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Sample records for severe metabolic acidosis

  1. Metabolic acidosis

    MedlinePlus

    Acidosis - metabolic ... Metabolic acidosis occurs when the body produces too much acid. It can also occur when the kidneys ... from the body. There are several types of metabolic acidosis. Diabetic acidosis develops when acidic substances, known ...

  2. An unusual case of severe high anion gap metabolic acidosis.

    PubMed

    Bavakunji, Riaz V; Turner, Jake D; Jujjavarapu, Sagar; Taal, Maarten W; Fluck, Richard J; Leung, Janson C; Kolhe, Nitin V; Selby, Nicholas M

    2011-04-01

    We present a case of high anion gap metabolic acidosis with an unusual aetiology in a 75-year-old lady with hypoglycaemia, encephalopathy and relatively preserved renal function. Full toxicology and biochemical analysis suggested that she had an inborn error of metabolism, riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency that can predispose to severe acidosis in situations where calorific intake is reduced. We believe this to be one of the few published cases and is remarkable for the presentation in late adulthood in addition to the requirement for emergency haemodialysis due to the severity of the metabolic disturbance.

  3. An unusual case of severe high anion gap metabolic acidosis

    PubMed Central

    Bavakunji, Riaz V.; Turner, Jake D.; Jujjavarapu, Sagar; Taal, Maarten W.; Fluck, Richard J.; Leung, Janson C.; Kolhe, Nitin V.

    2011-01-01

    We present a case of high anion gap metabolic acidosis with an unusual aetiology in a 75-year-old lady with hypoglycaemia, encephalopathy and relatively preserved renal function. Full toxicology and biochemical analysis suggested that she had an inborn error of metabolism, riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency that can predispose to severe acidosis in situations where calorific intake is reduced. We believe this to be one of the few published cases and is remarkable for the presentation in late adulthood in addition to the requirement for emergency haemodialysis due to the severity of the metabolic disturbance. PMID:25984120

  4. Severe metabolic acidosis in adult patients with Duchenne muscular dystrophy.

    PubMed

    Lo Cascio, Christian M; Latshang, Tsogyal D; Kohler, Malcolm; Fehr, Thomas; Bloch, Konrad E

    2014-01-01

    Duchenne muscular dystrophy (DMD) leads to progressive paresis, respiratory failure and premature death. Long-term positive pressure ventilation can improve quality of life and survival, but previously unrecognized complications may arise. We analyzed the characteristics of severe metabolic acidosis occurring in 8 of 55 DMD patients, of 20-36 years of age, observed over a 5-year period. All patients were on positive pressure ventilation and were being treated for chronic constipation. Before admission, they had had a reduced intake of fluids and food. Upon examination, they were severely ill, dyspneic and suffering from abdominal discomfort. Metabolic acidosis with a high anion gap was noted in 5 of the 8 patients and with a normal anion gap in the other 3. They all recovered after the administration of fluids and nutrition, the regulation of bowel movements and treatment with antibiotics, as appropriate. Metabolic acidosis is a life-threatening, potentially preventable complication in older DMD patients. Early recognition, subsequent administration of fluids, nutrition and antibiotics and regulation of bowel movements seem to be essential.

  5. Severe high anion gap metabolic acidosis in pregnancy.

    PubMed

    Hami, Maryam; Hasanzadeh Mofrad, Maliheh; Takallo, Reihaneh

    2013-05-01

    Ketoacidosis can occur most often as a result of uncontrolled diabetes mellitus. However, it can be seen with fasting and alcohol consumption, as well. Ketoacidosis in association with fasting has less severity, and ketoacid levels do not exceed 10 mEq/L. In the literature, there are a few reports about severe high anion gap acidosis that were associated with fasting. We report a case of pregnancy associated with high anion gap acidosis as a result of fasting.

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

    PubMed Central

    Venkatram, Sindhaghatta; Diaz-Fuentes, Gilda

    2014-01-01

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

  7. Unexpectedly severe metabolic acidosis associated with sodium thiosulfate therapy in a patient with calcific uremic arteriolopathy.

    PubMed

    Selk, Natalie; Rodby, Roger A

    2011-01-01

    Calcific uremic arteriolopathy, formerly known as calciphylaxis is a devastating condition that primarily affects patients with end-stage renal disease. The lesions can progress to massive ulcerations of the subcutaneous tissue that are associated with a high degree of morbidity and mortality, usually related to sepsis. Although the pathophysiology of this condition is poorly understood, it appears to be related to a derangement in calcium-phosphate metabolism. Thus, treatments have focused on the treatment of hyperparathyroidism albeit with poor results. More recently, sodium thiosulfate (STS) has emerged as a promising therapy following multiple case reports of marked disease regression following its use. As STS is a strong acid, metabolic acidosis has been described following its administration, although relatively mild in degree. We report a case of a patient with calciphylaxis who repeatedly developed a severe anion gap metabolic acidosis following each dose of STS requiring a significant reduction in the dose.

  8. Severe anion gap metabolic acidosis from acetaminophen use secondary to 5-oxoproline (pyroglutamic acid) accumulation.

    PubMed

    Zand, Ladan; Muriithi, Angela; Nelsen, Eric; Franco, Pablo M; Greene, Eddie L; Qian, Qi; El-Zoghby, Ziad M

    2012-12-01

    Anion gap metabolic acidosis (AGMA) is commonly encountered in medical practice. Acetaminophen-induced AGMA is, however, not widely recognized. We report 2 cases of high anion gap metabolic acidosis secondary to 5-oxoproline accumulation resulting from acetaminophen consumption: the first case caused by acute one-time ingestion of large quantities of acetaminophen and the second case caused by chronic repeated ingestion in a patient with chronic liver disease. Recognition of this entity facilitated timely diagnosis and effective treatment. Given acetaminophen is commonly used over the counter medication, increased recognition of this adverse effect is of important clinical significance.

