Figge methodology. Results Patients with cardiac arrest had a severe metabolic acidosis (standard base excess -19.1 versus -1.5; P < 0.0001) compared with the control patients. They were also hyperkalemic, hypochloremic, hyperlactatemic and hyperphosphatemic. Anion gap and strong ion gap were also higher in cardiac arrest patients. With the comparison group as a reference, lactate was found to be the strongest determinant of acidosis (-11.8 meq/l), followed by strong ion gap (-7.3 meq/l) and phosphate (-2.9 meq/l). This metabolic acidosis was attenuated by the alkalinizing effect of hypochloremia (+4.6 meq/l), hyperkalemia (+3.6 meq/l) and hypoalbuminemia (+3.5 meq/l). Conclusion The cause of metabolic acidosis in patients with out-of-hospital cardiac arrest is complex and is not due to hyperlactatemia alone. Furthermore, compensating changes occur spontaneously, attenuating its severity.
Makino, Jun; Uchino, Shigehiko; Morimatsu, Hiroshi; Bellomo, Rinaldo
Lactic acidosis and ketoacidosis: biochemical and clinical implications.
A case of lactic acidosis presented the opportunity for review of the association between lactic acidosis and ketoacidosis. The diagnosis of lactic acidosis or the combination of lactic acidosis and ketoacidosis is established clinically by the detection of a metabolic acidosis of the "unmeasured anion gap" type in the absence of significant renal failure, poison intake or a strongly positive clinical test for ketones. Before treatment can be planned the biochemical basis of lactic acidosis and ketoacidosis must be understood -- especially the fact that lactic acidosis is not a single disease entity but has many possible causes. Among important considerations is the relation between the blood concentrations of bicarbonate and organic acid anions. After recovery from metabolic acidosis of the unmeasured anion gap type, metabolic alkalosis is common. Decreased bicarbonate excretion plays an important role in the pathogenesis of the latter and may be the result of potassium or chloride loss, or both. The deficits, if present, should be corrected with appropriate therapy.
Halperin, M. L.
Protective Role of Acidic pH-Activated Chloride Channel in Severe Acidosis-Induced Contraction from the Aorta of Spontaneously Hypertensive Rats
Severe acidic pH-activated chloride channel (ICl,acid) has been found in various mammalian cells. In the present study, we investigate whether this channel participates in reactions of the thoracic aorta to severe acidosis and whether it plays a role in hypertension. We measured isometric contraction in thoracic aorta rings from spontaneously hypertensive rats (SHRs) and normotensive Wistar rats. Severe acidosis induced contractions of both endothelium-intact and -denuded thoracic aorta rings. In Wistar rats, contractions did not differ at pH 6.4, 5.4 and 4.4. However, in SHRs, contractions were higher at pH 5.4 or 4.4 than pH 6.4, with no difference between contractions at pH 5.4 and 4.4. Nifedipine, ICl,acid blockers 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and 4,4?-diisothiocyanatostilbene-2, 2?-disulfonic acid (DIDS) inhibited severe acidosis-induced contraction of aortas at different pH levels. When blocking ICl,acid, the remnant contraction was greater at pH 4.4 than pH 5.4 and 6.4 for both SHRs and Wistar rats. With nifedipine, the remnant contraction was greatly reduced at pH 4.4 as compared with at pH 6.4 and 5.4. With NPPB or DIDS, the ratio of remnant contractions at pH 4.4 and 5.4 (R4.4/5.4) was lower for SHRs than Wistar rats (all <1). However, with nifedipine, the R4.4/5.4 was higher for SHRs than Wistar rats (both >1). Furthermore, patch clamp recordings of ICl,acid and intracellular Ca2+ measurements in smooth muscle cells confirmed these findings. ICl,acid may protect arteries against excess vasoconstriction under extremely acidic extracellular conditions. This protective effect may be decreased in hypertension.
Ma, Zhiyong; Qi, Jia; Fu, Zhijie; Ling, Mingying; Li, Li; Zhang, Yun
Severe metabolic alkalosis and recurrent acute on chronic kidney injury in a patient with Crohn's disease
Background Diarrhea is common in patients with Crohn's disease and may be accompanied by acid base disorders, most commonly metabolic acidosis due to intestinal loss of bicarbonate. Case Presentation Here, we present a case of severe metabolic alkalosis in a young patient suffering from M. Crohn. The patient had undergone multiple resections of the intestine and suffered from chronic kidney disease. He was now referred to our clinic for recurrent acute kidney injury, the nature of which was pre-renal due to profound volume depletion. Renal failure was associated with marked hypochloremic metabolic alkalosis which only responded to high volume repletion and high dose blockade of gastric hypersecretion. Intestinal failure with stomal fluid losses of up to 5.7 litres per day required port implantation to commence parenteral nutrition. Fluid and electrolyte replacement rapidly improved renal function and acid base homeostasis. Conclusions This case highlights the important role of gastrointestinal function to maintain acid base status in patients with Crohn's disease.
Metabolic Management of Severe Acute Pancreatitis
.�� The metabolic management of severe acute pancreatitis involves early identification of patients with severe pancreatitis,\\u000a aggressive fluid resuscitation, organ support, and careful monitoring in an intensive care environment. Recent evidence has\\u000a helped to define the roles of enteral feeding, prophylactic antibiotics, endoscopic retrograde cholangiopancreatography, computed\\u000a tomography, and fine-needle aspiration for bacteriology. The most difficult decision in the management of
John A. Windsor; Hisham Hammodat
Lactic acidosis in diabetic ketoacidosis.
We describe the case of a 22-year-old man with insulin-dependent diabetes, who was admitted to the emergency department with hypotension, unconsciousness and a severe combined diabetic ketoacidosis (DKA) and lactic acid acidosis. In the discussion, we focus on the pathophysiological mechanisms underlying lactic acidosis in DKA, and we elaborate on the prognostic value of hyperlactataemia on such occasion. PMID:24654253
Feenstra, Rieneke A; Kiewiet, Mink K P; Boerma, E Christiaan; ter Avest, Ewoud
Parallel adaptation of the rabbit renal cortical sodium/proton antiporter and sodium/bicarbonate cotransporter in metabolic acidosis and alkalosis.
Recent studies have shown that the bicarbonate reabsorptive capacity of the proximal tubule is increased in metabolic acidosis. For net bicarbonate reabsorption to be regulated, there may be changes in the rate of apical H+ secretion as well as in the basolateral base exit step. The present studies examined the rate of Na+/H+ exchange (acridine orange method) and Na+/HCO3 cotransport (22Na uptake) in apical and basolateral membranes prepared from the rabbit renal cortex by sucrose density gradient centrifugation. NH4Cl loading was used to produce acidosis (arterial pH, 7.27 +/- 0.03), and Cl-deficient diet with furosemide was used to produce alkalosis (arterial pH, 7.51 +/- 0.02). Maximal transport rate (Vmax) of Na+/H+ antiporter and Na+/HCO3 cotransporter were inversely related with plasma bicarbonate concentration from 6 to 39 mM. Furthermore, the maximal transport rates of both systems varied in parallel; when Vmax for the Na+/HCO3 cotransporter was plotted against Vmax for the Na+/H+ antiporter for each of the 24 groups of rabbits, the regression coefficient (r) was 0.648 (P less than 0.001). There was no effect of acidosis or alkalosis on affinity for Na+ of either transporter. We conclude that both apical and basolateral H+/HCO3 transporters adapt during acid-base disturbances, and that the maximal transport rates of both systems vary in parallel during such acid-base perturbations.
Akiba, T; Rocco, V K; Warnock, D G
Fuel metabolism during severe rowing exercise
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.
Hoyt, R.W.; Lubowitz, J.; Asakura, T.; Stein, T.P.
A Homozygous Mutation in LYRM7/MZM1L Associated with Early Onset Encephalopathy, Lactic Acidosis, and Severe Reduction of Mitochondrial Complex III Activity
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 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.
Invernizzi, Federica; Tigano, Marco; Dallabona, Cristina; Donnini, Claudia; Ferrero, Ileana; Cremonte, Maurizio; Ghezzi, Daniele; Lamperti, Costanza; Zeviani, Massimo
Effects of nutritionally induced metabolic acidosis with or without glutamine infusion on acid-base balance, plasma amino acids, and plasma nonesterified fatty acids in sheep.
This study characterized the effects of nutritionally induced metabolic acidosis with or without Gln infusion on acid-base balance, plasma AA, and plasma NEFA in sheep. In a randomized complete block design with a 2 x 2 factorial arrangement of treatments, 24 fully fleeced sheep (Rideau-Arcott, 63.6 +/- 5.9 kg of BW) were fed a control supplement (CS; 300 g/d of canola meal) or an acidosis supplement (AS; 300 g/d of NutriChlor; HCl-treated canola meal), offered twice daily at 0700 and 1100 h. Sheep were infused at 1400 h daily with 0.3 g of L-glutamine per kg of BW or saline via jugular vein catheters for 7 d. The sheep were individually housed and limit-fed a basal diet of dehydrated alfalfa pellets (1.75 kg/d; 90% DM, 22% CP, and 1.2 Mcal of NE(g)/kg on a DM basis) offered twice daily at 1000 and 1300 h. Blood and urine was sampled daily between 1100 and 1130 h, and blood samples were analyzed for hematocrit, plasma pH, gases, strong ions, AA, and NEFA, whereas urine was analyzed for pH. The AS reduced (P < 0.01) DMI, urine and plasma pH, blood urea, partial pressure of CO(2), strong ion difference, and plasma HCO(3)(-), and increased (P < 0.01) plasma K(+), Ca(2+), and Cl(-). The AS with saline infusion increased (P
Odongo, N E; Greenwood, S L; Or-Rashid, M M; Radford, D; Alzahal, O; Shoveller, A K; Lindinger, M I; Matthews, J C; McBride, B W
Cerebral Acidosis Following Increased Intracranial Pressure.
National Technical Information Service (NTIS)
In 18 experiments on dogs, elevation of intracranial pressure resulted in an immediate and progressive fall in cerebral surface pH which preceded the arterial pressor response. In each experiment, cerebral acidosis preceded and was more severe than decrea...
J. R. Berman L. A. Rogers
Potassium restriction, high protein intake, and metabolic acidosis increase expression of the glutamine transporter SNAT3 (Slc38a3) in mouse kidney.
Kidneys produce ammonium to buffer and excrete acids through metabolism of glutamine. Expression of the glutamine transporter Slc38a3 (SNAT3) increases in kidney during metabolic acidosis (MA), suggesting a role during ammoniagenesis. Potassium depletion and high dietary protein intake are known to elevate renal ammonium excretion. In this study, we examined SNAT3, phosphate-dependent glutaminase (PDG), and phosphoenolpyruvate carboxykinase (PEPCK) regulation during a control (0.36%) or low-K(+) (0.02%) diet for 7 or 14 days or a control (20%) or high-protein (50%) diet for 7 days. MA was induced in control and low-K(+) groups by addition of NH(4)Cl. Urinary ammonium excretion increased during MA, after 14-day K(+) restriction alone, and during high protein intake. SNAT3, PDG, and PEPCK mRNA abundance were elevated during MA and after 14-day K(+) restriction but not during high protein intake. SNAT3 protein abundance was enhanced during MA (both control and low K(+)), after 14-day low-K(+) treatment alone, and during high protein intake. Seven-day dietary K(+) depletion alone had no effect. Immunohistochemistry showed SNAT3 staining in earlier parts of the proximal tubule during 14-day K(+) restriction with and without NH(4)Cl treatment and during high protein intake. In summary, SNAT3, PDG, and PEPCK mRNA expression were congruent with urinary ammonium excretion during MA. Chronic dietary K(+) restriction, high protein intake, and MA enhance ammoniagenesis, an effect that may involve enhanced SNAT3 mRNA and protein expression. Our data suggest that SNAT3 plays an important role as the glutamine uptake mechanism in ammoniagenesis under these conditions. PMID:19458124
Busque, Stephanie M; Wagner, Carsten A
Amish lethal microcephaly: a new metabolic disorder with severe congenital microcephaly and 2-ketoglutaric aciduria.
A new metabolic disorder characterized by severe congenital microcephaly, death within the first year, and severe 2-ketoglutaric aciduria has been found among the Old-Order Amish of Lancaster County, Pennsylvania. Amish lethal microcephaly segregates as an autosomal recessive disorder and has an unusually high incidence of at least 1 in 500 births. When the infants are well, the urine organic acid profiles show isolated, extreme elevations of 2-ketoglutaric acid. However, during otherwise simple viral illnesses, the infants often develop a metabolic acidosis, which may follow a lethal course. Cranial magnetic resonance imaging of a single patient showed a smooth, immature brain similar to that of a 20-week fetus except for a moderate degree of cerebellar vermal hypoplasia. Assay of 2-ketoglutarate dehydrogenase in cultured lymphoblasts of one patient showed normal activity. Amish lethal microcephaly maps to 17q25 and may be caused by a defect in a mitochondrial inner membrane protein functioning as a 2-ketoglutarate transporter. PMID:12376931
Kelley, Richard I; Robinson, Donna; Puffenberger, Erik G; Strauss, Kevin A; Morton, D Holmes
Sj?gren syndrome presenting with hypopotassemic periodic paralysis due to renal tubular acidosis
Summary Background: Sj�gren syndrome (SS) is an autoimmune-lymphoproliferative disorder characterized by mononuclear cell infiltration of exocrine glands. Clinically, Sj�gren syndrome (SS) has a wide spectrum, varying from autoimmune exocrinopathy to systemic involvement. There have been few cases reporting that primary SS developed with distal renal tubular acidosis clinically. Case Report: Here, we present a case with primary Sj�gren syndrome accompanied by hypopotassemic paralysis due to renal tubular acidosis. Severe hypopotassemia, hyperchloremic metabolic acidosis, alkaline urine and disorder in urinary acidification test were observed in the biochemical examination of the 16-year-old female patient, who had applied to our clinic for extreme loss of muscle force. After the examinations it was determined that the patient had developed Type 1 RTA (distal RTA) due to primary Sj�gren syndrome. Potassium and alkaline replacement was made and an immediate total recovery was achieved. Conclusions: Hypopotassemic paralysis due to primary Sj�gren syndrome is a rare but severe disorder that could lead to death if not detected early and cured appropriately. Thus, effective treatment should be immediately initiated in cases where severe hypopotassemia is accompanied by metabolic acidosis, and the cases should also be examined for extraglandular involvement of SS.
Ataoglu, Esra Hayriye; Demir, Betul; Tuna, Mazhar; Cavus, Bilger; Cetin, Faik; Temiz, Levent Umit; Ozturk, Savas; Yenigun, Mustafa
[Metformin-associated lactic acidosis: incidence, diagnosis, prognostic factors and treatment].
We describe the case of a patient with severe lactic acidosis, as well as presenting some data on its incidence, diagnosis, prognostic factors, and the most appropriate treatment. A 76 year-old male patient with diabetes on treatment with metformin, hypertension, dyslipaemia, and with mild cognitive impairment, was admitted to the Intensive Care Unit in a state of circulatory shock, requiring aggressive treatment with vasopressors and volume. The patient had acute kidney injury with an anuria of 3 days, probably secondary to dehydration to vomiting and to NSAIDs. As a result of the acute renal damage, the patient suffered a severe metformin-associated lactic acidosis. The rest of the causes of metabolic acidosis with an increased anion gap were ruled out, as well as a possible sepsis or rhabdomyolysis. Metformin-associated lactic acidosis is an uncommon metabolic condition, but with a high mortality. To reduce the mortality of these patients, it is important to make an early diagnosis using the clinical records, physical examination, and laboratory tests, with an early resuscitation with volume, vasopressors, bicarbonate, and renal replacement therapy. PMID:22609263
Vives, M; Romano, J; Stoll, E; Lafuente, A; Nagore, D; Monedero, P
... receives medical treatment, which would likely have included sodium bicarbonate and sodium citrate, alkaline agents to neutralize acidic ... goals of therapy. If acidosis is corrected with sodium bicarbonate or sodium citrate, then low blood-potassium, salt ...
Liver Pathology and the Metabolic Syndrome X in Severe Obesity
The metabolic syndrome X, characterized by insulin resistance, dyslipidemia, hypertension, and a male, visceral distribution of ad- ipose tissue, is associated with increased morbidity and mortality from several prevalent diseases, such as diabetes, cancers, myocardial infarction, and stroke. Because the liver has a central role in carbo- hydrate, lipid, and steroid metabolism, we investigated the relation- ships between liver pathology
P. Marceau; S. BIRON; F.-S. HOULD; S. MARCEAU; S. SIMARD; S. N. THUNG
Refractory rickets caused by mild distal renal tubular acidosis
Type I (distal) renal tubular acidosis (RTA) is a disorder associated with the failure to excrete hydrogen ions from the distal renal tubule. It is characterized by hyperchloremic metabolic acidosis, an abnormal increase in urine pH, reduced urinary excretion of ammonium and bicarbonate ions, and mild deterioration in renal function. Hypercalciuria is common in distal RTA because of bone resorption, which increases as a buffer against metabolic acidosis. This can result in intractable rickets. We describe a case of distal RTA with nephrocalcinosis during follow-up of rickets in a patient who presented with clinical manifestations of short stature, failure to thrive, recurrent vomiting, dehydration, and irritability.
Lee, Ji-Ho; Park, Joo Hyun; Ha, Tae-Sun
Distal renal tubular acidosis and amelogenesis imperfecta: A rare association.
Renal tubular acidosis (RTA) is characterized by a normal anion gap with hyperchloremic metabolic acidosis. Primary distal RTA (type I) is the most common RTA in children. Childhood presentation of distal RTA includes vomiting, failure to thrive, metabolic acidosis, and hypokalemia. Amelogenesis imperfecta (AI) represents a condition where the dental enamel and oral tissues are affected in an equal manner resulting in the hypoplastic or hypopigmented teeth. We report a 10-year-old girl, previously asymptomatic presented with the hypokalemic paralysis and on work-up found out to have type I RTA. The discoloration of teeth and enamel was diagnosed as AI. PMID:24339526
Ravi, P; Ekambaranath, T S; Arasi, S Ellil; Fernando, E
Distal renal tubular acidosis and amelogenesis imperfecta: A rare association
Renal tubular acidosis (RTA) is characterized by a normal anion gap with hyperchloremic metabolic acidosis. Primary distal RTA (type I) is the most common RTA in children. Childhood presentation of distal RTA includes vomiting, failure to thrive, metabolic acidosis, and hypokalemia. Amelogenesis imperfecta (AI) represents a condition where the dental enamel and oral tissues are affected in an equal manner resulting in the hypoplastic or hypopigmented teeth. We report a 10-year-old girl, previously asymptomatic presented with the hypokalemic paralysis and on work-up found out to have type I RTA. The discoloration of teeth and enamel was diagnosed as AI.
Ravi, P.; Ekambaranath, T. S.; Arasi, S. Ellil; Fernando, E.
Severe metabolic abnormalities after allogeneic hematopoietic cell transplantation
Severe metabolic abnormalities occurring within 100 days after allogeneic hematopoietic cell transplantation (HCT) were investigated in 311 patients. The metabolic abnormalities included hyper- and hypocalcemia, hypophosphatemia, hyper- and hypokalemia, hyper- and hyponatremia, hyper- and hypomagnesemia, hypercholesterolemia, hyper- and hypoglycemia, and hyperuricemia. Severe abnormalities, defined as grades III�V by NCI CTCAE v3.0, occurred in 269 patients (86.5%). Multivariate analysis revealed that
J-H Lee; S-J Choi; S-E Kim; M Seol; Y-S Lee; W-K Kim; K-H Lee
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)
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
A Review of metabolic staging in severely injured patients
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.
Positive Correlation between Severity of Blepharospasm and Thalamic Glucose Metabolism
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.
Murai, Hideki; Suzuki, Yukihisa; Kiyosawa, Motohiro; Wakakura, Masato; Mochizuki, Manabu; Ishiwata, Kiichi; Ishii, Kenji
Positive Correlation between Severity of Blepharospasm and Thalamic Glucose Metabolism.
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
Murai, Hideki; Suzuki, Yukihisa; Kiyosawa, Motohiro; Wakakura, Masato; Mochizuki, Manabu; Ishiwata, Kiichi; Ishii, Kenji
Metformin-Associated Lactic Acidosis following Intentional Overdose Successfully Treated with Tris-Hydroxymethyl Aminomethane and Renal Replacement Therapy
A 43-year-old woman was brought to the hospital with severe metabolic acidosis (pH 6.56, bicarbonate 3?mmol/L, and lactate 18.4?mmol/L) and a serum creatinine of 162??mol/L with a serum potassium of 7.8?mmol/L. A delayed diagnosis of metformin-associated lactic acidosis was made, and she was treated with tris-hydroxymethyl aminomethane (THAM) and renal replacement therapy (RRT). Following a complete recovery, she admitted to ingesting 180 tablets (90 grams) of metformin. Her peak serum metformin concentration was 170??g/mL (therapeutic range 1-2??g/mL). Our case demonstrates an intentional metformin overdose resulting in lactic acidosis in a nondiabetic patient who was successfully treated with THAM and RRT.
Lam, Ngan; Sekhon, Gurbir; House, Andrew A.
Cerebral hemodynamic change and metabolic alteration in severe hemorrhagic shock.
Understanding the biological mechanism and identifying biomarkers of hemorrhagic shock is important for diagnosis and treatment. We aim to use optical imaging to study how the cerebral blood circulation and metabolism change during the progression of severe hemorrhagic shock, especially the decompensatory stage. We used a multi-parameter (blood pressure (BP), cerebral blood flow (CBF), functional vascular density (FVD), blood oxygenation and mitochondrial NADH signal) cerebral cortex optical imaging system to observe brain hemodynamic change and metabolic alteration of rats in vivo for 4 h. Cerebral circulation and mitochondrial metabolism could be well preserved in the compensatory stage but impaired during the decompensatory stage. The changes of brain hemodynamics and metabolism may provide sensitive indicators for various shock stages including the transition from compensatory stage to decompensatory stage. Our novel imaging observations of hemodynamic and metabolic signals in vivo indicated that the rat brains under hemorrhagic shock suffered irreversible damage which could not be compensated by the autoregulation mechanism, probably due to injured mitochondria. PMID:24729236
Sun, Nannan; Li, Lin Z; Luo, Weihua; Luo, Qingming
Hemodynamic and Metabolic Correlates of Perinatal White Matter Injury Severity
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.
Riddle, Art; Maire, Jennifer; Cai, Victor; Nguyen, Thuan; Gong, Xi; Hansen, Kelly; Grafe, Marjorie R.; Hohimer, A. Roger; Back, Stephen A.
Examining the relationship between diet-induced acidosis and cancer
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.
Hyperkalemia in neonatal diarrheic calves depends on the degree of dehydration and the cause of the metabolic acidosis but does not require the presence of acidemia.
Hyperkalemia is a clinically important electrolyte imbalance in neonatal diarrheic calves that has previously been associated with skeletal muscle weakness and life-threatening cardiac arrhythmias. The aim of the present retrospective analysis was to identify risk factors for hyperkalemia in a convenience sample of 832 calves (? 21 d of age) with a clinical diagnosis of diarrhea admitted to a veterinary teaching hospital. Plasma potassium concentrations were most closely associated with parameters of dehydration and renal function such as serum creatinine [Spearman correlation (rs) = 0.61], urea (rs = 0.51), and inorganic phosphorus concentrations (rs = 0.64). Plasma potassium concentrations were weakly associated with venous blood pH (rs = -0.21). Although venous blood pH was not predictive in a multivariate linear regression analysis, the odds of having hyperkalemia (>5.8 mmol/L) in acidemic calves was found to be 8.6 times as high as in nonacidemic calves [95% confidence interval (CI): 4.8-15.4]. However, the presence of hyperkalemia depended on the nature of an existing acidosis, and the odds for the presence of hyperkalemia in acidemic calves with hyper-D-lactatemia (>3.96 mmol/L) were only 0.15 times as high as in acidemic calves with normal D-lactate concentrations (95% CI, 0.11-0.22). Acidemia in hyperkalemic diarrheic calves was associated with hyponatremia and increased concentrations of inorganic phosphorus, L-lactate, and unidentified strong anions that presumably included uremic anions such as sulfate. We conclude that hyper-D-lactatemia in neonatal diarrheic calves is not usually associated with elevated plasma potassium concentrations. Application of the simplified strong ion acid-base model indicated that dehydration is an important contributor to the pathogenesis of hyperkalemia and acidemia in neonatal calves with diarrhea. PMID:24011947
Trefz, F M; Constable, P D; Sauter-Louis, C; Lorch, A; Knubben-Schweizer, G; Lorenz, I
Acidosis and weight loss are induced by cyclosporin A in uninephrectomized rats.
The effects of cyclosporin A (CyA, 50 mg/kg body weight) or its commercial vehicle (cremophor) on the acid-base regulation of uninephrectomized rats were assessed for 7 days and in non-nephrectomized rats for 15 days. CyA induced a marked systemic acidosis, accompanied by decreases in blood PCO(2) and plasma bicarbonate. Untreated uninephrectomized rats did not show the acidosis. In CyA-treated rats the urine pH decreased (control 6. 65+/-0.06 vs. CyA 6.18+/-0.08; P<0.01) as well as urinary bicarbonate (non-nephrectomized rats 7.50+/-1.88 mM vs. uninephrectomy plus CyA 0.75+/- 0.06 mM; P<0.01), suggesting partial renal compensation of systemic acidosis. Titratable acidity increased in CyA-treated rats (control 21.6+/-1.2 vs. CyA 63.3+/-12.0 microEq/l; P<0.001). Phosphate, glucose, and osmolar clearances were not significantly altered in non-nephrectomized rats treated with CyA for 15 days. There was a striking decrease in body weight in CyA-treated rats (control 274.0+/-3.8 vs. CyA 225.0+/-5.1 g; P<0. 01), but compensatory growth of the remaining kidney was not prevented by this drug or by its vehicle. In summary, CyA induced a severe metabolic acidosis in uninephrectomized rats that was not compensated by the remaining kidney, in spite of the well-preserved compensatory weight gain of this organ. Loss of body weight was significant in CyA-treated animals. PMID:10684361
Jaramillo-Ju�rez, F; Rodr�guez-V�zquez, M L; Namorado, M C; Mart�n, D; Reyes, J L
[Metformin-associated lactic acidosis in a patient with pre-existing risk factors].
Lactic acidosis is a serious clinical situation associated with a high case fatality rate. Lactic acidosis is particularly found in conditions with an insufficient supply of oxigen in the tissue. Other causes for lactic acidosis can be hepatic or renal insufficiency. For the therapy of overweight patients with type 2 diabetes metformin is the first choice if diet and physical training have been ineffective. Metformin, however, has the potential to increase serumlactate. Therefore its ability to cause lactic acidosis is controversely discussed. We present a 64-year-old female patient with metformin-associated lactic acidosis. She had several pre-existing risk factors to develop a lactic acidosis. On her referral to the hospital she suffered from acute renal failure which is considered to be a contraindication for the use of metformin. PMID:16190374
Becker, C; Luginb�hl, A; Pittl, U; Schlienger, R
Water, acidosis, and experimental pyelonephritis
The effect of water restriction and ammonium chloride acidosis on the course of Escherichia coli pyelonephritis was determined in the nonobstructed kidney of the rat. To alter the chemical composition of the renal medulla, water intake was reduced in rats to one-half the normal daily intake. Water restriction increased the incidence of coliform pyelonephritis. Systemic acidosis, produced by giving a 300 mM solution of ammonium chloride, increased urinary osmolality to values comparable to water restriction and also predisposed to pyelonephritis. However, when rats were fed the same solution of ammonium chloride but were allowed access to tap water ad lib., urinary osmolality values were comparable to those observed in normal animals, and susceptibility to pyelonephritis was reduced or eliminated despite a degree of systemic acidosis similar to that observed in rats fed ammonium chloride solution without access to tap water. These results suggest that water diuresis may overcome the inactivation of complement produced by ammonium chloride acidosis and that renal medullary hypertonicity, produced by either water restriction or ammonium chloride acidosis, is a major determinant of this tissue's unique susceptibility to infection.
Andriole, Vincent T.
Glucose metabolism in adult survivors of severe acute malnutrition.
Context and Objectives: The clinical syndromes of severe acute malnutrition may have early life origins because children with marasmus have lower birth weight than those with kwashiorkor. We hypothesized that resultant metabolic effects may persist into adulthood. We investigated whether marasmus survivors (MS) are more insulin resistant and glucose intolerant than kwashiorkor survivors (KS). Research Design and Setting: This was a case-control study in Jamaican adults. Subjects: We performed oral glucose tolerance tests on 191 adults (aged 17-50 y; 52% male; body mass index 24.2 � 5.5 kg/m(2)). There were 43 MS; 38 KS; 70 age-, sex-, and body mass index-matched community controls; and 40 age- and birth weight-matched controls. Measurements: We measured insulin sensitivity with the whole-body insulin sensitivity index, and ?-cell function with the insulinogenic index and the oral disposition index. Results: Fasting glucose was comparable across groups, but glucose intolerance was significantly more common in MS (19%) than in KS (3%), community controls (11%), and birth weight-matched controls (10%). The whole-body insulin sensitivity index was lower in MS than KS (P = .06) but similar between MS and controls. The insulinogenic index and oral disposition index were lower in MS compared with all three groups (P < .01). Conclusions: Marasmus survivors tend to be less insulin sensitive, but have significantly lower insulin secretion and are more glucose intolerant compared with kwashiorkor survivors and controls. This suggests that poor nutrition in early life causes ?-cell dysfunction, which may predispose to the development of diabetes. PMID:24517147
Francis-Emmanuel, Patrice M; Thompson, Debbie S; Barnett, Alan T; Osmond, Clive; Byrne, Christopher D; Hanson, Mark A; Gluckman, Peter D; Forrester, Terrence E; Boyne, Michael S
Hypokalaemia and Renal Tubular Acidosis due to Abuse of Nurofen Plus
Nurofen Plus is a common analgesic containing ibuprofen and codeine. We present a case of a 38-year-old lady who developed renal tubular acidosis with severe hypokalaemia, after chronic abuse of Nurofen Plus tablets. She presented with confusion and profound biochemical abnormalities requiring critical care admission for electrolyte replacement. Ibuprofen causes renal tubular acidosis due to its effects on carbonic anhydrase activity.
Blackstock, M. J.; Lee, A.
Metformin overdose, but not lactic acidosis per se, inhibits oxygen consumption in pigs
Introduction Hepatic mitochondrial dysfunction may play a critical role in the pathogenesis of metformin-induced lactic acidosis. However, patients with severe metformin intoxication may have a 30 to 60% decrease in their global oxygen consumption, as for generalized inhibition of mitochondrial respiration. We developed a pig model of severe metformin intoxication to validate this clinical finding and assess mitochondrial function in liver and other tissues. Methods Twenty healthy pigs were sedated and mechanically ventilated. Ten were infused with a large dose of metformin (4 to 8 g) and five were not (sham controls). Five others were infused with lactic acid to clarify whether lactic acidosis per se diminishes global oxygen use. Arterial pH, lactatemia, global oxygen consumption (VO2) (metabolic module) and delivery (DO2) (cardiac output by thermodilution) were monitored for nine hours. Oxygen extraction was computed as VO2/DO2. Activities of the main components of the mitochondrial respiratory chain (complex I, II and III, and IV) were measured with spectrophotometry (and expressed relative to citrate synthase activity) in heart, kidney, liver, skeletal muscle and platelets taken at the end of the study. Results Pigs infused with metformin (6 � 2 g; final serum drug level 77 � 45 mg/L) progressively developed lactic acidosis (final arterial pH 6.93 � 0.24 and lactate 18 � 7 mmol/L, P < 0.001 for both). Their VO2 declined over time (from 115 � 34 to 71 � 30 ml/min, P < 0.001) despite grossly preserved DO2 (from 269 � 68 to 239 � 51 ml/min, P = 0.58). Oxygen extraction accordingly fell from 43 � 10 to 30 � 10% (P = 0.008). None of these changes occurred in either sham controls or pigs infused with lactic acid (final arterial pH 6.86 � 0.16 and lactate 22 � 3 mmol/L). Metformin intoxication was associated with inhibition of complex I in the liver (P < 0.001), heart (P < 0.001), kidney (P = 0.003), skeletal muscle (P = 0.012) and platelets (P = 0.053). The activity of complex II and III diminished in the liver (P < 0.001), heart (P < 0.001) and kidney (P < 0.005) while that of complex IV declined in the heart (P < 0.001). Conclusions Metformin intoxication induces lactic acidosis, inhibits global oxygen consumption and causes mitochondrial dysfunction in liver and other tissues. Lactic acidosis per se does not decrease whole-body respiration.
A patient with foot ulcer and severe metabolic alkalosis.
We report a case of triple acid-base disorder with metabolic alkalosis as the primary disorder in a 65-year-old man due to ingestion and application to leg ulcers of baking soda (calcium bicarbonate). The blood pH was 7.65 with hypochloremia, hypokalemia, and prerenal azotemia. He was treated with isotonic saline with K replacement, and the patient improved without any adverse clinical consequences. We discuss the causes, mechanisms, and management of Cl-responsive (depletion) metabolic alkalosis. PMID:21185672
John, Ruby Samuel; Simoes, Sonia; Reddi, Alluru S
Phenformin and lactic acidosis: a case report and review 1 1 Pharmacology in Emergency Medicine is coordinated by Richard Clark, md, of the University of California, San Diego Medical Center, and the San Diego Regional Poison Center, San Diego, California
Phenformin was removed from the U.S. market 20 years ago because of a high incidence of lactic acidosis. Unfortunately, this medication is still available from foreign sources. Another biguanide, metformin, was reintroduced to the United States market for the treatment of diabetes. Biguanide-induced lactic acidosis should be included in the differential diagnosis of elevated anion gap metabolic acidosis. We present
Shun C. Kwong; Jeffrey Brubacher
Positive Correlation between Severity of Blepharospasm and Thalamic Glucose Metabolism
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.
Hideki Murai; Yukihisa Suzuki; Motohiro Kiyosawa; Masato Wakakura; Manabu Mochizuki; Kiichi Ishiwata; Kenji Ishii
Comparisons of normal saline and lactated Ringer's resuscitation on hemodynamics, metabolic responses, and coagulation in pigs after severe hemorrhagic shock
Background Ongoing improvements in trauma care now recommend earlier use of blood products as part of damage control resuscitation, but generally these products are not available at far forward battlefield locations. For the military, questions continue to arise regarding efficacy of normal saline (NS) vs. lactated Ringer�s (LR). Thus, this study compared the effects of LR and NS after severe hemorrhage in pigs. Methods 20 anesthetized pigs were randomized into control (n?=?6), LR (n?=?7), and NS (n?=?7) groups. Hemorrhage of 60% estimated total blood volume was induced in LR and NS groups by removing blood from the left femoral artery using a computer-controlled pump. Afterwards, the pigs were resuscitated with either LR at 3 times the bled volume or the volume of NS to reach the same mean arterial pressure (MAP) as in LR group. Hemodynamics were measured hourly and blood samples were taken at baseline (BL), 15�min, 3�h and 6�h after resuscitation to measure changes in coagulation using thrombelastograph�. Results MAP was decreased by hemorrhage but returned to BL within 1�h after resuscitation with LR (119?�?7�ml/kg) or NS (183?�?9�ml/kg, p?0.05). Base excess (BE) was decreased by hemorrhage; resuscitation with LR recovered BE but not with NS. Total peripheral resistance was decreased with NS and LR, with a larger drop shown in NS. Serum potassium was increased with NS, but not affected with LR. Coagulation changes were similar between LR and NS. Conclusions NS may be inferior to LR in resuscitation due to its vasodilator effects and the risks of metabolic acidosis and hyperkalemia.
[The role of lactate besides the lactic acidosis].
Lactic acidosis (LA) is the most common form of metabolic acidosis defined by values of lactate greater than 5 mmol / l and by a pH <7.34. The pathogenesis of LA involves hypoxic (type A) and non hypoxic (type B) causes which are often coexisting. Lactic acidosis is usual in hospitalized population especially in subjects in intensive care units, in which lactate levels on admission could be predictors of mortality even in the absence of organ dysfunction or shock. The outcome is mainly dependent on the cardiovascular effects of acidosis. In subjects with cardiogenic shock, the increased lactate/pyruvate ratio, detectable at onset, is correladed with mortality. An early assessment of blood and tissue lactate levels could play a role in the therapeutic management as well as in outcome. LA could be a unfavorable prognostic factor in cancer. The lactate would act also as "signal molecule" and as a promoting factor in angiogenesis and tumor progression. In the presence of risk factors for LA the role of metformin may be overrated. Despite the doctrinal progress to understand the pathogenesis and pathophysiology, there is not univocal consensus on the therapeutic treatment of LA. The identification and the attempt to remove the cause of acidosis are main aims; treatment with sodium bicarbonate is a matter of debate as the data on the cardiovascular effects and mortality are unclear. The therapy with carbicarb, dichloroacetate or THAM has shown no specific advantages in terms of mortality. In experimental models of LA and shock the use of sodium-hydrogen exchanger-1 (NHE1) selective inhibitors reduces cell damage and inflammatory cytokines synthesis; it also improves cardiac performance and decreases mortality. PMID:23868642
Brucculeri, S; Urso, C; Caimi, G
Low-flow CO2 removal integrated into a renal-replacement circuit can reduce acidosis and decrease vasopressor requirements
Introduction Lung-protective ventilation in patients with ARDS and multiorgan failure, including renal failure, is often paralleled with a combined respiratory and metabolic acidosis. We assessed the effectiveness of a hollow-fiber gas exchanger integrated into a conventional renal-replacement circuit on CO2 removal, acidosis, and hemodynamics. Methods In ten ventilated critically ill patients with ARDS and AKI undergoing renal- and respiratory-replacement therapy, effects of low-flow CO2 removal on respiratory acidosis compensation were tested by using a hollow-fiber gas exchanger added to the renal-replacement circuit. This was an observational study on safety, CO2-removal capacity, effects on pH, ventilator settings, and hemodynamics. Results CO2 elimination in the low-flow circuit was safe and was well tolerated by all patients. After 4 hours of treatment, a mean reduction of 17.3 mm Hg (?28.1%) pCO2 was observed, in line with an increase in pH. In hemodynamically instable patients, low-flow CO2 elimination was paralleled by hemodynamic improvement, with an average reduction of vasopressors of 65% in five of six catecholamine-dependent patients during the first 24 hours. Conclusions Because no further catheters are needed, besides those for renal replacement, the implementation of a hollow-fiber gas exchanger in a renal circuit could be an attractive therapeutic tool with only a little additional trauma for patients with mild to moderate ARDS undergoing invasive ventilation with concomitant respiratory acidosis, as long as no severe oxygenation defects indicate ECMO therapy.