  9. Drug-Induced Metabolic Acidosis

    PubMed Central

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

    2015-01-01

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

  10. Drug-Induced Metabolic Acidosis.

    PubMed

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

    2015-01-01

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

  11. Metabolic acidosis may be as protective as hypercapnic acidosis in an ex-vivo model of severe ventilator-induced lung injury: a pilot study

    PubMed Central

    2011-01-01

    Background There is mounting experimental evidence that hypercapnic acidosis protects against lung injury. However, it is unclear if acidosis per se rather than hypercapnia is responsible for this beneficial effect. Therefore, we sought to evaluate the effects of hypercapnic (respiratory) versus normocapnic (metabolic) acidosis in an ex vivo model of ventilator-induced lung injury (VILI). Methods Sixty New Zealand white rabbit ventilated and perfused heart-lung preparations were used. Six study groups were evaluated. Respiratory acidosis (RA), metabolic acidosis (MA) and normocapnic-normoxic (Control - C) groups were randomized into high and low peak inspiratory pressures, respectively. Each preparation was ventilated for 1 hour according to a standardized ventilation protocol. Lung injury was evaluated by means of pulmonary edema formation (weight gain), changes in ultrafiltration coefficient, mean pulmonary artery pressure changes as well as histological alterations. Results HPC group gained significantly greater weight than HPMA, HPRA and all three LP groups (P = 0.024), while no difference was observed between HPMA and HPRA groups regarding weight gain. Neither group differ on ultrafiltration coefficient. HPMA group experienced greater increase in the mean pulmonary artery pressure at 20 min (P = 0.0276) and 40 min (P = 0.0012) compared with all other groups. Histology scores were significantly greater in HP vs. LP groups (p < 0.001). Conclusions In our experimental VILI model both metabolic acidosis and hypercapnic acidosis attenuated VILI-induced pulmonary edema implying a mechanism other than possible synergistic effects of acidosis with CO2 for VILI attenuation. PMID:21486492

  12. Novel ECHS1 mutation in an Emirati neonate with severe metabolic acidosis.

    PubMed

    Nair, Pratibha; Hamzeh, Abdul Rezzak; Mohamed, Madiha; Malik, Ethar Mustafa; Al-Ali, Mahmoud Taleb; Bastaki, Fatma

    2016-10-01

    ECHS1 is a mitochondrial matrix enzyme that catalyzes an important step in the β-oxidation spiral of fatty acid catabolism, and individuals with mutations in the ECHS1 gene suffer from an autosomal recessive condition typified by delayed psychomotor development, mitochondrial encephalopathy, hypotonia, and cardiomyopathy. Here we report the first Arab case of ECHS1 Deficiency. The patient was born to consanguineous parents with all growth parameters being low for gestational age, and was persistently desaturated. Cord blood gas and later blood analysis showed severe metabolic acidosis. Tandem MS revealed increased levels of valine, and Leucine/Isoleucine and decreased level of Glutamine. There was also a large patent ductus arteriosus with right to left shunt and a possible small muscular ventricular septal defect. Whole Exome Sequencing revealed a novel homozygous missense mutation in the ECHS1 gene; c.842 A > G (p.Glu281Gly). In-silico analysis suggests that the residue affected by this mutation may be involved in an important functional or structural role.

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

    PubMed Central

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

    2015-01-01

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

  14. Trimethoprim/Sulfamethoxazole-Induced Severe Lactic Acidosis

    PubMed Central

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

    2016-01-01

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

  15. Diet-induced metabolic acidosis.

    PubMed

    Adeva, María M; Souto, Gema

    2011-08-01

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

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

    PubMed Central

    2013-01-01

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

  17. A life-threatening double gap metabolic acidosis.

    PubMed

    Tsao, Yu-Tzu; Tsai, Wei-Chi; Yang, Shih-Ping

    2008-03-01

    Double gap metabolic acidosis represents the high anion gap metabolic acidosis combined with raised serum osmolal gap due to retention of unmeasured osmole with accompanied metabolite. We describe a 62-year-old man diagnosed with community-acquired pneumonia undergoing continuous sedation in the context of asynchronous mechanical ventilation. High anion gap metabolic acidosis coupled with high plasma osmolal gap was noted with resultant severe bradyarrhythmia. D-Lactic acidosis and high serum concentration of propylene glycol (PG) eventually established the diagnosis of lorazepam-induced PG intoxication. Discontinuation of lorazepam followed by emergent long-extended hemodialysis effectively resolved the metabolic derangement without further recurrence. Serum osmolal gap is a sensitive and convenient surrogate for both early bedside detection and monitoring the therapeutic efficacy. Therefore, PG intoxication must be considered in the differential diagnosis of double gap metabolic acidosis. Early recognition with prompt hemodialysis intervention can avoid a life-threatening catastrophe.

  18. Metabolic acidosis with an elevated anion gap.

    PubMed

    Hertford, J A; McKenna, J P; Chamovitz, B N

    1989-04-01

    Determining the cause of metabolic acidosis with a high anion gap may present a diagnostic challenge. Possible causes include ketoacidosis, certain toxic ingestions, renal failure and lactic acidosis. Many of these entities present with nausea, vomiting and changes in mental status; however, there are specific hallmarks in the signs, symptoms and laboratory findings that help to differentiate among them.

  19. Sodium Bicarbonate Therapy in Patients with Metabolic Acidosis

    PubMed Central

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

    2014-01-01

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

  20. Hemolytic anemia and metabolic acidosis: think about glutathione synthetase deficiency.

    PubMed

    Ben Ameur, Salma; Aloulou, Hajer; Nasrallah, Fehmi; Kamoun, Thouraya; Kaabachi, Naziha; Hachicha, Mongia

    2015-02-01

    Glutathione synthetase deficiency (GSSD) is a rare disorder of glutathione metabolism with varying clinical severity. Patients may present with hemolytic anemia alone or together with acidosis and central nervous system impairment. Diagnosis is made by clinical presentation and detection of elevated concentrations of 5-oxoproline in urine and low glutathione synthetase activity in erythrocytes or cultured skin fibroblasts. The prognosis seems to depend on early diagnosis and treatment. We report a 4 months old Tunisian male infant who presented with severe metabolic acidosis with high anion gap and hemolytic anemia. High level of 5-oxoproline was detected in her urine and diagnosis of GSSD was made. Treatment consists of the correction of acidosis, blood transfusion, and supplementation with antioxidants. He died of severe metabolic acidosis and sepsis at the age of 15 months.

  1. Profound metabolic acidosis from pyroglutamic acidemia: an underappreciated cause of high anion gap metabolic acidosis.

    PubMed

    Green, Thomas J; Bijlsma, Jan Jaap; Sweet, David D

    2010-09-01

    The workup of the emergency patient with a raised anion gap metabolic acidosis includes assessment of the components of “MUDPILES” (methanol; uremia; diabetic ketoacidosis; paraldehyde; isoniazid, iron or inborn errors of metabolism; lactic acid; ethylene glycol; salicylates). This approach is usually sufficient for the majority of cases in the emergency department; however, there are many other etiologies not addressed in this mnemonic. Organic acids including 5-oxoproline (pyroglutamic acid) are rare but important causes of anion gap metabolic acidosis. We present the case of a patient with profound metabolic acidosis with raised anion gap, due to pyroglutamic acid in the setting of malnutrition and chronic ingestion of acetaminophen.

  2. Hunting down a double gap metabolic acidosis.

    PubMed

    Yan, Ming-Tso; Chau, Tom; Cheng, Chih-Jen; Lin, Shih-Hua

    2010-05-01

    Double gap metabolic acidosis occurs in the setting of unmeasured active osmoles in the serum (osmolal gap) and anion gap (AG) metabolic acidosis. We describe a 67-year-old woman with acute respiratory failure on mechanical ventilator from pneumonia and anuric acute on chronic renal failure (urea nitrogen 21.4 mmol/L, creatinine 530.4 micromol/L) requiring haemodialysis (HD). On hospital day 5, she was found to have progressive metabolic acidosis (serum pH 7.16, PCO(2) 4.38 kPa, HCO(3)(-) 12.1 mmol/L and AG 21 mmol/L). There was no evidence of hypoxaemia, hypoperfusion or haemodynamic instability. Normal serum ketone and L-lactate but high serum osmolal gap (89.4 mmol/kg) was detected. A search for toxic alcohols revealed a high serum propylene glycol (PG 32.9 mmol/L), a stabilizing solvent for intravenous formulations of lorazepam, which was being used as sedation for mechanical ventilation. Unexpectedly, serum L- and D-lactate as metabolites of PG were not elevated. Although extended HD for eight hours completely removed serum PG and the osmolal gap, the predialysis high AG metabolic acidosis persisted, potentially related to hypercatabolism and anuric renal failure. PG should be in the differential diagnosis of the disorders with high osmolar gap and may not always be associated with L- or D-lactic acidosis.

  3. Use of anion gap in the evaluation of a patient with metabolic acidosis.

    PubMed

    Vichot, Alfred A; Rastegar, Asghar

    2014-10-01

    High anion gap (AG) metabolic acidosis, a common laboratory abnormality encountered in clinical practice, frequently is due to accumulation of organic acids such as lactic acid, keto acids, alcohol metabolites, and reduced kidney function. The cause of high AG metabolic acidosis often is established easily using historical and simple laboratory data. Despite this, several challenges in the diagnosis and management of high AG metabolic acidosis remain, including quantifying the increase in AG, understanding the relationship between changes in AG and serum bicarbonate level, and identifying the cause of high AG metabolic acidosis when common causes are ruled out. The present case was selected to highlight the importance of the correction of AG for serum albumin level, the use of actual baseline AG rather than mean normal AG, the relationship between changes in serum bicarbonate level and AG, and a systematic diagnostic approach to uncommon causes of high AG metabolic acidosis, such as 5-oxoproline acidosis (pyroglutamic acidosis).

  4. Metabolic Acidosis-Induced Insulin Resistance and Cardiovascular Risk

    PubMed Central

    Souto, Gema; Donapetry, Cristóbal; Calviño, Jesús

    2011-01-01

    Abstract Microalbuminuria has been conclusively established as an independent cardiovascular risk factor, and there is evidence of an association between insulin resistance and microalbuminuria, the former preceding the latter in prospective studies. It has been demonstrated that even the slightest degree of metabolic acidosis produces insulin resistance in healthy humans. Many recent epidemiological studies link metabolic acidosis indicators with insulin resistance and systemic hypertension. The strongly acidogenic diet consumed in developed countries produces a lifetime acidotic state, exacerbated by excess body weight and aging, which may result in insulin resistance, metabolic syndrome, and type 2 diabetes, contributing to cardiovascular risk, along with genetic causes, lack of physical exercise, and other factors. Elevated fruits and vegetables consumption has been associated with lower diabetes incidence. Diseases featuring severe atheromatosis and elevated cardiovascular risk, such as diabetes mellitus and chronic kidney failure, are typically characterized by a chronic state of metabolic acidosis. Diabetic patients consume particularly acidogenic diets, and deficiency of insulin action generates ketone bodies, creating a baseline state of metabolic acidosisworsened by inadequate metabolic control, which creates a vicious circle by inducing insulin resistance. Even very slight levels of chronic kidney insufficiency are associated with increased cardiovascular risk, which may be explained at least in part by deficient acid excretory capacity of the kidney and consequent metabolic acidosis-induced insulin resistance. PMID:21352078

  5. [Lactic acidosis in a child with acute severe asthma].

    PubMed

    Perrin, C; Savy, N; Lang, M; Caron, N; Labbé, A

    2014-10-01

    Lactic acidosis is a recognized event in adult patients with acute severe asthma (ASA). Only a few cases have been reported in children. Hereinafter is reported the case of a 2-year-old girl hospitalized in the pediatric intensive care unit for ASA, which was treated with high-flow oxygen therapy and intravenous methylprednisolone and salbutamol. During hospitalization, she had metabolic acidosis with a 7.29 pH, a 26mmHg hypocapnia, and a decrease in bicarbonates to 12 mmol/L. The anion gap was increased to 20 mmol/L and lactates to 8 mmol/L. The work-up for a congenital metabolic disease was normal. Progression was propitious with spontaneous improvement of lactic acidosis, and the child was discharged from the intensive care unit after 72 h. The origin of lactic acidosis during ASA seems to be multifactorial. Although its recovery can be spontaneous, it is important to know how to identify it because it can worsen respiratory symptoms and can lead to incongruous therapeutic escalation.