Renal tubular acidosis and nerve deafness.
Two brothers are described with renal tubular acidosis and nerve deafness: the elder also had rickets and hypokalaemia. The parents were unaffected. Studies of urinary acidification and bicarbonate excretion were consistent with a distal tubular abnormality. This report strengthens the view previously proposed in similar cases that nerve deafness and renal tubular acidosis constitute a genetic entity. Examination for nerve deafness is indicated in any child with renal tubular acidosis. Images Fig. 2
Dunger, D B; Brenton, D P; Cain, A R
Citric acid as the last therapeutic approach in an acute life-threatening metabolic decompensation of propionic acidaemia.
The tricarboxylic acid (TCA) cycle represents the key enzymatic steps in cellular energy metabolism. Once the TCA cycle is impaired in case of inherited metabolic disorders, life-threatening episodes of metabolic decompensation and severe organ failure can arise. We present the case of a 6 �-year-old girl with propionic acidaemia during an episode of acute life-threatening metabolic decompensation and severe lactic acidosis. Citric acid given as an oral formulation showed the potential to sustain the TCA cycle flux. This therapeutic approach may become a treatment option in a situation of acute metabolic crisis, possibly preventing severe disturbance of energy metabolism. PMID:23412866
Siekmeyer, Manuela; Petzold-Quinque, Stefanie; Terpe, Friederike; Beblo, Skadi; Gebhardt, Rolf; Schlensog-Schuster, Franziska; Kiess, Wieland; Siekmeyer, Werner
The effect of treatment of acidosis on calcium balance in patients with chronic azotemic renal disease.
Small but statistically significant negative calcium balances were found in each of eight studies in seven patients with chronic azotemic renal disease when stable metabolic acidosis was present. Only small quantities of calcium were excreted in the urine, but fecal calcium excretion equaled or exceeded dietary intake. Complete and continuous correction of acidosis by NaHCO(3) therapy reduced both urinary and fecal calcium excretion and produced a daily calcium balance indistinguishable from zero. Apparent acid retention was found throughout the studies during acidosis, despite no further reduction of the serum bicarbonate concentration. The negative calcium balances that accompanied acid retention support the suggestion that slow titration of alkaline bone salts provides an additional buffer reservoir in chronic metabolic acidosis. The treatment of metabolic acidosis prevented further calcium losses but did not induce net calcium retention. It is suggested that the normal homeostatic responses of the body to the alterations in ionized calcium and calcium distribution produced by raising the serum bicarbonate might paradoxically retard the repair of skeletal calcium deficits. PMID:6018764
Litzow, J R; Lemann, J; Lennon, E J
Distal renal tubular acidosis associated with concurrent leptospirosis in a dog.
A 9 yr old spayed female boxer was presented for evaluation of vomiting, lethargy, anorexia, and weight loss. Initial laboratory evaluation revealed a hyperchloremic normal anion gap metabolic acidosis with alkaline urine that was consistent with a diagnosis of distal renal tubular acidosis (RTA). Targeted therapy was initiated with Na bicarbonate (HCO3) and potassium (K) gluconate. Leptospirosis was subsequently diagnosed with paired microagglutination testing (MAT), and doxycycline was added to the other treatments. Clinical signs resolved, and 6 mo after diagnosis, although the dog remained on alkali therapy (i.e., NaHCO3 and K gluconate) and a mild metabolic acidosis persisted, the dog remained otherwise healthy with a good quality of life. To the authors' knowledge, this is the first report to describe the concomitant association of those two disorders. Leptospirosis should be considered for any case of RTA in dogs. PMID:24659721
Martinez, Stephen A; Hostutler, Roger A
Long-term follow-up in distal renal tubular acidosis with sensorineural deafness.
A 20-year-old man presented with failure to thrive and bilateral genu valgum. On the basis of growth failure, skeletal deformity, hyperchloremic metabolic acidosis with alkaline urine and hypokalemia, nephrocalcinosis, and hearing loss, a diagnosis of distal renal tubular acidosis (DRTA) with sensorineural deafness was made. The genu valgum was treated by corrective osteotomy. Skeletal deformity was corrected and impaired growth improved after sustained therapy of metabolic acidosis with alkali supplementation. During an 8-year follow-up period the patient's glomerular filtration rate remained stable, the nephrocalcinosis did not progress, and his height increased 10 cm. Although nephrolithiasis led to atrophy of the right kidney, at last follow-up, when the patient was 44 years old, his creatinine clearance was 50 ml/min per 1.73 m2 body surface. PMID:11095014
Peces, R
Metformin-induced lactic acidosis in the presence of acute renal failure
Summary��Lactic acidosis occourred in 6 metformin-treated diabetic patients. Five of them had received 1.6 to 2.4 g metformin per day over a period of weeks or years. Acute renal failure, induced by i. v. pyelography, arteriography, or severe dehydration, preceded lactic acidosis by a few days and apparently precipitated it. The sixth patient had normal renal function prior to taking
R. Assan; Ch. Heuclin; D. Ganeval; Ch. Bismuth; J. George; J. R. Girard
Waist circumference and related anthropometric indices are associated with metabolic traits in severely obese subjects.
Increased waist circumference (WC) and related anthropometric indices have been shown to be, independently of body weight and body mass index (BMI), associated with adverse metabolic traits in many populations. It is unknown, however, whether WC also predicts adverse metabolic traits in severely obese subjects displaying a BMI greater than 35�kg/m(2). To address this question, we analyzed a dataset including 838 severely obese patients (597 women, BMI 44.6?�?6.2�kg/m(2); 241 men, BMI 44.3?�?5.7�kg/m(2)). Body weight, height, WC, hip circumference, and blood pressure were measured in all subjects along with the following metabolic blood markers: fasting glucose, insulin, glycolized hemoglobin levels, triglycerides, total cholesterol, low- and high-density cholesterol, and uric acid. Multivariate regression analyses indicated that WC as well as related anthropometric indices, in particular those accounting for subjects' height, were associated with many metabolic variables independently of body weight and BMI. In general, height-adjusted WC indices were more closely associated with metabolic traits in women than in men. Collectively, our findings suggest that body fat distribution also plays an important role in determining metabolic traits in severely obese subjects and that WC represents a valuable marker of abdominal/visceral obesity in this population. PMID:24338435
Zazai, Runa; Wilms, Britta; Ernst, Barbara; Thurnheer, Martin; Schultes, Bernd
Acidosis and correction of acidosis does not affect rFVIIa function in swine
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 ?g/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.
Darlington, Daniel N; Kheirabadi, Bijan S; Scherer, Michael R; Martini, Wenjun Z; Cap, Andrew P; Dubick, Michael A
Mutations in the gene encoding B1 subunit of H+ATPase cause renal tubular acidosis with sensorineural deafness
H+-ATPases are ubiquitous in nature; V-ATPases pump protons against an electrochemical gradient, whereas F-ATPases reverse the process, synthesizing ATP. We demonstrate here that mutations in ATP6B1, encoding the B-subunit of the apical proton pump mediating distal nephron acid secretion, cause distal renal tubular acidosis, a condition characterized by impaired renal acid secretion resulting in metabolic acidosis. Patients with ATP6B1 mutations
Fiona E. Karet; Karin E. Finberg; Raoul D. Nelson; Ahmet Nayir; Hilal Mocan; Sami A. Sanjad; Juan Rodriguez-Soriano; Fernando Santos; Cor W. R. J. Cremers; Antonio Di Pietro; Barry I. Hoffbrand; Jacek Winiarski; Aysin Bakkaloglu; Seza Ozen; Ruhan Dusunsel; Paul Goodyer; Sally A. Hulton; Doris K. Wu; Anne B. Skvorak; Cynthia C. Morton; Michael J. Cunningham; Vivekanand Jha; Richard P. Lifton
Renal tubular acidosis secondary to FK506 in living donor liver transplantation: a case report.
FK506 is an immunosuppressant that is thought to be less nephrotoxic than cyclosporine A. However, complications due to renal tubular acidosis (RTA) have recently been reported. We report a case of RTA secondary to FK506 administration in liver transplantation. A 6-month-old girl was treated with FK506 after undergoing living donor liver transplantation for fulminant hepatitis. On postoperative day 17, she demonstrated hyperkalaemia and metabolic acidosis; she was diagnosed to have hyperkalaemic distal RTA with aldosterone deficiency (type IV). Intravenous sodium bicarbonate and furosemide, and intrarectal calcium polystyrenesulfonate were administered to correct the acidosis and promote potassium secretion. Thereafter, the FK506 concentration in whole blood gradually decreased, and the hyperkalaemia and metabolic acidosis following RTA improved. RTA is one type of nephrotoxicity induced by FK506, and it is reversible in mild cases when appropriately treated. The mechanism of RTA induced by FK506 has not yet been clearly elucidated. Surgeons and physicians should therefore be aware of the potential for RTA to occur with FK506 after any organ transplantation. The treatment for acidosis and hyperkalaemia should be started as soon as RTA is diagnosed, and the dosage of FK506 should also be reduced if possible. PMID:14530108
Ogita, Keiko; Takada, Narito; Taguchi, Tomoaki; Suita, Sachiyo; Soejima, Yuji; Suehiro, Taketoshi; Shimada, Mitsuo; Maehara, Yoshihiko
Genetic signatures in choline and 1-carbon metabolism are associated with the severity of hepatic steatosis
Choline metabolism is important for very low-density lipoprotein secretion, making this nutritional pathway an important contributor to hepatic lipid balance. The purpose of this study was to assess whether the cumulative effects of multiple single nucleotide polymorphisms (SNPs) across genes of choline/1-carbon metabolism and functionally related pathways increase susceptibility to developing hepatic steatosis. In biopsy-characterized cases of nonalcoholic fatty liver disease and controls, we assessed 260 SNPs across 21 genes in choline/1-carbon metabolism. When SNPs were examined individually, using logistic regression, we only identified a single SNP (PNPLA3 rs738409) that was significantly associated with severity of hepatic steatosis after adjusting for confounders and multiple comparisons (P=0.02). However, when groupings of SNPs in similar metabolic pathways were defined using unsupervised hierarchical clustering, we identified groups of subjects with shared SNP signatures that were significantly correlated with steatosis burden (P=0.0002). The lowest and highest steatosis clusters could also be differentiated by ethnicity. However, unique SNP patterns defined steatosis burden irrespective of ethnicity. Our results suggest that analysis of SNP patterns in genes of choline/1-carbon metabolism may be useful for prediction of severity of steatosis in specific subsets of people, and the metabolic inefficiencies caused by these SNPs should be examined further.�Corbin, K. D., Abdelmalek, M. F., Spencer, M. D., da Costa, K.-A., Galanko, J. A., Sha, W., Suzuki, A., Guy, C. D., Cardona, D. M., Torquati, A., Diehl, A. M., Zeisel, S. H. Genetic signatures in choline and 1-carbon metabolism are associated with the severity of hepatic steatosis.
Corbin, Karen D.; Abdelmalek, Manal F.; Spencer, Melanie D.; da Costa, Kerry-Ann; Galanko, Joseph A.; Sha, Wei; Suzuki, Ayako; Guy, Cynthia D.; Cardona, Diana M.; Torquati, Alfonso; Diehl, Anna Mae; Zeisel, Steven H.
Rumen microbiome composition determined using two nutritional models of subacute ruminal acidosis.
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
Khafipour, Ehsan; Li, Shucong; Plaizier, Jan C; Krause, Denis O
[Comparative results of various methods of surgical treatment of severe forms of metabolic syndrome].
The data about metabolic syndrome (MS), characteristic for interrelationship of the main pathogenetic factors, are adduced. Along with positive moments, the faults of conservative therapy for MS are described, the indications for surgical treatment performance were substantiated and the results of its application in 220 patients, suffering severe forms of MS, were analyzed. PMID:22950270
Sedletski?, Iu I; Mirchuk, I I; Ne?mark, A E; Sedletskaia, � Iu; Anisimova, K A
Enkephalins and hormonal-metabolic reactions in experimental stress depending on its severity
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
Yu. B. Lishmanov; T. V. Lasukova; L. A. Alekminskaya
Effects of hyperbaric oxygenation therapy on cerebral metabolism and intracranial pressure in severely brain injured patients
OBJECT: Hyperbaric oxygenation (HBO) therapy has been shown to reduce mortality by 50% in a prospective randomized trial of severely brain injured patients conducted at the authors' institution. The purpose of the present study was to determine the effects of HBO on cerebral blood flow (CBF), cerebral metabolism, and intracranial pressure (ICP), and to determine the optimal HBO treatment paradigm.
Sarah B. Rockswold; Gaylan L. Rockswold; Janet M. Vargo; Carla A. Erickson; Richard L. Sutton; Thomas A. Bergman; Michelle H. Biros
Severe acute oxidant exposure: morphological damage and aerobic metabolism in the lung
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.
Montgomery, M.R.; Teuscher, F.; LaSota, I.; Niewoehner, D.E.
Metabolic Implications of Severe Burn Injuries and Their Management: A Systematic Review of the Literature
Background��Severe burn patients are some of the most challenging critically ill patients, with an extreme state of physiologic stress\\u000a and an overwhelming systemic metabolic response. A major component of severe burn injury is a hypermetabolic state associated\\u000a with protein losses and a significant reduction of lean body mass. The second prominent component is hyperglycemia. Reversal\\u000a of the hypermetabolic response by
Bishara S. Atiyeh; S. William A. Gunn; Saad A. Dibo
Lactic acidosis in the setting of antiretroviral therapy for the acquired immunodeficiency syndrome. A case report and review of the literature.
Type B lactic acidosis, a rare but often fatal disorder, has been reported in 21 AIDS patients on antiretroviral therapy (ART). We present an AIDS patient with severe and prolonged lactic acidosis on stavudine and lamivudine. The lactic acidosis occurred in the absence of mitochondrial myopathy, hepatomegaly, or liver failure. This is the second report of lactic acidosis in a patient on stavudine and lamivudine. This patient recovered after aggressive supportive therapy including intravenous alkali and fluid administration as well as continuous venovenous hemodiafiltration. A single dose of dichloroacetate (DCA) was associated with a decrease in the serum lactate level by 20%, which persisted for more than 24 h. Seventeen months after recovery, the patient was rechallenged with ART without recurrence of lactic acidosis. We review and summarize all reported cases of patients with ART-associated lactic acidosis reported in the English literature. PMID:10970989
Shaer, A J; Rastegar, A
Severe metabolic alkalosis due to baking soda ingestion: case reports of two patients with unsuspected antacid overdose.
Oral ingestion of baking soda (sodium bicarbonate) has been used for decades as a home remedy for acid indigestion. Excessive bicarbonate ingestion places patients at risk for a variety of metabolic derangements including metabolic alkalosis, hypokalemia, hypernatremia, and even hypoxia. The clinical presentation is highly variable but can include seizures, dysrhythmias, and cardiopulmonary arrest. We present two cases of severe metabolic alkalosis in patients with unsuspected antacid overdose. The presentation and pathophysiology of antacid-related metabolic alkalosis is reviewed. PMID:9950389
Fitzgibbons, L J; Snoey, E R
Metabolomic profiling reveals severe skeletal muscle group-specific perturbations of metabolism in aged FBN rats.
Mammalian skeletal muscles exhibit age-related adaptive and pathological remodeling. Several muscles in particular undergo progressive atrophy and degeneration beyond median lifespan. To better understand myocellular responses to aging, we used semi-quantitative global metabolomic profiling to characterize trends in metabolic changes between 15-month-old adult and 32-month-old aged Fischer 344�נBrown Norway (FBN) male rats. The FBN rat gastrocnemius muscle exhibits age-dependent atrophy, whereas the soleus muscle, up until 32�months, exhibits markedly fewer signs of atrophy. Both gastrocnemius and soleus muscles were analyzed, as well as plasma and urine. Compared to adult gastrocnemius, aged gastrocnemius showed evidence of reduced glycolytic metabolism, including accumulation of glycolytic, glycogenolytic, and pentose phosphate pathway intermediates. Pyruvate was elevated with age, yet levels of citrate and nicotinamide adenine dinucleotide were reduced, consistent with mitochondrial abnormalities. Indicative of muscle atrophy, 3-methylhistidine and free amino acids were elevated in aged gastrocnemius. The monounsaturated fatty acids oleate, cis-vaccenate, and palmitoleate also increased in aged gastrocnemius, suggesting altered lipid metabolism. Compared to gastrocnemius, aged soleus exhibited far fewer changes in carbohydrate metabolism, but did show reductions in several glycolytic intermediates, fumarate, malate, and flavin adenine dinucleotide. Plasma biochemicals showing the largest age-related increases included glycocholate, heme, 1,5-anhydroglucitol, 1-palmitoleoyl-glycerophosphocholine, palmitoleate, and creatine. These changes suggest reduced insulin sensitivity in aged FBN rats. Altogether, these data highlight skeletal muscle group-specific perturbations of glucose and lipid metabolism consistent with mitochondrial dysfunction in aged FBN rats. PMID:24652515
Garvey, Sean M; Dugle, Janis E; Kennedy, Adam D; McDunn, Jonathan E; Kline, William; Guo, Lining; Guttridge, Denis C; Pereira, Suzette L; Edens, Neile K
Growth hormone action is blunted by acidosis in experimental uremia or acid load.
The effects of rhGH (H) daily injection (2 IU/d) and of vehicle (V) during two weeks were studied in young (60 g) growing rats. Experiment I was performed in uremic rats (mean plasma creatinine: 65-71 mumol/l) either acidotic (mean HCO3-:11.5 mmol/l: UAH, n = 20; UAV, n = 18), or with corrected acidosis by addition of NaHCO3 in the diet (mean HCO3-:26 mmol/l: UBH, n = 25; UBV, n = 23). Experiment II used rats with normal renal function (plasma creatinine: 25 mumol/l), either non-acidotic but food restricted to the dietary intake of uremic rats (CRH: n = 18, CRV: n = 18), or rendered acidotic by NH4Cl (CAH: n = 16, CAV: n = 16). GH induced an augmentation of body weight and length gains in non-acidotic uremic rats (+33% and +41%: p < 0.01), and in non-acidotic food restricted rats (+13% and 42%: p < 0.05 and p < 0.0001). This was associated with increased protein synthesis rate in muscle and with little change of food intake as well as of plasma IGF 1. Plasma IGF 1 kept the same relationship to food intake, regardless of treatment, but length gain for each level of plasma IGF 1 was enhanced by GH in GH responding groups. In both acidotic rat groups, GH altered none of the parameters studied. Thus: 1) the presence of severe metabolic acidosis blunts the response to GH in uremic and non-uremic rats. 2) The increment of growth rate does not depend on a rise of plasma IGF 1. PMID:8832158
Maniar, S; Kleinknecht, C; Zhou, X; Motel, V; Yvert, J P; Dechaux, M
Comparison of metabolic substrates in alligators and several birds of prey.
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 ?-hydroxybutyrate (10-21mg/dl) compared to alligators (2.81�0.16mg/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, ?-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
Sweazea, Karen L; McMurtry, John P; Elsey, Ruth M; Redig, Patrick; Braun, Eldon J
Fulminant and fatal course of acute lymphoblastic leukemia due to lactic acidosis and suspected abdominal compartment syndrome.
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and its prognosis has considerably improved over the past 2 decades due to new therapeutic approaches. In some cases, however, it can develop very rapidly and cause possibly fatal complications. We report on the case of an 11-year-old boy with ALL, who rapidly developed severe lactic acidosis and abdominal compartment syndrome. He died of multiorgan failure only 5 days after diagnosis of ALL had been established. Autopsy revealed systemic leukemic infiltrations. We suppose that the mass of tumor cells induced a cascade of metabolic and endocrine reactions, which not only triggered the rapid progression of the disease but were also accountable for the lack of response to treatment. The pathophysiology of abdominal compartment syndrome as a rare and in our case ultimately fatal complication of ALL is described. PMID:22134616
Terpe, Friederike; Siekmeyer, Manuela; Bierbach, Uta; Siekmeyer, Werner; Kratzsch, J�rgen; Till, Holger; Wittekind, Christian; Kiess, Wieland
Side Effects of HIV Medicines: HIV and Lactic Acidosis
Side Effects of HIV Medicines HIV and Lactic Acidosis (Last updated 9/30/2013; last reviewed 9/30/2013) Key Points Lactic acidosis is a ... side effect of some HIV medicines. Which HIV medicines can cause lactic acidosis? HIV medicines in the ...
Acidosis Activation of the Proton-Sensing GPR4 Receptor Stimulates Vascular Endothelial Cell Inflammatory Responses Revealed by Transcriptome Analysis
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.
Dong, Lixue; Li, Zhigang; Leffler, Nancy R.; Asch, Adam S.; Chi, Jen-Tsan; Yang, Li V.
Lactic acidosis and hypoglycemia in a patient with high-grade non-Hodgkin's lymphoma and elevated circulating TNF-?
A 71-year-old patient with high-grade non-Hodgkin's lymphoma stage IVB, severe lactic acidosis and tumor-associated hypoglycemia is described. Endocrine causes of hypoglycemic episodes were excluded because of low serum concentrations of insulin and �insulin-like growth factor 1�, and normal concentrations of growth hormone and thyroid hormone. Clinical conditions associated with lactic acidosis such as diabetes mellitus, biguanide intoxication, septicemia, acute hypoxemia,
J. DiirigW; W. Fiedler; M. Wit; M. Steffen; D. K. Hossfeld
A case of life-threatening lactic acidosis after smoke inhalation � interference between ?-adrenergic agents and ethanol?
A 49-year-old male developed bronchospasm and severe lactic acidosis after exposition to fire smoke. The correction of lactic acidosis following �-adrenergic agents withdrawal, and the transitory increase in lactate after salbutamol reintroduction are consistent with hypersensitivity to salbutamol. However, the plasma lactate concentration (32.6 mmol\\/l) that we observed 9.5 h after admission is far above those currently seen after administration
P. Taboulet; J.-L. Clemessy; A. Fr�minet; F. J. Baud
[Characteristics of amino acid metabolism in patients with severe sepsis and septic shock].
The development of the multiorgan dysfunction syndrome, directly determining the severity of the septic process, is characterized by not only inverse ratio of the energy and plastic material, but by metabolic changes which are still unclear and cannot yet be explained. Our purpose was to detect some features of amino acid metabolism in patients with grave sepsis and septic shock. The concentrations of plasma free amino acids were measured on days 1, 3, and 5 in 37 patients with grave sepsis and septic shock. The diagnosis of grave sepsis, septic shock, and organ dysfunction was made proceeding from the criteria defined by R. Bone. The study revealed reliably increased (p < 0.05) levels of arginine, proline, alanine, and the arginine-ornithine index reflecting the direction of arginine transformation in patients with septic shock and grave organ dysfunction (for at least 3 systems). This may be explained by active degradation of endogenous proteins of skeletal muscles, which is characteristic of septic hypermetabolism. Strong correlations were revealed between arginine level and the APACHE-II score (r = 0.57), proline and the same score (r = 0.51), mean arterial pressure and the arginine-ornithine index (r = -0.72), APACHE-II score and the arginine-ornithine index (r = 0.79), arterial lactate and the arginine-ornithine index (r = 0.64). Hence, amino acid metabolism apparently mediates the effects of septic cascade mediators on the following cell. PMID:9173819
Le?derman, I N; Rudnov, V A; Logvinenko, N N; Kogan, E O
Adipose deficiency of Nrf2 in ob/ob mice results in severe metabolic syndrome.
Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that functions as a master regulator of the cellular adaptive response to oxidative stress. Our previous studies showed that Nrf2 plays a critical role in adipogenesis by regulating expression of CCAAT/enhancer-binding protein ? and peroxisome proliferator-activated receptor ?. To determine the role of Nrf2 in the development of obesity and associated metabolic disorders, the incidence of metabolic syndrome was assessed in whole-body or adipocyte-specific Nrf2-knockout mice on a leptin-deficient ob/ob background, a model with an extremely positive energy balance. On the ob/ob background, ablation of Nrf2, globally or specifically in adipocytes, led to reduced white adipose tissue (WAT) mass, but resulted in an even more severe metabolic syndrome with aggravated insulin resistance, hyperglycemia, and hypertriglyceridemia. Compared with wild-type mice, WAT of ob/ob mice expressed substantially higher levels of many genes related to antioxidant response, inflammation, adipogenesis, lipogenesis, glucose uptake, and lipid transport. Absence of Nrf2 in WAT resulted in reduced expression of most of these factors at mRNA or protein levels. Our findings support a novel role for Nrf2 in regulating adipose development and function, by which Nrf2 controls the capacity of WAT expansion and insulin sensitivity and maintains glucose and lipid homeostasis. PMID:23238296
Xue, Peng; Hou, Yongyong; Chen, Yanyan; Yang, Bei; Fu, Jingqi; Zheng, Hongzhi; Yarborough, Kathy; Woods, Courtney G; Liu, Dianxin; Yamamoto, Masayuki; Zhang, Qiang; Andersen, Melvin E; Pi, Jingbo
Differential influence of arterial blood glucose on cerebral metabolism following severe traumatic brain injury
Introduction��Maintaining arterial blood glucose within tight limits is beneficial in critically ill patients. Upper and lower limits of\\u000a detrimental blood glucose levels must be determined.\\u000a \\u000a \\u000a \\u000a \\u000a Methods��In 69 patients with severe traumatic brain injury (TBI), cerebral metabolism was monitored by assessing changes in arterial\\u000a and jugular venous blood at normocarbia (partial arterial pressure of carbon dioxide (paCO2) 4.4 to 5.6 kPa),
Monika Holbein; Markus B�chir; Silke Ludwig; Jutta Sommerfeld; Silvia R Cottini; Marius Keel; Reto Stocker; John F Stover
Type 2 Diabetes Mellitus and the Metabolic Syndrome Following Sleeve Gastrectomy in Severely Obese Subjects
Background��Data on the effectiveness of sleeve gastrectomy in improving or resolving type 2 diabetes mellitus (T2DM) and the metabolic\\u000a syndrome (MS) are scarce.\\u000a \\u000a \\u000a \\u000a Methods��A twelve-month prospective study on the changes in glucose homeostasis and the MS in 91 severely obese T2DM subjects undergoing\\u000a laparoscopic SG (SG; n?=?39) or laparoscopic Roux-en-Y gastric bypass (GBP; n?=?52), matched for DM duration, type of
J. Vidal; A. Ibarzabal; F. Romero; S. Delgado; D. Mombl�n; L. Flores; A. Lacy
Enkephalins and hormonal-metabolic reactions in experimental stress depending on its severity
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.
Lishmanov, Y.B.; Alekminskaya, L.A.; Lasukova, T.V.
In various functional conditions involving peripheral vasoconstriction a more or less widespread change toward acidity takes place within certain tissues. The change is frequently independent of any in the blood. Indeed the blood can become more alkaline while the tissue acidosis is developing. When the blood volume is diminished abruptly but not too greatly, by hemorrhage or by anhydremia, the acidosis which develops in the superficial connective tissue and in the skeletal muscles is patchy in distribution, being limited to areas of local ischemia themselves the result of a compensatory vasoconstriction which affects certain regions only. There is a second type of patchy ischemia (and of acidosis) which occurs under circumstances of moderate depletion and is referable to local pressure differences that are so slight as to be ineffective under normal circumstances. A generalized acidosis throughout the superficial tissue develops when depletion is extreme. All these are outlying acidoses, since they lie without the influence of the blood. In the viscera no such acidoses have been found.
Rous, Peyton; Drury, Douglas R.
Differential influence of arterial blood glucose on cerebral metabolism following severe traumatic brain injury
Introduction Maintaining arterial blood glucose within tight limits is beneficial in critically ill patients. Upper and lower limits of detrimental blood glucose levels must be determined. Methods In 69 patients with severe traumatic brain injury (TBI), cerebral metabolism was monitored by assessing changes in arterial and jugular venous blood at normocarbia (partial arterial pressure of carbon dioxide (paCO2) 4.4 to 5.6 kPa), normoxia (partial arterial pressure of oxygen (paO2) 9 to 20 kPa), stable haematocrit (27 to 36%), brain temperature 35 to 38�C, and cerebral perfusion pressure (CPP) 70 to 90 mmHg. This resulted in a total of 43,896 values for glucose uptake, lactate release, oxygen extraction ratio (OER), carbon dioxide (CO2) and bicarbonate (HCO3) production, jugular venous oxygen saturation (SjvO2), oxygen-glucose index (OGI), lactate-glucose index (LGI) and lactate-oxygen index (LOI). Arterial blood glucose concentration-dependent influence was determined retrospectively by assessing changes in these parameters within pre-defined blood glucose clusters, ranging from less than 4 to more than 9 mmol/l. Results Arterial blood glucose significantly influenced signs of cerebral metabolism reflected by increased cerebral glucose uptake, decreased cerebral lactate production, reduced oxygen consumption, negative LGI and decreased cerebral CO2/HCO3 production at arterial blood glucose levels above 6 to 7 mmol/l compared with lower arterial blood glucose concentrations. At blood glucose levels more than 8 mmol/l signs of increased anaerobic glycolysis (OGI less than 6) supervened. Conclusions Maintaining arterial blood glucose levels between 6 and 8 mmol/l appears superior compared with lower and higher blood glucose concentrations in terms of stabilised cerebral metabolism. It appears that arterial blood glucose values below 6 and above 8 mmol/l should be avoided. Prospective analysis is required to determine the optimal arterial blood glucose target in patients suffering from severe TBI.
Holbein, Monika; Bechir, Markus; Ludwig, Silke; Sommerfeld, Jutta; Cottini, Silvia R; Keel, Marius; Stocker, Reto; Stover, John F
Body composition, energy utilization, and nitrogen metabolism with a severely restricted diet supplemented with dihydroxyacetone and pyruvate13
ABSTRACF To determine the effect ofdietary modification on energy utilization during severely restrictive hypocaloric feeding, we measured body composition, energy deficit, and ni- trogen metabolism in 13 obese women housed in a metabolic ward consuming a 2. 1-MJ diet for 21 d with the three-carbon compounds dihydroxyacetone and pyruvate (DHAP), partially, isocalorically substituted for glucose. Body composition and amino acid
Ronald T Stanko; Denise L Tietze; Judith E Arch
Severe metabolic alkalosis due to baking soda ingestion: case reports of two patients with unsuspected antacid overdose
Oral ingestion of baking soda (sodium bicarbonate) has been used for decades as a home remedy for acid indigestion. Excessive bicarbonate ingestion places patients at risk for a variety of metabolic derangements including metabolic alkalosis, hypokalemia, hypernatremia, and even hypoxia. The clinical presentation is highly variable but can include seizures, dysrhythmias, and cardiopulmonary arrest. We present two cases of severe
Leslie J. Fitzgibbons; Eric R. Snoey
[The correction of metabolic disorders in severely burned patients by enteral hyperalimentation].
An investigation was carried out of the metabolic processes, and some procedures for standardizing them, for patients with severe burns receiving uniformly distributed dosified high-calorie catheter alimentation, i.e. enteral hyperalimentation, in addition to the hospital's daily diet. Fifteen types of mixtures of Combustal were used, made and preserved ad hoc, and two commercial probe alimentation liquid products--Biosorbin-MCT (Pfrimmer-Kabi) and Fresubin (Fresenius AG). The average period taken to normalize the nitrogen balance was sixteen days counted from commencement of hyperalimentation. While it shifted the nitrogen balance figures from negative to positive, it was also seen to reduce A and C phospholipase activities in serum, while the level of excretion of nitrogenated amino acids and creatine remained high. During this time, pseudocholinesterase activity dropped, with the concentration of fibronectine in serum, which indicates low levels of biosynthetic processes and insufficiency in the reticuloendothelial system. The average value for the determination of lipids in general remained normal throughout the catheter feeding period. To ensure complete normalization of the metabolic process in patients suffering severe burns, enteral hyperalimentation must be extended for at least one month. PMID:1477152
Zaets, T L; Tarasov, A V
A defect in carbohydrate metabolism ameliorates symptom severity in virus-infected Arabidopsis thaliana.
Altered starch accumulation is a characteristic biochemical symptom of virus infection in plants. To assess its biological importance, infection of Arabidopsis thaliana with Turnip vein-clearing virus, Cucumber mosaic virus or Cauliflower mosaic virus was investigated in plants grown under continuous illumination (under which there is no net breakdown of starch) and in pgm1 mutant plants lacking chloroplastic phosphoglucomutase, an enzyme required for starch biosynthesis. Virus-infected wild-type plants grown under continuous light exhibited more severe leaf symptoms, but no reduction in growth compared with plants grown under diurnal illumination. Comparing lines grown in perpetual light, pgm1 mutant plants displayed less severe symptoms than the wild-type controls. However, accumulation of all three viruses was similar in wild-type and mutant plants and was unaffected by the light regime. The results show that, although changes in starch accumulation during infection are not required for successful viral infection, carbohydrate metabolism does influence symptom development. PMID:17170466
Handford, Michael G; Carr, John P
Acute isoniazid intoxication: an uncommon cause of convulsion, coma and acidosis.
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
Uzman, Sinan; Uluda? Yanaral, T�may; Topta?, Mehmet; Ko�, Alparslan; Ta?, Ayt�l; Bican, G�l?en
Atp6v0a4 knockout mouse is a model of distal renal tubular acidosis with hearing loss, with additional extrarenal phenotype
Autosomal recessive distal renal tubular acidosis (dRTA) is a severe disorder of acid�base homeostasis, often accompanied by sensorineural deafness. We and others have previously shown that mutations in the tissue-restricted a4 and B1 subunits of the H+-ATPase underlie this syndrome. Here, we describe an Atp6v0a4 knockout mouse, which lacks the a4 subunit. Using ?-galactosidase as a reporter for the null gene, developmental a4 expression was detected in developing bone, nose, eye, and skin, in addition to that expected in kidney and inner ear. By the time of weaning, Atp6v0a4?/? mice demonstrated severe metabolic acidosis, hypokalemia, and early nephrocalcinosis. Null mice were hypocitraturic, but hypercalciuria was absent. They were severely hearing-impaired, as shown by elevated auditory brainstem response thresholds and absent endocochlear potential. They died rapidly unless alkalinized. If they survived weaning with alkali supplementation, treatment could later be withdrawn, but ?/? animals remained acidotic with alkaline urine. They also had an impaired sense of smell. Heterozygous animals were biochemically normal until acid-challenged, when they became more acidotic than +/+ animals. This mouse model recapitulates the loss of H+-ATPase function seen in human disease and can provide additional insights into dRTA and the physiology of the a4 subunit.
Norgett, Elizabeth E.; Golder, Zoe J.; Lorente-Canovas, Beatriz; Ingham, Neil; Steel, Karen P.; Karet Frankl, Fiona E.
Congenital lactic acidosis due to pyruvate carboxylase deficiency: Absence of an inhibitor of TPP-ATP phosphoryl transferase
Two children are described who suffered from episodes of metabolic acidosis and progressive mental and motor deterioration. The patients showed periodic elevation of blood lactate, pyruvate and alanine, which was accompanied by vomiting, hypotonia or convulsions. The concentrations of lactate and pyruvate in cerebrospinal fluid were found to be increased. Liver biopsies revealed a decrease in pyruvate carboxylase activity and
Keiya Tada; Goro Takada; Kiyoshi Omura; Yoshinori Itokawa
The ATP-sensitive K+ channel mediates hypotension in endotoxemia and hypoxic lactic acidosis in dog.
Endotoxemia causes hypotension characterized by vasodilation and resistance to vasopressor agents. The molecular mechanisms responsible for these changes are unclear. The ATP-regulated K+ (K+ATP) channel has recently been found to be an important modulator of vascular smooth muscle tone which may transduce local metabolic changes into alterations of vascular flow. We report here that in endotoxic hypotension, the sulfonylurea glyburide, a specific inhibitor for the K+ATP channel, caused vasoconstriction and restoration of blood pressure. Glyburide also induced vasoconstriction and restoration of blood pressure in the vasodilatory hypotension caused by hypoxic lactic acidosis, while it was ineffective in the hypotension induced by sodium nitroprusside. Thus, vasodilation and hypotension in septic shock are, at least in part, due to activation of the K+ATP channel in vascular smooth muscle, and anaerobic metabolism with acidosis is a sufficient stimulus for channel activation. Because anaerobic metabolism and acidosis are common features in shock of any etiology, sulfonylureas may be effective therapeutic agents in the treatment of shock.
Landry, D W; Oliver, J A
Earlier Onset and Greater Severity of Disordered Mineral Metabolism in Diabetic Patients With Chronic Kidney Disease
OBJECTIVE Disordered mineral metabolism is a common complication of chronic kidney disease (CKD) and a novel risk factor for CKD progression, cardiovascular disease, and mortality. Although diabetes is the leading cause of CKD and is associated with worse clinical outcomes than other etiologies, few studies have evaluated mineral metabolism in CKD according to diabetes status. RESEARCH DESIGN AND METHODS Using the Chronic Renal Insufficiency Cohort Study, we tested the hypothesis that diabetes is independently associated with lower serum calcium and higher serum phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23). RESULTS Compared with participants without diabetes (n = 1,936), those with diabetes (n = 1,820) were more likely to have lower estimated glomerular filtration rate (eGFR), lower serum albumin, and higher urinary protein excretion (all P < 0.001). Unadjusted serum phosphate, PTH, and FGF23 levels were higher and calcium was lower among those with compared with those without diabetes (all P < 0.001). After multivariate adjustment, diabetes remained a significant predictor of serum phosphate, PTH, and FGF23 but not calcium. The eGFR cut point at which 50% of participants met criteria for secondary hyperparathyroidism or elevated FGF23 was higher in participants with diabetes compared with those without (PTH: eGFR 30�39 vs. 20�29, P < 0.001; FGF23: eGFR 50�59 vs. 40�49, P < 0.001). CONCLUSIONS Disordered mineral metabolism begins earlier in the course of CKD and is more severe among CKD patients with compared with those without diabetes. Future studies should explore mechanisms for these differences and whether they contribute to excess risks of adverse clinical outcomes among diabetic patients with CKD.
Wahl, Patricia; Xie, Huiliang; Scialla, Julia; Anderson, Cheryl A.M.; Bellovich, Keith; Brecklin, Carolyn; Chen, Jing; Feldman, Harold; Gutierrez, Orlando M.; Lash, Jim; Leonard, Mary B.; Negrea, Lavinia; Rosas, Sylvia E.; Anderson, Amanda Hyre; Townsend, Raymond R.; Wolf, Myles; Isakova, Tamara
Severe hypokalemia, metabolic alkalosis and hypertension in a 54 year old male with ectopic ACTH syndrome: a case report.
Ectopic ACTH syndrome is a rare cause of Cushing's syndrome accounting for about 15% of all cases. Small cell lung cancer and bronchial carcinoids account for about half of the cases. Malignant neoplasm has rapid and more aggressive metabolic effects. We report a 54-year-old male patient with phenotypic features of Cushing's syndrome with severe hypokalemia, metabolic alkalosis, hypertension and altered mental status as manifestations of an ACTH-secreting small cell carcinoma from the lung. Ectopic ACTH syndrome should be highly considered in patients with hypertension and severe hypokalemic metabolic alkalosis, especially when a lung mass is discovered. PMID:19829770
Mart�nez-Valles, Miguel Angel; Palafox-Cazarez, Asael; Paredes-Avina, Jose Antonio
Role of drugs in recovery of metabolic function of rat brain following severe hypoglycemia.
Severe hypoglycemia with isoelectric EEG induced extensive deterioration of the energy state and gross alteration of amino acid contents on the rat cerebral and cerebellar cortex. During recovery, tissue glucose concentration returned to normal, while both lactate and pyruvate concentrations increased to above normal. In the recovery period, the ATP concentration increased but the adenine nucleotide pool remained reduced, even if the ADP and AMP contents were close to normal. Phosphocreatine was restored to normal concentration with reciprocal changes in creatine content. During recovery there was a rise in glutamate and glutamine concentrations, gamma-aminobutyrate content returning to normal value. Ammonia and aspartate decreased below normal, while alanine increased above normal. The effect of some pharmacological agents on the posthypoglycemic recovery was tested: (a) Ergot alkaloids (dihydroergocristine, dihydroergocriptine, dihydroergocornine); (b) Vinca minor alkaloids (vincamine TPS, (-) eburnamonine); (c) Rauwolfia serpentina alkaloids (reserpine, raubasine); (d) synthetic agent (piracetam). During the posthypoglycemic recovery, these different agents exhibited different, or even contrasting, interferences on glycolytic metabolites, amino acids and energy-rich phosphates. The metabolic alterations in the cerebellar cortex were qualitatively of the same character of those in neocortex. However, the metabolic alterations were less extensive and more sensitive to drug action. PMID:6504232
Benzi, G; Villa, R F; Dossena, M; Vercesi, L; Gorini, A; Pastoris, O
Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting.
The relative contribution of immunological dysregulation and impaired epithelial barrier function to allergic diseases is still a matter of debate. Here we describe a new syndrome featuring severe dermatitis, multiple allergies and metabolic wasting (SAM syndrome) caused by homozygous mutations in DSG1. DSG1 encodes desmoglein 1, a major constituent of desmosomes, which connect the cell surface to the keratin cytoskeleton and have a crucial role in maintaining epidermal integrity and barrier function. Mutations causing SAM syndrome resulted in lack of membrane expression of DSG1, leading to loss of cell-cell adhesion. In addition, DSG1 deficiency was associated with increased expression of a number of genes encoding allergy-related cytokines. Our deciphering of the pathogenesis of SAM syndrome substantiates the notion that allergy may result from a primary structural epidermal defect. PMID:23974871
Samuelov, Liat; Sarig, Ofer; Harmon, Robert M; Rapaport, Debora; Ishida-Yamamoto, Akemi; Isakov, Ofer; Koetsier, Jennifer L; Gat, Andrea; Goldberg, Ilan; Bergman, Reuven; Spiegel, Ronen; Eytan, Ori; Geller, Shamir; Peleg, Sarit; Shomron, Noam; Goh, Christabelle S M; Wilson, Neil J; Smith, Frances J D; Pohler, Elizabeth; Simpson, Michael A; McLean, W H Irwin; Irvine, Alan D; Horowitz, Mia; McGrath, John A; Green, Kathleen J; Sprecher, Eli
Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting
The relative contribution of immunological dysregulation and impaired epithelial barrier function to allergic diseases is still a matter of debate. Here we describe a new syndrome featuring severe dermatitis, multiple allergies and metabolic wasting (SAM syndrome) caused by homozygous mutations in DSG1. DSG1 encodes desmoglein 1, a major constituent of desmosomes, which connect the cell surface to the keratin cytoskeleton and play a crucial role in maintaining epidermal integrity and barrier function. SAM syndrome-causing mutations resulted in lack of membrane expression of DSG1, leading to loss of cell-cell adhesion. In addition, DSG1 deficiency was associated with increased expression of a number of genes encoding allergy-related cytokines. The deciphering of the pathogenesis of SAM syndrome substantiates the notion that allergy may result from a primary structural epidermal defect.
Rapaport, Debora; Ishida-Yamamoto, Akemi; Isakov, Ofer; Koetsier, Jennifer L; Gat, Andrea; Goldberg, Ilan; Bergman, Reuven; Spiegel, Ronen; Eytan, Ori; Geller, Shamir; Peleg, Sarit; Shomron, Noam; Goh, Christabelle S M; Wilson, Neil J; Smith, Frances J D; Pohler, Elizabeth; Simpson, Michael A; McLean, W H Irwin; Irvine, Alan D; Horowitz, Mia; McGrath, John A; Green, Kathleen J; Sprecher, Eli
SUMMARY Acute acidosis problems in ruminants is the result of excessive consumption of fermentable carbohydrates which causes a non-physiological reduction in pH and the production of a toxic factor(s). The low ruminal pH is the result of the production of large quantities of volatile fatty acids as well as other acids (such as lactic, which has a pK of 3.7)
Leonard L. Slyter
Ruminant Nutrition Symposium: Productivity, digestion, and health responses to hindgut acidosis in ruminants.
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
Gressley, T F; Hall, M B; Armentano, L E
Carbamylated erythropoietin ameliorates the metabolic stress induced in vivo by severe chronic hypoxia
Ischemia and chronic hypoxia (CH) trigger a variety of adverse effects arising from metabolic stress that injures cells. In response to reduced O2, hypoxia-inducible factor 1? (HIF-1?) activates erythropoietin (Epo) as well as many other target genes that counteract the effects of O2 deficiency. Epo produced by the kidney stimulates erythrocyte production, leading to decreased HIF-1? production by improved tissue O2 delivery. However, Epo is produced by many other tissues, and it is currently unclear to what extent, if any, locally produced Epo modulates HIF-1? expression. Derivatives of Epo that possess tissue-protective activities but do not stimulate erythropoiesis [e.g., carbamylated Epo (CEpo)] are useful tools with which to determine whether exogenous Epo modulates HIF-1? in the absence of changes in hemoglobin concentration. We compared the effects of CH (6.5% O2 for 10 days) with or without CEpo administered by daily s.c. injection (10 ?g/kg of body weight). CEpo administration did not alter the survival rate, weight loss, or increased hemoglobin concentration associated with CH. Therefore, CEpo does not directly suppress HIF-mediated erythropoiesis. CEpo does, however, prevent CH-induced neuronal increases of HIF-1? and Epo receptor-associated immunoreactivity (a measure of stress) while reducing the apoptotic index. In contrast, the myocardium did not exhibit increased HIF-1? expression during CH, although CEpo did reduce the apoptotic index. These observations therefore demonstrate that CEpo administration reduces the metabolic stress caused by severe CH, resulting in improved cellular survival independent of erythrocyte production.
Fantacci, Monica; Bianciardi, Paola; Caretti, Anna; Coleman, Thomas R.; Cerami, Anthony; Brines, Michael; Samaja, Michele
Carbamylated erythropoietin ameliorates the metabolic stress induced in vivo by severe chronic hypoxia.
Ischemia and chronic hypoxia (CH) trigger a variety of adverse effects arising from metabolic stress that injures cells. In response to reduced O2, hypoxia-inducible factor 1alpha (HIF-1alpha) activates erythropoietin (Epo) as well as many other target genes that counteract the effects of O2 deficiency. Epo produced by the kidney stimulates erythrocyte production, leading to decreased HIF-1alpha production by improved tissue O2 delivery. However, Epo is produced by many other tissues, and it is currently unclear to what extent, if any, locally produced Epo modulates HIF-1alpha expression. Derivatives of Epo that possess tissue-protective activities but do not stimulate erythropoiesis [e.g., carbamylated Epo (CEpo)] are useful tools with which to determine whether exogenous Epo modulates HIF-1alpha in the absence of changes in hemoglobin concentration. We compared the effects of CH (6.5% O2 for 10 days) with or without CEpo administered by daily s.c. injection (10 microg/kg of body weight). CEpo administration did not alter the survival rate, weight loss, or increased hemoglobin concentration associated with CH. Therefore, CEpo does not directly suppress HIF-mediated erythropoiesis. CEpo does, however, prevent CH-induced neuronal increases of HIF-1alpha and Epo receptor-associated immunoreactivity (a measure of stress) while reducing the apoptotic index. In contrast, the myocardium did not exhibit increased HIF-1alpha expression during CH, although CEpo did reduce the apoptotic index. These observations therefore demonstrate that CEpo administration reduces the metabolic stress caused by severe CH, resulting in improved cellular survival independent of erythrocyte production. PMID:17090665
Fantacci, Monica; Bianciardi, Paola; Caretti, Anna; Coleman, Thomas R; Cerami, Anthony; Brines, Michael; Samaja, Michele
Rate-dependent distal renal tubular acidosis and carnitine palmitoyltransferase I deficiency.
An infant girl presented with recurrent episodes of Reye-like syndrome associated with hypoketosis and plasma carnitine levels in the high-normal range. A liver biopsy revealed massive macrovesicular steatosis. Ketogenesis was absent after a long-chain triglyceride loading test; in contrast, the medium-chain triglyceride loading test resulted in a brisk rise in plasma ketone concentration. Carnitine palmitoyltransferase I deficiency was demonstrated in cultured skin fibroblasts. Hypoglycemia was only found once in the neonatal period. Renal carnitine handling was normal except for a higher renal threshold for free carnitine. Mild, persistent metabolic acidosis was a constant feature, even during periods between metabolic decompensation. Evaluation of the renal acidification capacity showed a failure to acidify the urine during spontaneous acidosis but increased acid excretion and a normal decrease of urinary pH after acid loading. Also, a small difference between urine and blood PCO2 was found after bicarbonate administration. This acidification defect can best be explained as an abnormality in distal tubular H+ secretion: a rate-dependent distal tubular acidosis.off is speculated that long-chain acylcarnitines, substances that cannot be formed by carnitine palmitoyltransferase I-deficient patients, play an essential role in renal acid-base homeostasis. PMID:7877875
Bergman, A J; Donckerwolcke, R A; Duran, M; Smeitink, J A; Mousson, B; Vianey-Saban, C; Poll-The, B T
Regional cerebral metabolic patterns demonstrate the role of anterior forebrain mesocircuit dysfunction in the severely injured brain.
Although disorders of consciousness (DOCs) demonstrate widely varying clinical presentations and patterns of structural injury, global down-regulation and bilateral reductions in metabolism of the thalamus and frontoparietal network are consistent findings. We test the hypothesis that global reductions of background synaptic activity in DOCs will associate with changes in the pattern of metabolic activity in the central thalamus and globus pallidus. We compared 32 [(18)F]fluorodeoxyglucose PETs obtained from severely brain-injured patients (BIs) and 10 normal volunteers (NVs). We defined components of the anterior forebrain mesocircuit on high-resolution T1-MRI (ventral, associative, and sensorimotor striatum; globus pallidus; central thalamus and noncentral thalamus). Metabolic profiles for BI and NV demonstrated distinct changes in the pattern of uptake: ventral and association striatum (but not sensorimotor) were significantly reduced relative to global mean uptake after BI; a relative increase in globus pallidus metabolism was evident in BI subjects who also showed a relative reduction of metabolism in the central thalamus. The reversal of globus pallidus and central thalamus profiles across BIs and NVs supports the mesocircuit hypothesis that broad functional (or anatomic) deafferentation may combine to reduce central thalamus activity and release globus pallidus activity in DOCs. In addition, BI subjects showed broad frontoparietal metabolic down-regulation consistent with prior studies supporting the link between central thalamic/pallidal metabolism and down-regulation of the frontoparietal network. Recovery of left hemisphere frontoparietal metabolic activity was further associated with command following. PMID:24733913
Fridman, Esteban A; Beattie, Bradley J; Broft, Allegra; Laureys, Steven; Schiff, Nicholas D
Modelling Acidosis and the Cell Cycle in Multicellular Tumour Spheroids
A partial differential equation model is developed to understand the effect that nutrient and acidosis have on the distribution of proliferating and quiescent cells within a multicellular tumour spheroid. The rates of cell quiescence and necrosis are assumed to depend upon the local nutrient and acid concentrations. Quiescent cells are assumed to consume less nutrient and produce less acid than proliferating cells and a description of anaerobic metabolism by the cells is included. Parameterised with data from the literature, our model predicts that the tumour size is reduced in the presence of acid. Analysis of the differences in nutrient consumption and acid production by quiescent and proliferating cells shows low nutrient levels do not necessarily lead to increased acid concentration via anaerobic metabolism. Instead it is the balance between proliferating and quiescent cells within the tumour which is important; decreased nutrient levels lead to more quiescent cells, which produce less acid than proliferating cells. We examine this effect via a sensitivity analysis which also includes a quantification of the effect that nutrient and acid concentrations have on the rates of cell quiescence and necrosis.
Tindall, M.J.; Dyson, L.; Smallbone, K.; Maini, P.K.
Is lactic acidosis a cause of exercise induced hyperventilation at the respiratory compensation point?
Objectives: The respiratory compensation point (RCP) marks the onset of hyperventilation ("respiratory compensation") during incremental exercise. Its physiological meaning has not yet been definitely determined, but the most common explanation is a failure of the body's buffering mechanisms which leads to metabolic (lactic) acidosis. It was intended to test this experimentally. Methods: During a first ramp-like exercise test on a cycle ergometer, RCP (range: 2.51�3.73 l*min�1 oxygen uptake) was determined from gas exchange measurements in five healthy subjects (age 26�42; body mass index (BMI) 20.7�23.9 kg*m�2; VO2peak 51.3�62.1 ml*min�1*kg�1). On the basis of simultaneous determinations of blood pH and base excess, the necessary amount of bicarbonate to completely buffer the metabolic acidosis was calculated. This quantity was administered intravenously in small doses during a second, otherwise identical, exercise test. Results: In each subject sufficient compensation for the acidosis, that is, a pH value constantly above 7.37, was attained during the second test. A delay but no disappearance of the hyperventilation was present in all participants when compared with the first test. RCP occurred on average at a significantly (p = 0.043) higher oxygen uptake (+0.15 l*min�1) compared with the first test. Conclusions: For the first time it was directly demonstrated that exercise induced lactic acidosis is causally involved in the hyperventilation which starts at RCP. However, it does not represent the only additional stimulus of ventilation during intense exercise. Muscle afferents and other sensory inputs from exercising muscles are alternative triggering mechanisms.
Meyer, T; Faude, O; Scharhag, J; Urhausen, A; Kindermann, W
Prevalence and severity of disordered mineral metabolism in Blacks with chronic kidney disease.
Disorders of mineral metabolism develop early in chronic kidney disease, but it appears that Blacks with stage-5 disease have more severe secondary hyperparathyroidism than other races. We measured levels of parathyroid hormone, calcium, phosphorus, 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D) in 227 Black and 1633 non-Black participants in the SEEK study, a multi-center cohort of patients with early chronic kidney disease. Overall, Blacks had similar 1,25D levels compared with non-Blacks, but significantly lower levels of 25D with higher levels of calcium, phosphorus, and parathyroid hormone, and were significantly more likely to have hyperphosphatemia than non-Blacks. In multivariable analyses adjusted for age, gender, estimated glomerular filtration rate, body mass index, and diabetes, Blacks had significantly lower 25D and higher parathyroid hormone levels than non-Blacks, with the latter parameter remaining significant after further adjustment for calcium, phosphorus, 25D, and 1,25D. The association between Black race and secondary hyperparathyroidism, independent of known risk factors, suggests that novel mechanisms contribute to secondary hyperparathyroidism in Blacks with chronic kidney disease. PMID:18256597
Guti�rrez, O M; Isakova, T; Andress, D L; Levin, A; Wolf, M
Effects of HIV Infection on the Metabolic and Hormonal Status of Children with Severe Acute Malnutrition
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.
Hornik, Christoph P.; Kiyimba, Tonny; Bain, James; Muehlbauer, Michael; Kiboneka, Elizabeth; Stevens, Robert; St. Peter, John V.; Newgard, Christopher B.; Bartlett, John; Freemark, Michael
Distal Renal Tubular Acidosis and Calcium Nephrolithiasis
NASA Astrophysics Data System (ADS)
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.
Moe, Orson W.; Fuster, Daniel G.; Xie, Xiao-Song
Contribution of respiratory acidosis to diaphragmatic fatigue at exercise
Contribution of respiratory acidosis to diaphragmatic fatigue at exercise. S. Jonville, N. Delpech, A. Denjean. #ERS Journals Ltd 2002. ABSTRACT: The factors that may modulate ventilatory muscle fatigue during exercise are controversial. In this study the contribution of acidosis to exercise-induced diaphragmatic fatigue was investigated, using measurements of the twitch mouth pressure response (tw,Pmo) to cervical magnetic stimulation. After learning
S. Jonville; N. Delpech; A. Denjean
The Influence of Vasoconstriction and Acidosis on Disseminated Intravascular Coagulation.
National Technical Information Service (NTIS)
CONCLUSIONS: (1) Acute hemorrhage produces an immediate venous acidosis which is shortly followed by arterial acidosis if blood volume is not replaced. (2) Vasodilators bring about an immediate improvement in both arterial and venous pH. (3) Acid pH's in ...
W. R. Brewster R. M. Hardaway M. J. Elovitz
Metformin-associated lactic acidosis presenting as an ischemic gut in a patient who then survived a cardiac arrest: a case report
Introduction Lactic acidosis is the most common cause of metabolic acidosis in hospitalized patients. It is recognized as a potential complication of metformin use, particularly in patients with risk factors such as renal dysfunction, liver disease, and heavy alcohol ingestion. These conditions are associated with systemic hypoxemia, which may be caused by cardiorespiratory disease, major surgery, sepsis, dehydration, old age, and overdose. The reported frequency of lactic acidosis is 0.06 per 1000 patient-years, mostly in patients with predisposing factors. This case is important because it details the seriousness of metformin-associated lactic acidosis in a critically ill patient and because, to the best of our knowledge, our patient survived with minimal residual defect despite experiencing a cardiac arrest. Case presentation A 66-year-old Caucasian woman presented to our hospital with profound lactic acidosis, which was initially thought to be ischemic gut. She then survived an in-hospital pulseless electrical activity arrest. Conclusion Metformin-associated lactic acidosis is a diagnosis by exclusion; however, a high degree of clinical suspicion supplemented by prompt multisystem organ support can significantly influence the outcome in critically ill patients.
Exercise intolerance, lactic acidosis, and abnormal cardiopulmonary regulation in exercise associated with adult skeletal muscle cytochrome c oxidase deficiency.
A 27-yr-old woman with lifelong severe exercise intolerance manifested by muscle fatigue, lactic acidosis, and prominent symptoms of dyspnea and tachycardia induced by trivial exercise was found to have a skeletal muscle respiratory chain defect characterized by low levels of reducible cytochromes a + a3 and b in muscle mitochondria and marked deficiency of cytochrome c oxidase (complex IV) as assessed biochemically and immunologically. Investigation of the pathophysiology of the exercise response in the patient revealed low maximal oxygen uptake (1/3 that of normal sedentary women) in cycle exercise and impaired muscle oxygen extraction as indicated by profoundly low maximal systemic arteriovenous oxygen difference (5.8 ml/dl; controls = 15.4 +/- 1.4, mean +/- SD). The increases in cardiac output and ventilation during exercise, normally closely coupled to muscle metabolic rate, were markedly exaggerated (more than two- to threefold normal) relative to oxygen uptake and carbon dioxide production accounting for prominent tachycardia and dyspnea at low workloads. Symptoms in our patient are similar to those reported in other human skeletal muscle respiratory chain defects involving complexes I and III, and the exaggerated circulatory response resembles that seen during experimental inhibition of the mitochondrial respiratory chain. These results suggest that impaired oxidative phosphorylation in working muscle disrupts the normal regulation of cardiac output and ventilation relative to muscle metabolic rate in exercise.
Haller, R G; Lewis, S F; Estabrook, R W; DiMauro, S; Servidei, S; Foster, D W
Influence of Inhaled Corticosteroids and Dietary Intake on Bone Density and Metabolism in Patients With Moderate to Severe Asthma
Objectives Compare the effect of high doses of inhaled corticosteroids on bone loss in subjects with moderate to severe asthma or mild asthma, and examine the influence of dietary intake on bone metabolism. Design A survey on the effects of corticotherapy and nutrition on bone density was conducted in 74 subjects currently being treated for asthma in the asthma clinic
Evidence for a Detrimental Effect of Bicarbonate Therapy in Hypoxic Lactic Acidosis
NASA Astrophysics Data System (ADS)
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.
Graf, Helmut; Leach, William; Arieff, Allen I.
Functional metabolomics uncovers metabolic alterations associated to severe oxidative stress in MCF7 breast cancer cells exposed to ascididemin.
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
Morvan, Daniel
Cleistanthus collinus induces type I distal renal tubular acidosis and type II respiratory failure in rats
Background and Purpose: A water decoction of the poisonous shrub Cleistanthus collinus is used for suicidal purposes. The mortality rate is 28%. The clinical profile includes distal renal tubular acidosis (DRTA) and respiratory failure. The mechanism of toxicity is unclear. Objectives: To demonstrate features of C. collinus toxicity in a rat model and to identify its mechanism(s) of action. Materials and Methods: Rats were anesthetized and the carotid artery was cannulated. Electrocardiogram and respiratory movements were recorded. Either aqueous extract of C. collinus or control solution was administered intraperitoneally. Serial measurements of blood gases, electrolytes and urinary pH were made. Isolated brush border and basolateral membranes from rat kidney were incubated with C. collinus extract and reduction in ATPase activity was assessed. Venous blood samples from human volunteers and rats were incubated with an acetone extract of C. collinus and plasma potassium was estimated as an assay for sodium�potassium pump activity. Results: The mortality was 100% in tests and 17% in controls. Terminal event in test animals was respiratory arrest. Controls had metabolic acidosis, respiratory compensation acidic urine and hyperkalemia. Test animals showed respiratory acidosis, alkaline urine and low blood potassium as compared to controls. C. collinus extract inhibited ATPase activity in rat kidney. Plasma K+ did not increase in human blood incubated with C. collinus extract. Conclusions and Implications: Active principles of C. collinus inhibit proton pumps in the renal brush border, resulting in type I DRTA in rats. There is no inhibition of sodium�potassium pump activity. Test animals develop respiratory acidosis, and the immediate cause of death is respiratory arrest.
Maneksh, Delinda; Sidharthan, Anita; Kettimuthu, Kavithapriya; Kanthakumar, Praghalathan; Lourthuraj, Amala A.; Ramachandran, Anup; Subramani, Sathya
Severe dietary lysine restriction affects growth and body composition and hepatic gene expression for nitrogen metabolism in growing rats.
Dietary lysine restriction may differentially affect body growth and lipid and nitrogen metabolism, depending on the degree of lysine restriction. This study was conducted to examine the effect of dietary lysine restriction on growth and lipid and nitrogen metabolism with two different degree of lysine restriction. Isocaloric amino acid-defined diets containing 1.4% lysine (adequate), 0.70% lysine (50% moderate lysine restriction) and 0.35% lysine (75% severe lysine restriction) were fed from the age of 52 to 77�days for 25�days in male Sprague-Dawley rats. The 75% severe lysine restriction increased (p�<�0.05) food intake, but retarded (p�<�0.05) growth, increased (p�<�0.05) liver and muscle lipid contents and abdominal fat accumulation, increased (p�<�0.05) blood urea nitrogen levels and mRNA levels of the serine-synthesizing 3-phosphoglycerate dehydrogenase gene, but decreased (p�<�0.05) urea cycle arginase gene mRNA levels. In contrast, the 50% lysine restriction did not significantly (p�>�0.05) affect body growth and lipid and nitrogen metabolism. Our results demonstrate that severe 75% lysine restriction has detrimental effects on body growth and deregulate lipid and nitrogen metabolism. PMID:23441935
Kim, J; Lee, K S; Kwon, D-H; Bong, J J; Jeong, J Y; Nam, Y S; Lee, M S; Liu, X; Baik, M
[A case of sever septic shock following transurethral lithotripsy].
A 62-year-old man was scheduled for transurethral lithotripsy. Systemic shivering, vomiting and decreased blood pressure occurred after extubation. Blood gas analysis showed metabolic acidosis. After 45 minute observation, he became unconsciousness. He was reintubated. Elevated procalcitonin (PCT) and endotoxin activity assay (EAA) brought us to the diagnosis of severe septic shock. He was treated by a standard therapy conforming to early goal direct therapy and PMX-DHP with CHDF. He showed full recovery, and was discharged 9 days after the procedure. TUL is commonly performed, but it seldom leads to sepsis. We need to pay a careful attention peri- and postoperatively. PMID:24979868
Tobaru, Shiho; Izumi, Shunsuke; Saikawa, Satoko; Miyata, Yuji; Kakinohana, Manabu
Controlled Clinical Trial of Dichloroacetate for Treatment of Congenital Lactic Acidosis in Children
OBJECTIVE.Open-label studies indicate that oral dichloroacetate (DCA) may be effec- tive in treating patients with congenital lactic acidosis. We tested this hypothesis by conducting the first double-blind, randomized, control trial of DCA in this disease. METHODS.Forty-three patients who ranged in age from 0.9 to 19 years were enrolled. All patients had persistent or intermittent hyperlactatemia, and most had severe psychomotor
Peter W. Stacpoole; Douglas S. Kerr; Carie Barnes; S. Terri Bunch; Paul R. Carney; Eileen M. Fennell; Natalia M. Felitsyn; Robin L. Gilmore; Melvin Greer; George N. Henderson; Alan D. Hutson; Richard E. Neiberger; Ralph G. O'Brien; Ronald G. Quisling; Albert L. Shroads; Jonathan J. Shuster; Janet H. Silverstein; Douglas W. Theriaque; Edward Valenstein
Metabolism refers to all the physical and chemical processes in the body that convert or use energy, ... Elsas LJ II. Approach to inborn errors of metabolism. In: Goldman L, Schafer AI, eds. Cecil Medicine . ...
Cardiovascular Fitness, Insulin Resistance and Metabolic Syndrome in Severely Obese Prepubertal Italian Children
Aim: To evaluate if insulin resistance (IR) and metabolic syndrome (MS) were associated with poor cardiovascular fitness in very obese prepubertal Italian subjects. Methods: Children referred to the Endocrinology and Diabetes Unit of Bambino Ges� Children�s Hospital underwent an OGTT with glucose and insulin assays. QUICKI, ISI and HOMA-IR were calculated. Total and HDL cholesterol, triglycerides and percentage of body
Claudia Brufani; Armando Grossi; Danilo Fintini; Rossana Fiori; Graziamaria Ubertini; Diego Colabianchi; Paolo Ciampalini; Alberto Tozzi; Fabrizio Barbetti; Marco Cappa
Dilutional acidosis: where do the protons come from?
Purpose��To investigate the mechanism of acidosis developing after saline infusion (dilutional acidosis or hyperchloremic acidosis).\\u000a \\u000a \\u000a \\u000a Methods��We simulated normal extracellular fluid dilution by infusing distilled water, normal saline and lactated Ringer�s solution.\\u000a Simulations were performed either in a closed system or in a system open to alveolar gases using software based on the standard\\u000a laws of mass action and mass conservation.
Luciano Gattinoni; E. Carlesso; G. Maiocchi; F. Polli; P. Cadringher
Impact of hypoxia-related tumor acidosis on cytotoxicity of different chemotherapeutic drugs in vitro and in vivo.
Extracellular acidosis in tumors leads to an activation of the p-glycoprotein (Pgp) drug transporter. In the present study the cytotoxicity of different chemotherapeutic drugs and its dependence on the Pgp activity during acidosis were analyzed in vitro and in vivo. Treating R3327-AT1, Pgp-positive tumor cells at pH 7.4 with daunorubicin, cisplatin or docetaxel led to marked apoptosis induction and cell death. Under acidic (pH 6.6) conditions cytotoxicity of daunorubicin or docetaxel was significantly reduced whereas cisplatin-induced cell death was almost pH-independent. Inhibiting Pgp with verapamil reversed the acidosis-induced chemoresistance against daunorubicin and docetaxel. The Pgp expression was unaffected by pH. In vivo the cytotoxicity of daunorubicin and docetaxel was also pH dependent. When acidifying the tumors by forcing glycolytic metabolism, apoptosis induction decreased significantly indicating a reduced chemosensitivity. The cytotoxic effect of cisplatin in vivo was unaffected by the tumor pH. Since daunorubicin and docetaxel (but not cisplatin) are substrates of the Pgp, these results underline the influence of the tumor acidosis on the Pgp-mediated chemoresistance which can be counteracted by inhibition of the drug transporter. PMID:24729214
Thews, Oliver; Riemann, Anne; Nowak, Martin; Gekle, Michael
Serum leptin concentration in moderate and severe obesity: relationship with clinical, anthropometric and metabolic factors
OBJECTIVE: To study clinical, anthropometric and metabolic determinants of serum leptin concentrations in a series of patients with a wide range of obesity.SUBJECTS: 400 patients, 116 males and 284 females, aged 44�12.3 years with body mass index (BMI) ranging from 31 to 82 kg\\/m2 (mean 41.4�7.1).MEASUREMENTS: Energy intake by 7-day recall, resting energy expenditure (REE) by indirect calorimetry, body composition
A Liuzzi; G Savia; M Tagliaferri; R Lucantoni; ME Berselli; ML Petroni; C De Medici; GC Viberti
Alterations in Coagulation Induced by Hypothermia and Acidosis in Swine.
National Technical Information Service (NTIS)
Although clinical coagulopathy is associated with acidosis and hypothermia, the underlying mechanisms by which these factors alter the coagulation process remains unclear. The primary purpose of this study was to investigate the contributory effects of ac...
W. Z. Martini J. B. Holcomb J. M. Uscilowicz A. V. Delgado A. E. Pusateri
Vasodilator Effects of Local Hypercapnic Acidosis in Dog Skeletal Muscle.
National Technical Information Service (NTIS)
Local hypercapnic acidosis, produced by intra-arterial administration of acid solutions decreased vascular resistance or the perfused gastrocnemius muscle of the dog. The response or venous blood pH, was less pronounced than previously found in the human ...
H. A. Kontos M. D. Thames A. Lombana C. O. Watlington F. Jessee
Distal Renal Tubular Acidosis in Infancy: A Bicarbonate Wasting State
ERIC Educational Resources Information Center
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)
Rodriguez-Soriano, J.; And Others
Increased blood flow prevents intramucosal acidosis in sheep endotoxemia: a controlled study
Introduction Increased intramucosal�arterial carbon dioxide tension (PCO2) difference (?PCO2) is common in experimental endotoxemia. However, its meaning remains controversial because it has been ascribed to hypoperfusion of intestinal villi or to cytopathic hypoxia. Our hypothesis was that increased blood flow could prevent the increase in ?PCO2. Methods In 19 anesthetized and mechanically ventilated sheep, we measured cardiac output, superior mesenteric blood flow, lactate, gases, hemoglobin and oxygen saturations in arterial, mixed venous and mesenteric venous blood, and ileal intramucosal PCO2 by saline tonometry. Intestinal oxygen transport and consumption were calculated. After basal measurements, sheep were assigned to the following groups, for 120 min: (1) sham (n = 6), (2) normal blood flow (n = 7) and (3) increased blood flow (n = 6). Escherichia coli lipopolysaccharide (5 ?g/kg) was injected in the last two groups. Saline solution was used to maintain blood flood at basal levels in the sham and normal blood flow groups, or to increase it to about 50% of basal in the increased blood flow group. Results In the normal blood flow group, systemic and intestinal oxygen transport and consumption were preserved, but ?PCO2 increased (basal versus 120 min endotoxemia, 7 � 4 versus 19 � 4 mmHg; P < 0.001) and metabolic acidosis with a high anion gap ensued (arterial pH 7.39 versus 7.35; anion gap 15 � 3 versus 18 � 2 mmol/l; P < 0.001 for both). Increased blood flow prevented the elevation in ?PCO2 (5 � 7 versus 9 � 6 mmHg; P = not significant). However, anion-gap metabolic acidosis was deeper (7.42 versus 7.25; 16 � 3 versus 22 � 3 mmol/l; P < 0.001 for both). Conclusions In this model of endotoxemia, intramucosal acidosis was corrected by increased blood flow and so might follow tissue hypoperfusion. In contrast, anion-gap metabolic acidosis was left uncorrected and even worsened with aggressive volume expansion. These results point to different mechanisms generating both alterations.
Dubin, Arnaldo; Murias, Gaston; Maskin, Bernardo; Pozo, Mario O; Sottile, Juan P; Baran, Marcelo; Edul, Vanina S Kanoore; Canales, Hector S; Badie, Julio C; Etcheverry, Graciela; Estenssoro, Elisa
Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPAR?.
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 (PPAR?) 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 PPAR? 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 PPAR? knockout (PPAR? FKO) mouse model with almost no visible brown and white adipose tissue at age 3 mo. As a consequence, PPAR? 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. PPAR? 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 PPAR? in these tissues. Together, our data reveal the necessity of fat PPAR? in adipose formation, whole-body metabolic homeostasis, and normal development of fat-containing tissues. PMID:24167256
Wang, Fenfen; Mullican, Shannon E; DiSpirito, Joanna R; Peed, Lindsey C; Lazar, Mitchell A
Relationship between rickets and incomplete distal renal tubular acidosis in children
Background In the Sub Saharan Africa Rickets has now been established to be due primarily to calcium deficiency and sometimes in combination with vitamin D deficiency. The main thrust of management is calcium supplementation with or without vitamin D. An observation was made that some children with nutritional rickets do not respond to this management modality. The recently reported high prevalence of Incomplete Distal Renal Tubular Acidosis (idRTA) in adults with osteoporosis as brought to fore the possibility of this being a possible cause of calcium wastage and therefore the poor response in these group of children with rickets. Aim To determine the prevalence of idRTA amongst a cohort of subjects with rickets To show a relationship between rickets and incomplete distal renal acidosis To determine the response of children with rickets and idRTA to addition of Shohl's solution to therapy Methodology Two separate cohorts of children with rickets performed the ammonium chloride loading test to detect those with incomplete renal tubular acidosis. Following identification for idRTA, Shohl's solution was added to therapy of calcium and vitamin D supplementation and their response compared to those without idRTA on calcium and vitamin D supplementation solely. Results 50 children with rickets aged from two to six years of age and composed of 29 females and 21males were investigated. Incomplete renal tubular acidosis was found in 38% of them. Prevalence of idRTA was highest amongst those aged 3-6 years of age. Those with idRTA had worse limb deformities, biochemical and radiological parameters than those who hadn't. Rate of response on those with idRTA treated with Shohl's solution was at par with those without idRTA. Conclusion Incomplete idRTA exist amongst children with rickets and should be looked out for in severe rickets and older children. Treatment of idRTA will lead to optimal response and healing of rickets.