  6. Metabolic Acidosis of CKD: An Update.

    PubMed

    Kraut, Jeffrey A; Madias, Nicolaos E

    2016-02-01

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

  7. Metabolic Acidosis of CKD: An Update.

    PubMed

    Kraut, Jeffrey A; Madias, Nicolaos E

    2016-02-01

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

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

    PubMed

    Raphael, Kalani L

    2016-04-01

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

  9. A Peculiar Cause for Metabolic Acidosis in the Newborn

    PubMed Central

    Sen, Sudipta; Joseph Thomas, Reju; Dastidar, Arindam; Thomas, Niranjan

    2012-01-01

    Metabolic acidosis is often encountered in a sick neonate and intestinal duplication with heterotopic gastric mucosa is a well-established condition. We present a previously unreported relationship between neonatal metabolic acidosis, resulting from transperitoneal absorption of hydrochloric acid, and a ruptured non- communicating ileal duplication cyst with gastric mucosal heterotopia. The neonate recovered rapidly after resection of the ileal duplication. We present this case to highlight a rare but surgically correctable cause of neonatal metabolic acidosis. PMID:26023415

  10. A peculiar cause for metabolic acidosis in the newborn.

    PubMed

    Kisku, Sundeep; Sen, Sudipta; Joseph Thomas, Reju; Dastidar, Arindam; Thomas, Niranjan

    2012-01-01

    Metabolic acidosis is often encountered in a sick neonate and intestinal duplication with heterotopic gastric mucosa is a well-established condition. We present a previously unreported relationship between neonatal metabolic acidosis, resulting from transperitoneal absorption of hydrochloric acid, and a ruptured non- communicating ileal duplication cyst with gastric mucosal heterotopia. The neonate recovered rapidly after resection of the ileal duplication. We present this case to highlight a rare but surgically correctable cause of neonatal metabolic acidosis. PMID:26023415

  11. Metabolic acidosis during parenteral nutrition: Pathophysiological mechanisms

    PubMed Central

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

    2015-01-01

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

  12. Treatment of acute non-anion gap metabolic acidosis.

    PubMed

    Kraut, Jeffrey A; Kurtz, Ira

    2015-02-01

    Acute non-anion gap metabolic acidosis, also termed hyperchloremic acidosis, is frequently detected in seriously ill patients. The most common mechanisms leading to this acid-base disorder include loss of large quantities of base secondary to diarrhea and administration of large quantities of chloride-containing solutions in the treatment of hypovolemia and various shock states. The resultant acidic milieu can cause cellular dysfunction and contribute to poor clinical outcomes. The associated change in the chloride concentration in the distal tubule lumen might also play a role in reducing the glomerular filtration rate. Administration of base is often recommended for the treatment of acute non-anion gap acidosis. Importantly, the blood pH and/or serum bicarbonate concentration to guide the initiation of treatment has not been established for this type of metabolic acidosis; and most clinicians use guidelines derived from studies of high anion gap metabolic acidosis. Therapeutic complications resulting from base administration such as volume overload, exacerbation of hypertension and reduction in ionized calcium are likely to be as common as with high anion gap metabolic acidosis. On the other hand, exacerbation of intracellular acidosis due to the excessive generation of carbon dioxide might be less frequent than in high anion gap metabolic acidosis because of better tissue perfusion and the ability to eliminate carbon dioxide. Further basic and clinical research is needed to facilitate development of evidence-based guidelines for therapy of this important and increasingly common acid-base disorder.

  13. Late Metabolic Acidosis Caused by Renal Tubular Acidosis in Acute Salicylate Poisoning.

    PubMed

    Sakai, Norihiro; Hirose, Yasuo; Sato, Nobuhiro; Kondo, Daisuke; Shimada, Yuko; Hori, Yasushi

    2016-01-01

    A 16-year-old man was transferred to our emergency department seven hours after ingesting 486 aspirin tablets. His blood salicylate level was 83.7 mg/dL. He was treated with fluid resuscitation and sodium bicarbonate infusion, and his condition gradually improved, with a decline in the blood salicylate level. However, eight days after admission, he again reported nausea, a venous blood gas revealed metabolic acidosis with a normal anion gap. The blood salicylate level was undetectable, and a urinalysis showed glycosuria, proteinuria and elevated beta-2 microglobulin and n-acetyl glucosamine levels, with a normal urinary pH despite the acidosis. We diagnosed him with relapse of metabolic acidosis caused by renal tubular acidosis. PMID:27181539

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

    PubMed

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

    2014-06-01

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

  15. Recurrent high anion gap metabolic acidosis secondary to 5-oxoproline (pyroglutamic acid).

    PubMed

    Tailor, Prayus; Raman, Tuhina; Garganta, Cheryl L; Njalsson, Runa; Carlsson, Katarina; Ristoff, Ellinor; Carey, Hugh B

    2005-07-01

    High anion gap metabolic acidosis in adults is a severe metabolic disorder for which the primary organic acid usually is apparent by clinical history and standard laboratory testing. We report a case of recurrent high anion gap metabolic acidosis in a 48-year-old man who initially presented with anorexia and malaise. Physical examination was unrevealing. Arterial pH was 6.98, P co 2 was 5 mm Hg, and chemistry tests showed a bicarbonate level of 3 mEq/L (3 mmol/L), anion gap of 32 mEq/L (32 mmol/L), and a negative toxicology screen result, except for an acetaminophen (paracetamol) level of 7.5 mug/mL. Metabolic acidosis resolved with administration of intravenous fluids. Subsequently, he experienced 5 more episodes of high anion gap metabolic acidosis during an 8-month span. Methanol, ethylene glycol, acetone, ethanol, d -lactate, and hippuric acid screens were negative. Lactate levels were modestly elevated, and acetaminophen levels were elevated for 5 of 6 admissions. These episodes defied explanation until 3 urinary organic acid screens, obtained on separate admissions, showed striking elevations of 5-oxoproline levels. Inborn errors of metabolism in the gamma-glutamyl cycle causing recurrent 5-oxoprolinuria and high anion gap metabolic acidosis are rare, but well described in children. Recently, there have been several reports of apparent acquired 5-oxoprolinuria and high anion gap metabolic acidosis in adults in association with acetaminophen use. Acetaminophen may, in susceptible individuals, disrupt regulation of the gamma-glutamyl cycle and result in excessive 5-oxoproline production. Suspicion for 5-oxoproline-associated high anion gap metabolic acidosis should be entertained when the cause of high anion gap metabolic acidosis remains poorly defined, the anion gap cannot be explained reasonably by measured organic acids, and there is concomitant acetaminophen use.

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

    PubMed

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

    2014-11-01

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

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

    PubMed

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

    2014-11-01

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

  18. Metabolic acidosis in an infant associated with permethrin toxicity.

    PubMed

    Goksugur, Sevil B; Karatas, Zehra; Goksugur, Nadir; Bekdas, Mervan; Demircioglu, Fatih

    2015-01-01

    Pyrethroids are broad-spectrum insecticides. Permethrin intoxication due to topical application has not been documented in humans. We report a 20-month-old infant who had used 5% permethrin lotion topically for scabies treatment. Approximately 60 mL (20 mL/day) was used and after the third application he developed agitation, nausea, vomiting, respiratory distress, tachycardia, and metabolic acidosis. His clinical symptoms and metabolic acidosis normalized within 20 hours. His follow-up was unremarkable. Toxicity of permethrin is rare, and although permethrin is a widely and safely used topical agent in the treatment of scabies and lice, inappropriate use may rarely cause toxicity. Moreover, in cases of unexplained metabolic acidosis, topically applied medications should be carefully investigated.

  19. Metabolic acidosis in an infant associated with permethrin toxicity.

    PubMed

    Goksugur, Sevil B; Karatas, Zehra; Goksugur, Nadir; Bekdas, Mervan; Demircioglu, Fatih

    2015-01-01

    Pyrethroids are broad-spectrum insecticides. Permethrin intoxication due to topical application has not been documented in humans. We report a 20-month-old infant who had used 5% permethrin lotion topically for scabies treatment. Approximately 60 mL (20 mL/day) was used and after the third application he developed agitation, nausea, vomiting, respiratory distress, tachycardia, and metabolic acidosis. His clinical symptoms and metabolic acidosis normalized within 20 hours. His follow-up was unremarkable. Toxicity of permethrin is rare, and although permethrin is a widely and safely used topical agent in the treatment of scabies and lice, inappropriate use may rarely cause toxicity. Moreover, in cases of unexplained metabolic acidosis, topically applied medications should be carefully investigated. PMID:25487692

  20. Metabolic Acidosis with Ophthalmic Dorzolamide in a Neonate

    PubMed Central

    Capino, Amanda C.; Dannaway, Douglas C.

    2016-01-01

    Carbonic anhydrase inhibitors are a common cause of normal anion gap metabolic acidosis; however, development is less commonly associated with ophthalmic administration of these agents. We report a case of a premature neonate who was being treated at our institution with betaxolol, dorzolamide, and latanoprost ophthalmic products for suspected bilateral congenital glaucoma. In addition, the patient was also receiving caffeine, ursodiol, and acidified liquid human milk fortifier. The patient developed a normal anion gap metabolic acidosis, and both dorzolamide ophthalmic solution and the acidified human milk fortifier were considered potential causes. Upon discontinuation of the dorzolamide ophthalmic solution and the switching of liquid human milk fortifiers, the normal anion gap metabolic acidosis gradually resolved. As a result of the pH and acidity, the acidified liquid human milk fortifier is thought to be associated with an anion gap acidosis; therefore, dorzolamide is suspected to be the primary cause of a normal gap acidosis. This case demonstrates that systemic effects can occur with ophthalmic administration of dorzolamide in a premature neonate. Ophthalmic agents should not be overlooked as a potential cause of systemic toxicity. PMID:27453705

  1. Metabolic Acidosis with Ophthalmic Dorzolamide in a Neonate.

    PubMed

    Capino, Amanda C; Dannaway, Douglas C; Miller, Jamie L

    2016-01-01

    Carbonic anhydrase inhibitors are a common cause of normal anion gap metabolic acidosis; however, development is less commonly associated with ophthalmic administration of these agents. We report a case of a premature neonate who was being treated at our institution with betaxolol, dorzolamide, and latanoprost ophthalmic products for suspected bilateral congenital glaucoma. In addition, the patient was also receiving caffeine, ursodiol, and acidified liquid human milk fortifier. The patient developed a normal anion gap metabolic acidosis, and both dorzolamide ophthalmic solution and the acidified human milk fortifier were considered potential causes. Upon discontinuation of the dorzolamide ophthalmic solution and the switching of liquid human milk fortifiers, the normal anion gap metabolic acidosis gradually resolved. As a result of the pH and acidity, the acidified liquid human milk fortifier is thought to be associated with an anion gap acidosis; therefore, dorzolamide is suspected to be the primary cause of a normal gap acidosis. This case demonstrates that systemic effects can occur with ophthalmic administration of dorzolamide in a premature neonate. Ophthalmic agents should not be overlooked as a potential cause of systemic toxicity. PMID:27453705

  2. Metabolic engineering of lactate dehydrogenase rescues mice from acidosis.

    PubMed

    Acharya, Abhinav P; Rafi, Mohammad; Woods, Elliot C; Gardner, Austin B; Murthy, Niren

    2014-06-05

    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.

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

    PubMed

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

    2016-04-01

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

  4. Metabolic acidosis-induced hypercalcemia in an azotemic patient with primary hyperparathyroidism

    PubMed Central

    Rastegar, Mandana; Levine, Barton S.; Felsenfeld, Arnold J.

    2014-01-01

    A 58-year-old man with Stage 3b chronic kidney disease and primary hyperparathyroidism treated with cinacalcet was admitted for acute cholecystitis. A cholecystostomy tube was placed, estimated glomerular filtration rate decreased, metabolic acidosis developed and ionized calcium increased from 1.33 to 1.76 mM despite cinacalcet administration. A sodium bicarbonate infusion corrected the metabolic acidosis restoring ionized calcium to normal despite no improvement in renal function. The correlation between the increase in serum bicarbonate and decrease in ionized calcium was r = −0.93, P < 0.001. In summary, severe hypercalcemia was attributable to metabolic acidosis increasing calcium efflux from bone while renal failure decreased the capacity to excrete calcium. PMID:25852894

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

    In this report, we describe a case of high anion gap metabolic acidosis with a significant osmolal gap attributed to the ingestion of liquor containing propylene glycol. Recently, several reports have characterized severe lactic acidosis occurring in the setting of iatrogenic unintentional overdosing of medications that use propylene glycol as a diluent, including lorazepam and diazepam. To date, no studies have explored potential effects of excess propylene glycol in the setting of alcohol intoxication. Our patient endorsed drinking large volumes of cinnamon flavored whiskey, which was likely Fireball Cinnamon Whisky. To our knowledge, this is the first case of propylene glycol toxicity from an intentional ingestion of liquor containing propylene glycol. PMID:26904700

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

    PubMed Central

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

    1992-01-01

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

  8. A rare metabolic complication of acute lymphoblastic leukemia in childhood: lactic acidosis.

    PubMed

    Gökçe, Müge; Unal, Sule; Gülşen, Hayriye; Başaran, Ozge; Cetin, Mualla; Gümrük, Fatma; Beşbaş, Nesrin; Gürgey, Aytemiz

    2012-01-01

    A 13-year-old boy presented with nausea, fatigue, weight loss, and bone pain for two months. Complete blood count and serum renal and liver function tests were all normal. Blood gas analysis revealed severe metabolic acidosis with high anion gap. Lactate level was 61.2 mmol/L. Abdominal ultrasonography yielded bilateral nephromegaly and hepatomegaly with increased echogenicity. Peripheral blood smear revealed 2% blasts. Bone marrow aspiration showed 'Common ALL Antigen'-negative acute lymphoblastic leukemia by flow cytometric analysis. Metabolic acidosis dissolved as soon as chemotherapy was begun. Lactic acidosis at the presentation of acute lymphoblastic leukemia--especially with low tumor burden--is a very rare and almost always fatal complication. Our patient is still alive and in remission, which is a point of interest in this child.