Electrolyte imbalances and nephrocalcinosis in acute phosphate poisoning on chronic type 1 renal tubular acidosis due to Sj�gren's syndrome.
Although renal calcium crystal deposits (nephrocalcinosis) may occur in acute phosphate poisoning as well as type 1 renal tubular acidosis (RTA), hyperphosphatemic hypocalcemia is common in the former while normocalcemic hypokalemia is typical in the latter. Here, as a unique coexistence of these two seperated clinical entities, we report a 30-yr-old woman presenting with carpal spasm related to hypocalcemia (ionized calcium of 1.90 mM/L) due to acute phosphate poisoning after oral sodium phosphate bowel preparation, which resolved rapidly after calcium gluconate intravenously. Subsequently, type 1 RTA due to Sj�gren's syndrome was unveiled by sustained hypokalemia (3.3 to 3.4 mEq/L), persistent alkaline urine pH (> 6.0) despite metabolic acidosis, and medullary nephrocalcinosis. Through this case report, the differential points of nephrocalcinosis and electrolyte imbalances between them are discussed, and focused more on diagnostic tests and managements of type 1 RTA. PMID:23400265
Cho, Sung-Gun; Yi, Joo-Hark; Han, Sang-Woong; Kim, Ho-Jung
Characterization of the interaction between local cerebral metabolic rate for glucose and acid-base index in ischemic rat brain employing a double-isotope methodology
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.
Peek, K.E.H.
Putrescine catabolism is a metabolic response to several stresses in Escherichia coli.
Genes whose products degrade arginine and ornithine, precursors of putrescine synthesis, are activated by either regulators of the nitrogen-regulated (Ntr) response or ?(S) -RNA polymerase. To determine if dual control regulates a complete putrescine catabolic pathway, we examined expression of patA and patD, which specify the first two enzymes of one putrescine catabolic pathway. Assays of PatA (putrescine transaminase) activity and ?-galactosidase from cells with patA-lacZ transcriptional and translational fusions indicate dual control of patA transcription and putrescine-stimulated patA translation. Similar assays for PatD indicate that patD transcription required ?(S) -RNA polymerase, and Nac, an Ntr regulator, enhanced the ?(S) -dependent transcription. Since Nac activation via ?(S) -RNA polymerase is without precedent, transcription with purified components was examined and the results confirmed this conclusion. This result indicates that the Ntr regulon can intrude into the ?(S) regulon. Strains lacking both polyamine catabolic pathways have defective responses to oxidative stress, high temperature and a sublethal concentration of an antibiotic. These defects and the ?(S) -dependent expression indicate that polyamine catabolism is a core metabolic response to stress. PMID:23531166
Schneider, Barbara L; Hernandez, V James; Reitzer, Larry
Cerebrospinal fluid lactic acidosis in bacterial meningitis.
A rapid, microenzymatic method was used to measure cerebrospinal fluid lactate levels in 205 children with suspected bacterial meningitis. Fifty children with normal CSF containing fewer than 0.005 X 10(9)/l WBC, no segmented neutrophils, glucose 3.4 +/- 0.8 mmol/l (61.2 +/- 14.4 mg/100 ml), and a protein of less than 0.30 g/l had CSF lactate levels below 2.0 mmol/l (18 mg/100 ml) (mean and standard deviation 1.3 +/- 0.3 mmol/l (11.8 +/- 2.7 mg/100 ml)). In 31 cases of proved viral meningitis as with 58 cases of clinically diagnosed viral meningitis, levels were below 3.8 mmol/l (34.5 mg/100 ml), being 2.3 +/- 0.6 mmol/l (20.9 +/- 5.4 mg/100 ml), and 2.1 +/- 0.7 mmol/l (19.1 +/- 6.4 mg/100 ml) respectively. Sixty-six cases of bacterial meningitis had CSF lactate levels ranging from 3.9 mmol/l (35.4 mg/100 ml) to greater than 10.0 mmol/l (90.0 mg/100 ml). Longitudinal studies in 7 children with bacterial meningitis showed that cerebrospinal fluid lactate levels differentiated bacterial from viral meningitis up to 4 days after starting treatment with antibiotics. Use of CSF lactate measurement for monitoring the efficacy of treatment is illustrated in a case of bacterial meningitis due to Pseudomonas aeruginosa. The origin of the cerebrospinal fluid lactate acidosis and the role of lactate in the pathophysiological cycle leading to intensification of brain tissue hypoxia and cellular damage is discussed with respect to the short-term prognosis and the long-term neurological sequelae.
Eross, J; Silink, M; Dorman, D
Traditional Anthropometric Parameters Still Predict Metabolic Disorders in Women With Severe Obesity
It is well established that fat distribution rather than the total quantity of fat is the major determinant of cardiovascular risk in overweight subjects. However, it is not known whether the concept of fat distribution still makes sense in severely obese subjects. Particularly, the role of visceral fat accumulation and\\/or of adipocyte hypertrophy in insulin resistance (IR) has not been
S�verine Ledoux; Muriel Coupaye; Marie Essig; Simon Msika; Carine Roy; Isabelle Queguiner; Christine Clerici; Etienne Larger
Role of drugs in recovery of metabolic function of rat brain following severe hypoglycemia
Severe hypoglycemia with isoelectric EEG induced extensive deterioration of the energy state and gross alteration of amino acid contents on the rat cerebral and cerebellar cortex. During recovery, tissue glucose concentration returned to normal, while both lactate and pyruvate concentrations increased to above normal. In the recovery period, the ATP concentration increased but the adenine nucleotide pool remained reduced, even
Gianni Benzi; Roberto F. Villa; Maurizia Dossena; Lorena Vercesi; Antonella Gorini; Ornella Pastoris
Regional variation in adipose tissue metabolism of severely obese premenopausal women
Lipolytic and lipoprotein lipase (LPL) activities were studied in isolated human adipocytes obtained from two intraab- domina1 depots (round ligament and omental) and from the sub- cutaneous abdominal region of nine severely obese premenopausal women (with body mass indices ranging from 37 to 51 kg\\/m*), aged 36 f 3 yr, undergoing gastrointestinal surgery. Both fat cell weight and LPL activity
P. Mauriige; A. Marette; C. Atgii; C. Bouchard; L. K. Bukaviecki; P. Marceau; S. Biron; A. Nadeau
Severity of neuropsychological impairment in cocaine and alcohol addiction: association with metabolism in the prefrontal cortex
We used exploratory and confirmatory statistical approaches to study the severity of neuropsychological (NP) impairment in 42 crack\\/cocaine addicted subjects and in 112 comparison subjects (40 alcoholics and 72 controls). Twenty neuropsychological test indices most reliably defining predetermined cognitive domains were submitted to exploratory factor analysis. A four-dimensional model of neurocognitive function was derived: Verbal Knowledge, Visual Memory, Verbal Memory,
Rita Z. Goldstein; Andreana C. Leskovjan; Anne L. Hoff; Robert Hitzemann; Francine Bashan; Sahib Singh Khalsa; Gene-Jack Wang; Joanna S. Fowler; Nora D. Volkow
Severe Drug-induced Liver Injury Associated with Prolonged Use of Linezolid
This study aims to describe a patient developing concomitant severe liver failure and lactic acidosis after long-term treatment\\u000a with linezolid. A 55-year-old Caucasian woman developed concomitant severe liver failure and lactic acidosis after a treatment\\u000a with linezolid for 50�days because of infected hip prosthesis. Other causes of liver failure and lactic acidosis were excluded\\u000a by extensive diagnostic workup. A liver
Liesbet De Bus; Pieter Depuydt; Louis Libbrecht; Linos Vandekerckhove; Joke Nollet; Dominique Benoit; Dirk Vogelaers; Hans Van Vlierberghe
Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis
Metabolic dysfunction is an important modulator of disease course in amyotrophic lateral sclerosis (ALS). We report here that a familial mouse model (transgenic mice over-expressing the G93A mutation of the Cu/Zn superoxide dismutase 1 gene) of ALS enters a progressive state of acidosis that is associated with several metabolic (hormonal) alternations that favor lipolysis. Extensive investigation of the major determinants of H+ concentration (i.e., the strong ion difference and the strong ion gap) suggests that acidosis is also due in part to the presence of an unknown anion. Consistent with a compensatory response to avert pathological acidosis, ALS mice harbor increased accumulation of glycogen in CNS and visceral tissues. The altered glycogen is associated with fluctuations in lysosomal and neutral ?-glucosidase activities. Disease-related changes in glycogen, glucose, and ?-glucosidase activity are also found in spinal cord tissue samples of autopsied patients with ALS. Collectively, these data provide insights into the pathogenesis of ALS as well as potential targets for drug development.
Dodge, James C.; Treleaven, Christopher M.; Fidler, Jonathan A.; Tamsett, Thomas J.; Bao, Channa; Searles, Michelle; Taksir, Tatyana V.; Misra, Kuma; Sidman, Richard L.; Cheng, Seng H.; Shihabuddin, Lamya S.
Successful treatment of uterine torsion in a cat with severe metabolic and haemostatic complications.
A peri-parturient fifteen-month-old female Maine Coon cat was presented with extreme weakness and depression, profound hypovolaemia and hypothermia. Severe hyperkalaemia, hyponatraemia and anaemia were detected. Disseminated intravascular coagulation was suspected due to marked prolongation of activated partial thromboplastin time. Uterine torsion was diagnosed at exploratory laparotomy. The cat made a full recovery following ovariohysterectomy and intensive supportive therapy. PMID:11716604
Ridyard, A E; Welsh, E A; Gunn-Moore, D A
Oxidative damage in muscular dystrophy correlates with the severity of the pathology: role of glutathione metabolism.
Muscular dystrophies (MDs) such as Duchenne muscular dystrophy (DMD), sarcoglycanopathy (Sgpy) and dysferlinopathy (Dysfy) are recessive genetic neuromuscular diseases that display muscle degeneration. Although these MDs have comparable endpoints of muscle pathology, the onset, severity and the course of these diseases are diverse. Different mechanisms downstream of genetic mutations might underlie the disparity in these pathologies. We surmised that oxidative damage and altered antioxidant function might contribute to these differences. The oxidant and antioxidant markers in the muscle biopsies from patients with DMD (n�=�15), Sgpy (n�=�15) and Dysfy (n�=�15) were compared to controls (n�=�10). Protein oxidation and lipid peroxidation was evident in all MDs and correlated with the severity of pathology, with DMD, the most severe dystrophic condition showing maximum damage, followed by Sgpy and Dysfy. Oxidative damage in DMD and Sgpy was attributed to the depletion of glutathione (GSH) and lowered antioxidant activities while loss of GSH peroxidase and GSH-S-transferase activities was observed in Dysfy. Lower GSH level in DMD was due to lowered activity of gamma-glutamyl cysteine ligase, the rate limiting enzyme in GSH synthesis. Similar analysis in cardiotoxin (CTX) mouse model of MD showed that the dystrophic muscle pathology correlated with GSH depletion and lipid peroxidation. Depletion of GSH prior to CTX exposure in C2C12 myoblasts exacerbated oxidative damage and myotoxicity. We deduce that the pro and anti-oxidant mechanisms could be correlated to the severity of MD and might influence the dystrophic pathology to a different extent in various MDs. On a therapeutic note, this could help in evolving novel therapies that offer myoprotection in MD. PMID:22219131
Renjini, R; Gayathri, N; Nalini, A; Srinivas Bharath, M M
Effect of a severe hypoxia on some aspects of nitrogen metabolism in the crab cancer pagurus
Resting C. pagurus was exposed to severe hypoxia (Pw02 = 40 Torr and 15 Torr) for 5h at 15�C. Ammonia excretion rate and GDH activity in muscle tissue were measured in regularly fed and starved crabs.A 50% and 60% decrease in ammonia excretion rate was observed at a Pw02 of 40 Torr and 15 Torr, respectively, in regularly fed crabs.
Mich�le Regnault
Comparison of the dipeptidyl peptidase-4 gene methylation levels between severely obese subjects with and without the metabolic syndrome
Background The dipeptidyl peptidase-4 (DPP4) enzyme is a novel adipokine potentially involved in the development of the metabolic syndrome (MetS). Previous observations demonstrated higher visceral adipose tissue (VAT) DPP4 gene expression in non-diabetic severely obese men with (MetS+) vs. without (MetS?) MetS. DPP4 mRNA abundance in VAT correlated also with CpG site methylation levels (%Meth) localized within and near its exon 2 (CpG94 to CpG102) in non-diabetic severely obese women, regardless of their MetS status. The actual study tested whether DPP4 %Meth levels in VAT are different between MetS? and MetS+ non-diabetic severely obese subjects, whether variable metabolic and plasma lipid profiles are observed between DPP4 %Meth quartiles, and whether correlation exists in DPP4 %Meth levels between VAT and white blood cells (WBCs). Methods DNA was extracted from the VAT of 26 men (MetS?: n=12, MetS+: n=14) and 79 women (MetS?: n=60; MetS+: n=19), as well as from WBCs in a sub-sample of 17 women (MetS?: n=9; MetS+: n=8). The %Meth levels of CpG94 to CpG102 were assessed by pyrosequencing of sodium bisulfite-treated DNA. ANOVA analyses were used to compare the %Meth of CpGs between MetS? and MetS+ groups, and to compare the metabolic phenotype and plasma lipid levels between methylation quartiles. Pearson correlation coefficient analyses were computed to test the relationship between VAT and WBCs CpG94-102 %Meth levels. Results No difference was observed in CpG94-102 %Meth levels between MetS? and MetS+ subjects in VAT (P=0.67), but individuals categorized into CpG94-102 %Meth quartiles had variable plasma total-cholesterol concentrations (P=0.04). The %Meth levels of four CpGs in VAT were significantly correlated with those observed in WBCs (r=0.55?0.59, P?0.03). Conclusions This study demonstrated that %Meth of CpGs localized within and near the exon 2 of the DPP4 gene in VAT are not associated with MetS status. The actual study also revealed an association between the %Meth of this locus with plasma total-cholesterol in severe obesity, which suggests a link between the DPP4 gene and plasma lipid levels.
Severe hyperkalemia as a complication of timolol, a topically applied beta-adrenergic antagonist
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.
Swenson, E.R.
Severe hyperkalemia as a complication of timolol, a topically applied beta-adrenergic antagonist.
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. PMID:3718111
Swenson, E R
Mitochondrial uncoupling reduces exercise capacity despite several skeletal muscle metabolic adaptations.
The effects of mitochondrial uncoupling on skeletal muscle mitochondrial adaptation and maximal exercise capacity are unknown. In this study, rats were divided into a control group (CTL, n = 8) and a group treated with 2,4-dinitrophenol, a mitochondrial uncoupler, for 28 days (DNP, 30 mg�kg(-1)�day(-1) in drinking water, n = 8). The DNP group had a significantly lower body mass (P < 0.05) and a higher resting oxygen uptake (Vo2, P < 0.005). The incremental treadmill test showed that maximal running speed and running economy (P < 0.01) were impaired but that maximal Vo2 (Vo2max) was higher in the DNP-treated rats (P < 0.05). In skinned gastrocnemius fibers, basal respiration (V0) was higher (P < 0.01) in the DNP-treated animals, whereas the acceptor control ratio (ACR, Vmax/V0) was significantly lower (P < 0.05), indicating a reduction in OXPHOS efficiency. In skeletal muscle, DNP activated the mitochondrial biogenesis pathway, as indicated by changes in the mRNA expression of PGC1-? and -?, NRF-1 and -2, and TFAM, and increased the mRNA expression of cytochrome oxidase 1 (P < 0.01). The expression of two mitochondrial proteins (prohibitin and Ndufs 3) was higher after DNP treatment. Mitochondrial fission 1 protein (Fis-1) was increased in the DNP group (P < 0.01), but mitofusin-1 and -2 were unchanged. Histochemical staining for NADH dehydrogenase and succinate dehydrogenase activity in the gastrocnemius muscle revealed an increase in the proportion of oxidative fibers after DNP treatment. Our study shows that mitochondrial uncoupling induces several skeletal muscle adaptations, highlighting the role of mitochondrial coupling as a critical factor for maximal exercise capacities. These results emphasize the importance of investigating the qualitative aspects of mitochondrial function in addition to the amount of mitochondria. PMID:24336883
Schlagowski, A I; Singh, F; Charles, A L; Gali Ramamoorthy, T; Favret, F; Piquard, F; Geny, B; Zoll, J
Persistent metabolic sequelae of severe head injury in humans in vivo.
Six patients who had suffered severe non-penetrating high velocity head injuries were investigated with phosphorus (31P) magnetic resonance spectroscopy (MRS) to determine, non-invasively, long-term alteration in intracellular biochemistry. The normal subjects were found to have a constant intracellular pH (pHi, 7.03 +/- 0.03) with depth into the brain. The adenosine triphosphate (ATP, 3.46 +/- 0.66 mmol/L of brain tissue), inorganic phosphate (Pi, 1.15 +/- 0.41 mmol/L) and phosphomonester (PME, 2.76 +/- 1.0 mmol/L) tissue concentrations did not alter significantly with depth into normal brain. The phosphocreatine (PCr, 2 cm = 5.21 +/- 1.25, 5 cm = 4.85 +/- 1.49 mmol/L) was slightly reduced, whilst phosphodiesters (PDE, 2 cm = 9.53 +/- 2.6, 5 cm = 14.41 +/- 4.2 mmol/L) rose significantly between tissue comprising mainly of gray (2 cm) and white matter (5 cm). In comparison the contra-lateral hemisphere to the side of worst spasticity showed significant changes a considerable time after injury (6-18 months). The intracellular metabolite tissue concentrations were all reduced by 30% (ATP 2.53 +/- 1.0 mmol/L, PCr 3.44 +/- 0.8 mmol/L) with PDE reduced most significantly at depth (5 cm = 8.4 +/- 3.4 mmol/L), compatible with the cerebral atrophy seen in these patients. In white matter the pHi also decreased with depth (2 cm = 7.03 +/- 0.03, 5 cm = 6.89 +/- 0.05). The reduction in pHi so long after injury is difficult to explain in these steady-state conditions. A structural abnormality, such as a disorder in the blood brain barrier or accumulation of large acidic lysosomes, could cause these pHi changes. There may also be a failure in blood flow regulation, with near critical fluctuations in blood flow both with time and space. PMID:2386083
Cadoux-Hudson, T A; Wade, D; Taylor, D J; Rajagopalan, B; Ledingham, J G; Briggs, M; Radda, G K
Severe acute malnutrition in childhood: hormonal and metabolic status at presentation, response to treatment, and predictors of mortality.
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
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; Freemark, Michael
Changes in the Rumen Epimural Bacterial Diversity of Beef Cattle as Affected by Diet and Induced Ruminal Acidosis
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.
Petri, R. M.; Schwaiger, T.; Penner, G. B.; Beauchemin, K. A.; Forster, R. J.; McKinnon, J. J.
The spectrum of renal tubular acidosis in paediatric Sjogren syndrome
Objectives. Renal tubular acidosis (RTA) is a well-recognized extraglandular complication of adult Sjogren syndrome (SS) but has been reported only rarely in paediatric SS. We wished to describe the natural history of RTA in paediatric SS. Methods. We performed a chart and literature review. Inclusion criteria were primary or secondary SS with onset before 18 yr of age, complicated by
F. Pessler; H. Emery; L. Dai; Y.-M. Wu; B. Monash; R. Q. Cron; M. Pradhan
Acidosis, magnesium and acetylsalicylic acid: Effects on thrombin
NASA Astrophysics Data System (ADS)
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.
Borisevich, Nikolaj; Loznikova, Svetlana; Sukhodola, Aleksandr; Halets, Inessa; Bryszewska, Maria; Shcharbin, Dzmitry
Sodium Bicarbonate for the Treatment of Lactic Acidosis
Lactic acidosis often challenges the intensivist and is associated with a strikingly high mortality. Treatment involves discerning and correcting its underlying cause, ensuring adequate oxygen delivery to tissues, reducing oxygen demand through sedation and mechanical ventilation, and (most controversially) attempting to alkalinize the blood with IV sodium bicarbonate. Here we review the literature to answer the following questions: Is a
Sean M. Forsythe; Gregory A. Schmidt
Analysis of metabolic flux phenotypes for two Arabidopsis mutants with severe impairment in seed storage lipid synthesis
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}.
Lonien, J.; Schwender, J.
Bench-to-bedside review: Oxygen debt and its metabolic correlates as quantifiers of the severity of hemorrhagic and post-traumatic shock
Evidence is increasing that oxygen debt and its metabolic correlates are important quantifiers of the severity of hemorrhagic and post-traumatic shock and and may serve as useful guides in the treatment of these conditions. The aim of this review is to demonstrate the similarity between experimental oxygen debt in animals and human hemorrhage\\/post-traumatic conditions, and to examine metabolic oxygen debt
Dieter Rixen; John H Siegel
Central role of lactic acidosis in cancer cell resistance to glucose deprivation-induced cell death.
Solid tumours are dependent on glucose, but are generally glucose-deprived due to poor vascularization. Nevertheless, cancer cells can generally survive glucose deprivation better than their normal counterparts. Thus, to render cancer cells sensitive to glucose depletion may potentially provide an effective strategy for cancer intervention. We propose that lactic acidosis, a tumour microenvironment factor, may allow cancer cells to develop resistance to glucose deprivation-induced death, and that disruption of lactic acidosis may resume cancer cells' sensitivity to glucose depletion. Lactic acidosis, lactosis, or acidosis was generated by adding pure lactic acid, sodium lactate, or HCl to the culture medium. Cell death, cell cycle, autophagy, apoptosis, and gene expression profiling of the surviving cancer cells under glucose deprivation with lactic acidosis were determined. Under glucose deprivation without lactic acidosis, 90% of 4T1 cancer cells died within a single day; in a sharp contrast, under lactic acidosis, 90% of 4T1 cells died in a period of 10 days, with viable cells identified even 65 days after glucose was depleted. Upon glucose restoration, surviving cells resumed proliferation. Lactic acidosis also significantly extended survival of other cancer cells under glucose deprivation. G1/G0 arrest, autophagy induction, and apoptosis inhibition were tightly associated with lactic acidosis-mediated resistance to glucose deprivation. Lactosis alone had no effect on cell survival under glucose deprivation; acidosis alone can prolong cell survival time but is not as potent as lactic acidosis. Thus, the ability of cancer cells to resist glucose deprivation-induced cell death is conferred, at least in part, by lactic acidosis, and we envision that disrupting the lactic acidosis may resume the sensitivity of cancer cells to glucose deprivation. PMID:22190257
Wu, Hao; Ding, Zonghui; Hu, Danqing; Sun, Feifei; Dai, Chunyan; Xie, Jiansheng; Hu, Xun
Effects of ulinastatin on cerebral oxygen metabolism and CRP levels in patients with severe traumatic brain injury
The aim of the present study was to investigate the effects of ulinastatin on cerebral oxygen metabolism and C-reactive protein (CRP) levels in patients with severe traumatic brain injury (sTBI). A total of 92 patients with sTBI, admitted to the First Affiliated Hospital of Xinxiang Medical University (Xinxiang, China), were randomly divided into control and observation groups. The control group received conventional therapy plus a placebo (0.9% sodium chloride), while the observation group were administered conventional therapy plus 200,000 units ulinastatin via intravenous injection twice a day for seven days. Arterial and jugular venous blood was collected for blood gas analysis. The jugular venous blood lactate (JVBL), jugular venous bulb oxygen saturation (SjvO2), arteriovenous oxygen content difference (AVDO2) and cerebral extraction of oxygen (CEO2) levels were measured on day 1, 3, 5 and 7, as well as the level of CRP in the peripheral blood. In the control group, the level of JVBL decreased as compared with the level at day 1, however, no statistically significant differences were observed (P>0.05). By contrast, the observation group exhibited a significant reduction in the level of JVBL (P<0.05), which was also significantly lower compared with the control group (P<0.05). Statistically significant differences were observed between the two groups with regard to SjvO2, AVDO2 and CEO2 on day 3, 5 and 7. The CRP levels in the two groups increased and peaked on day 3. However, the CRP level in the observation group significantly decreased on day 5 (35.27�15.18 mg/l) and day 7 (22.65�10.48 mg/l), which was lower compared with the control group (56.19�13.24 mg/l and 47.36�15.73 mg/l, respectively); statistically significant differences were observed (P<0.05). Therefore, ulinastatin effectively improved cerebral oxygen metabolism and reduced the CRP level in patients with sTBI.
Distal renal tubular acidosis in mice that lack the forkhead transcription factor Foxi1
While macro- and microscopic kidney development appear to proceed normally in mice that lack Foxi1, electron microscopy reveals an altered ultrastructure of cells lining the distal nephron. Northern blot analyses, cRNA in situ hybridizations, and immunohistochemistry demonstrate a complete loss of expression of several anion transporters, proton pumps, and anion exchange proteins expressed by intercalated cells of the collecting ducts, many of which have been implicated in hereditary forms of distal renal tubular acidosis (dRTA). In Foxi1-null mutants the normal epithelium with its two major cell types � principal and intercalated cells � has been replaced by a single cell type positive for both principal and intercalated cell markers. To test the functional consequences of these alterations, Foxi1�/� mice were compared with WT littermates in their response to an acidic load. This revealed an inability to acidify the urine as well as a lowered systemic buffer capacity and overt acidosis in null mutants. Thus, Foxi1�/� mice seem to develop dRTA due to altered cellular composition of the distal nephron epithelium, thereby denying this epithelium the proper gene expression pattern needed for maintaining adequate acid-base homeostasis.
Blomqvist, Sandra Rodrigo; Vidarsson, Hilmar; Fitzgerald, Sharyn; Johansson, Bengt R.; Ollerstam, Anna; Brown, Russell; Persson, A. Erik G.; Bergstrom, Goran; Enerback, Sven
A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations
Nuclear-encoded disorders of mitochondrial translation are clinically and genetically heterogeneous. Genetic causes include defects of mitochondrial aminoacyl-tRNA synthetases, and factors required for initiation, elongation and termination of protein synthesis as well as ribosome recycling. We report on a new case of myopathy, lactic acidosis and sideroblastic anemia (MLASA) syndrome caused by defective mitochondrial tyrosyl aminoacylation. The patient presented at 1 year with anemia initially attributed to iron deficiency. Bone marrow aspirate at 5 years revealed ringed sideroblasts but transfusion dependency did not occur until 11 years. Other clinical features included lactic acidosis, poor weight gain, hypertrophic cardiomyopathy and severe myopathy leading to respiratory failure necessitating ventilatory support. Long-range PCR excluded mitochondrial DNA rearrangements. Clinical diagnosis of MLASA prompted direct sequence analysis of the YARS2 gene encoding the mitochondrial tyrosyl-tRNA synthetase, which revealed homozygosity for a known pathogenic mutation, c.156C>G;p.F52L. Comparison with four previously reported cases demonstrated remarkable clinical homogeneity. First line investigation of MLASA should include direct sequence analysis of YARS2 and PUS1 (encoding a tRNA modification factor) rather than muscle biopsy. Early genetic diagnosis is essential for counseling and to facilitate appropriate supportive therapy. Reasons for segregation of specific clinical phenotypes with particular mitochondrial aminoacyl tRNA-synthetase defects remain unknown. � 2013 Wiley Periodicals, Inc.
Shahni, Rojeen; Wedatilake, Yehani; Cleary, Maureen A; Lindley, Keith J; Sibson, Keith R; Rahman, Shamima
Multiple Intestinal Intussusceptions as a Complication of Severe Hyperglycemia in a Patient with Diabetic Ketoacidosis
Intussusception in adults is a rare phenomenon, occurring in approximately 1 in 30,000 hospital admissions annually. When it does occur, the majority of cases involve an organic lesion serving as a lead point for intussusception, such as tumors or postoperative adhesions. In a small percentage of cases, a lead point is not found, and intussusception is thought to be idiopathic or secondary to a disease process contributing to dysrhythmic peristalsis of the gastrointestinal tract. A few cases of functional intussusception have been reported as being secondary to severe hyperglycemia and metabolic derangements, including metabolic acidosis and hyperkalemia, by causing impaired gastrointestinal motility. We present a case of a 23-year-old Caucasian male who presented with severe hyperglycemia and diabetic ketoacidosis. Imaging of the abdomen revealed three intussusceptions involving the small intestine, which were easily reduced manually during exploratory laparotomy.
Raghavan, Pooja; Salon, Jeffrey; Rajan, Dhyan
Human cytochrome p450 2s1: lack of activity in the metabolic activation of several cigarette smoke carcinogens and in the metabolism of nicotine.
Cytochrome P450 (P450) enzymes play a critical role in the metabolic activation of a wide variety of environmental carcinogens. Recently, a novel human P450 enzyme, CYP2S1, has been identified. It is inducible by dioxin and other classical aryl hydrocarbon receptor ligands. However, little is known regarding the substrates and the functional role of CYP2S1. Since CYP2S1 is predominantly expressed in human lung and trachea, it is reasonable to speculate that CYP2S1 may play an important role in metabolizing the environmental chemicals to which human respiratory tissues are exposed. In the present study, we examined the activity of human CYP2S1 in the metabolism of nicotine and in the activation of three potent carcinogens in cigarette smoke, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), benzo[a]pyrene (BaP), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). The full-length CYP2S1 cDNA was amplified by nested polymerase chain reaction from a human lung cDNA library and was expressed in both Chinese hamster ovary (CHO) cells and Sf9 insect cells. In contrast to the positive controls, i.e., CHO cells expressing human CYP2A13 (for NNK activation) or human CYP1A1 (for BaP activation), there was no increase in NNK- or BaP-induced toxicity in the CHO cells expressing CYP2S1. The heterologously expressed CYP2S1 proteins showed no detectable activity in metabolizing nicotine and PhIP. These results clearly demonstrate that CYP2S1 does not catalyze the metabolism of nicotine and the metabolic activation of these lung carcinogens. PMID:15608128
Wang, Shou-Lin; He, Xiao-Yang; Hong, Jun-Yan
Severe necrosis of oesophageal and gastric mucosa in fatal methanol poisoning.
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
Cascallana, Jos� L; Gordo, Ver�nica; Montes, Rosario
MTO1 Mutations are Associated with Hypertrophic Cardiomyopathy and Lactic Acidosis and Cause Respiratory Chain Deficiency in Humans and Yeast
We report three families presenting with hypertrophic cardiomyopathy, lactic acidosis, and multiple defects of mitochondrial respiratory chain (MRC) activities. By direct sequencing of the candidate gene MTO1, encoding the mitochondrial-tRNA modifier 1, or whole exome sequencing analysis, we identified novel missense mutations. All MTO1 mutations were predicted to be deleterious on MTO1 function. Their pathogenic role was experimentally validated in a recombinant yeast model, by assessing oxidative growth, respiratory activity, mitochondrial protein synthesis, and complex IV activity. In one case, we also demonstrated that expression of wt MTO1 could rescue the respiratory defect in mutant fibroblasts. The severity of the yeast respiratory phenotypes partly correlated with the different clinical presentations observed in MTO1 mutant patients, although the clinical outcome was highly variable in patients with the same mutation and seemed also to depend on timely start of pharmacological treatment, centered on the control of lactic acidosis by dichloroacetate. Our results indicate that MTO1 mutations are commonly associated with a presentation of hypertrophic cardiomyopathy, lactic acidosis, and MRC deficiency, and that ad hoc recombinant yeast models represent a useful system to test the pathogenic potential of uncommon variants, and provide insight into their effects on the expression of a biochemical phenotype.
Baruffini, Enrico; Dallabona, Cristina; Invernizzi, Federica; Yarham, John W; Melchionda, Laura; Blakely, Emma L; Lamantea, Eleonora; Donnini, Claudia; Santra, Saikat; Vijayaraghavan, Suresh; Roper, Helen P; Burlina, Alberto; Kopajtich, Robert; Walther, Anett; Strom, Tim M; Haack, Tobias B; Prokisch, Holger; Taylor, Robert W; Ferrero, Ileana; Zeviani, Massimo; Ghezzi, Daniele
MTO1 mutations are associated with hypertrophic cardiomyopathy and lactic acidosis and cause respiratory chain deficiency in humans and yeast.
We report three families presenting with hypertrophic cardiomyopathy, lactic acidosis, and multiple defects of mitochondrial respiratory chain (MRC) activities. By direct sequencing of the candidate gene MTO1, encoding the mitochondrial-tRNA modifier 1, or whole exome sequencing analysis, we identified novel missense mutations. All MTO1 mutations were predicted to be deleterious on MTO1 function. Their pathogenic role was experimentally validated in a recombinant yeast model, by assessing oxidative growth, respiratory activity, mitochondrial protein synthesis, and complex IV activity. In one case, we also demonstrated that expression of wt MTO1 could rescue the respiratory defect in mutant fibroblasts. The severity of the yeast respiratory phenotypes partly correlated with the different clinical presentations observed in MTO1 mutant patients, although the clinical outcome was highly variable in patients with the same mutation and seemed also to depend on timely start of pharmacological treatment, centered on the control of lactic acidosis by dichloroacetate. Our results indicate that MTO1 mutations are commonly associated with a presentation of hypertrophic cardiomyopathy, lactic acidosis, and MRC deficiency, and that ad hoc recombinant yeast models represent a useful system to test the pathogenic potential of uncommon variants, and provide insight into their effects on the expression of a biochemical phenotype. PMID:23929671
Baruffini, Enrico; Dallabona, Cristina; Invernizzi, Federica; Yarham, John W; Melchionda, Laura; Blakely, Emma L; Lamantea, Eleonora; Donnini, Claudia; Santra, Saikat; Vijayaraghavan, Suresh; Roper, Helen P; Burlina, Alberto; Kopajtich, Robert; Walther, Anett; Strom, Tim M; Haack, Tobias B; Prokisch, Holger; Taylor, Robert W; Ferrero, Ileana; Zeviani, Massimo; Ghezzi, Daniele
The importance of early haemodiafiltration in the treatment of lactic acidosis associated with the administration of metformin.
Metformin is a drug widely used in type 2 diabetic patients. Metformin-associated lactic acidosis (MALA) in diabetic patients is rare but can be serious. However, the relationship between metformin and lactic acidosis is under debate. We present seven cases of patients with MALA who came to our centre over a period of one year and who were treated early with haemodiafiltration. There are some risk factors that appear to predispose patients to this pathology, such as: acute renal failure, situations of hypoxemia and sepsis, cardiac or respiratory failure, previous history of lactic acidosis, liver disease and dehydration. As such, the use of metformin is discouraged in patients with GFR below 30 ml/min/1.73 m(2). All patients in our study were treated early with haemodiafiltration. The mortality in our study was 16.6%. We believe that MALA is a serious condition that requires prompt diagnosis and early treatment. Renal replacement therapy is not the solution for all patients, but can improve prognosis in more severe cases if started early. We should limit the use of metformin in diabetic patients with impaired renal function, although there is still controversy in the medical literature. PMID:23013954
Bar�-Serra, Anna; Guasch-Aragay, Bernat; Mart�n-Alemany, N�dia; Sirvent, Josep M; Vall�s-Prats, Mart�
Introduction of an additional pathway for lactate oxidation in the treatment of lactic acidosis and mitochondrial dysfunction in Caenorhabditis elegans
Mitochondrial dysfunction, with an estimated incidence of 1 in 5,000 births, is associated with a wide variety of multisystem degenerative diseases. Among the most prevalent forms of dysfunction are defects in the NADH:ubiquinone oxidoreductase (complex I). Caenorhabditis elegans strains with complex I mutations exhibit characteristic features of human mitochondrial disease including decreased rates of respiration and lactic acidosis. We hypothesized that introducing an additional pathway for the direct oxidation of lactate would be beneficial for energy metabolism. The yeast CYB2 gene encodes an l-lactate:cytochrome c oxidoreductase that oxidizes lactate, donates electrons directly into the mitochondrial respiratory chain, and supports lactate-dependent respiration. Cyb2p expression markedly increases lifespan, fertility, respiration rates, and ATP content in complex I-deficient animals. Our results indicate that metabolic imbalance leading to lactic acidosis and energy depletion are central mechanisms of pathogenesis in mitochondrial dysfunction and that introduction of an additional pathway for lactate oxidation should be considered as a treatment.
Grad, Leslie I.; Sayles, Leanne C.; Lemire, Bernard D.
Brain metabolism is significantly impaired at blood glucose below 6 mM and brain glucose below 1 mM in patients with severe traumatic brain injury
INTRODUCTION: The optimal blood glucose target following severe traumatic brain injury (TBI) must be defined. Cerebral microdialysis was used to investigate the influence of arterial blood and brain glucose on cerebral glucose, lactate, pyruvate, glutamate, and calculated indices of downstream metabolism. METHODS: In twenty TBI patients, microdialysis catheters inserted in the edematous frontal lobe were dialyzed at 1 ?l\\/min, collecting
Roman Meierhans; Markus B�chir; Silke Ludwig; Jutta Sommerfeld; Giovanna Brandi; Christoph Haberth�r; Reto Stocker; John F Stover
An enzymatic bridge between carbohydrate and amino acid metabolism: regulation of glutamate dehydrogenase by reversible phosphorylation in a severe hypoxia-tolerant crayfish.
Glutamate dehydrogenase (GDH) (EC 188.8.131.52) is a crucial enzyme involved in bridging two metabolic pathways, gating the use of glutamate for either amino acid metabolism, or carbohydrate metabolism. The present study investigated GDH from tail muscle of the freshwater crayfish Orconectes virilis exploring changes to kinetic properties, phosphorylation levels and structural stability between two forms of the enzyme (aerobic control and 20-h severe hypoxic). Evidence indicated that GDH was converted to a high phosphate form under oxygen limitation. ProQ Diamond phosphoprotein staining showed a 42% higher bound phosphate content on GDH from muscle of severely hypoxic crayfish compared with the aerobic form, and treatment of this GDH with commercial phosphatase (alkaline phosphatase), and treatments that stimulated the activities of different endogenous protein phosphatases (stimulating PP1�+�PP2A, PP2B, and PP2C) yielded significant increases in the fold activation by ADP of GDH from both control and severe hypoxic conditions. By contrast, stimulation of the activities of endogenous protein kinases (AMPK, PKA or CaMK) significantly reduced the ADP fold activation from control animals. The physiological consequence of severe hypoxia-induced GDH phosphorylation may be to suppress GDH activity under low oxygen, shutting off this critical bridge point between two metabolic pathways. PMID:22076534
Dawson, Neal J; Storey, Kenneth B
Metabolic studies of transient tyrosinemia in premature infants
NASA Technical Reports Server (NTRS)
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.
Fernbach, S. A.; Summons, R. E.; Pereira, W. E.; Duffield, A. M.
Metabolic Shifts in Immunity and Inflammation
Sites of ongoing inflammation and triggered immune responses are characterized by significant changes in metabolic activity. Recent studies have indicated that such shifts in tissue metabolism result from a combination of profound recruitment of inflammatory cells (neutrophils and monocytes) and high proliferation rates among lymphocyte populations. The resultant shifts in energy supply and demand can result in metabolic acidosis and diminished delivery and/or availability of oxygen, leading to hypoxia extensive enough to trigger transcriptional and translation changes in tissue phenotype. Such phenotypic shifts can imprint fundamental changes to tissue metabolism. Here, we review recent work addressing metabolic changes and metabolic control of inflammation and immunity.
Kominsky, Douglas J.; Campbell, Eric L.; Colgan, Sean P.
Acidosis slows electrical conduction through the atrio-ventricular node
Acidosis affects the mechanical and electrical activity of mammalian hearts but comparatively little is known about its effects on the function of the atrio-ventricular node (AVN). In this study, the electrical activity of the epicardial surface of the left ventricle of isolated Langendorff-perfused rabbit hearts was examined using optical methods. Perfusion with hypercapnic Tyrode's solution (20% CO2, pH 6.7) increased the time of earliest activation (Tact) from 100.5 � 7.9 to 166.1 � 7.2 ms (n = 8) at a pacing cycle length (PCL) of 300 ms (37�C). Tact increased at shorter PCL, and the hypercapnic solution prolonged Tact further: at 150 ms PCL, Tact was prolonged from 131.0 � 5.2 to 174.9 � 16.3 ms. 2:1 AVN block was common at shorter cycle lengths. Atrial and ventricular conduction times were not significantly affected by the hypercapnic solution suggesting that the increased delay originated in the AVN. Isolated right atrial preparations were superfused with Tyrode's solutions at pH 7.4 (control), 6.8 and 6.3. Low pH prolonged the atrial-Hisian (AH) interval, the AVN effective and functional refractory periods and Wenckebach cycle length significantly. Complete AVN block occurred in 6 out of 9 preparations. Optical imaging of conduction at the AV junction revealed increased conduction delay in the region of the AVN, with less marked effects in atrial and ventricular tissue. Thus acidosis can dramatically prolong the AVN delay, and in combination with short cycle lengths, this can cause partial or complete AVN block and is therefore implicated in the development of brady-arrhythmias in conditions of local or systemic acidosis.
Nisbet, Ashley M.; Burton, Francis L.; Walker, Nicola L.; Craig, Margaret A.; Cheng, Hongwei; Hancox, Jules C.; Orchard, Clive H.; Smith, Godfrey L.
Influence of ammonia and pH on protein and amino acid metabolism in LLC-PK1 cells
Influence of ammonia and pH on protein and amino acid metabolism in LLC-PK1 cells. Metabolic acidosis inhibits protein synthesis (PS) and stimulates protein degradation (PD) in muscle and cultured myocytes but causes hypertrophy of the proximal tubule. The reason for this tissue-specific difference in response to acidosis is unknown, but it might be related to stimulation of renal ammonia production
Claudine T Jurkovitz; Brian K England; Ronald G Ebb; William E Mitch
Treatment of chronic congenital lactic acidosis by oral administration of dichloroacetate
Sodium dichloroacetate (DCA) was administered orally at a dose of 50 mg per kg body weight twice or three times per day to a newborn infant with lactic acidosis of unknown cause (patient 1) and to a 15-year-old boy with mitochondrial encephalomyopathy associated with lactic acidosis (patient 2). In patient 1, during treatment with DCA, DCA accumulated in the blood
Y. Kuroda; M. Ito; K. Toshima; E. Takeda; E. Naito; T. HASHIMOTO; M. MASUDA; K. Yamashita; T. Adachi; Y. Suzuki; K. Nishiyama
Acute renal failure and metformin-associated lactic acidosis following colonoscopy.
Two patients with type 2 DM developed acute kidney injury and lactic acidosis following colonoscopy despite withholding metformin. We recommend that DM patients on metformin also withhold ACEI, ARB until their dehydration is reversed after colonoscopy. This should reduce the risk of acute renal failure (ARF) and of lactic acidosis. PMID:24877743
Hussain, Mohammad I; Hall, Bruce M; Depczynski, Barbara; Connor, Susan J
Modeling and simulation of the main metabolism in Escherichia coli and its several single-gene knockout mutants with experimental verification
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.
Effects of adiposity and 30 days of caloric restriction upon protein metabolism in moderately vs. severely obese women.
Protein metabolism adapts during caloric restriction (CR) to minimize protein loss, and it is unclear whether greater fat stores favorably affect this response. We sought to determine whether protein metabolism is related to degree of obesity and whether the response to CR is impacted by pre-CR adiposity level. Whole body protein metabolism was studied in 12 obese women over a wide range of BMI (30-53 kg/m(2)) as inpatients using [1-(13)C]leucine as a tracer following 5 days of a weight-maintaining diet and then after 30 days of CR (1,400 kcal deficit with maintained protein intake). When expressed as total rates, per body weight (BW) or per fat-free mass (FFM), leucine rate of appearance (Ra), and nonoxidative leucine disposal (NOLD) were significantly higher in the individuals with a greater degree of obesity (P < 0.05). Leucine oxidation (Rox) was also higher in more highly obese women when expressed as a total rate (P < 0.05) but not if expressed per BW or FFM. CR reduced BW, FFM, and fat mass (P < 0.001), and declines were relatively similar between individuals. CR reduced Ra (P < 0.001), NOLD (P < 0.01), and Rox (P < 0.05), and the relative decline was not affected by differences in fat mass. CR-induced declines were significant even when Ra and NOLD were normalized to BW or FFM. We conclude that fat mass, like FFM, is a key determinant of protein turnover. However, during CR, higher fat mass does not favorably alter the response of protein metabolism and does not mitigate the loss of FFM. PMID:20134416
Henderson, Gregory C; Nadeau, Daniel; Horton, Edward S; Nair, K Sreekumaran
Measurement of urinary free and acylcarnitines: quantitative acylcarnitine profiling in normal humans and in several patients with metabolic errors
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.
Montgomery, J.A.; Mamer, O.A.
The prediction of basal metabolic rate in young adult, severely obese patients using single-frequency bioimpedance analysis
To evaluate whether bioimpedance analysis (BIA) is a useful tool for predicting basal metabolic rate (BMR), sex, age, height, weight, BMI, and single-frequency BIA variables (resistance index and phase angle) were assessed in 61 young adult non-diabetic obese patients (BMI >35 kg\\/m 2). BMR was measured by indirect calorimetry. In both sexes BMR significantly correlated with weight, BMI, and resistance
M. Marra; F. Pasanisi; L. Scalfi; P. Colicchio; M. Chelucci; F. Contaldo
Clinical profile of severe malaria: study from a tertiary care center in north India.
One hundred and sixty patients having clinical features of severe malaria reported during monsoon season-August-October 2010 at this tertiary care center of north India. Of these 110 (68.75�%) had Plasmodium vivax infection, 30 (18.75�%) were infected with P. falciparum and 20 (12.5�%) had co-infection due to P. vivax and P. falciparum. The diagnosis was made using Rapid Card Test and was confirmed by peripheral smear examination of thick and thin films. Several complications such as acute kidney injury, jaundice, severe anemia, metabolic acidosis, shock, hyperpyrexia, hypoglycemia, generalized tonic-clonic convulsions etc. were found to be more prevalent in patients with P. vivax infection. These symptoms were until recently known to be associated with falciparum malaria. PMID:24505170
Nandwani, Shafali; Pande, Apurva; Saluja, Mahip
Diisopropylamine Dichloroacetate, a Novel Pyruvate Dehydrogenase Kinase 4 Inhibitor, as a Potential Therapeutic Agent for Metabolic Disorders and Multiorgan Failure in Severe Influenza
Severe influenza is characterized by cytokine storm and multiorgan failure with metabolic energy disorders and vascular hyperpermeability. In the regulation of energy homeostasis, the pyruvate dehydrogenase (PDH) complex plays an important role by catalyzing oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle and fatty acid synthesis, and thus its activity is linked to energy homeostasis. The present study tested the effects of diisopropylamine dichloroacetate (DADA), a new PDH kinase 4 (PDK4) inhibitor, in mice with severe influenza. Infection of mice with influenza A PR/8/34(H1N1) virus resulted in marked down-regulation of PDH activity and ATP level, with selective up-regulation of PDK4 in the skeletal muscles, heart, liver and lungs. Oral administration of DADA at 12-h intervals for 14 days starting immediately after infection significantly restored PDH activity and ATP level in various organs, and ameliorated disorders of glucose and lipid metabolism in the blood, together with marked improvement of survival and suppression of cytokine storm, trypsin up-regulation and viral replication. These results indicate that through PDK4 inhibition, DADA effectively suppresses the host metabolic disorder-cytokine cycle, which is closely linked to the influenza virus-cytokine-trypsin cycle, resulting in prevention of multiorgan failure in severe influenza.
Yamane, Kazuhiko; Indalao, Irene L.; Chida, Junji; Yamamoto, Yoshikazu; Hanawa, Masaaki; Kido, Hiroshi
Diisopropylamine dichloroacetate, a novel pyruvate dehydrogenase kinase 4 inhibitor, as a potential therapeutic agent for metabolic disorders and multiorgan failure in severe influenza.
Severe influenza is characterized by cytokine storm and multiorgan failure with metabolic energy disorders and vascular hyperpermeability. In the regulation of energy homeostasis, the pyruvate dehydrogenase (PDH) complex plays an important role by catalyzing oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle and fatty acid synthesis, and thus its activity is linked to energy homeostasis. The present study tested the effects of diisopropylamine dichloroacetate (DADA), a new PDH kinase 4 (PDK4) inhibitor, in mice with severe influenza. Infection of mice with influenza A PR/8/34(H1N1) virus resulted in marked down-regulation of PDH activity and ATP level, with selective up-regulation of PDK4 in the skeletal muscles, heart, liver and lungs. Oral administration of DADA at 12-h intervals for 14 days starting immediately after infection significantly restored PDH activity and ATP level in various organs, and ameliorated disorders of glucose and lipid metabolism in the blood, together with marked improvement of survival and suppression of cytokine storm, trypsin up-regulation and viral replication. These results indicate that through PDK4 inhibition, DADA effectively suppresses the host metabolic disorder-cytokine cycle, which is closely linked to the influenza virus-cytokine-trypsin cycle, resulting in prevention of multiorgan failure in severe influenza. PMID:24865588
Yamane, Kazuhiko; Indalao, Irene L; Chida, Junji; Yamamoto, Yoshikazu; Hanawa, Masaaki; Kido, Hiroshi
Metabolic programming of obesity by energy restriction during the perinatal period: different outcomes depending on gender and period, type and severity of restriction
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.
Pico, Catalina; Palou, Mariona; Priego, Teresa; Sanchez, Juana; Palou, Andreu
Cerebral blood flow and metabolism in children with severe head injury. Part 1: Relation to age, Glasgow coma score, outcome, intracranial pressure, and time after injury.
Understanding the pathophysiology of paediatric head trauma is essential for rational acute management. It has been proposed that the response to severe head injury in children differs from that in adults, with increased cerebral blood flow (cerebral hyperaemia) representing the most common cause of raised intracranial pressure, but this has recently been disputed. The relation between the pathophysiological response and time after injury has not been defined in children. This paper describes 151 serial measurements of cerebral blood flow, arteriojugular venous oxygen difference (AJVDO2), and cerebral metabolic rate for oxygen (CMRO2) that were performed in 21 children with severe head injury, mean age 8 (range 2-16) years, Glasgow coma score < or = 8. Absolute cerebral hyperaemia was uncommon, only 10 (7%) of the 151 cerebral blood flow values being at or above the upper limit of the range published in normal children. There was an inverse correlation between cerebral blood flow and intracranial pressure. (r = -0.24, p = 0.009). Contrary to the widespread assumption that cerebral metabolic rate in patients with head injury is always low, CMRO2 was initially within the normal range in 17/21 (81%) children. Both CMRO2 and AJVDO2 fell significantly between the first and third days after injury. There was a non-significant rise in cerebral blood flow over time. These data represent the first evidence that the temporal change in cerebral metabolic rate reported in experimental models of traumatic brain injury also occurs in patients with head injury. The changes in the pathophysiological response over time suggest that the management may need to be modified accordingly. If cerebral metabolic rate and cerebral oxygen extraction are maximal shortly after injury in children with severe head injury then the children are most likely to sustain secondary damage during this period. Images
Sharples, P M; Stuart, A G; Matthews, D S; Aynsley-Green, A; Eyre, J A
Beyond Warburg effect - dual metabolic nature of cancer cells.
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
Xie, Jiansheng; Wu, Hao; Dai, Chunyan; Pan, Qiangrong; Ding, Zonghui; Hu, Danqing; Ji, Bingyan; Luo, Yan; Hu, Xun
Beyond Warburg effect - dual metabolic nature of cancer cells
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.
Xie, Jiansheng; Wu, Hao; Dai, Chunyan; Pan, Qiangrong; Ding, Zonghui; Hu, Danqing; Ji, Bingyan; Luo, Yan; Hu, Xun
Genealogy Profiling through Strain Improvement by Using Metabolic Network Analysis: Metabolic Flux Genealogy of Several Generations of Lysine-Producing Corynebacteria
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.
Wittmann, Christoph; Heinzle, Elmar
Effects of increased red cell mass on subclinical tissue acidosis in hyaline membrane disease.
AIM: To determine whether there are subclinical deficits in oxygen delivery in ventilated premature neonates. METHOD: Ventilated premature neonates weighing less than 1500 g, who were transfused for anaemia or who were given colloids for clotting abnormalities (or oedema), were haemodynamically monitored during the first week of life. Calf muscle surface pH (pH) was measured in conjunction with peripheral limb blood flow by occlusion plethysmography. RESULTS: Packed red blood cell transfusions corrected a subclinical regional tissue acidosis (low tpH) without affecting arterial pH or limb blood flow. This observation also correlated with an increase in regional oxygen delivery. The data were also suggestive of a pattern of pathological, supply dependent, oxygen delivery and are similar to other observations made in adults with adult respiratory distress syndrome. CONCLUSIONS: Packed red blood cells increase regional oxygen delivery and tissue surface pH. In contrast, colloid infusion provided no substantial cardiovascular or metabolic benefit to these patients and should be avoided when oxygen delivery is at issue and when there may be leaky pulmonary capillaries.
La Gamma, E F; Krauss, A; Auld, P A
Neural Correlates of the Severity of Cocaine, Heroin, Alcohol, MDMA and Cannabis Use in Polysubstance Abusers: A Resting-PET Brain Metabolism Study
Introduction Functional imaging studies of addiction following protracted abstinence have not been systematically conducted to look at the associations between severity of use of different drugs and brain dysfunction. Findings from such studies may be relevant to implement specific interventions for treatment. The aim of this study was to examine the association between resting-state regional brain metabolism (measured with 18F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) and the severity of use of cocaine, heroin, alcohol, MDMA and cannabis in a sample of polysubstance users with prolonged abstinence from all drugs used. Methods Our sample consisted of 49 polysubstance users enrolled in residential treatment. We conducted correlation analyses between estimates of use of cocaine, heroin, alcohol, MDMA and cannabis and brain metabolism (BM) (using Statistical Parametric Mapping voxel-based (VB) whole-brain analyses). In all correlation analyses conducted for each of the drugs we controlled for the co-abuse of the other drugs used. Results The analysis showed significant negative correlations between severity of heroin, alcohol, MDMA and cannabis use and BM in the dorsolateral prefrontal cortex (DLPFC) and temporal cortex. Alcohol use was further associated with lower metabolism in frontal premotor cortex and putamen, and stimulants use with parietal cortex. Conclusions Duration of use of different drugs negatively correlated with overlapping regions in the DLPFC, whereas severity of cocaine, heroin and alcohol use selectively impact parietal, temporal, and frontal-premotor/basal ganglia regions respectively. The knowledge of these associations could be useful in the clinical practice since different brain alterations have been associated with different patterns of execution that may affect the rehabilitation of these patients.
Moreno-Lopez, Laura; Stamatakis, Emmanuel A.; Fernandez-Serrano, Maria Jose; Gomez-Rio, Manuel; Rodriguez-Fernandez, Antonio; Perez-Garcia, Miguel; Verdejo-Garcia, Antonio
Hyperglycaemic crises and lactic acidosis in diabetes mellitus
Diabetic ketoacidosis, hyperglycaemic hyperosmolar state, and lactic acidosis represent three of the most serious acute complications of diabetes. There have been some advances in our understanding of the pathogenesis of these conditions over the last three decades, together with more uniform agreement on their treatment and innovations in technology. Accordingly their incidence, morbidity, and mortality are decreasing, but at rates that fall short of our aspirations. Hyperglycaemic crises in particular remain an important cause of morbidity and mortality in diabetic populations around the world. In this article, understanding of these conditions and advances in their management, and the available guidelines for their treatment, are reviewed. As far as is possible, the recommendations are based on clear published evidence; failing that, what is considered to be a common sense synthesis of consensus guidelines and recommendations is provided.
English, P; Williams, G
X-linked adrenoleukodystrophy: very long-chain fatty acid metabolism is severely impaired in monocytes but not in lymphocytes.
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 ?-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 ?-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 ?-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
Weber, Franziska D; Wiesinger, Christoph; Forss-Petter, Sonja; Regelsberger, G�nther; Einwich, Angelika; Weber, Willi H A; K�hler, Wolfgang; Stockinger, Hannes; Berger, Johannes
Lactic acidosis and hypoglycemia with ALL relapse following engrafted bone marrow transplant.
Lactic acidosis together with hypoglycemia in the face of hematologic malignancy is a grave development. A 7-year-old male with pre-B-cell ALL following hematopoietic cell transplant was admitted to our hospital in his second relapse. On hospital days 4 and 5, he developed refractory hypoglycemia, lactic acidosis, central respiratory failure, and acute renal failure. Bicarbonate infusion, B vitamins, and hemodialysis were not effective. Care was withdrawn on hospital day 9. Further understanding of the mechanisms that cause the combined onset of lactic acidosis and hypoglycemia will help clinicians in implementing timely therapies that may reduce mortality. PMID:19405138
Luscri, Nathan; Mauer, Michael; Sarafoglou, Kyriakie; Moran, Antoinette; Tolar, Jakub
Metabolic and Nutritional Status Changes After 10% WeightLoss in Severely Obese Patients Treated with Laparoscopic Surgery vs Integrated Medical Treatment
Background��Bariatric surgery is considered the most effective treatment for reducing excess body weight and maintaining weight loss (WL)\\u000a in severely obese patients. There are limited data evaluating metabolic and body composition changes after different treatments\\u000a in type III obese (body mass index [BMI]?>?40�kg\\/m2).\\u000a \\u000a \\u000a \\u000a Methods��Twenty patients (9 males, 11 females; 37.6?�?8�years; BMI?=?50.1?�?8�kg\\/m2) treated with dietary therapy and lifestyle correction (group 1)
Federica del Genio; Lucia Alfonsi; Maurizio Marra; Carmine Finelli; Gianmattia del Genio; Gianluca Rossetti; Alberto del Genio; Franco Contaldo; Fabrizio Pasanisi
Sequence and genetic organization of a Zymomonas mobilis gene cluster that encodes several enzymes of glucose metabolism
The Zymomonas mobilis genes that encode glucose-6-phosphate dehydrogenase (zwf), 6-phosphogluconate dehydratase (edd), and glucokinase (glk) were cloned independently by genetic complementation of specific defects in Escherichia coli metabolism. The identify of these cloned genes was confirmed by various biochemical means. Nucleotide sequence analysis established that these three genes are clustered on the genome and revealed an additional open reading frame in this region that has significant amino acid identity to the E.coli xylose-proton symporter and the human glucose transporter. On the basis of this evidence and structural analysis of the deduced primary amino acid sequence, this gene is believed to encode the Z. mobilis glucose-facilitated diffusion protein, glf. The four genes in the 6-kb cluster are organized in the order glf, zwf, edd, glk. The glf and zwf genes are separated by 146 bp. The zwf and edd genes overlap by 8 bp, and their expression may be translationally coupled. The edd and glk genes are separated by 203 bp. The glk gene is followed by tandem transcriptional terminators. The four genes appear to be organized in an operon. Such an arrangement of the genes that govern glucose uptake and the first three steps of the Entner-Doudoroff glycolytic pathway provides the organism with a mechanism for carefully regulating the levels of the enzymes that control carbon flux into the pathway.
Barnell, W.O.; Kyung Cheol Yi; Conway, T. (Univ. of Nebraska, Lincoln (United States))
Sequence and genetic organization of a Zymomonas mobilis gene cluster that encodes several enzymes of glucose metabolism.
The Zymomonas mobilis genes that encode glucose-6-phosphate dehydrogenase (zwf), 6-phosphogluconate dehydratase (edd), and glucokinase (glk) were cloned independently by genetic complementation of specific defects in Escherichia coli metabolism. The identity of these cloned genes was confirmed by various biochemical means. Nucleotide sequence analysis established that these three genes are clustered on the genome and revealed an additional open reading frame in this region that has significant amino acid identity to the E. coli xylose-proton symporter and the human glucose transporter. On the basis of this evidence and structural analysis of the deduced primary amino acid sequence, this gene is believed to encode the Z. mobilis glucose-facilitated diffusion protein, glf. The four genes in the 6-kb cluster are organized in the order glf, zwf, edd, glk. The glf and zwf genes are separated by 146 bp. The zwf and edd genes overlap by 8 bp, and their expression may be translationally coupled. The edd and glk genes are separated by 203 bp. The glk gene is followed by tandem transcriptional terminators. The four genes appear to be organized in an operon. Such an arrangement of the genes that govern glucose uptake and the first three steps of the Entner-Doudoroff glycolytic pathway provides the organism with a mechanism for carefully regulating the levels of the enzymes that control carbon flux into the pathway. Images
Barnell, W O; Yi, K C; Conway, T
Antioxidant and metabolic impairment result in DNA damage in arsenic-exposed individuals with severe dermatological manifestations in Eastern India.
Arsenic is an environmental toxicant, free-radical generator, carcinogenic agent, and aging promoter. Recently, blood samples were analyzed from individuals (control- male 12, female 13; arsenic-exposed- male 16, female 14; and exposed to ?100 ?g/L As, ?10 y) with dermatological symptoms in few affected villages in Eastern India to unravel their hematopoietic, metabolic, and antioxidant profiles. White blood cells recovered from buffy coat were used for DNA fragmentation test. Present observation suggests that significant number of individuals developed pigmentation and palmoplantar hyperkeratosis with black-brownish patch on their body and many of those developed carcinomas. Hematopoietic data show a significant increase in eosinophil and decrease in monocyte count in either sex. Though insignificant, an increase in neutrophil in female and lymphocyte count in male arsenic-exposed individuals are supported by the earlier report on sex dimorphic immune sensitization. Significant increase in serum alanine transaminase in both sexes and bilirubin only in male suggests the eventuality of hepatic disintegration. Arsenic exposure significantly decreased serum amylase in female. A significant decrease in antioxidant components like catalase, soluble thiol, and recently recognized uric acid worsened the situation by generating free radicals as observed in significant rise in malondialdehyde level, which finally increased DNA fragmentation and arsenic-associated mutagenesis and carcinogenesis. This could attribute to lowering in immune competence and related necrotic and/or apoptotic manifestations. PMID:20925122
Maiti, Smarajit; Chattopadhyay, Sandip; Deb, Bimal; Samanta, Tanmoy; Maji, Gurupada; Pan, Bappaditya; Ghosh, Amar; Ghosh, Debidas
Cerebral energy metabolism measured in vivo by 31P-NMR in middle cerebral artery occlusion in the cat--relation to severity of stroke.
The energy metabolism of the brain has been measured in a middle cerebral artery (MCA) occlusion model in the cat utilizing 31P-nuclear magnetic resonance (NMR). 31P-NMR spectra were serially obtained during 2 h of ischemia and a subsequent 4-h recovery period. The ratio of creatine phosphate (PCr) to inorganic phosphate (Pi) (PCr/Pi) showed a precipitous decrease in parallel with changes in electroencephalographic (EEG) amplitude in severe strokes during ischemia as well as during recirculation. Animals with mild strokes, as determined by EEG criteria, exhibited a much smaller decrease in PCr/Pi during ischemia. In the severe strokes, there was a splitting and significant shift of the Pi peak immediately after occlusion. In addition, the shifted Pi peak rapidly increased and remained elevated throughout the study. In the mild strokes, Pi also increased, but not as markedly. Intracellular pH determination by chemical shift of the Pi peak revealed a decrease from 7.1 to 6.2-6.3 during ischemia and the subsequent recovery period in the animals with severe strokes, whereas the pH in the animals with mild strokes did not show a significant change. A gradual decrease in adenosine triphosphate (ATP) to 57-79% of the control was exhibited in severely stroked animals during both the ischemia and the recovery period, whereas there was no change in ATP in the mild stroked animals. These results suggest that the dynamic process of pathophysiological changes in an MCA occlusion model in the cat leads to significant differences in cerebral metabolism between animals with mild and severe strokes. PMID:3654795
Komatsumoto, S; Nioka, S; Greenberg, J H; Yoshizaki, K; Subramanian, V H; Chance, B; Reivich, M
Effects of nitric oxide donors on cybrids harbouring the mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) A3243G mitochondrial DNA mutation
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.
Highly sensitive C-reactive protein and male gender are independently related to the severity of coronary disease in patients with metabolic syndrome and an acute coronary event.
Patients with metabolic syndrome are at high-risk for development of atherosclerosis and cardiovascular events. The objective of this study was to examine the major determinants of coronary disease severity, including those coronary risk factors associated with metabolic syndrome, during the early period after an acute coronary episode. We tested the hypothesis that inflammatory markers, especially highly sensitive C-reactive protein (hsCRP), are related to coronary atherosclerosis, in addition to traditional coronary risk factors. Subjects of both genders aged 30 to 75 years (N = 116) were prospectively included if they had suffered a recent acute coronary syndrome (acute myocardial infarction or unstable angina pectoris requiring hospitalization) and if they had metabolic syndrome diagnosed according to the National Cholesterol Education Program/Adult Treatment Panel III. Patients were submitted to a coronary angiography and the burden of atherosclerosis was estimated by the Gensini score. The severity of coronary disease was correlated (Spearman's or Pearson's coefficient) with gender (r = 0.291, P = 0.008), age (r = 0.218, P = 0.048), hsCRP (r = 0.256, P = 0.020), ApoB/ApoA ratio (r = 0.233, P = 0.041), and carotid intima-media thickness (r = 0.236, P = 0.041). After multiple linear regression, only male gender (P = 0.046) and hsCRP (P = 0.012) remained independently associated with the Gensini score. In this high-risk population, male gender and high levels of hsCRP, two variables that can be easily obtained, were associated with more extensive coronary disease, identifying patients with the highest potential of developing new coronary events. PMID:20209376
Monteiro, C M C; Pinheiro, L F; Izar, M C; Barros, S W; Vasco, M B; Fischer, S M; Povoa, R M; Brand�o, S A; Santos, A O; Oliveira, L; Carvalho, A C; Fonseca, F A H
Effect of strain and diet upon constitutive and chemically induced activities of several xenobiotic-metabolizing enzymes in rats
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
W. T. Stott; H. L. Kan; L. G. McFadden; B. R. Sparrow; B. B. Gollapudi
Treating Intraoperative Hyperchloremic Acidosis with Sodium Bicarbonate or Tris-Hydroxymethyl Aminomethane: A Randomized Prospective Study
In this study, we evaluated the action of two buffer so- lutions on acid-base equilibrium in cases of hyperchlo- remic acidosis. Twenty-four patients undergoing major gynecological intraabdominal surgery received 40 mL � kg1 �h 1 of 0.9% saline per protocol. During surgery, in every patient, hyperchloremic acidosis oc- curred. At a standard base excess of 7 mmol\\/L, the patients were
Markus Rehm; Udilo Finsterer
Sheep fed grain prefer foods and solutions that attenuate acidosis.
We conducted experiments to determine whether lambs fed grain prefer foods and solutions containing sodium bicarbonate (NaHCO3) and lasalocid, compounds capable of attenuating acidosis. In Exp. 1, we determined whether lambs fed barley preferred flavored rabbit pellets (RP) containing NaHCO3 and lasalocid. Lambs in two groups (n = 10/group) were fed increasing amounts of barley on d 1 to 12 (300 to 1,100 g) and again on d 23 to 34 (300 to 1,350 g). After ingesting barley on d 1 to 12, lambs were fed ground RP containing lasalocid and NaHCO3 (i.e., medicated) and flavored with either 2% onion (group 1) or 2% oregano (group 2). During d 23 to 34, lambs were fed unmedicated RP containing NaCl and flavored with either 2% oregano (group 1) or 2% onion (group 2). During preference tests on d 35 to 40, lambs fed grain preferred RP with NaHCO3 to RP with NaCl (151 vs. 96 g; P < .01). In the Exp. 2, we determined whether wheat ingestion affected consumption of aqueous solutions containing NaHCO3. In trial 1, 28 lambs were assigned to four treatments: 1) low-wheat + 2% NaHCO3, 2) high-wheat + 2% NaHCO3, 3) low-wheat + water, and 4) high-wheat + water. For 12 d from 0800 to 0830, lambs in treatments 1 and 3 were fed 300 g of wheat and lambs in treatments 2 and 4 were fed up to 1,300 g of wheat; fluids (NaHCO3 and water) were then offered from 0930 to 1230 daily. Lambs drank more NaHCO3 on the high- than on the low-wheat diet (1,332 vs 890 g; P = .03); water consumption was similar for lambs on the high- and low-wheat diets (1,675 vs 1,700 g; P > .10). In trial 2, lambs in treatments 3 and 4 were offered a solution containing 1.4% NaCl. For 13 d from 0800 to 0830, lambs in treatments 1 and 3 were fed 500 g of wheat and lambs in treatments 2 and 4 were fed up to 1,700 g of wheat. Lambs had access to fluids from 0800 to 1200 daily. Lambs drank nearly twice as much NaHCO3 solution on the high- than on the low-wheat diet (1,066 vs 572 g), whereas they drank only 1.4 times more NaCl solution on the high- than on the low-wheat diet (888 vs. 634 g; P < .001). Fewer lambs showed signs of acidosis in treatment 2 than in treatment 4 in trials 1 (2 vs 9) and 2 (7 vs 17). Collectively, these results are consistent with the hypothesis that lambs fed grain prefer substances that attenuate acidosis. PMID:9581916
Phy, T S; Provenza, F D
The anion gap does not accurately screen for lactic acidosis in emergency department patients
Introduction Lactic acidosis portends a poor prognosis in trauma, sepsis, and other shock states and is useful for triaging and resuscitating emergency department (ED) patients. The authors sought to determine whether the AG is a reliable screen for lactic acidosis when applied specifically in the ED setting. Methods The authors performed a retrospective cohort study over a seven month period. Subjects were all ED patients that had a serum lactate obtained. Sensitivity analyses of the AG for detecting presence of lactic acidosis were calculated for the traditional AG normal value (AG <12) and for the lower AG normal value when using newer ion selective electrode assays (AG <6). Results Serum lactate levels were ordered in the ED on 440 occasions. 137 samples were excluded by protocol. Using an AG cutoff of 12, the sensitivity for detecting lactic acidosis was 58.2%, specificity was 81.0%, and the negative predictive value was 89.7%. Using the AG cutoff of 6, the sensitivity was 93.2%, the specificity was 17.3%, and the negative predictive value was 91.8%. Conclusions The traditional definition of AG >12 was insensitive for the presence of lactic acidosis. Using the revised AG of >6 is more sensitive but non?specific for lactic acidosis. The authors conclude that employing the AG as a screen for LA may be inappropriate in ED patients. Instead, they recommend ordering a serum lactate immediately upon suspicion of a shock state. A prospective study to confirm these findings is needed.
Adams, B D; Bonzani, T A; Hunter, C J
A Retrospective Analysis of the Haemodynamic and Metabolic Effects of Fluid Resuscitation in Vietnamese Adults with Severe Falciparum Malaria
Background Optimising the fluid resuscitation of patients with severe malaria is a simple and potentially cost-effective intervention. Current WHO guidelines recommend central venous pressure (CVP) guided, crystalloid based, resuscitation in adults. Methods Prospectively collected haemodynamic data from intervention trials in Vietnamese adults with severe malaria were analysed retrospectively to assess the responses to fluid resuscitation. Results 43 patients were studied of whom 24 received a fluid load. The fluid load resulted in an increase in cardiac index (mean increase: 0.75 L/min/m2 (95% Confidence interval (CI): 0.41 to 1.1)), but no significant change in acid-base status post resuscitation (mean increase base deficit 0.6 mmol/L (95% CI: ?0.1 to 1.3). The CVP and PAoP (pulmonary artery occlusion pressure) were highly inter-correlated (rs?=?0.7, p<0.0001), but neither were correlated with acid-base status (arterial pH, serum bicarbonate, base deficit) or respiratory status (PaO2/FiO2 ratio). There was no correlation between the oxygen delivery (DO2) and base deficit at the 63 time-points where they were assessed simultaneously (rs?=??0.09, p?=?0.46). Conclusions In adults with severe falciparum malaria there was no observed improvement in patient outcomes or acid-base status with fluid loading. Neither CVP nor PAoP correlated with markers of end-organ perfusion or respiratory status, suggesting these measures are poor predictors of their fluid resuscitation needs.
Bethell, Delia; Mai, Nguyen Thi Hoang; Chau, Tran Thi Hong; Chuong, Ly Van; Loc, Pham Phu; Sinh, Dinh Xuan; Dondorp, Arjen; White, Nicholas; Hien, Tran Tinh; Day, Nicholas
Long-term Safety of Dichloroacetate in Congenital Lactic Acidosis
We followed 8 patients (4 males) with biochemically and/or molecular genetically proven deficiencies of the E1? subunit of the pyruvate dehydrogenase complex (PDC; 3 patients) or respiratory chain complexes I (1 patient), IV (3 patients) or I+IV (1 patient) who received oral dichloroacetate (DCA; 12.5 mg/kg/12 hours) for 9.7 to 16.5 years. All subjects originally participated in randomized controlled trials of DCA and were continued on an open-label chronic safety study. Patients (1 adult) ranged in age from 3.5 to 40.2 years at the start of DCA administration and are currently aged 16.9 to 49.9 years (mean � SD: 23.5 � 10.9 years). Subjects were either normal or below normal body weight for age and gender. The 3 PDC deficient patients did not consume high fat (ketogenic) diets. DCA maintained normal blood lactate concentrations, even in PDC deficient children on essentially unrestricted diets. Hematological, electrolyte, renal and hepatic status remained stable. Nerve conduction either did not change or decreased modestly and led to reduction or temporary discontinuation of DCA in 3 patients, although symptomatic worsening of peripheral neuropathy did not occur. We conclude that chronic DCA administration is generally well-tolerated in patients with congenital causes of lactic acidosis and is effective in maintaining normal blood lactate levels, even in PDC-deficient children not consuming strict ketogenic diets.
Abdelmalak, Monica; Lew, Alicia; Ramezani, Ryan; Shroads, Albert L.; Coats, Bonnie S.; Langaee, Taimour; Shankar, Meena N.; Neiberger, Richard E.; Subramony, S.H.; Stacpoole, Peter W.
Long-term safety of dichloroacetate in congenital lactic acidosis.