  9. Severe hypophosphataemia during recovery from acute respiratory acidosis.

    PubMed

    Storm, T L

    1984-08-25

    Three elderly patients with established chronic obstructive airways disease were admitted with a short history of increasing dyspnoea and tiredness and (in two cases) a deterioration in mental state. Acute respiratory acidosis was diagnosed and mechanical ventilation instituted. Two hours after beginning mechanical ventilation the mean arterial pH had risen to 7.40, but all patients showed a dramatic fall in the serum phosphate concentration (lowest value 0.3 mmol/l (0.9 mg/100 ml] accompanied by a low urinary excretion of phosphate. No patient could tolerate withdrawal of mechanical ventilation until the serum and urinary concentrations of phosphate had returned to normal. Recovery from acute respiratory acidosis should be added to the list of conditions associated with severe hypophosphataemia.

  10. Efficacy of hemodiafiltration in a child with severe lactic acidosis due to thiamine deficiency.

    PubMed

    Pela, I; Seracini, D; Lavoratti, G C; Sarti, A

    2000-05-01

    We report the case of a child in whom severe lactic acidosis (LA) and hyperammonemia developed after twenty days of total parenteral nutrition (TPN) for diffuse esophageal damage due to caustic ingestion. The revision of TPN preparation revealed that thiamine was never included and the hypothesis of thiamine deficiency was later confirmed measuring the serum thiamine level. Because severe metabolic acidosis the dialytic treatment with hemodiafiltration (HDF) and bicarbonate infusion were performed: the patient very quickly recovered with dramatic reestablishment of the acid-basic balance. Thiamine administration restored lactate metabolism. We emphasize that HDF is a useful and prompt treatment for LA to get over the critical phase of neurological and cardiological damage. PMID:11305815

  11. Krebs cycle anions in metabolic acidosis.

    PubMed

    Bowling, Francis G; Morgan, Thomas J

    2005-10-05

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

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

    PubMed Central

    Mostert, Monique; Bonavia, Anthony

    2016-01-01

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

  13. An unusual cause of high anion gap metabolic acidosis: pyroglutamic acidemia. A case report.

    PubMed

    Romero, Jorge E; Htyte, Nay

    2013-01-01

    Pyroglutamic acidemia is an uncommon metabolic disorder, which is usually diagnosed at early ages. The mechanism of action is thought to be glutathione depletion, and its clinical manifestations consist of hemolytic anemia, mental retardation, ataxia, and chronic metabolic acidosis. However, an acquired form has been described in adult patients, who usually present with confusion, respiratory distress, and high anion gap metabolic acidosis (HAGMA). It is also associated with many conditions, including chronic acetaminophen consumption. A 68-year-old white male, with chronic acetaminophen use presented to our service on multiple occasions with severe HAGMA. The patient was admitted to the intensive care unit and required mechanical ventilation and aggressive supportive measures. After ruling out the most frequent etiologies for his acid-base disorder and considering the long history of Tylenol ingestion, his 5-oxiproline (pyroglutamic acid) levels were sent to diagnose pyroglutamic acidemia. Clinicians need to be aware of this cause for metabolic acidosis since it might be a more common metabolic disturbance in compromised patients than would be expected. Subjects with HAGMA that cannot be explained by common causes should be tested for the presence of 5-oxoproline. Discontinuation of the offending drug is therapeutic.

  14. Acidosis

    MedlinePlus

    ... Medications, such as salicylates MELAS (a very rare genetic mitochondrial disorder that affects energy production) Prolonged lack of oxygen from shock, heart failure, or severe anemia Seizures Sepsis -- severe illness due to infection with bacteria or other germs

  15. Acute metabolic acidosis enhances circulating parathyroid hormone, which contributes to the renal response against acidosis in the rat.

    PubMed Central

    Bichara, M; Mercier, O; Borensztein, P; Paillard, M

    1990-01-01

    Acute PTH administration enhances final urine acidification in the rat. HCl was infused during 3 h in rats to determine the parathyroid and renal responses to acute metabolic acidosis. Serum immunoreactive PTH (iPTH) concentration significantly increased and nephrogenous adenosine 3H,5H-cyclic monophosphate tended to increase during HCl loading in intact and adrenalectomized (ADX) rats despite significant increments in plasma ionized calcium. Strong linear relationships existed between serum iPTH concentration and arterial bicarbonate or proton concentration (P less than 0.0001). Serum iPth concentration and NcAMP remained stable in intact time-control rats and decreased in CaCl2-infused, nonacidotic animals. Urinary acidification was markedly reduced in parathyroidectomized (PTX) as compared with intact rats during both basal and acidosis states; human PTH-(1-34) infusion in PTX rats restored in a dose-dependent manner the ability of the kidney to acidify the urine and excrete net acid. Acidosis-induced increase in urinary net acid excretion was observed in intact, PTX, and ADX, but not in ADX-thyroparathyroidectomized rats. We conclude that (a) acute metabolic acidosis enhances circulating PTH activity, and (b) PTH markedly contributes to the renal response against acute metabolic acidosis by enhancing urinary acidification. PMID:2166755

  16. Risk Factors for Developing Metabolic Acidosis after Radical Cystectomy and Ileal Neobladder

    PubMed Central

    Yoon, Hyun Suk; Yoon, Hana; Chung, Woo Sik; Sim, Bong Suk; Ryu, Dong-Ryeol; Lee, Dong Hyeon