We followed 8 patients (4 males) with biochemically and/or molecular genetically proven deficiencies of the E1? subunit of the pyruvate dehydrogenase complex (PDC; 3 patients) or respiratory chain complexes I (1 patient), IV (3 patients) or I+IV (1 patient) who received oral dichloroacetate (DCA; 12.5 mg/kg/12 h) for 9.7 to 16.5 years. All subjects originally participated in randomized controlled trials of DCA and were continued on an open-label chronic safety study. Patients (1 adult) ranged in age from 3.5 to 40.2 years at the start of DCA administration and are currently aged 16.9 to 49.9 years (mean � SD: 23.5 � 10.9 years). Subjects were either normal or below normal body weight for age and gender. The 3 PDC deficient patients did not consume high fat (ketogenic) diets. DCA maintained normal blood lactate concentrations, even in PDC deficient children on essentially unrestricted diets. Hematological, electrolyte, renal and hepatic status remained stable. Nerve conduction either did not change or decreased modestly and led to reduction or temporary discontinuation of DCA in 3 patients, although symptomatic worsening of peripheral neuropathy did not occur. We conclude that chronic DCA administration is generally well-tolerated in patients with congenital causes of lactic acidosis and is effective in maintaining normal blood lactate levels, even in PDC-deficient children not consuming strict ketogenic diets. PMID:23611579
Abdelmalak, Monica; Lew, Alicia; Ramezani, Ryan; Shroads, Albert L; Coats, Bonnie S; Langaee, Taimour; Shankar, Meena N; Neiberger, Richard E; Subramony, S H; Stacpoole, Peter W
Expression of Glutamine Transporter Slc38a3 (SNAT3) During Acidosis is Mediated by a Different Mechanism than Tissue-Specific Expression.
Background: Despite homeostatic pH regulation, systemic and cellular pH changes take place and strongly influence metabolic processes. Transcription of the glutamine transporter SNAT3 (Slc38a3) for instance is highly up-regulated in the kidney during metabolic acidosis to provide glutamine for ammonia production. Methods: Slc38a3 promoter activity and messenger RNA stability were measured in cultured cells in response to different extracellular pH values. Results: Up-regulation of SNAT3 mRNA was mediated both by the stabilization of its mRNA and by the up-regulation of gene transcription. Stabilisation of the mRNA involved a pH-response element, while enhanced transcription made use of a second pH-sensitive Sp1 binding site in addition to a constitutive Sp1 binding site. Transcriptional regulation dominated the early response to acidosis, while mRNA stability was more important for chronic adaptation. Tissue-specific expression of SNAT3, by contrast, appeared to be controlled by promoter methylation and histone modifications. Conclusions: Regulation of SNAT3 gene expression by extracellular pH involves post-transcriptional and transcriptional mechanisms, the latter being distinct from the mechanisms that control the tissue-specific expression of the gene. � 2014 S. Karger AG, Basel. PMID:24854847
Balkrishna, Sarojini; Br�er, Angelika; Welford, Scott M; Hatzoglou, Maria; Br�er, Stefan
Development of Metabolic Indicators of Burn Injury: Very Low Density Lipoprotein (VLDL) and Acetoacetate Are Highly Correlated to Severity of Burn Injury in Rats
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.
Izamis, Maria-Louisa; Uygun, Korkut; Sharma, Nripen S.; Uygun, Basak; Yarmush, Martin L.; Berthiaume, Francois
Subacute rumen acidosis in lactating cows: an investigation in intensive Italian dairy herds.
Subacute rumen acidosis (SARA) represents one of the most important metabolic disorders in intensive dairy farms that affects rumen fermentations, animal welfare, productivity and farm profitability. The aim of the present study was to study the occurrence of SARA in intensive Italian dairy herds and to determine the relationship between diet composition, ruminal pH and short chain fatty acids (SCFA) concentration. Ten commercial dairy herds were investigated; twelve cows in each herd were selected randomly among animal without clinical signs of disease, with good body condition and between 5 and 60 day-in-milk (DIM), to perform rumenocentesis and obtain rumen fluid. Ruminal pH was determined immediately after sampling and concentration of SCFA in ruminal fluid was determined on samples after storage. An other objective of this research was to study in detail the effects of rumenocentesis on animal health: this study could confirm the extreme validity of this technique as ruminal sampling. Results were subject to anova and correlation analysis using SIGMA STAT 2.03. The results indicated the presence of SARA in three herds (more than 33% cows with rumen pH < 5.5), a critical situation (more than 33% cows with rumen pH < 5.8) in five farms and a normal rumen pH condition in two herds. In particular, dairy herds show on average SCFA concentration of 150, 145, 123 mmol/l for low pH, critical pH and normal pH herds respectively. There were not significant differences among diet composition even if herds with SARA showed a light discordance between initially chemistry composition and residual feed. In the affected herds it was not possible to understand the exact causes of SARA. Animal management seems to be one of the most important factors in developing SARA including total mixed ration preparation. PMID:17516944
Morgante, M; Stelletta, C; Berzaghi, P; Gianesella, M; Andrighetto, I
Reversible lactic acidosis in a newborn with thiamine transporter-2 deficiency.
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 ?-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
P�rez-Due�as, Bel�n; Serrano, Mercedes; Rebollo, M�nica; Muchart, Jordi; Gargallo, Eva; Dupuits, Celine; Artuch, Rafael
Altered glucose metabolism rather than naive type 2 diabetes mellitus (T2DM) is related to vitamin D status in severe obesity
Context The last decades have provided insights into vitamin D physiology linked to glucose homeostasis. Uncertainties remain in obesity due to its intrinsic effects on vitamin D and glucose tolerance. Objectives To assess the relationship between vitamin D and glucose abnormalities in severely obese individuals previously unknown to suffer from abnormal glucose metabolism. Setting Tertiary care centre. Patients 524 obese patients (50.3?�?14.9�yrs; BMI, 47.7?�?7.3�kg/m2) screened by OGTT, HbA1c and the lipid profile. Vitamin D status was assessed by 25(OH)D3, PTH and electrolyte levels. 25(OH)D3 deficiency/insufficiency were set at 20 and 30�ng/ml, respectively. All comparative and regression analyses were controlled for age, BMI and gender. Results The prevalence of vitamin D deficiency/insufficiency and secondary hyperparathyroidism were 95% and 50.8%, respectively. Normal glucose tolerance (NGT), impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM) were found in 37.8%, 40.5% and 21.7% of cases, respectively. Large variations in metabolic parameters were seen across categories of vitamin D status, but the only significant differences were found for C-peptide, tryglicerides, LDL- and HDL-cholesterol levels (p?0.05 for all). The prevalence of vitamin D deficiency was documented to be slightly but significantly more frequent in glucose-intolerant patients (IFG?+?IGT?+?T2DM) compared to the -normotolerant counterpart (87% vs. 80%, p?0.05). In partial correlation analyses, there was no association between vitamin D levels and glucose-related markers but for HbA1c (r?=??0.091, p?0.05), and both basal and OGTT-stimulated insulin levels (r?=?0.097 and r?=?0.099; p?0.05 for all). Vitamin D levels were also correlated to HDL-cholesterol (r?=?0.13, p?=?0.002). Multivariate regression analysis inclusive of vitamin D, age, BMI, gender and fat mass as independent variables, showed that vitamin D was capable of predicting HbA1c levels (??=??0.101, p?0.05). Conclusions Given the inherent effect of obesity on vitamin D and glucose homeostasis, current data suggest a potential independent role for vitamin D in the regulation of glucose metabolism in a setting of obese patients previously unknown to harbour glucose metabolism abnormalities.
Extracellular Acidosis Is a Novel Danger Signal Alerting Innate Immunity via the NLRP3 Inflammasome
Local extracellular acidification has been demonstrated at sites of ischemia and inflammation. IL-1? is one of the key proinflammatory cytokines, and thus, its synthesis and secretion are tightly regulated. The NLRP3 (nucleotide-binding domain leucine-rich repeat containing family, pyrin domain containing 3) inflammasome complex, assembled in response to microbial components or endogenous danger signals, triggers caspase-1-mediated maturation and secretion of IL-1?. In this study, we explored whether acidic environment is sensed by immune cells as an inflammasome-activating danger signal. Human macrophages were exposed to custom cell culture media at pH 7.5�6.0. Acidic medium triggered pH-dependent secretion of IL-1? and activation of caspase-1 via a mechanism involving potassium efflux from the cells. Acidic extracellular pH caused rapid intracellular acidification, and the IL-1?-inducing effect of acidic medium could be mimicked by acidifying the cytosol with bafilomycin A1, a proton pump inhibitor. Knocking down the mRNA expression of NLRP3 receptor abolished IL-1? secretion at acidic pH. Remarkably, alkaline extracellular pH strongly inhibited the IL-1? response to several known NLRP3 activators, demonstrating bipartite regulatory potential of pH on the activity of this inflammasome. The data suggest that acidic environment represents a novel endogenous danger signal alerting the innate immunity. Low pH may thus contribute to inflammation in acidosis-associated pathologies such as atherosclerosis and post-ischemic inflammatory responses.
Rajamaki, Kristiina; Nordstrom, Tommy; Nurmi, Katariina; ?kerman, Karl E. O.; Kovanen, Petri T.; Oorni, Katariina; Eklund, Kari K.
Val2Ala mutation in the Atp6v0a4 gene causes early-onset sensorineural hearing loss in children with recessive distal renal tubular acidosis: a case report.
Abstract A young female patient born to consanguineous parents was admitted to our clinic at the age of 3 years with a 5-month history of weight loss and recurrent urinary tract infections. Based on clinical findings (delayed growth and O-bein deformity) and laboratory tests (hypokalemia, hyperchloremia, partially compensated metabolic acidosis, alkaline urine and nephrocalsinosis), a diagnosis of distal renal tubular acidosis (dRTA) was made. Then, the audiogram revealed a bilateral sensorineural hearing loss (SNHL). On follow-up, bilateral SNHL progressively worsened requiring the need for hearing aid. The ATP6V0A4 gene mutation analysis showed homozygote Val2Ala mutation. To the best of our knowledge, this is the first report describing a Turkish girl with dRTA who suffered from early-onset SNHL caused by Val2Ala mutation in the ATP6V0A4 gene. PMID:24564331
Kose, Engin; Sirin Kose, Seda; Alparslan, Caner; Kasap Demir, Belde; Berdeli, Afig; Mutlubas Ozsan, Fatma; Yavascan, Onder; Aksu, Nejat
A dynamic model of excitation-contraction coupling during acidosis in cardiac ventricular myocytes.
Acidosis in cardiac myocytes is a major factor in the reduced inotropy that occurs in the ischemic heart. During acidosis, diastolic calcium concentration and the amplitude of the calcium transient increase, while the strength of contraction decreases. This has been attributed to the inhibition by protons of calcium uptake and release by the sarcoplasmic reticulum, to a rise of intracellular sodium caused by activation of sodium-hydrogen exchange, decreased calcium binding affinity to Troponin-C, and direct effects on the contractile machinery. The relative contributions and concerted action of these effects are, however, difficult to establish experimentally. We have developed a mathematical model to examine altered calcium-handling mechanisms during acidosis. Each of the alterations was incorporated into a dynamical model of pH regulation and excitation-contraction coupling to predict the time courses of key ionic species during acidosis, in particular intracellular pH, sodium and the calcium transient, and contraction. This modeling study suggests that the most significant effects are elevated sodium, inhibition of sodium-calcium exchange, and the direct interaction of protons with the contractile machinery; and shows how the experimental data on these contributions can be reconciled to understand the overall effects of acidosis in the beating heart. PMID:16473911
Crampin, Edmund J; Smith, Nicolas P
Analysis of Metabolic Flux Phenotypes for Two Arabidopsis Mutants with Severe Impairment in Seed Storage Lipid Synthesis1[W][OA
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?1pkp?; At5g52920 and At3g22960). Both already biochemically well-characterized mutants were now studied by 13C 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 (PKp) provides most of the pyruvate for plastidic fatty acid synthesis, the flux through PKp is reduced in pkp?1pkp? by 43% of the wild-type value. In wri1-1, PKp flux is even more reduced (by 82%), although the genes PKp?1 and PKp? are still expressed. Along a common paradigm of metabolic control theory, it is hypothesized that a large reduction in PKp enzyme activity in pkp?1pkp? has less effect on PKp flux than multiple smaller reductions in glycolytic enzymes in wri1-1. In addition, only in the wri1-1 mutant is the large reduction in PKp 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?1pkp?.
Lonien, Joachim; Schwender, Jorg
Brain metabolism is significantly impaired at blood glucose below 6 mM and brain glucose below 1 mM in patients with severe traumatic brain injury
Introduction The optimal blood glucose target following severe traumatic brain injury (TBI) must be defined. Cerebral microdialysis was used to investigate the influence of arterial blood and brain glucose on cerebral glucose, lactate, pyruvate, glutamate, and calculated indices of downstream metabolism. Methods In twenty TBI patients, microdialysis catheters inserted in the edematous frontal lobe were dialyzed at 1 ?l/min, collecting samples at 60 minute intervals. Occult metabolic alterations were determined by calculating the lactate- pyruvate (L/P), lactate- glucose (L/Glc), and lactate- glutamate (L/Glu) ratios. Results Brain glucose was influenced by arterial blood glucose. Elevated L/P and L/Glc were significantly reduced at brain glucose above 1 mM, reaching lowest values at blood and brain glucose levels between 6-9 mM (P < 0.001). Lowest cerebral glutamate was measured at brain glucose 3-5 mM with a significant increase at brain glucose below 3 mM and above 6 mM. While L/Glu was significantly increased at low brain glucose levels, it was significantly decreased at brain glucose above 5 mM (P < 0.001). Insulin administration increased brain glutamate at low brain glucose, but prevented increase in L/Glu. Conclusions Arterial blood glucose levels appear to be optimal at 6-9 mM. While low brain glucose levels below 1 mM are detrimental, elevated brain glucose are to be targeted despite increased brain glutamate at brain glucose >5 mM. Pathogenity of elevated glutamate appears to be relativized by L/Glu and suggests to exclude insulin- induced brain injury.
Usefulness of metabolic syndrome score in the prediction of angiographic coronary artery disease severity according to the presence of diabetes mellitus: relation with inflammatory markers and adipokines
Background It is a matter of debate whether metabolic syndrome (MS) improves cardiovascular risk prediction beyond the risk associated with its individual components. The present study examined the association of MS score with high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), resistin, adiponectin, and angiographic coronary artery disease (CAD) severity according to the presence of DM. In addition, the predictive value of various clinical and biochemical parameters were analyzed, including the MS score for angiographic CAD. Methods The study enrolled 363 consecutive patients (196 men, 62?�?11�years of age) who underwent coronary angiography for evaluation of chest pain. Blood samples were taken prior to elective coronary angiography. MS was defined by the National Cholesterol Education Program criteria, with MS score defined as the numbers of MS components. CAD was defined as?>?50% luminal diameter stenosis of at least one major epicardial coronary artery. CAD severity was assessed using the Gensini score. Results Of the 363 patients studied, 174 (48%) had CAD and 178 (49%) were diagnosed with MS. When the patients were divided into 4 subgroups according to MS score (0�1, 2, 3, 4�5), IL-6 levels and the CAD severity as assessed by the Gensini score increased as MS scores increased. In contrast, adiponectin levels decreased significantly as MS scores increased. When subjects were divided into two groups according to the presence of DM, the relationships between MS score and IL-6, adiponectin, and Gensini score were maintained only in patients without DM. Age, smoking, DM, MS score, and adiponectin independently predicted angiographic CAD in the whole population. However, age is the only predictor for angiographic CAD in patients with DM. Conclusions In the presence of DM, neither adipokines nor MS score predicted angiographic CAD. However, in non-diabetic patients, IL-6 and adiponectin showed progressive changes according to MS score, and MS score was an independent predictor of CAD in patients without DM.
Disruption of Glycerol Metabolism by RNAi Targeting of Genes Encoding Glycerol Kinase Results in a Range of Phenotype Severity in Drosophila
In Drosophila, RNAi targeting of either dGyk or dGK can result in two alternative phenotypes: adult glycerol hypersensitivity or larval lethality. Here we compare these two phenotypes at the level of glycerol kinase (GK) phosphorylation activity, dGyk and dGK-RNA expression, and glycerol levels. We found both phenotypes exhibit reduced but similar levels of GK phosphorylation activity. Reduced RNA expression levels of dGyk and dGK corresponded with RNAi progeny that developed into glycerol hypersensitive adult flies. However, quantification of dGyk/dGK expression levels for the larval lethality phenotype revealed unexpected levels possibly due to a compensatory mechanism between dGyk and dGK or RNAi inhibition. The enzymatic role of glycerol kinase converts glycerol to glycerol 3-phosphate. As expected, elevated glycerol levels were observed in larvae that went on to develop into glycerol hypersensitive adults. Interestingly, larvae that died before eclosion revealed extremely low glycerol levels. Further characterization identified a wing phenotype that is enhanced by a dGpdh null mutation, indicating disrupted glycerol metabolism underlies the wing phenotype. In humans, glycerol kinase deficiency (GKD) exhibits a wide range of phenotypic variation with no obvious genotype-phenotype correlations. Additionally, disease severity often does not correlate with GK phosphorylation activity. It is intriguing that both human GKD patients and our GKD Drosophila model show a range of phenotype severity. Additionally, the lack of correlation between GK phosphorylation and dGyk/dGK-RNA expression with phenotypic severity suggests further study including understanding the alternative functions of the GK protein, could provide insights into the complex pathogenic mechanism observed in human GKD patients.
Wightman, Patrick J.; Jackson, George R.; Dipple, Katrina M.
Metformin accumulation: lactic acidosis and high plasmatic metformin levels in a retrospective case series of 66 patients on chronic therapy.
OBJECTIVE. The relationship between metformin accumulation and lactate increase is still debated. This observational case series aims to evaluate the correlation of metformin plasma levels with the pH, lactate and creatinine levels, and with the mortality rate in selected patients with metformin accumulation confirmed through metformin plasma concentration detection at hospital admission. MATERIAL AND METHODS. All cases of lactic acidosis (pH, ? 7.35; arterial lactate, ? 5 mmol/L) related to metformin accumulation (plasma level ? 4 mcg/mL) from 2007 to 2011 were retrospectively reviewed. Erroneous ingestion and voluntary overdoses were excluded. Epidemiological, medical history, clinical and laboratory data were evaluated in all cases. RESULTS. Sixty-six patients were included. Thirty-one patients (47%) had contraindication to therapy with metformin. All patients showed severe lactic acidosis (pH, 6.91 � 0.18; lactate, 14.36 � 4.90 mmol/L) and acute renal failure (creatinine, 7.24 � 3.29 mg/dL). The mean metformin plasma concentration was 40.68 � 27.70 mcg/mL. Metformin plasma concentrations showed a correlation, statistically significant even if not strong, with creatinine (p = 0.002, R = 0.37), pH (p < 0.0001, R = - 0.43) and plasma lactate levels (p = 0.001, R = 0.41). Sixty-two (94%) underwent dialysis. Early mortality (before discharge from ICU) was 26% (17 cases). Lactate and metformin concentrations had mean levels not statistically different in surviving and deceased patients. CONCLUSIONS. Patients on chronic therapy with metformin may develop a mitochondrial-related toxicity that should be considered when patients present with lactic acidosis, renal failure, and frequently, a medical history of gastrointestinal manifestations during the days preceding the hospital admission. The correlation between metformin plasma concentrations and creatinine, pH, and lactate levels seems to be related to the mechanism of action (inhibition of complex I of the mitochondrial respiratory chain) and to the kinetic properties (high distribution volume and low protein binding) of the drug. The relevant early mortality seems not correlated with the levels of metformin or lactates: this could be due to the possible role of concurrent illness even if, such as for the relationships with lactate and creatinine, a more proper toxicological evaluation could be obtained by assessing metformin erythrocyte concentrations instead of the plasmatic ones. PMID:24283301
Vecchio, S; Giampreti, A; Petrolini, V M; Lonati, D; Protti, A; Papa, P; Rognoni, C; Valli, A; Rocchi, L; Rolandi, L; Manzo, L; Locatelli, C A
Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension
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.
Christou, Helen; Reslan, Ossama M.; Mam, Virak; Tanbe, Alain F.; Vitali, Sally H.; Touma, Marlin; Arons, Elena; Mitsialis, S. Alex; Kourembanas, Stella
Everything you need to know about distal renal tubular acidosis in autoimmune disease.
Renal acid-base homeostasis is a complex process, effectuated by bicarbonate reabsorption and acid secretion. Impairment of urinary acidification is called renal tubular acidosis (RTA). Distal renal tubular acidosis (dRTA) is the most common form of the RTA syndromes. Multiple pathophysiologic mechanisms, each associated with various etiologies, can lead to dRTA. The most important consequence of dRTA is (recurrent) nephrolithiasis. The diagnosis is based on a urinary acidification test. Potassium citrate is the treatment of choice. PMID:24682397
Both, Tim; Zietse, Robert; Hoorn, Ewout J; van Hagen, P Martin; Dalm, Virgil A S H; van Laar, Jan A M; van Daele, Paul L A
Carbenoxolone Treatment Ameliorated Metabolic Syndrome in WNIN/Ob Obese Rats, but Induced Severe Fat Loss and Glucose Intolerance in Lean Rats
Background 11beta-hydroxysteroid dehydrogenase type 1 (11?-HSD1) regulates local glucocorticoid action in tissues by catalysing conversion of inactive glucocorticoids to active glucocorticoids. 11?-HSD1 inhibition ameliorates obesity and associated co-morbidities. Here, we tested the effect of 11?-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 11?-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 11?-HSD1 inhibition by CBX decreases obesity and associated co-morbidities in WNIN/Ob obese rats. Our study supports the hypothesis that inhibition of 11?-HSD1 is a key strategy to treat metabolic syndrome. Severe fat loss and glucose -intolerance by CBX treatment in lean rats suggest that chronic 11?-HSD1 inhibition may lead to insulin resistance in normal conditions.
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
[Impact of lactic acid fermentation in the large intestine on acute lactic acidosis in cattle].
Microbial and fermentation changes in the ingesta of the large intestine and their influence on the pathogenesis of acute lactic acidosis were studied in 4 cows fitted with permanent cannulas in the ileum and cecum. Feed mixture containing 65% of maize was infused into the cecum for several days in amounts of 2 and 4 kg per day. The daily amount was divided in 8 equal portions and given with 3 l of warm physiologic saline solution. During the period of ad libitum feeding of hay, the pH values in cecal digesta were 7.4 to 7.6 and the amount of total volatile fatty acids 40-60 mmol/kg with high molar percentage (87-90 mol%) of acetic acid. As to lactic acid only the L(+) lactic isomer was found in a concentration of about 0.4 mmol/kg. Infusion of low amounts of starch induced mild lactic acid fermentation in the cecum associated with a pronounced increase in the concentration of L(+) and D (-) lactic acid to peak levels of 80 +/- 10 mmol/kg and 7 +/- 1 mmol/kg, respectively. Lactic acid fermentation ceased within 2 to 3 days indicating that the gut microflora had adapted to the starch infusion. Slight decreases of blood pH and bicarbonates in blood as well as a moderate increase of netto acid-base excretion in urine indicated mild changes of acid-base balance, but clinically no pathological symptoms were observed. Higher amounts of infused starch caused pronounced lactic acid production in the large intestine which persisted throughout the experiment. Peak L(+) and D(-) lactic acid concentration in cecal digesta reached on the average 137 +/- 16 mmol/kg and 45 +/- 7 mmol/kg respectively. Significant decreases of blood pH values from 7.41 +/- 0.02 to 7.18 +/- 0.08 (P < 0.001), actual bicarbonate from 28.2 +/- 3.2 to 11.0 +/- 2.6 mmol/l (P < 0.001) and base excess from 3.9 +/- 3.6 to -15.2 +/- 3.8 mmol/l (P < 0.001) were observed. D (-) lactic acid concentration in blood increased to 3.2 +/- 0.4 mmol/l, but L(+) lactic acid values remained unchanged under 1 mmol/l. Clear clinical symptoms of indigestion and intoxication characterized by severe inappetence, ruminal stasis and general weakness were also observed. Typical clinical symptoms of disease as well as blood and urine changes in acid-base balance indicated that lactic acid fermentation in the large intestine contributes considerably to the pathogenesis of acute ruminant lactic acidosis. PMID:11471493
Zust, J; Pestevsek, U; Vengust, A
An integrated analysis of glucose, fat, and protein metabolism in severely traumatized patients. Studies in the basal state and the response to total parenteral nutrition.
A series of isotopic infusions were performed in 43 severely ill patients suffering from blunt trauma (mean injury severity score of 31). The patient data have been compared with data obtained from 32 normal volunteers, and in addition the metabolic response of the trauma patient to total nutritional support (TPN) has been assessed. The rate of VO2 was elevated in the trauma patients compared with that of the volunteers (160 mumol/kg/minute vs. 103 mumol/kg/minute). Glucose production was significantly increased in the patients compared with the volunteers (21 +/- 2 mumol/kg/minute vs. 14 +/- 1 mumol/kg/minute), but the trauma patients had an impaired capacity to directly oxidize plasma glucose. The percentage of glucose uptake oxidized in the volunteers was 36 +/- 2%, and the percentage of glucose uptake recycled was 10 +/- 1%. By contrast, in the trauma patients, 23 +/- 4% of the glucose uptake was directly oxidized, and 29 +/- 11% was recycled. The rate of glycerol turnover in the trauma patients (5.3 +/- 0.3 mumol/kg/minute) was significantly elevated compared with the volunteer value (2.2 +/- 0.1 mumol/kg/minute), and the basal rate of fat oxidation was twice as high in the patients as in the volunteers (2 mg/kg/minute vs. 1 mg/kg/minute). The rate of whole body protein catabolism was significantly higher in the patients (5.8 +/- 0.7 g/kg/day vs. 4.3 +/- 0.3 g/kg/day), and as a result, the rate of net protein catabolism was significantly elevated in the patients. The response to TPN (amino acids and a 50:50 mixture of glucose and fat) included an increase in the percentage of glucose uptake oxidized (up to 45 +/- 12%), a decrease in the oxidation of fat (up to 0.8 mg/kg/minute), and a significant increase in whole body protein synthesis (up to 6.1 +/- 1.1 g/kg/day) so that the rate of net protein loss was minimized but not prevented. (The rate of net protein catabolism during TPN was 1.3 +/- 0.5 g/kg/day.) There was no correlation between the injury severity score (ISS) and the degree of metabolic abnormality. The rate of NPC in the patients with ISS less than 20 was higher than in the volunteers (ISS = 0), but the values for NPC in patients with ISS 21-40, and ISS greater than 40 were virtually identical to the corresponding values in patients with ISS less than 20. It is concluded from these studies that: 1) Trauma patients have a high rate of VO2.(ABSTRACT TRUNCATED AT 250 WORDS)
Shaw, J H; Wolfe, R R
Complete recovery after profound acidosis (pH 6.49).
We describe an infant with profound acidosis caused by chronic therapeutic salicylate poisoning. The confirmed arterial blood pH of 6.49 must be close to the limit of tolerable acidity and is the lowest such value in our experience. Full recovery was made.
Khan, M I; Miller, M T; Bartlett, M
Hypercapnic acidosis modulates inflammation, lung mechanics, and edema in the isolated perfused lung
ObjectiveLow tidal volume (VT) ventilation strategies may be associated with permissive hypercapnia, which has been shown by ex vivo and in vivo studies to have protective effects. We hypothesized that hypercapnic acidosis may be synergistic with low VT ventilation; therefore, we studied the effects of hypercapnia and VT on unstimulated and lipopolysaccharide-stimulated isolated perfused lungs.
Hilde R. De Smet; Andrew D. Bersten; Heather A. Barr; Ian R. Doyle
The syndrome of osteopetrosis, renal acidosis and cerebral calcification in two sisters.
The syndrome of osteopetrosis associated with renal tubular acidosis and cerebral calcification, inherited as an autosomal recessive disorder, as seen in two sisters, is described. The primary defect in this rare syndrome is deficiency of carbonic anhydrase (CA) II. Significant reduction in blood levels of CA II were found in both parents and another sister, suggesting that these individuals are heterozygotic carriers. PMID:3221988
Al Rajeh, S; el Mouzan, M I; Ahlberg, A; Ozaksoy, D
Feeding Wet Corn Gluten Feed to Reduce Subacute Acidosis in Cattle1
Two experiments were conducted to evaluate the effects of feeding wet corn gluten feed (WCGF) on subacute acidosis in cattle. In Exp. 1, 60 individually fed yearling steers (270 � 22 kg BW) were used in a 5 � 2 factorial arrangement of treatments. Steers were assigned to one of five dietary treatments: 1 ) dry-rolled corn (DRC), 2 )
C. R. Krehbiel; R. A. Stock; D. W. Herold; D. H. Shain; G. A. Ham; J. E. Carulla
Identification of Differentially Expressed Proteins in Liver in Response to Subacute Ruminal Acidosis (SARA) Induced by High-concentrate Diet
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.
Jiang, X. Y.; Ni, Y. D.; Zhang, S. K.; Zhang, Y. S.; Shen, X. Z.
Acidosis downregulates platelet haemostatic functions and promotes neutrophil proinflammatory responses mediated by platelets.
Acidosis is one of the hallmarks of tissue injury such as trauma, infection, inflammation, and tumour growth. Although platelets participate in the pathophysiology of all these processes, the impact of acidosis on platelet biology has not been studied outside of the quality control of laboratory aggregation assays or platelet transfusion optimization. Herein, we evaluate the effect of physiologically relevant changes in extracellular acidosis on the biological function of platelets, placing particular emphasis on haemostatic and secretory functions. Platelet haemostatic responses such as adhesion, spreading, activation of ?IIb?3 integrin, ATP release, aggregation, thromboxane B2 generation, clot retraction and procoagulant activity including phosphatidilserine exposure and microparticle formation, showed a statistically significant inhibition of thrombin-induced changes at pH of 7.0 and 6.5 compared to the physiological pH (7.4). The release of alpha granule content was differentially regulated by acidosis. At low pH, thrombin or collagen-induced secretion of vascular endothelial growth factor and endostatin were dramatically reduced. The release of von Willebrand factor and stromal derived factor-1? followed a similar, albeit less dramatic pattern. In contrast, the induction of CD40L was not changed by low pH, and P-selectin exposure was significantly increased. While the generation of mixed platelet-leukocyte aggregates and the increased chemotaxis of neutrophils mediated by platelets were further augmented under acidic conditions in a P-selectin dependent manner, the increased neutrophil survival was independent of P-selectin expression. In conclusion, our results indicate that extracellular acidosis downregulates most of the haemostatic platelet functions, and promotes those involved in amplifying the neutrophil-mediated inflammatory response. PMID:22159527
Etulain, Julia; Negrotto, Soledad; Carestia, Agostina; Pozner, Roberto Gabriel; Romaniuk, Mar�a Albertina; D'Atri, Lina Paola; Klement, Giannoula Lakka; Schattner, Mirta
Prolactin-Stat5 signaling in breast cancer is potently disrupted by acidosis within the tumor microenvironment
Introduction Emerging evidence in estrogen receptor-positive breast cancer supports the notion that prolactin-Stat5 signaling promotes survival and maintenance of differentiated luminal cells, and loss of nuclear tyrosine phosphorylated Stat5 (Nuc-pYStat5) in clinical breast cancer is associated with increased risk of antiestrogen therapy failure. However, the molecular mechanisms underlying loss of Nuc-pYStat5 in breast cancer remain poorly defined. Methods We investigated whether moderate extracellular acidosis of pH 6.5 to 6.9 frequently observed in breast cancer inhibits prolactin-Stat5 signaling, using in vitro and in vivo experimental approaches combined with quantitative immunofluorescence protein analyses to interrogate archival breast cancer specimens. Results Moderate acidosis at pH 6.8 potently disrupted signaling by receptors for prolactin but not epidermal growth factor, oncostatin M, IGF1, FGF or growth hormone. In breast cancer specimens there was mutually exclusive expression of Nuc-pYStat5 and GLUT1, a glucose transporter upregulated in glycolysis-dependent carcinoma cells and an indirect marker of lactacidosis. Mutually exclusive expression of GLUT1 and Nuc-pYStat5 occurred globally or regionally within tumors, consistent with global or regional acidosis. All prolactin-induced signals and transcripts were suppressed by acidosis, and the acidosis effect was rapid and immediately reversible, supporting a mechanism of acidosis disruption of prolactin binding to receptor. T47D breast cancer xenotransplants in mice displayed variable acidosis (pH 6.5 to 6.9) and tumor regions with elevated GLUT1 displayed resistance to exogenous prolactin despite unaltered levels of prolactin receptors and Stat5. Conclusions Moderate extracellular acidosis effectively blocks prolactin signaling in breast cancer. We propose that acidosis-induced prolactin resistance represents a previously unrecognized mechanism by which breast cancer cells may escape homeostatic control.
Diffuse large B-cell lymphoma: A metabolic disorder?
Patient Male, 81 Final Diagnosis: Non-Hodgkin lymphoma Symptoms: General weakness � hypoglycemia � metabolic acidosis Medication: � Clinical Procedure: � Specialty: Hematology Objective: Challenging differential diagnosis Background: B cell lymphoma constitutes 80�85% of cases of Non Hodgkin�s lymphoma in the Untied States. Metabolic complications may arise from the disease itself or through its end organ involvement. Case Report: We describe a case of a diffuse large B cell lymphoma diagnosed by abdominal computed tomography after it initially presented as hypoglycemia not correctable by dextrose infusion that instead resulted in increased anion gap metabolic acidosis with elevated lactate levels. Conclusions: The case illustrates how lymphomas can present unusually with hypoglycemia and lactic acidosis, the latter being an ominous sign that can occur without liver involvement. In this regard, the case demonstrates the metabolic sequelae of lymphoma that should raise suspicion for an underlying process. This has implications for diagnosis, treatment, and patient survival. Attention should be paid especially in the primary care setting in order to minimize delays in diagnosis.
Tanios, Georges; Aranguren, Ines M.; Goldstein, Jack S.; Patel, Chirag B.
Transcriptional analysis of hnRNPA0, A1, A2, B1, and A3 in lung cancer cell lines in response to acidosis, hypoxia, and serum deprivation conditions.
The ribonucleoproteins (hnRNPs) have important roles in multiple aspects of nucleic acid metabolism and in the regulation of different cellular processes. Abnormal expression of hnRNPs has been reported in several types of cancer including lung, pancreatic, and gastric carcinomas. Heterogenous tumor cell populations generate a tumor microenvironment that can present normoxic, hypoxic, or acidic regions. The analysis of hnRNP transcriptional responses considering the changing nature of the tumor microenvironment is important to understand tumor cell survival under stress conditions. We analyzed the transcriptional response of hnRNPA0, A1, A2, B1, and A3 in lung tumor cell lines under acidosis, hypoxia, and serum deprivation conditions. We used qRT-PCR to obtain a relative quantification of the hnRNPA/B transcript levels. We found that the hnRNPA2 transcript was the most abundant, followed by B1, A0, and A1. Expression of hnRNPA3 was the lowest, although its transcript levels were the most constant. hnRNPA/B transcript levels in lung tumor cell lines responded to changes in the microenvironment; however, hnRNPB1 transcript levels relative to hnRNPA2 expression did no change in all tested stress conditions, indicating that the alternative splicing between these isoforms was constant. hnRNPA1, A2, and B1 transcript levels were upregulated under serum deprivation conditions; possibly to promote a migration phenotype. Our data provide new insights into the transcriptional responses of ribonucleoproteins that might favor tumor cell survival and migration. PMID:24246049
Romero-Garcia, Susana; Prado-Garcia, Heriberto; Lopez-Gonzalez, Jose Sullivan
Disruption of mouse cytochrome p450 4f14 (Cyp4f14 gene) causes severe perturbations in vitamin E metabolism.
Vitamin E is a family of naturally occurring and structurally related lipophilic antioxidants, one of which, ?-tocopherol (?-TOH), selectively accumulates in vertebrate tissues. The ?-hydroxylase cytochrome P450-4F2 (CYP4F2) is the only human enzyme shown to metabolize vitamin E. Using cDNA cloning, cell culture expression, and activity assays, we identified Cyp4f14 as a functional murine ortholog of CYP4F2. We then investigated the effect of Cyp4f14 deletion on vitamin E metabolism and status in vivo. Cyp4f14-null mice exhibited substrate-specific reductions in liver microsomal vitamin E-?-hydroxylase activity ranging from 93% (?-TOH) to 48% (?-tocotrienol). In vivo data obtained from metabolic cage studies showed whole-body reductions in metabolism of ?-TOH of 90% and of 68% for ?- and ?-TOH. This metabolic deficit in Cyp4f14(-/-) mice was partially offset by increased fecal excretion of nonmetabolized tocopherols and of novel ?-1- and ?-2-hydroxytocopherols. 12'-OH-?-TOH represented 41% of whole-body production of ?-TOH metabolites in Cyp4f14(-/-) mice fed a soybean oil diet. Despite these counterbalancing mechanisms, Cyp4f14-null mice fed this diet for 6 weeks hyper-accumulated ?-TOH (2-fold increase over wild-type littermates) in all tissues and appeared normal. We conclude that CYP4F14 is the major but not the only vitamin E-?-hydroxylase in mice. Its disruption significantly impairs whole-body vitamin E metabolism and alters the widely conserved phenotype of preferential tissue deposition of ?-TOH. This model animal and its derivatives will be valuable in determining the biological actions of specific tocopherols and tocotrienols in vivo. PMID:22665481
Bardowell, Sabrina A; Duan, Faping; Manor, Danny; Swanson, Joy E; Parker, Robert S
Rumen microbial and fermentation characteristics are affected differently by bacterial probiotic supplementation during induced lactic and subacute acidosis in sheep
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.
Metabolism and Hormonal Regulation Collagen Production in Fasted and Food-Restricted Rats: Response to Duration and Severity of Food Deprivation1'2
Malnutritionis associated with defects in connective tissue metabolism such as altered growth and wound healing. Because collagen is the major protein in most tissues, we determined the threshold for induction of altered collagen production by partial food restriction in rats. Groups of animals were fasted 2 or 4 d or were fed 20-100% of a predetermined food intake for 4
ROBERT SPANHEIMER; NKO ZLATEV; GUILLERMO ÜMPIERREZ; MARIO DiGIROLAMO
Regulation of apoA1 gene expression with acidosis: requirement for a transcriptional repressor
Serum apolipoprotein A1 (apoA1) concentration is inversely correlated with the risk of premature atherosclerosis. Serum apoA1 concentrations are regulated, in part, at the transcriptional level. ApoA1 mRNA is synthesized primarily in the liver and small intestine, under the direction of a number of signaling molecules and tissue-specific regulatory elements. Previously, we demonstrated that extra- cellular acidosis suppresses apoA1 mRNA levels
M J Haas; D Reinacher; NCW Wong
Troponin T isoforms alter the tolerance of transgenic mouse cardiac muscle to acidosis
Troponin T (TnT) is an essential protein in the Ca2+ regulatory system of striated of muscle. Three fiber type-specific TnT genes have evolved in higher vertebrates to encode cardiac, slow and fast skeletal muscle TnT isoforms. To understand the functional significance of TnT isoforms, we studied the effects of acidosis on the contractility of transgenic mouse cardiac muscle that expresses
Thomas M. Nosek; Marco A. Brotto; Jian-Ping Jin
Summary Inclusion of thiopeptin, a sulfur-containing peptide antibiotic, at O, 2.75, 5.5, 8.25, 11 and 22 ppm in the feed was evaluated in 8-week growth trials with 252 lambs. An abrupt diet shift to micronized milo at the start of the trials was used to provide a lactic acidosis chal- lenge. Five of 78 control lambs died within 48 hr
Larry A. Muir; Paul F. Duquette; Eric L. Rickes; Gary E. Smith
Cytoplasmic acidosis induces multiple conductance states in ATP-sensitive potassium channels of cardiac myocytes
We studied the effect of cytoplasmic acidosis on the ionic conducting states of ATP-sensitive potassium channels in heart\\u000a ventricular cells of guinea pigs and rabbits by using a patch-clamp technique with inside-out patch configuration. Under normal\\u000a conditions (pH 7.4), the channel alternated between a closed state and a main open state in the absence of nucleotides on\\u000a the cytoplasmic side.
Zheng Fan; Tetsushi Furukawa; Tohru Sawanobori; Jonathan C. Makielski; Masayasu Hiraoka
Kidney stone inhibitors in patients with renal stones and endemic renal tubular acidosis in northeast Thailand
Distal renal tubular acidosis (dRTA) is generally associated with hypercalciuria, hypocitraturia, and nephrolithiasis. Our intention was to study glycosaminoglycans (GAGS) and nephrocalcin (NC), two well-known crystal growth inhibitors, in a population with endemic dRTA and nephrolithiasis in northeast (NE) Thailand. We studied 13 patients, six with dRTA and seven with nephrolithiasis with normal or undefined acidification function. Six healthy adults
Yasushi Nakagawa; Mauricio Carvalho; Prida Malasit; Sumalee Nimmannit; Suchai Sritippaywan; Somkiat Vasuvattakul; Somchai Chutipongtanate; Vipada Chaowagul; Sanga Nilwarangkur
Topical acetylsalicylic, salicylic acid and indomethacin suppress pain from experimental tissue acidosis in human skin
Topically applied acetylsalicylic acid (ASA), salicylic acid (SA) and indomethacin were tested in an experimental pain model that provides direct nociceptor excitation through cutaneous tissue acidosis. In 30 volunteers, sustained burning pain was produced in the palmar forearm through a continuous intradermal pressure infusion of a phosphate-buffered isotonic solution (pH 5.2). In 5 different, double-blind, randomized cross-over studies with 6
Kay H. Steen; Peter W. Reeh; Hans W. Kreysel
Hypercapnic Acidosis Impairs Plasma Membrane Wound Resealing in Ventilator-injured Lungs
The objective of this study was to assess the effects of hypercapnic acidosis on lung cell injury and repair by confocal microscopy in a modelofventilator-inducedlunginjury.Threegroupsofnormocap- nic, hypocapnic, and hypercapnic rat lungs were perfused ex vivo, either during or after injurious ventilation, with a solution con- tainingthemembrane-impermeantlabelpropidiumiodide.Inlungs labeled during injurious ventilation, propidium iodide fluorescence identifies all cells with plasma membrane wounds,
Clinton H. Doerr; Ognjen Gajic; Jorge C. Berrios; Sean Caples; Matthew Abdel; James F. Lymp; Rolf D. Hubmayr
A mouse model for distal renal tubular acidosis reveals a previously unrecognized role of the V-ATPase a4 subunit in the proximal tubule
The V-ATPase is a multisubunit complex that transports protons across membranes. Mutations of its B1 or a4 subunit are associated with distal renal tubular acidosis and deafness. In the kidney, the a4 subunit is expressed in intercalated cells of the distal nephron, where the V-ATPase controls acid/base secretion, and in proximal tubule cells, where its role is less clear. Here, we report that a4 KO mice suffer not only from severe acidosis but also from proximal tubule dysfunction with defective endocytic trafficking, proteinuria, phosphaturia and accumulation of lysosomal material and we provide evidence that these findings may be also relevant in patients. In the inner ear, the a4 subunit co-localized with pendrin at the apical side of epithelial cells lining the endolymphatic sac. As a4 KO mice were profoundly deaf and displayed enlarged endolymphatic fluid compartments mirroring the alterations in pendrin KO mice, we propose that pendrin and the proton pump co-operate in endolymph homeostasis. Thus, our mouse model gives new insights into the divergent functions of the V-ATPase and the pathophysiology of a4-related symptoms.
Hennings, J Christopher; Picard, Nicolas; Huebner, Antje K; Stauber, Tobias; Maier, Hannes; Brown, Dennis; Jentsch, Thomas J; Vargas-Poussou, Rosa; Eladari, Dominique; Hubner, Christian A
Acid-sensing ion channels in acidosis-induced injury of human brain neurons
Acidosis is a common feature of the human brain during ischemic stroke and is known to cause neuronal injury. However, the mechanism underlying acidosis-mediated injury of the human brain remains elusive. We show that a decrease in the extracellular pH evoked inward currents characteristic of acid-sensing ion channels (ASICs) and increased intracellular Ca2+ in cultured human cortical neurons. Acid-sensing ion channels in human cortical neurons show electrophysiological and pharmacological properties distinct from those in neurons of the rodent brain. Reverse transcriptase-PCR and western blot detected a high level of the ASIC1a subunit with little or no expression of other ASIC subunits. Treatment of human cortical neurons with acidic solution induced substantial cell injury, which was attenuated by the ASIC1a blockade. Thus, functional homomeric ASIC1a channels are predominantly expressed in neurons from the human brain. Activation of these channels has an important role in acidosis-mediated injury of human brain neurons.
Li, Minghua; Inoue, Koichi; Branigan, Deborah; Kratzer, Eric; Hansen, Jillian C; Chen, Jeff W; Simon, Roger P; Xiong, Zhi-Gang
Edaravone alleviates hypoxia-acidosis/reoxygenation-induced neuronal injury by activating ERK1/2.
Edaravone, a free radical scavenger, is the first clinical drug of neuroprotection for ischemic stroke patients in the world, and has been shown to be an effective agent to alleviate cerebral ischemic injury. It has been established that acidosis is a common feature of cerebral ischemia and underlies the pathogenesis of ischemic stroke. In the present study, we investigated the role of edaravone in hypoxia-acidosis/reoxygenation (H-A/R)-induced neuronal injury that is partially mediated by the activation of acid-sensing ion channels (ASICs). Here, we observed that pretreatment of cultured neurons with edaravone largely reduced LDH release induced by acidosis or H-A/R. We also found that edaravone exhibited its neuroprotective roles by enhancing brain-derived neurotrophic factor (BDNF) and Bcl-2 expression, suppressing caspase-3 activity and promoting extracellular signal-regulated kinase1/2 (ERK1/2) activation. Furthermore, the addition of MEK (mitogen-activated protein kinase/ERK kinase) antagonists PD98059 and U0126 nearly abolished the beneficial effects of edaravone. Similarly, ASICs blockade produced the protective effects comparable to edaravone administration. These results indicate that edaravone is capable of attenuating H-A/R-mediated neurotoxicity at least partially through activating ERK1/2. PMID:23562504
Wang, Guibin; Su, Jingjing; Li, Lingjuan; Feng, Jie; Shi, Lei; He, Wei; Liu, Yunhai
Subacute Ruminal Acidosis and Evaluation of Blood Gas Analysis in Dairy Cow
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.
Gianesella, Matteo; Morgante, Massimo; Cannizzo, Chiara; Stefani, Annalisa; Dalvit, Paolo; Messina, Vanessa; Giudice, Elisabetta
Effect of haemodilution, acidosis, and hypothermia on the activity of recombinant factor VIIa (NovoSeven�)
Background A range of plasma volume expanders is used clinically, often in settings where haemostasis may already be impaired. The haemostatic agent, recombinant activated factor VII (rFVIIa, NovoSeven�), may be used to improve haemostasis but potential interactions with different volume expanders are poorly understood. Methods Clot formation was measured by thromboelastography (TEG) using blood from healthy volunteers. In vitro effects of rFVIIa with haemodilution, acidosis, and hypothermia were examined. Conditions were induced by dilution with NaCl (0.9%), lactated Ringer's solution, albumin 5%, or hydroxyethyl starch (HES) solutions [MW (molecular weight) 130�670 kDa]; by adjusting pH to 6.8 with 1 M HEPES (N-2-hydroxyethylpiperazine-N?-2-ethanesulphonic acid) buffer; or by reducing temperature to 32�C. We also studied the effect of low vs high MW HES (MW 200 vs 600 kDa) and rFVIIa on in vivo bleeding time (BT) in rabbits. Results Haemodilution progressively altered TEG parameters. rFVIIa improved TEG parameters in the presence of acidosis, hypothermia or 20% haemodilution (P<0.05). At 40% haemodilution, the rFVIIa effect was diminished particularly with high MW HES. In vivo, rFVIIa shortened the BT (P<0.05) with low but not high MW HES. Conclusions Efficacy of rFVIIa was affected by the degree of haemodilution and type of volume expander, but not by acidosis or hypothermia.
Viuff, D.; Lauritzen, B.; Pusateri, A. E.; Andersen, S.; Rojkjaer, R.; Johansson, P. I.
Effects of the ionophores monensin and tetronasin on simulated development of ruminal lactic acidosis in vitro.
A continuous coculture of four ruminal bacteria, Megasphaera elsdenii, Selenomonas ruminantium, Streptococcus bovis, and Lactobacillus sp. strain LB17, was used to study the effects of the ionophores monensin and tetronasin on the changes in ruminal microbial ecology that occur during the onset of lactic acidosis. In control incubations, the system simulated the development of lactic acidosis in vivo, with an initial overgrowth of S. bovis when an excess of glucose was added to the fermentor. Lactobacillus sp. strain LB17 subsequently became dominant as pH fell and lactate concentration rose. Both ionophores were able to prevent the accumulation of lactic acid and maintain a healthy non-lactate-producing bacterial population when added at the same time as an excess of glucose. Tetronasin was more potent in this respect than monensin. When tetronasin was added to the culture 24 h after glucose, the proliferation of lactobacilli was reversed and a non-lactate-producing bacterial population developed, with an associated drop in lactate concentration in the fermentor. Rises in culture pH and volatile fatty acid concentrations accompanied these changes. Monensin was unable to suppress the growth of lactobacilli; therefore, in contrast to tetronasin, monensin added 24 h after the addition of glucose failed to reverse the acidosis. Numbers of lactobacilli and lactate concentrations remained high, whereas pH and volatile fatty acid concentrations were low.
Newbold, C J; Wallace, R J
Amino acid and protein metabolism in the human kidney and in patients with chronic kidney disease.
The progressive loss of kidney function in patients with chronic kidney disease (CKD) is associated with a number of complications, including cardiovascular diseases, anemia, hyperparathyroidism, inflammation, metabolic acidosis, malnutrition and protein-energy wasting. The excess cardiovascular risk related to CKD is due in part to a higher prevalence of traditional atherosclerotic risk factors, in part to non-traditional, emerging risk factors peculiar to CKD. While even minor renal dysfunction is an independent predictor of adverse cardiovascular prognosis, nutritional changes are more often observed in an advanced setting. In addition, factors related to renal-replacement treatment may be implicated in the pathogenesis of heart disease and protein-energy wasting in dialysis-treated patients. Progressive alterations in kidney metabolism may cause progressive effects on cardiovascular status and nutrition. Altered kidney amino acid/protein metabolism and or excretion may be a key factor in the homeostasis of several vasoactive compounds and hormones in patients with more advanced disease. In this discussion recent research regarding the kidney handling of amino acids and protein turnover and their potential link with cardiovascular disease, progressive kidney dysfunction and nutritional status are reviewed. PMID:20207454
Garibotto, Giacomo; Sofia, Antonella; Saffioti, Stefano; Bonanni, Alice; Mannucci, Irene; Verzola, Daniela
Metabolic cardiac imaging in severe coronary disease: assessment of viability with iodine-123-iodophenylpentadecanoic acid and multicrystal gamma camera, and correlation with biopsy.
Fifteen patients with coronary disease and resting left ventricular ejection fractions of less than or equal to 0.35 underwent resting metabolic cardiac imaging utilizing 1 mCi [123I]iodophenylpentadecanoic acid (IPPA) intravenously and a multicrystal gamma camera. Parametric images of regional rates of IPPA clearance and accumulation were generated. Forty-two vascular territories (22 infarcted) were evaluated by metabolic imaging as well as transmural myocardial biopsy. Despite resting akinesis or dyskinesis in 20/22 (91%) infarcted territories, 16/22 (73%) of these territories were metabolically viable. Transmural myocardial biopsies in all patients (43 sites, 42 vascular territories) during coronary bypass surgery confirmed IPPA results in 39/43 patients (91%). When compared to biopsy, scan sensitivity for viability was 33/36 (92%) with a specificity of 6/7 (86%). Eighty percent of bypassed, infarcted but IPPA viable segments demonstrated improved regional systolic wall motion postoperatively as assessed by exercise radionuclide angiography. We conclude resting IPPA imaging identifies viable myocardium, thereby providing a safe, cost-effective technique for myocardial viability assessment. PMID:1613564
Murray, G; Schad, N; Ladd, W; Allie, D; vander Zwagg, R; Avet, P; Rockett, J
In vivo indices for predicting acidosis risk of grains in cattle: Comparison with in vitro methods.
Our objective was to evaluate a near-infrared reflectance spectroscopy (NIRS) used in the feed industry to estimate the potential for grains to increase the risk of ruminal acidosis. The existing NIRS calibration was developed from in sacco and in vitro measures in cattle and grain chemical composition measurements. To evaluate the existing model, 20 cultivars of 5 grain types were fed to 40 Holstein heifers using a grain challenge protocol and changes in rumen VFA, ammonia, lactic acids, and pH that are associated with acidosis were measured. A method development study was performed to determine a grain feeding rate sufficient to induce non-life threatening but substantial ruminal changes during grain challenge. Feeding grain at a rate of 1.2% of BW met these criteria, lowering rumen pH (P = 0.01) and increasing valerate (P < 0.01) and propionate concentrations (P = 0.01). Valerate was the most discriminatory measure indicating ruminal change during challenge. Heifers were assigned using a row by column design in an in vivo study to 1 of 20 grain cultivars and were reassigned after a 9 d period (n = 4 cattle/treatment). The test grains were dry rolled oats (n = 3), wheat (n = 6), barley (n = 4), triticale (n = 4), and sorghum (n = 3) cultivars. Cattle were adapted to the test grain and had ad libitum access to grass silage 11 d before the challenge. Feed was withheld for 14 h before challenge feeding with 0.3 kg DM of silage followed by the respective test grain fed at 1.2% of BW. A rumen sample was taken by stomach tube 5, 65, 110, 155, and 200 min after grain consumption. The rumen is not homogenous and samples of rumen fluid obtained by stomach tube will differ from those gained by other methods. Rumen pH was measured immediately; individual VFA, ammonia, and D- and L-lactate concentrations were analyzed later. Rumen pH (P = 0.002) and all concentrations of fermentation products differed among grains (P = 0.001). A previously defined discriminant score calculated at 200 min after challenge was used to rank grains for acidosis risk. A significant correlation between the discriminant score and the NIRS ranking (r = 0.731, P = 0.003) demonstrated the potential for using NIRS calibrations for predicting acidosis risk of grains in cattle. The overall rankings of grains for acidosis risk were wheat > triticale > barley > oats > sorghum. PMID:23482574
Lean, I J; Golder, H M; Black, J L; King, R; Rabiee, A R
Acid-base imbalance in uncomplicated ST-elevation myocardial infarction: the clinical role of tissue acidosis.
Little information is available on acid-base imbalance in uncomplicated ST-elevation myocardial infarction (STEMI) submitted to primary percutaneous intervention (PCI). We therefore assessed acid-base imbalance in 257 consecutive uncomplicated STEMI patients submitted to PCI to determine whether its evaluation could help in identifying patients at higher risk for in-hospital complications (acute pulmonary edema and dysrhythmias). A basic metabolic profile was performed at hospital admission, that is before PCI. After PCI, we measured: creatinine, uric acid and NT-pro BNP and serum electrolytes. Peak troponin I was also considered. Acidemia was present in 11 patients (4.2%), HCO(3) < 22 in 62 (24.1%). Base excess < -3 was detectable in 70 patients (27.2%), anion gap > 12 in 13 (5.1%), Cl/Na < 0.79 in 93 patients (38.5%). Patients with a Cl/Na < 0.79 had a lower LVEF (p = 0.042) and higher values of NT-pro-BNP (p = 0.019) and of latency (p = 0.029) together with a higher length of stay (p = 0.017) and a higher incidence of in-hospital complications (p = 0.017). At backward stepwise regression analysis, the following variables resulted independent predictors of in-hospital complications: base excess OR 1.47 (95% CI 1.04-2.10) p = 0.031; Cl/Na ratio O.R. 1.85 (95% CI 1.05-3.27) p = 0.035. In STEMI patients submitted to mechanical revascularization the evaluation of acid-base status and, in particular the detection of even mild degrees of acidosis may help in risk stratification for in-hospital complications. A Cl/Na < 0.79 ratio and a base excess are independent predictors for in-hospital complications. PMID:19998062
Lazzeri, Chiara; Valente, Serafina; Chiostri, Marco; Picariello, Claudio; Gensini, Gian Franco
Individual animal variability in ruminal bacterial communities and ruminal acidosis in primiparous Holstein cows during the periparturient period.
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
Mohammed, R; Stevenson, D M; Weimer, P J; Penner, G B; Beauchemin, K A
Interstrain differences in the severity of liver injury induced by a choline- and folate-deficient diet in mice are associated with dysregulation of genes involved in lipid metabolism
Nonalcoholic fatty liver disease (NAFLD) is a major health problem and a leading cause of chronic liver disease in the United States and developed countries. In humans, genetic factors greatly influence individual susceptibility to NAFLD. The goals of this study were to compare the magnitude of interindividual differences in the severity of liver injury induced by methyl-donor deficiency among individual inbred strains of mice and to investigate the underlying mechanisms associated with the variability. Feeding mice a choline- and folate-deficient diet for 12 wk caused liver injury similar to NAFLD. The magnitude of liver injury varied among the strains, with the order of sensitivity being A/J ? C57BL/6J ? C3H/HeJ < 129S1/SvImJ ? CAST/EiJ < PWK/PhJ < WSB/EiJ. The interstrain variability in severity of NAFLD liver damage was associated with dysregulation of genes involved in lipid metabolism, primarily with a down-regulation of the peroxisome proliferator receptor ? (PPAR?)-regulated lipid catabolic pathway genes. Markers of oxidative stress and oxidative stress-induced DNA damage were also elevated in the livers but were not correlated with severity of liver damage. These findings suggest that the PPAR?-regulated metabolism network is one of the key mechanisms determining interstrain susceptibility and severity of NAFLD in mice.�Tryndyak, V., de Conti, A., Kobets, T., Kutanzi, K., Koturbash, I., Han, T., Fuscoe, J. C., Latendresse, J. R., Melnyk, S., Shymonyak, S., Collins, L., Ross, S. A., Rusyn, I., Beland, F. A., Pogribny, I. P. Interstrain differences in the severity of liver injury induced by a choline- and folate-deficient diet in mice are associated with dysregulation of genes involved in lipid metabolism.
Tryndyak, Volodymyr; de Conti, Aline; Kobets, Tetyana; Kutanzi, Kristy; Koturbash, Igor; Han, Tao; Fuscoe, James C.; Latendresse, John R.; Melnyk, Stepan; Shymonyak, Svitlana; Collins, Leonard; Ross, Sharon A.; Rusyn, Ivan; Beland, Frederick A.; Pogribny, Igor P.
QTL for several metabolic traits map to loci controlling growth and body composition in an F2 intercross between high- and low-growth chicken lines.
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
Nadaf, Javad; Pitel, Fr�d�rique; Gilbert, H�l�ne; Duclos, Michel J; Vignoles, Florence; Beaumont, Catherine; Vignal, Alain; Porter, Tom E; Cogburn, Larry A; Aggrey, Samuel E; Simon, Jean; Le Bihan-Duval, Elisabeth
Functional effects of a tropomyosin mutation linked to FHC contribute to maladaptation during acidosis
Familial Hypertrophic Cardiomyopathy (FHC) is a leading cause of sudden cardiac death among young athletes but the functional effects of the myofilament mutations during FHC-associated ischemia and acidosis, due in part to increased extravascular compressive forces and microvascular dysfunction, are not well characterized. We tested the hypothesis that the FHC-linked tropomyosin (Tm) mutation Tm-E180G alters the contractile response to acidosis via increased myofilament Ca2+ sensitivity. Intact papillary muscles from transgenic (TG) mice expressing Tm-E180G and exposed to acidic conditions (pH 6.9) exhibited a significantly smaller decrease in normalized isometric tension compared to non-transgenic (NTG) preparations. Times to peak tension and to 90% of twitch force relaxation in TG papillary muscles were significantly prolonged. Intact single ventricular TG myocytes demonstrated significantly less inhibition of unloaded shortening during moderate acidosis (pH 7.1) than NTG myocytes. The peak Ca2+ transients were not different for TG or NTG at any pH tested. The time constant of re-lengthening was slower in TG myocytes, but not the rate of Ca2+ decline. TG detergent-extracted fibers demonstrated increased Ca2+ sensitivity of force and maximal tension compared to NTG at both normal and acidic pH (pH 6.5). Tm phosphorylation was not different between TG and NTG muscles at either pH. Our data indicate that acidic pH diminished developed force in hearts of TG mice less than in NTG due to their inherently increased myofilament Ca2+ sensitivity, thus potentially contributing to altered energy demands and increased propensity for contractile dysfunction.
Sheehan, Katherine A.; Arteaga, Grace M.; Hinken, Aaron C.; Dias, Fernando A.; Ribeiro, Cibele; Wieczorek, David F.; Solaro, R. John; Wolska, Beata M.
Metabolic management of the horse with an acute abdominal crisis.
The horse with an abdominal crisis caused by acute gastro-intestinal tract obstruction develops hypovolaemia, haemoconcentration, electrolyte depletion, metabolic acidosis and shock. During preparation for operation, treatment with fluids, antibiotics and bicarbonate will impede metabolic imbalance. Stomach decompression may slow the passage of sodium, water and potassium to the gut lumen, reduce pain and minimize the risk of stomach rupture. Selected laboratory determinations and the monitoring of arterial and venous pressures will provide a measure of security, and serve as a guide to replacement therapy. In the post-surgical period, vigilance must be directed towards potassium and bicarbonate imbalance and adequate hydration. PMID:1100823
Donawick, W J
Emergency Department Hemodialysis in a Case of Severe Ethylene Glycol Poisoning
A 36-year-old man with a history of depression presented to the emergency department after ingesting approximately 3,000 mL of ethylene glycol antifreeze in a suicide attempt. The patient�s ethylene glycol concentration, 1,889 mg\\/dL, was higher than any level previously documented in the medical literature. Although his course was complicated by nausea, emesis, lethargy, metabolic acidosis, and kidney failure, the patient
Byron Johnson; William J Meggs; Carl J Bentzel
Modulation of ventricular transient outward K+ current by acidosis and its effects on excitation-contraction coupling
The contribution of transient outward current (Ito) to changes in ventricular action potential (AP) repolarization induced by acidosis is unresolved, as is the indirect effect of these changes on calcium handling. To address this issue we measured intracellular pH (pHi), Ito, L-type calcium current (ICa,L), and calcium transients (CaTs) in rabbit ventricular myocytes. Intracellular acidosis [pHi 6.75 with extracellular pH (pHo) 7.4] reduced Ito by ?50% in myocytes with both high (epicardial) and low (papillary muscle) Ito densities, with little effect on steady-state inactivation and activation. Of the two candidate ?-subunits underlying Ito, human (h)Kv4.3 and hKv1.4, only hKv4.3 current was reduced by intracellular acidosis. Extracellular acidosis (pHo 6.5) shifted Ito inactivation toward less negative potentials but had negligible effect on peak current at +60 mV when initiated from ?80 mV. The effects of low pHi-induced inhibition of Ito on AP repolarization were much greater in epicardial than papillary muscle myocytes and included slowing of phase 1, attenuation of the notch, and elevation of the plateau. Low pHi increased AP duration in both cell types, with the greatest lengthening occurring in epicardial myocytes. The changes in epicardial AP repolarization induced by intracellular acidosis reduced peak ICa,L, increased net calcium influx via ICa,L, and increased CaT amplitude. In summary, in contrast to low pHo, intracellular acidosis has a marked inhibitory effect on ventricular Ito, perhaps mediated by Kv4.3. By altering the trajectory of the AP repolarization, low pHi has a significant indirect effect on calcium handling, especially evident in epicardial cells.
Saegusa, Noriko; Garg, Vivek
Neurologic presentation, diagnostics, and therapeutic insights in a severe case of adenylosuccinate lyase deficiency.
Epilepsy in adenylosuccinate lyase deficiency may be difficult to treat, and there is no standardized therapy. The authors describe a case of severe adenylosuccinate lyase deficiency resulting from a heterozygous mutation of the ADSL gene (p.D215H/p.I351T). The patient presented with tonic-clonic seizures, opisthotonus, tremor, and myoclonus in the 4th day of life. The seizures were refractory on various combinations of antiepileptic treatment. A ketogenic diet was introduced at the age of 2 resulting in a seizure-free period. The patient, however, developed a metabolic hyperchloremic acidosis with Fanconi syndrome, which disappeared a month after cessation of the diet at the age of 5. Since the withdrawal of the ketogenic diet, seizures have returned to a frequency of several times a day. In conclusion, a ketogenic diet could be considered a valid therapeutic option in patients with intractable seizures in a course of adenylosuccinate lyase deficiency; however, it requires a formal study. PMID:22140128
Jurecka, Agnieszka; Opoka-Winiarska, Violetta; Rokicki, Dariusz; Tylki-Szyma?ska, Anna
Subacute ruminal acidosis induces ruminal lipopolysaccharide endotoxin release and triggers an inflammatory response.
Subacute ruminal acidosis (SARA) was induced in 3 rumen fistulated Jersey steers by offering them different combinations of wheat-barley pellets and chopped alfalfa hay. Steers were offered 4, 5, and 6 kg/d of pelleted concentrate and 6, 5, and 4 kg/d of chopped alfalfa hay for diets 1, 2, and 3, respectively, during 5-d treatment periods and were fed chopped alfalfa hay between treatment periods. Inducing SARA increased blood concentrations of haptoglobin and serum amyloid-A. Dry matter intake of concentrate and hay decreased from d 1 to 5 in each period. Subacute ruminal acidosis was induced in all steers during d 4 and 5 when concentrate was fed, with ruminal pH remaining below 5.6 for an average of 187 and 174 min/d on these days. Lipopolysaccharide concentration increased significantly during periods of grain feeding compared with times when only hay was fed. Inducing SARA by feeding wheat-barley pellets activated a systemic inflammatory response in the steers. PMID:15778308
Gozho, G N; Plaizier, J C; Krause, D O; Kennedy, A D; Wittenberg, K M
Respiratory signaling of locus coeruleus neurons during hypercapnic acidosis in the bullfrog, Lithobates catesbeianus.
The locus coeruleus (LC) in the brainstem senses alterations in CO(2)/pH and influences ventilatory adjustments that restore blood gas values to starting levels in bullfrogs (Lithobates catesbeianus). We hypothesized that neurons of the bullfrog LC are sensitive to changes in CO(2)/pH and that chemosensitive responses are intrinsic to individual neurons. In addition, we hypothesized putative respiratory control neurons of the bullfrog LC would be stimulated by hypercapnic acidosis within physiological ranges of P(CO(2))/pH. 84% of LC neurons depolarized and increased firing rates during exposure to hypercapnic acidosis (HA). A pH dose response curve shows LC neurons from bullfrogs increase firing rates during physiologically relevant CO(2)/pH changes. With chemical synapses blocked, half of chemosensitive neurons lost sensitivity to HA; however, gap junction blockade did not alter chemosensitive responses. Intrinsically chemosensitive neurons increased input resistance during HA. These data demonstrate that majority of neurons within the bullfrog LC elicit robust firing responses during physiological ?CO(2)/pH, likely enabling adjustment of acid-base balance through breathing. PMID:23146875
Santin, J M; Hartzler, L K
Role of lactic acidosis in the ventilatory response to heavy exercise.
The purpose of this study was to determine the role of lactic acidosis in the ventilatory response to heavy exercise above anaerobic threshold. Seven subjects ingested either NaHCO3 or CaCO3 at a dose of 300 mg/kg body weight and ran on a motor-driven treadmill at a work load corresponding to 90% of VO2max and above anaerobic threshold for a period of 5 min while minute ventilation and PETCO2 were recorded breath by breath. A total of 10 runs, 5 with CaCO3 and 5 with NaHCO3 in a randomized and blind order, were done in each subject. Statistical analyses of the effects of the chemicals on minute ventilation during the 15 s between min 4.75 and 5 of exercise showed that the differences in ventilation did not reach statistical significance (p greater than 0.05) in 5 of the 7 subjects. Venous pH measurements at the end of exercise revealed a significant increase with NaHCO3 (p much less than 0.05). It is concluded that lactic acidosis is not an essential determinant of ventilatory response to heavy exercise above anaerobic threshold in the majority of the subjects. PMID:2595103
Jeyaranjan, R; Goode, R; Duffin, J
Glycogen Storage Disease Type Ia: Linkage of Glucose, Glycogen, Lactic Acid, Triglyceride, and Uric Acid Metabolism
Case Summary A female presented in infancy with hypotonia, undetectable serum glucose, lactic acidosis, and triglycerides > 5,000 mg/dl. The diagnosis of type 1A glycogen storage disease (GSD) was made by liver biopsy that showed increased glycogen and absent glucose-6-phosphatase enzyme activity. She was treated with dextrose feeding, which was replaced by frequent cornstarch feeding, with improvement of her metabolic parameters. At age 18 years she had marked hypertriglyceridemia (3,860 mg/dl) and eruptive xanthomas, and was treated with fenofibrate, atorvastatin, and fish oil. At age 29 years she was noted to have multiple liver adenomas, severe anemia, and hyperuricemia. Aggressive cornstarch therapy was commenced with a goal of maintaining her blood glucose levels > 75 mg/dl and lactate levels < 2 mmol/L. After 15 months on this regimen, her lipids levels (measured in mg/dl) off all medications were: total cholesterol 222, triglycerides 179, high density lipoprotein cholesterol 32, and calculated low density lipoprotein cholesterol 154. Her weight was stable with a body mass index of 24.8 kg/m2. Her liver adenomas had decreased in size, and her anemia and hyperuricemia had improved. She was homozygous for the R83C missense mutation in G6PC. Our data indicate that optimized metabolic control to maintain blood glucose levels > 75 mg/dl is critical in the management of this disease.
Sever, Sakine; Weinstein, David A.; Wolfsdorf, Joseph I.; Gedik, Reyhan; Schaefer, Ernst J.
National Technical Information Service (NTIS)
Many assumptions and compromises must be made in order to establish blood lactate as a reliable parameter of tissue oxygenation. One must think not only of reactions and cells as having oxidation-reduction potentials, but the concept of the Redox potentia...
A. H. Harken
In the treatment of severe Plasmodium falciparum infection antimalarial drugs should, ideally, be given by controlled rate intravenous infusion until the patient is able to swallow tablets. In cases where infection has been acquired in a chloroquine resistant area, and where it has broken through chloroquine prophylaxis or where the geographical origin or species are uncertain, quinine is the treatment of choice. When access to parenteral quinine is likely to be delayed, parenteral quinidine is an effective alternative. A loading dose of quinine is recommended in order to achieve therapeutic plasma concentrations as quickly as possible. In the case of chloroquine sensitive P. falciparum infection, chloroquine, which can be given safely by slow intravenous infusion, may be more rapidly effective and has fewer toxic effects than quinine. There is limited experience with parenteral administration of pyrimethamine sulphonamide combinations such as Fansidar, and resistance to these drugs has developed in South East Asia and elsewhere. Mefloquine and halofantrine cannot be given parenterally. Qinghaosu derivatives are not readily available and have not been adequately tested outside China. Supportive treatment includes the prevention or early detection and treatment of complications, strict attention to fluid balance, provision of adequate nursing for unconscious patients and avoidance of harmful ancillary treatments. Anaemia is inevitable and out of proportion to detectable parasitaemia. Hypotension and shock ('algid malaria') are often attributable to secondary gram-negative septicaemia requiring appropriate antimicrobial therapy and haemodynamic resuscitation. Many patients with severe falciparum malaria are hypovolaemic on admission to hospital and require cautious fluid replacement. Failure to rehydrate these patients may lead to circulatory collapse, lactic acidosis, renal failure and severe hyponatraemia.(ABSTRACT TRUNCATED AT 250 WORDS)
Warrell, D A
Effects of interval and continuous training on O2 uptake kinetics during severe-intensity exercise initiated from an elevated metabolic baseline.
The purpose of this study was to test the hypothesis that Vo2 kinetics would be speeded to a greater extent following repeated sprint training (RST), compared with continuous endurance training (ET), in the transition from moderate- to severe-intensity exercise. Twenty-three recreationally active subjects were randomly assigned to complete six sessions of ET (60-110 min of moderate-intensity cycling) or RST (four to seven 30-s all-out Wingate tests) over a 2-wk period. Subjects completed three identical work-to-work cycling exercise tests before and after the intervention period, consisting of baseline cycling at 20 W followed by sequential step increments to moderate- and severe-intensity work rates. The severe-intensity bout was continued to exhaustion on one occasion and was followed by a 60-s all-out sprint on another occasion. Phase II pulmonary Vo2 kinetics were speeded by a similar magnitude in both the lower (ET pre, 28 � 4; ET post, 22 � 4 s; RST pre, 25 � 8; RST post, 20 � 7 s) and upper (ET pre, 50 � 10; ET post, 39 � 11 s; RST pre, 54 � 7; RST post, 40 � 11 s) steps of the work-to-work test following ET and RST (P < 0.05). The tolerable duration of exercise and the total amount of sprint work completed in the exercise performance test were also similarly enhanced by ET and RST (P < 0.05). Therefore, ET and RST provoked comparable improvements in Vo2 kinetics and exercise performance in the transition from an elevated baseline work rate, with RST being a more time-efficient approach to elicit these adaptations. PMID:24526579
Da Boit, Mariasole; Bailey, Stephen J; Callow, Steven; Dimenna, Fred J; Jones, Andrew M
... page from the NHLBI on Twitter. What Is Metabolic Syndrome? Metabolic (met-ah-BOL-ik) syndrome is the ... three metabolic risk factors to be diagnosed with metabolic syndrome. A large waistline. This also is called abdominal ...
Topological Location and Structural Importance of the NBCe1-A Residues Mutated in Proximal Renal Tubular Acidosis*
NBCe1-A electrogenically cotransports Na+ and HCO3? across the basolateral membrane of renal proximal tubule cells. Eight missense mutations and 3 nonsense mutations in NBCe1-A cause severe proximal renal tubular acidosis (pRTA). In this study, the topologic properties and structural importance of the 8 endogenous residues mutated in pRTA and the in situ topology of NBCe1-A were examined by the substituted cysteine accessibility method. Of the 55 analyzed individually introduced cysteines, 8 were labeled with both membrane permeant (biotin maleimide (BM)) and impermeant (2-((5(6)-tetramethylrhodamine)carboxylamino)ethyl methanethiosulfonate (MTS-TAMRA)) sulfhydryl reagents, 4 with only BM, and 3 with only MTS-TAMRA. The location of the labeled and unlabeled introduced cysteines clearly indicates that the transmembrane region of NBCe1-A contains 14 transmembrane segments (TMs). In this in situ based NBCe1-A topology, residues mutated in pRTA (pRTA residues) are assigned as: Ser427, TM1; Thr485 and Gly486, TM3; Arg510 and Leu522, TM4; Ala799, TM10; and Arg881, TM12. Substitution of pRTA residues with cysteines impaired the membrane trafficking of R510C and R881C, the remaining membrane-processed constructs had various impaired transport function. Surprisingly, none of the membrane-processed constructs was accessible to labeling with BM and MTS-TAMRA, nor were they functionally sensitive to the inhibition by (2-aminoethyl)methanethiosulfonate. Functional analysis of Thr485 with different amino acid substitutions indicated it resides in a unique region important for NBCe1-A function. Our findings demonstrate that the pRTA residues in NBCe1-A are buried in the protein complex/lipid bilayer where they perform important structural roles.