    2016-01-01

    Purpose To investigate the serial changes of metabolic acidosis and identify associated risk factors in patients who underwent radical cystectomy and ileal neobladder. Material and Methods From January 2010 to August 2014, 123 patients who underwent radical cystectomy and ileal neobladder reconstruction for bladder cancer were included in this study. Metabolic acidosis was defined as a serum bicarbonate level less than 22 mEq/L and impaired renal function was defined as a GFR <50ml/min. The presence of metabolic acidosis was evaluated at 1 month, 1 year, and 2 years after surgery. Multivariate logistic regression analysis was conducted to identify risk factors associated with development of metabolic acidosis. Results Metabolic acidosis was observed in 52%, 19.5%, and 7.3% of patients at 1 month, 1 year, and 2 years after surgery, respectively. At 1 month after surgery, impaired renal function was the only independent risk factor associated with metabolic acidosis (OR 3.87, P = 0.046). At 1 year after surgery, diabetes was the only independent risk factor associated with metabolic acidosis (OR 5.68, P = 0.002). At 2 years post-surgery, both age and diabetes were significant risk factors associated with metabolic acidosis. Conclusion Approximately, half of patients experienced metabolic acidosis one month after ileal neobladder reconstruction. Preoperative impaired renal function was the most significant risk factor for developing metabolic acidosis in the early postoperative period. However, the incidence of metabolic acidosis decreased to less than 20% 1 year after surgery, and diabetes was an independent risk factor during this period. PMID:27384686

  17. High anion gap refractory metabolic acidosis as a critical presentation of endosulfan poisoning.

    PubMed

    Sharma, Raj Kumar; Kaul, Anupama; Gupta, Anurag; Bhadauria, Dharmendra; Prasad, Narayan; Jain, Apoorva; Gurjar, M; Rao, Bhaskar P

    2011-07-01

    Organochloride insecticides are chlorinated cyclic hydrocarbons. One of such insecticides is endosulfan (6,7,8,9,10-10 hexachloro 1,5,5a,6,9,9a-hexahydro-6-methano-2,4,3-hexadithioxanthiep in 3-oxide) and it has been widely used in agriculture since 1960. The uncontrolled use of these compounds in developing countries has resulted in the deaths of animals and humans. Characteristic clinical signs following acute exposure are indicative of CNS disturbances or overstimulation. Mortality and morbidity rates are high and there is no specific antidote. We present an uncommon presentation of endosulfan poisoning in a 32-year-old male with high anion gap severe refractory metabolic acidosis. The patient was treated with continuous renal replacement therapy and was salvaged. Till date, there is no case report from India for endosulfan poisoning with severe metabolic acidosis and hypotension. Through this case report, we emphasize the role of continuous renal replacement therapy as a rescue therapy for endosulfan poisoning with severe refractory metabolic acidosis and hypotension, even though it is a non dialyzable poison.

  18. 5-oxoproline-induced anion gap metabolic acidosis after an acute acetaminophen overdose.

    PubMed

    Lawrence, David T; Bechtel, Laura K; Charlton, Nathan P; Holstege, Christopher P

    2010-09-01

    Metabolic acidosis after acute acetaminophen overdose is typically attributed to either transient lactic acidosis without evidence of hepatic injury or hepatic failure. High levels of the organic acid 5-oxoprolinuria are usually reported in patients with predisposing conditions, such as sepsis, who are treated in a subacute or chronic fashion with acetaminophen. The authors report a case of a 40-year-old woman who developed anion gap metabolic acidosis and somnolence after an acute acetaminophen overdose. Substantial hepatic damage did not occur, which ruled out acetaminophen-induced hepatic insufficiency as a cause of the patient's acidosis or altered mental status. Urinalysis revealed elevated levels of 5-oxoproline, suggesting that the patient's acute acetaminophen overdose was associated with marked anion gap metabolic acidosis due solely to 5-oxoproline without hepatic complications. The acidosis fully resolved with N-acetylcysteine treatment and supportive care including hydration.

  19. Treatment of Metabolic Acidosis in Patients With CKD

    PubMed Central

    Chen, Wei; Abramowitz, Matthew K.

    2013-01-01

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

  20. Approach to the evaluation of a patient with an increased serum osmolal gap and high-anion-gap metabolic acidosis.

    PubMed

    Kraut, Jeffrey A; Xing, Shelly Xiaolei

    2011-09-01

    An increase in serum osmolality and serum osmolal gap with or without high-anion-gap metabolic acidosis is an important clue to exposure to one of the toxic alcohols, which include methanol, ethylene glycol, diethylene glycol, propylene glycol, or isopropanol. However, the increase in serum osmolal gap and metabolic acidosis can occur either together or alone depending on several factors, including baseline serum osmolal gap, molecular weight of the alcohol, and stage of metabolism of the alcohol. In addition, other disorders, including diabetic or alcoholic ketoacidosis, acute kidney injury, chronic kidney disease, and lactic acidosis, can cause high-anion-gap metabolic acidosis associated with an increased serum osmolal gap and therefore should be explored in the differential diagnosis. It is essential for clinicians to understand the value and limitations of osmolal gap to assist in reaching the correct diagnosis and initiating appropriate treatment. In this teaching case, we present a systematic approach to diagnosing high serum osmolality and increased serum osmolal gap with or without high-anion-gap metabolic acidosis.

  1. Effect of metabolic acidosis on the potassium content of bone.

    PubMed

    Bushinsky, D A; Gavrilov, K; Chabala, J M; Featherstone, J D; Levi-Setti, R

    1997-10-01

    Metabolic acidosis induces resorption of cultured bone, resulting in a net efflux of calcium (Ca) from the bone and an apparent loss of mineral potassium (K). However, in these organ cultures, there is diffusion of K between the medium and the crystal lattice, causing difficulty in interpretation of the acid-induced changes in mineral ion composition. To determine the effects of acidosis on bone mineral K, we injected 4-day-old neonatal mice with pure stable isotope 41K, equal to approximately 5% of their total body K. Calvariae were dissected 24 h later and then cultured for 24 h in medium without added 41K, either at pH approximately 7.4 (Ctl) or at pH approximately 7.1 (Ac), with or without the osteoclastic inhibitor calcitonin (3 x 10(-9) M, CT). The bone isotopic ion content was determined with a high-resolution scanning ion microprobe utilizing secondary ion mass spectrometry. 41K is present in nature at 6.7% of total K. The injected 41K raised the ratio of bone 41K/(39K+41K) to 9.8+/-0.5% on the surface (ratios of counts per second of detected secondary ions, mean+/-95% confidence interval) but did not alter the ratio in the interior (6.9+/-0.4%), indicating biological incorporation of the 41K into the mineral surface. The ratios of 41K/40Ca on the surface of Ctl calvariae was 14.4+/-1.2, indicating that bone mineral surface is rich in K compared with Ca. Compared with Ctl, Ac caused a marked increase in the net Ca efflux from bone that was blocked by CT. Ac also induced a marked fall in the ratio of 41K/40Ca on the surface of the calvariae (43+/-0.5, p < 0.01 vs. Ctl), which was partially blocked by CT (8.2+/-0.9, p < 0.01 vs. Ctl and vs. Ac), indicating that Ac causes a greater release of bone mineral K than Ca which is partially blocked by CT. Thus, bone mineral surface is rich in K relative to Ca, acidosis induces a greater release of surface mineral K than Ca, and osteoclastic function is necessary to support the enriched levels of surface mineral K in

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

    PubMed

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

    2015-01-01

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

  3. [5-0xoproline (pyroglutamic acid) acidosis and acetaminophen- a differential diagnosis in high anion gap metabolic acidosis].