Zhu, Quansheng; Kao, Liyo; Azimov, Rustam; Newman, Debra; Liu, Weixin; Pushkin, Alexander; Abuladze, Natalia; Kurtz, Ira
Nisoldipine Selectively Induces Coronary Vasodilation and Improves Mild Myocardial Ischemia in Dogs: A Potential Role of Cellular Acidosis
We examined whether nisoldipine, a calcium (Ca) channel blocker, increases coronary blood flow (CBF) without decreasing aortic blood pressure (AoP) with ischemic and nonischemic hearts, and whether the presence of cellular acidosis in ischemic myocardium contributes to the augmentation of coronary vasodilation due to nisoldipine. In 42 dogs, coronary perfusion pressure (CPP) was reduced so that CBF decreased to 60%
Masafumi Kitakaze; Hiroharu Funaya; Kazuo Komamura; Koichi Node; Tetsuo Minamino; Hidezo Mori; Hiroshi Takeda; Tsunehiko Kuzuya; Masatsugu Hori
Tumor Environmental Factors Glucose Deprivation and Lactic Acidosis Induce Mitotic Chromosomal Instability - An Implication in Aneuploid Human Tumors
Mitotic chromosomal instability (CIN) plays important roles in tumor progression, but what causes CIN is incompletely understood. In general, tumor CIN arises from abnormal mitosis, which is caused by either intrinsic or extrinsic factors. While intrinsic factors such as mitotic checkpoint genes have been intensively studied, the impact of tumor microenvironmental factors on tumor CIN is largely unknown. We investigate if glucose deprivation and lactic acidosis � two tumor microenvironmental factors � could induce cancer cell CIN. We show that glucose deprivation with lactic acidosis significantly increases CIN in 4T1, MCF-7 and HCT116 scored by micronuclei, or aneuploidy, or abnormal mitosis, potentially via damaging DNA, up-regulating mitotic checkpoint genes, and/or amplifying centrosome. Of note, the feature of CIN induced by glucose deprivation with lactic acidosis is similar to that of aneuploid human tumors. We conclude that tumor environmental factors glucose deprivation and lactic acidosis can induce tumor CIN and propose that they are potentially responsible for human tumor aneuploidy.
Zhu, Chunpeng; Hu, Xun
Oral rehydration therapy: efficacy of sodium citrate equals to sodium bicarbonate for correction of acidosis in diarrhoea.
Forty patients with moderate degrees of dehydration and acidosis because of acute watery diarrhoea were successfully treated randomly with either WHO recommended oral rehydration solution containing 2.5 g sodium bicarbonate or an oral solution containing 2.94 g sodium citrate in place of sodium bicarbonate per litre of oral rehydration rehydration solution. Efficacies were compared by measuring oral fluid intake, stool and vomitus output, change in body weight, hydration status, and rate of correction of acidosis during a period of 48 hours. Seventy five per cent (21 cases) in the citrate group and 83% (19 cases) in the bicarbonate group were successfully rehydrated (p greater than 0.05). There were no significant differences in intake, output, gain in body weight, fall in haematocrit and plasma specific gravity, and correction of acidosis between the two groups of patients within 48 hours after initiation of therapy. The solution with sodium citrate base was as effective as WHO-oral rehydration solution for management of diarrhoea. This study shows the efficacy, safety, and acceptability of citrate containing oral rehydration solution for rehydration and correction of acidosis in diarrhoea.
Islam, M R; Samadi, A R; Ahmed, S M; Bardhan, P K; Ali, A
Extracellular acidosis stimulates NHE2 expression through activation of transcription factor Egr-1 in the intestinal epithelial cells.
Na(+)/H(+) exchangers (NHEs) play important roles in regulating internal pH (pHi), cell volume and neutral Na(+) absorption in the human intestine. Earlier studies have shown that low extracellular pH (pHe) and metabolic acidosis increases the expression and function of NHE1-3 genes. However, transcriptional mechanisms involved remained unknown. Therefore, we investigated the molecular mechanisms underlying acid-induced NHE2 expression in C2BBe1 and SK-CO15 intestinal epithelial cells. Assessing total RNA and protein by RT-PCR and Western blot analysis, respectively, displayed significant increases in the NHE2 mRNA and protein levels in cells exposed to acidic media (pH 6.5 and 6.7) compared to normal medium. Acid treatment was also associated with a significant enhancement in NHE2 transport activity. Quantification of the heterogeneous nuclear RNA indicated that the rate of NHE2 transcription was increased in response to acid. Furthermore, acid caused a significant increase in NHE2 promoter activity confirming transcriptional upregulation. Through functional and mutational studies the acid-response element was mapped to a 15-nucleotide GC-rich sequence at bp -337 to -323 upstream from the transcription start site. We previously identified this element as an overlapping Egr-1/Sp1/Egr-1 motif that was essential for the NHE2 upregulation by mitogen-induced transcription factor Egr-1. Cells exposed to acid exhibited a temporal increase in Egr-1 mRNA and protein expression. These events were followed by Egr-1 nuclear accumulation, as detected by immunofluorescence microscopy, and potentiated its in vitro and in vivo interaction with the NHE2 promoter. Disruption of ESE motif and knockdown of Egr-1 expression by targeted small interfering RNA abrogated the acid-induced NHE2 transcriptional activity. These data indicate that the acid-dependent NHE2 stimulation is implemented by transcriptional upregulation of NHE2 via acid-induced Egr-1 in the intestinal epithelial cells. PMID:24376510
Muthusamy, Saminathan; Cheng, Ming; Jeong, Jong-Jin; Kumar, Anoop; Dudeja, Pradeep K; Malakooti, Jaleh
Extracellular Acidosis Stimulates NHE2 Expression through Activation of Transcription Factor Egr-1 in the Intestinal Epithelial Cells
Na+/H+ exchangers (NHEs) play important roles in regulating internal pH (pHi), cell volume and neutral Na+ absorption in the human intestine. Earlier studies have shown that low extracellular pH (pHe) and metabolic acidosis increases the expression and function of NHE1-3 genes. However, transcriptional mechanisms involved remained unknown. Therefore, we investigated the molecular mechanisms underlying acid-induced NHE2 expression in C2BBe1 and SK-CO15 intestinal epithelial cells. Assessing total RNA and protein by RT-PCR and Western blot analysis, respectively, displayed significant increases in the NHE2 mRNA and protein levels in cells exposed to acidic media (pH 6.5 and 6.7) compared to normal medium. Acid treatment was also associated with a significant enhancement in NHE2 transport activity. Quantification of the heterogeneous nuclear RNA indicated that the rate of NHE2 transcription was increased in response to acid. Furthermore, acid caused a significant increase in NHE2 promoter activity confirming transcriptional upregulation. Through functional and mutational studies the acid-response element was mapped to a 15-nucleotide GC-rich sequence at bp ?337 to ?323 upstream from the transcription start site. We previously identified this element as an overlapping Egr-1/Sp1/Egr-1 motif that was essential for the NHE2 upregulation by mitogen-induced transcription factor Egr-1. Cells exposed to acid exhibited a temporal increase in Egr-1 mRNA and protein expression. These events were followed by Egr-1 nuclear accumulation, as detected by immunofluorescence microscopy, and potentiated its in vitro and in vivo interaction with the NHE2 promoter. Disruption of ESE motif and knockdown of Egr-1 expression by targeted small interfering RNA abrogated the acid-induced NHE2 transcriptional activity. These data indicate that the acid-dependent NHE2 stimulation is implemented by transcriptional upregulation of NHE2 via acid-induced Egr-1 in the intestinal epithelial cells.
Jeong, Jong-Jin; Kumar, Anoop; Dudeja, Pradeep K.; Malakooti, Jaleh
Factors associated with thrombocytopenia in severe leptospirosis (Weil's disease)
OBJECTIVE: This study was conducted to investigate factors associated with thrombocytopenia in a large cohort of patients with leptospirosis in an endemic area. METHODS: This retrospective study included 374 consecutive patients with leptospirosis who were admitted to tertiary hospitals in Fortaleza, Brazil. All patients had a diagnosis of severe leptospirosis (Weil's disease). Acute kidney injury was defined according to the RIFLE criteria. Thrombocytopenia was defined as a platelet count <100,000/mm3. RESULTS: A total of 374 patients were included, with a mean age of 36.1�15.5 years, and 83.4% were male. Thrombocytopenia was present at the time of hospital admission in 200 cases (53.5%), and it developed during the hospital stay in 150 cases (40.3%). The patients with thrombocytopenia had higher frequencies of dehydration (53% vs. 35.3%, p?=?0.001), epistaxis (5.7% vs. 0.8%, p?=?0.033), hematemesis (13% vs. 4.6%, p?=?0.006), myalgia (91.5% vs. 84.5%, p?=?0.038), hematuria (54.8% vs. 37.6%, p?=?0.011), metabolic acidosis (18% vs. 9.2%, p?=?0.016) and hypoalbuminemia (17.8% vs. 7.5%, p?=?0.005). The independent risk factors associated with thrombocytopenia during the hospital stay were lengthy disease (OR: 1.2, p?=?0.001) and acute kidney injury (OR: 6.6, p?=?0.004). Mortality was not associated with thrombocytopenia at admission (12.5% vs. 12.6%, p?=?1.000) or during the hospital stay (12.6% vs. 11.3%, p?=?0.748). CONCLUSIONS: Thrombocytopenia is a frequent complication in leptospirosis, and this condition was present in more than half of patients at the time of hospital admission. Lengthy disease and acute kidney injury are risk factors for thrombocytopenia. There was no significant association between thrombocytopenia and mortality.
Daher, Elizabeth F.; Silva, Geraldo B.; Silveira, Charles O.; Falcao, Felipe S.; Alves, Marilia P.; Mota, Jorio A. A. A.; Lima, Joyce B.; Mota, Rosa M. S.; Vieira, Ana Patricia F.; da Justa Pires Neto, Roberto; Liborio, Alexandre B.
Clinical spectrum and treatment outcome of severe malaria caused by Plasmodium vivax in 18 children from northern India
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.
Gehlawat, Virender Kumar; Arya, Vandana; Kaushik, Jaya Shankar; Gathwala, Geeta
Loss of multidrug and toxin extrusion 1 (MATE1) is associated with metformin-induced lactic acidosis
BACKGROUNDS AND PURPOSE Lactic acidosis is a fatal adverse effect of metformin, but the risk factor remains unclear. Multidrug and toxin extrusion 1 (MATE1) is expressed in the luminal membrane of the kidney and liver. MATE1 was revealed to be responsible for the tubular and biliary secretion of metformin. Therefore, some MATE polymorphisms, that cause it to function abnormally, are hypothesized to induce lactic acidosis. The purpose of this study is to clarify the association between MATE dysfunction and metformin-induced lactic acidosis. EXPERIMENTAL APPROACH Blood lactate, pH and bicarbonate ion (HCO3-) levels were evaluated during continuous administration of 3 mg�mL?1 metformin in drinking water using Mate1 knockout (?/?), heterozygous (+/?) and wild-type (+/+) mice. To determine the tissue accumulation of metformin, mice were given 400 mg�kg?1 metformin orally. Furthermore, blood lactate data were obtained from diabetic patients given metformin. KEY RESULTS Seven days after metformin administration in drinking water, significantly higher blood lactate, lower pH and HCO3- levels were observed in Mate1?/? mice, but not in Mate1+/? mice. The blood lactate levels were not affected in patients with the heterozygous MATE variant (MATE1-L125F, MATE1-G64D, MATE2-K-G211V). Sixty minutes after metformin administration (400 mg�kg?1, p.o.) the hepatic concentration of metformin was markedly higher in Mate1?/? mice than in Mate1+/+ mice. CONCLUSION AND IMPLICATIONS MATE1 dysfunction caused a marked elevation in the metformin concentration in the liver and led to lactic acidosis, suggesting that the homozygous MATE1 variant could be one of the risk factors for metformin-induced lactic acidosis.
Toyama, K; Yonezawa, A; Masuda, S; Osawa, R; Hosokawa, M; Fujimoto, S; Inagaki, N; Inui, K; Katsura, T
Re-engineering Cytochrome P450 2B11dH for Enhanced Metabolism of Several Substrates Including the Anti-cancer Prodrugs Cyclophosphamide and Ifosfamide
Based on recent directed evolution of P450 2B1, six P450 2B11 mutants at three positions were created in an N-terminal modified construct termed P450 2B11dH and characterized for enzyme catalysis using five substrates. Mutant I209A demonstrated a 3.2-fold enhanced kcat/Km for 7-ethoxy-4-trifluoromethylcourmarin O-deethylation, largely due to a dramatic decrease in Km (0.72 vs. 18 ?M). I209A also demonstrated enhanced selectivity for testosterone 16?-hydroxylation over 16?-hydroxylation. In contrast, V183L showed a 4-fold increased kcat for 7-benzyloxyresorufin debenzylation and a 4.7-fold increased kcat/Km for testosterone 16?-hydroxylation. V183L also displayed a 1.7-fold higher kcat/Km than P450 2B11dH with the anti-cancer prodrugs cyclophosphamide and ifosfamide, resulting from a ~4-fold decrease in Km. Introduction of the V183L mutation into full-length P450 2B11 did not enhance the kcat/Km. Overall, the re-engineered P450 2B11dH enzymes exhibited enhanced catalytic efficiency with several substrates including the anti-cancer prodrugs.
Sun, Ling; Chen, Chong S.; Waxman, David J.; Liu, Hong; Halpert, James R.; Kumar, Santosh
Aeromedical transfer to Belgium of severely burned patients during the initial days following the Volendam fire.
Nineteen critical burn patients were transferred to burn centers in Belgium soon after an indoor fire in The Netherlands. This evacuation was done by helicopter and by ambulance. The first arterial blood gases and pH measurements of the patients on arrival in the burn centers were analyzed and compared. All patients were in metabolic acidosis, but the respiratory component to the pH and the resulting pH was variable. Although an efficient fluid resuscitation to maintain an adequate urine output and arterial pressure is essential, the arterial blood gases and pH should also be monitored during the early evacuation of severe burn patients. Because hyperkaliemia is associated with a low pH value, we suggest that during the evacuation of these patients the ventilation setting should maintain the pH between 7.35 and 7.45. The comparison of the measurements between the group of patients transferred by air and the group transferred by road showed here differences in favor of a road transfer. PMID:12775169
Pirson, Jean; Degrave, Etienne
A study of recurrent stone formers with special reference to renal tubular acidosis.
Forty-five patients with recurrent renal stone were examined for distal renal tubular acidosis (dRTA) defects by acid challenge test (150 mg ammonium chloride/kg body weight). Their 24-h urine samples were analysed for creatinine, calcium, oxalic acid, inorganic phosphorus, uric acid, magnesium and citric acid. One-hour urine samples before acid load and hourly samples for the 7 h following acid challenge test were collected and analysed for creatinine, calcium, citric acid, inorganic phosphorus, titratable acidity, and ammonium. The incidence of distal RTA defect was 22.2% in the patients examined. The major biochemical characteristics in RTA patients compared with patients without RTA were: (a) significantly higher urinary pH, (b) significantly lower excretion of citric acid, (c) no significant difference in calcium excretion and (d) a tendency toward lower titratable acidity and ammonium excretion. PMID:7483148
Singh, P P; Pendse, A K; Ahmed, A; Ramavataram, D V; Rajpurohit, S K
Dermal bone in early tetrapods: a palaeophysiological hypothesis of adaptation for terrestrial acidosis.
The dermal bone sculpture of early, basal tetrapods of the Permo-Carboniferous is unlike the bone surface of any living vertebrate, and its function has long been obscure. Drawing from physiological studies of extant tetrapods, where dermal bone or other calcified tissues aid in regulating acid-base balance relating to hypercapnia (excess blood carbon dioxide) and/or lactate acidosis, we propose a similar function for these sculptured dermal bones in early tetrapods. Unlike the condition in modern reptiles, which experience hypercapnia when submerged in water, these animals would have experienced hypercapnia on land, owing to likely inefficient means of eliminating carbon dioxide. The different patterns of dermal bone sculpture in these tetrapods largely correlates with levels of terrestriality: sculpture is reduced or lost in stem amniotes that likely had the more efficient lung ventilation mode of costal aspiration, and in small-sized stem amphibians that would have been able to use the skin for gas exchange. PMID:22535781
Janis, Christine M; Devlin, Kelly; Warren, Daniel E; Witzmann, Florian
Cellular metabolism and disease: what do metabolic outliers teach us?
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.
DeBerardinis, Ralph J.; Thompson, Craig B.
Regulation of intracellular pH in cnidarians: response to acidosis in Anemonia viridis.
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 CO?-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 NH?Cl 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
Laurent, Julien; Venn, Alexander; Tambutt�, �ric; Ganot, Philippe; Allemand, Denis; Tambutt�, Sylvie
[Orthotopic ileal neobladder: urodynamic and metabolic aspects. Our experience].
We subjected to a functional and metabolic evaluation (urodynamic examination + cystography) 10 patients underwent to radical cystectomy with a ileal orthotopic reservoir (VIP) for bladder cancer. At the moment patients have a minimum 3-years follow-up and they are out of disease. The medium capacity of the reservoir is about 447 ml, with a low pressure flow, a medium pressure of ureteral closing of 62.5 cm of H2O. At the cystography neither ureteral reflux nor post miction residuum have been proved. All the patients are continent, with the exception of one patient suffering from episodes of nocturnal enuresis. The metabolic evaluation hasn't proved substantial changes except the presence of hypocitraturia in the only patient in metabolic acidosis. In conclusion the ileal orthotopic reservoir showed a good long-term functionality without considerable complication of metabolism. PMID:9026236
Mangiarotti, B; Ceresoli, A; Del Nero, A; Parravicini, M; Prati, G; Curr�, A; Zanetti, G P; Trinchieri, A; Pisani, E
Metabolic Complications are Common in Elderly Patients with Chronic Kidney Disease
BACKGROUND/OBJECTIVES Significant controversy exists as to the meaning of a low glomerular filtration rate (GFR) in the elderly. The goal of the study was to evaluate whether elderly patients with low GFR are at risk for anemia, hyperkalemia, acidosis, and hyperphosphatemia. DESIGN Retrospective study SETTING Veterans Affairs Medical Center PARTICIPANTS All patients over 65 years of age with chronic kidney disease (CKD) and a GFR between 15 and 60 mL/min/1.73m2. MEASUREMENTS Anemia was defined as a hemoglobin <10g/dL, hyperkalemia as a potassium >5.5mEq/L, acidosis as a bicarbonate <21mEq/L, and hyperphosphatemia as a phosphorus >4.6mg/dL. Multivariable logistic regression was used to evaluate whether age modifies the effect of low GFR on metabolic complications by including an interaction term between age and GFR in each model. RESULTS 13874 veterans were included in the study. The average age was 79, the average GFR was 46.5; 3.1% had anemia, 2.5% hyperkalemia, 2.3% acidosis, and 4.4% had hyperphosphatemia. Lower GFR was associated with increased rates of metabolic complications across all age groups (odds ratio per 5mL/min/1.73m2 decrease in GFR in multivariable models was 1.21 for anemia, 1.26 for hyperkalemia, 1.45 for acidosis, and 1.72 for hyperphosphatemia). There was no significant interaction between age and GFR in models including only age and GFR or in multivariable models (p values for the age X GFR interaction term: 0.66 for anemia, 0.19 for hyperkalemia, 0.54 for acidosis, and 0.22 for hyperphosphatemia). CONCLUSION Elderly patients with CKD are at risk for anemia, hyperkalemia, acidosis, and hyperphosphatemia; age does not modify the relationship between GFR and development of metabolic complications. Elderly patients with low GFR should be monitored for metabolic complications, regardless of age.
Drawz, Paul E.; Babineau, Denise C.; Rahman, Mahboob
Coagulopathy after severe pediatric trauma.
Trauma remains the leading cause of morbidity and mortality in the United States among children aged 1 to 21 years. The most common cause of lethality in pediatric trauma is traumatic brain injury. 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 include hypothermia, acidosis, hemodilution, and consumption of coagulation factors secondary to local activation of the coagulation system after severe traumatic injury. Furthermore, there is also recent evidence for a distinct mechanism of trauma-induced coagulopathy 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
Christiaans, Sarah C; Duhachek-Stapelman, Amy L; Russell, Robert T; Lisco, Steven J; Kerby, Jeffrey D; Pittet, Jean-Fran�ois
Metabolic fate of glutamate carbon in rat renal tubules. Studies with 13C nuclear magnetic resonance and gas chromatography-mass spectrometry.
13C-n.m.r. spectroscopy and g.c.-m.s. were used to determine the metabolic fate of glutamate carbon in rat kidney. The main purpose was to characterize the effect of chronic metabolic acidosis on the utilization of glutamate carbon. Renal tubules obtained from normal and chronically acidotic rats were incubated in Krebs buffer, pH 7.4, in the presence of 2.5 mM-[3-13C]glutamate. During the course of incubation the concentrations of total glucose and NH3 were significantly (P less than 0.05) higher in tissue from acidotic rats. The levels of some tricarboxylic-acid-cycle intermediates were higher (P less than 0.05) in control tissue. In control tissue, 13C-n.m.r. spectra demonstrated a significantly higher rate of 13C appearance of aspartate, glutamine and [2,4-13C]glutamate. However, in acidosis the resonances of [13C]glucose carbon atoms were significantly higher. In the control, approx. 15% of glutamate carbon was accounted for by [13C]glucose formation as against 30% in chronic acidosis. However, in control tissue, 44% of glutamate carbon utilization was accounted for by recycling to glutamate and formation of aspartate, glutamine and GABA. In acidosis, only 11% was so recovered. Analysis of 15NH3 formation during the course of incubation with 2.5 mM-[15N]glutamate demonstrated a positive association between the appearance of [13C]glucose and 15NH3 both in the control and in acidosis. The data suggest that the control of gluconeogenesis and ammoniagenesis in acidosis is, in part, referable to a diminution in the rate of the reductive amination of alpha-oxoglutarate, that of the transamination reaction and that of glutamine synthesis.
Nissim, I; Yudkoff, M; Segal, S
Predicting the risk of metabolic acidosis for newborns based on fetal heart rate signal classification using support vector machines
Cardiotocography is the main method used for fetal assessment in everyday clinical practice for the last 30 years. Many attempts have been made to increase the effectiveness of the evaluation of cardiotocographic recordings and minimize the variations of their interpretation utilizing technological advances. This research work proposes and focuses on an advanced method able to identify fetuses compromised and suspicious
George Georgoulas; D. Stylios; Peter P. Groumpos
Dialysis Disequilibrium Syndrome: Brain death following hemodialysis for metabolic acidosis and acute renal failure � A case report
BACKGROUND: Dialysis disequilibrium syndrome (DDS) is the clinical phenomenon of acute neurologic symptoms attributed to cerebral edema that occurs during or following intermittent hemodialysis (HD). We describe a case of DDS-induced cerebral edema that resulted in irreversible brain injury and death following acute HD and review the relevant literature of the association of DDS and HD. CASE PRESENTATION: A 22-year-old
Sean M Bagshaw; Adam D Peets; Morad Hameed; Paul JE Boiteau; Kevin B Laupland; Christopher J Doig
Phenotypic variability and identification of novel YARS2 mutations in YARS2 mitochondrial myopathy, lactic acidosis and sideroblastic anaemia
Background Mutations in the mitochondrial tyrosyl-tRNA synthetase (YARS2) gene have previously been identified as a cause of the tissue specific mitochondrial respiratory chain (RC) disorder, Myopathy, Lactic Acidosis, Sideroblastic Anaemia (MLASA). In this study, a cohort of patients with a mitochondrial RC disorder for who anaemia was a feature, were screened for mutations in YARS2. Methods Twelve patients were screened for YARS2 mutations by Sanger sequencing. Clinical data were compared. Functional assays were performed to confirm the pathogenicity of the novel mutations and to investigate tissue specific effects. Results PathogenicYARS2 mutations were identified in three of twelve patients screened. Two patients were found to be homozygous for the previously reported p.Phe52Leu mutation, one severely and one mildly affected. These patients had different mtDNA haplogroups which may contribute to the observed phenotypic variability. A mildly affected patient was a compound heterozygote for two novel YARS2 mutations, p.Gly191Asp and p.Arg360X. The p.Gly191Asp mutation resulted in a 38-fold loss in YARS2 catalytic efficiency and the p.Arg360X mutation did not produce a stable protein. The p.Phe52Leu and p.Gly191Asp/p.Arg360X mutations resulted in more severe RC deficiency of complexes I, III and IV in muscle cells compared to fibroblasts, but had relatively normal YARS2 protein levels. The muscle-specific RC deficiency can be related to the increased requirement for RC complexes in muscle. There was also a failure of mtDNA proliferation upon myogenesis in patient cells which may compound the RC defect. Patient muscle had increased levels of PGC1-? and TFAM suggesting mitochondrial biogenesis was activated as a potential compensatory mechanism. Conclusion In this study we have identified novel YARS2 mutations and noted marked phenotypic variability among YARS2 MLASA patients, with phenotypes ranging from mild to lethal, and we suggest that the background mtDNA haplotype may be contributing to the phenotypic variability. These findings have implications for diagnosis and prognostication of the MLASA and related phenotypes.
A prebiotic origin of metabolism has been proposed as one of several scenarios for the origin of life. In their recent work, Ralser and colleagues (Keller et�al, 2014) observe an enzyme-free, metabolism-like reaction network under conditions reproducing a possible prebiotic environment. PMID:24771086
Luisi, Pier Luigi
Responses of glomus cells to hypoxia and acidosis are uncoupled, reciprocal and linked to ASIC3 expression: selectivity of chemosensory transduction
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.
Lu, Yongjun; Whiteis, Carol A; Sluka, Kathleen A; Chapleau, Mark W; Abboud, Francois M
Novel mutations in ATP6V0A4 are associated with atypical progressive sensorineural hearing loss in a Chinese patient with distal renal tubular acidosis
Mutations in ATP6V0A4 lead to distal renal acidosis (MIM 602722) with a highly variable range of hearing phenotype. We identified two novel ATP6V0A4 mutations in a Chinese patient with distal renal tubular acidosis and late onset hearing loss, and presented the first direct evidence of progressive hearing loss associated with ATP6V0A4 mutations by sequential audiological assessments. A unique audiometric profile
Xiaohua Li; Yongchuan Chai; Zheng Tao; Lei Li; Zhiwu Huang; Yun Li; Hao Wu; Tao Yang
UPLC/ESI-MS/MS-based determination of metabolism of several new illicit drugs, ADB-FUBINACA, AB-FUBINACA, AB-PINACA, QUPIC, 5F-QUPIC and ?-PVT, by human liver microsome.
The metabolism by human liver microsomes of several new illicit drugs, that is, N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3- carboxamide (ADB-FUBINACA), N-(1-amino-3-methyl-1-oxobutan-2-yl)-1- (4-fluorobenzyl)-1H-indazole-3-carboxamide (AB-FUBINACA), N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (AB-PINACA), quinolin-8-yl 1-pentyl-(1H-indole)-3-carboxylate (QUPIC), quinolin-8-yl 1-(5-fluoropentyl)-(1H-indole)-3-carboxylate (5?F-QUPIC) and ?-pyrrolidinovalerothiophenone (?-PVT), which have indole, indazole, quinolinol ester and thiophene structures, was investigated using reversed-phase chromatography and mass spectrometry. The present method is based upon the oxidation by cytochrome p450 superfamily enzymes in the microsomes. The oxidation of ADB-FUBINACA and AB-FUBINACA mainly occurred on the N-(1-amino-alkyl-1-oxobutan) moiety. However, the oxidation of AB-PINACA seemed to occur on the 1-pentyl moiety. On the other hand, QUPIC and 5?F-QUPIC, which have a quinolinol ester structure, predominantly underwent a cleavage reaction to produce indoleacetic acid type metabolites. In contrast, the metabolism reaction of ?-PVT was different from that of the other tested drugs, and various oxidation products were observed on the chromatograms. The obtained metabolites are not in conflict with the results predicted by MetaboLynx software. However, the exact structures of the metabolites, except for 1-pentyl-1H-indole-3-carboxylic acid (QUPIC metabolite) and 1-(5-fluoropentyl)-1H-indole-3-carboxylic acid (5?F-QUPIC metabolite), are currently not proven, because we have no authentic compounds for comparison. The proposed approach using human liver microsome seems to provide a new technology for the prediction of possible metabolites occuring in humans. Copyright � 2014 John Wiley & Sons, Ltd. PMID:24861751
Takayama, Takahiro; Suzuki, Mayu; Todoroki, Kenichiro; Inoue, Koichi; Min, Jun Zhe; Kikura-Hanajiri, Ruri; Goda, Yukihiro; Toyo'oka, Toshimasa
Targeting the Metabolic Microenvironment of Tumors
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 HIF1?, 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.
Bailey, Kate M.; Wojtkowiak, Jonathan W.; Hashim, Arig Ibrahim; Gillies, Robert J.
Acidosis Decreases c-Myc Oncogene Expression in Human Lymphoma Cells: A Role for the Proton-Sensing G Protein-Coupled Receptor TDAG8
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.
Li, Zhigang; Dong, Lixue; Dean, Eric; Yang, Li V.
Non-Hodgkins lymphoma with lactic acidosis at presentation: A case report of a rare oncologic emergency
Lactic acidosis (LA) has been reported to be associated with high grade lymphoma as a terminal event. Its causes are multi-factorial. It can either occur due to overproduction of lactic acid by rapidly dividing tumor or due to its underutilization due to involvement of liver by lymphomatous deposits. The prognosis of lymphoma associated with LA is dismal. We present a patient of non-Hodgkins lymphoma (NHL) who presented with LA, after an initial response succumbed.
Kumar, Arvind; Raina, Vinod
Acidosis, lactate, electrolytes, muscle enzymes, and other factors in the blood of Sus scrofa following repeated TASER1 exposures
Repeated exposure to electro-muscular incapacitating devices could result in repetitive, sustained muscle contraction, with little or no muscle recovery period. Therefore, rhabdomyolysis and other physiological responses, including acidosis, hyperkalaemia, and altered levels of muscle enzymes in the blood, would be likely to occur. Experiments were performed to investigate effects of repeated exposures of TASER1 International's Advanced TASER1 X26 on muscle
James R. Jauchem; Clifford J. Sherry; David A. Fines; Michael C. Cook
Oxidative response of neutrophils to platelet-activating factor is altered during acute ruminal acidosis induced by oligofructose in heifers
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.
Concha, Claudia; Carretta, Maria Daniella; Alarcon, Pablo; Conejeros, Ivan; Gallardo, Diego; Hidalgo, Alejandra Isabel; Tadich, Nestor; Caceres, Dante Daniel; Hidalgo, Maria Angelica
Alterations in malondialdehyde concentration of jugular vein blood following transient brain ischemia. The effect of lactic acidosis.
Ischemia was induced for 10 min with a subsequent 60-min reperfusion and the changes of the malondialdehyde (MDA) concentration in the blood samples from the jugular vein were investigated in normo- and hyperglycemic dogs. Selective brain ischemia was evoked by the increase in cerebrospinal fluid (CSF) pressure. The experiments were carried out in 4 experimental groups. In sham operated animals (Group I) the blood MDA concentration did not change. The venous blood MDA content significantly elevated for 10 min after the start of reperfusion in normoglycemic animals (Group II). To study the effect of acidosis during ischemia and reperfusion on brain lipid peroxidation (LP) processes 1 and 2 g/kg glucose infusion was used in Groups III and IV. As an effect of ischemic lactic acidosis due to hyperglycemia the elevation of MDA concentration in the jugular vein blood was higher and it lasted longer than in the cases of normoglycemia. This finding supports the hypothesis that free radical reactions and LP processes play an important role in the enhanced brain damage caused by tissue acidosis. PMID:7717085
Lantos, J; Temes, G; R�th, R; Morvay, G
Expression of tumor-promoting Cyr61 is regulated by hTRA2-?1 and acidosis.
The matricellular protein Cysteine rich 61 (Cyr61) displays a remarkable diversity of multiple cellular functions involved in significant physiologic and pathologic processes. Cyr61 is known as an important player in tumor progression, promoting neovascularization and metastasis. Our prior investigations elucidated an oxygen-dependent Cyr61 alternative splicing process characterized by retention of its intron 3, regulating its biological function in a hypoxia-driven on/off switch mechanism. In this work, we identified extracellular acidosis as a potent inducer for altered Cyr61 alternative splicing pattern regulating Cyr61 expression. Intriguingly, splicing factor hTRA2-beta1 displayed an opposite effect on Cyr61 expression. Nuclear hTRA2-beta1 protein expression was found markedly reduced under acidic conditions. In keeping with these conclusions, we show that hTRA2-beta1 can specifically bind a 'GAAG' motif in Cyr61 exon 3 RNA, that the splicing factor displays acidosis-dependent protein localization in cellular compartments, and shRNA-mediated hTRA2-beta1 knock-down triggers the same effects on Cyr61 alternative splicing like acidosis or hypoxia. Our findings strongly support the hypothesis of a specific regulation of Cyr61 expression by hTRA2-beta1. PMID:21447598
Hirschfeld, Marc; Jaeger, Markus; Buratti, Emanuele; Stuani, Cristiana; Grueneisen, Johannes; Gitsch, Gerald; Stickeler, Elmar
Carnosine inhibits carbonic anhydrase IX-mediated extracellular acidosis and suppresses growth of HeLa tumor xenografts
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 (?-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-1? 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-1? 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-1? 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.
Intracolonic Vancomycin for Severe Clostridium difficile Colitis
Abstract Background: Clostridium difficile colitis is associated with increased age, antibiotic usage, and hospitalization. Severe C. difficile colitis refractory to medical therapy may require surgical intervention including subtotal colectomy. We initiated an adjuvant intracolonic vancomycin (ICV) enema protocol for inpatients with severe C. difficile colitis and compared the response to this therapy in patients from the community and nursing homes. Methods: A single-hospital, retrospective chart review was done on 47 consecutive patients with C. difficile colitis treated with ICV (1?g/500?mL normal saline q6h) from January 2007 through October 2009. The proportions of patients with the outcomes of response to the ICV protocol, need for subtotal colectomy, and death were described. Associations of patient characteristics with these outcomes were examined with bivariate tests and multivariable logistic models with adjustment for age, hypoalbuminemia, acidosis, and nursing-home status. Results: Thirty-three of 47 patients (70%) with severe C. difficile colitis responded to adjunct ICV with complete resolution without surgery. Incomplete responders who had surgery were more likely to survive than those patients who did not undergo subtotal colectomy (p<0.01). Seven of nine patients who underwent surgery survived >90 d, and overall, 37 of 47 patients (79%) survived after ICV therapy. Nursing-home residence, acidosis, and hypoalbuminemia were significantly associated with the non-resolution of colitis in bivariate analyses (all p<0.01), whereas nursing-home residence and hypoalbuminemia showed non-significant trends toward association with death (p=0.07 and p=0.06, respectively). Multivariate logistic-regression models showed significant associations of acidosis with an incomplete response to ICV (p=0.02), of older age with death (p=0.04), and of hypoalbuminemia with both an incomplete response to ICV and death (both p=0.04). No complications were attributable to ICV. Conclusion: Complete resolution without surgery was achieved in 70% in this series of patients with severe C. difficile colitis who received adjunct ICV therapy. A clinical trial will be needed to determine whether ICV as compared with standard therapy alone can reduce the need for surgery with non-inferior or superior outcomes.
Huh, Heesun C.; Cohen, Hillel W.; Feinberg, Elyssa J.; Ahmad, Salman; Coyle, Christina; Teperman, Sheldon; Boothe, Hugh
Hypoxia-induced Acidosis Uncouples the STIM-Orai Calcium Signaling Complex*
The endoplasmic reticulum Ca2+-sensing STIM proteins mediate Ca2+ entry signals by coupling to activate plasma membrane Orai channels. We reveal that STIM-Orai coupling is rapidly blocked by hypoxia and the ensuing decrease in cytosolic pH. In smooth muscle cells or HEK293 cells coexpressing STIM1 and Orai1, acute hypoxic conditions rapidly blocked store-operated Ca2+ entry and the Orai1-mediated Ca2+ release-activated Ca2+ current (ICRAC). Hypoxia-induced blockade of Ca2+ entry and ICRAC was reversed by NH4+-induced cytosolic alkalinization. Hypoxia and acidification both blocked ICRAC induced by the short STIM1 Orai-activating region. Although hypoxia induced STIM1 translocation into junctions, it did not dissociate the STIM1-Orai1 complex. However, both hypoxia and cytosolic acidosis rapidly decreased F�rster resonance energy transfer (FRET) between STIM1-YFP and Orai1-CFP. Thus, although hypoxia promotes STIM1 junctional accumulation, the ensuing acidification functionally uncouples the STIM1-Orai1 complex providing an important mechanism protecting cells from Ca2+ overload under hypoxic stress conditions.
Mancarella, Salvatore; Wang, Youjun; Deng, Xiaoxiang; Landesberg, Gavin; Scalia, Rosario; Panettieri, Reynold A.; Mallilankaraman, Karthik; Tang, Xian