    PubMed

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

    2015-12-01

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

  4. High anion gap metabolic acidosis in suicide: don't forget metformin intoxication--two patients' experiences.

    PubMed

    Chang, Chin-Tung; Chen, Yung-Chang; Fang, Ji-Tseng; Huang, Chiu-Ching

    2002-09-01

    Lactic acidosis is a well-recognized side effect of metformin, especially in patients with renal failure. Only a few cases of deliberate self-poisoning with metformin have been described in the literature. We report two patients who took a large dose of metformin in an attempt to harm themselves and both of them presented with severe lactic acidosis. The first patient was admitted because of taking large amounts of her father's unknown drug for suicide. Arterial blood gas showed severe metabolic acidosis with high anion gap and blood lactate level which metformin intoxication was documented. She died of multiple organ failure although we provided aggressive management including continuous renal replacement therapy. The second case, a type 2 diabetic patient, was sent to the emergency department after taking 110 tablets of metformin (500 mg). Arterial blood gas showed severe metabolic acidosis with high anion gap and blood lactate level. Hypotension and consciousness disturbance occurred later. After one session of hemodialysis, she recovered completely. In our experiences, metformin intoxication should be suspected when patients presented by wide anion gap metabolic acidosis after suicide attempt by taking drugs. Hemodialysis or continuous renal replacement should be initiated as soon as possible in addition to other supportive care.

  5. Hypernatraemic dehydration in infants in Kuwait with special reference to therapy of associated metabolic acidosis.

    PubMed

    John, A I; Fedeczko, D; Fernando, N P

    1984-12-01

    Over a period of 16 months 510 children with diarrhoea were admitted to the Al-Adan Hospital, Kuwait, of whom 26 (5.1%) developed hypernatraemic dehydration. Prominent clinical features included vomiting (92.3%), fever (84.6%) and convulsions (19.2%). The majority were below six months of age with a mean age of 3.1 months. The sex distribution was equal. Twenty infants (77%) had severe metabolic acidosis and were treated with a combination of sodium bicarbonate and 5% glucose in water until the acidosis was corrected after which a solution of sodium chloride replaced the use of sodium bicarbonate. The sodium concentration of the intravenous fluid varied from 15 to 30 mmol/l and was given at a rate of 100 to 120 ml/kg/day. One infant died. The 25 survivors, (96.15%), which included three who developed convulsions during treatment, recovered without any neurologic sequelae.

  6. Increased anion gap metabolic acidosis as a result of 5-oxoproline (pyroglutamic acid): a role for acetaminophen.

    PubMed

    Fenves, Andrew Z; Kirkpatrick, Haskell M; Patel, Viralkumar V; Sweetman, Lawrence; Emmett, Michael

    2006-05-01

    The endogenous organic acid metabolic acidoses that occur commonly in adults include lactic acidosis; ketoacidosis; acidosis that results from the ingestion of toxic substances such as methanol, ethylene glycol, or paraldehyde; and a component of the acidosis of kidney failure. Another rare but underdiagnosed cause of severe, high anion gap metabolic acidosis in adults is that due to accumulation of 5-oxoproline (pyroglutamic acid). Reported are four patients with this syndrome, and reviewed are 18 adult patients who were reported previously in the literature. Twenty-one patients had major exposure to acetaminophen (one only acute exposure). Eighteen (82%) of the 22 patients were women. Most of the patients were malnourished as a result of multiple medical comorbidities, and most had some degree of kidney dysfunction or overt failure. The chronic ingestion of acetaminophen, especially by malnourished women, may generate high anion gap metabolic acidosis. This undoubtedly is an underdiagnosed condition because measurements of serum and/or urinary 5-oxoproline levels are not readily available.

  7. Negative anion gap metabolic acidosis in salicylate overdose--a zebra!

    PubMed

    Kaul, Viren; Imam, Syed Haider; Gambhir, Harvir Singh; Sangha, Arindam; Nandavaram, Sravanthi

    2013-10-01

    Salicylate poisoning classically results in an increased anion gap metabolic acidosis. We discuss a case of normal anion gap metabolic acidosis despite elevated serum salicylate concentration. This diagnostic dilemma stemmed from aberrant reading of salicylate ions by analyzer electrodes as chloride ions leading to falsely negative anion gap. On review, this phenomenon is found to be possible with a number of commonly used analyzers. In emergency department settings, high level of clinical suspicion for salicylate poisoning should be maintained, and metabolic acidosis with normal anion gap should not be used to rule out salicylate overdose. This can prevent significant avoidable morbidity and mortality.

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

    PubMed

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

    2012-09-01

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

  9. Effects of metabolic acidosis and alkalosis on sodium and calcium transport in the dog kidney.

    PubMed

    Sutton, R A; Wong, N L; Dirks, J H

    1979-05-01

    Clearance and micropuncture studies have been performed in dogs to examine the effects of acute and chronic metabolic acidosis and acute alkalosis on tubular sodium and calcium transport. Acute metabolic acidosis, induced by the infusion of hydrochloric acid, decreased proximal fluid reabsorption and increased the fractional delivery of sodium and calcium to the distal tubule, but not to the final urine. In comparison with normal dogs, dogs with chronic metabolic acidosis (induced by feeding ammonium chloride) showed an increase in proximal fluid reabsorption and a dissociation of calcium from sodium reabsorption more distally, leading to an increased delivery of calcium relative to sodium at the distal tubule and in the final urine. The infusion of sodium bicarbonate to correct chronic metabolic acidosis, both in intact and thyroparathyroidectomized (TPTX) dogs, reduced proximal fluid reabsorption and caused a selective enhancement of calcium reabsorption relative to sodium in the more distal nephron, resulting in a reversal of the dissociation observed in acidosis, both at the distal tubule and in the final urine. By contrastin fusion of sodium chloride in parathyroid-intact acidotic dogs did not reduce proximal fluid reabsorption or enhance tubular calcium reabsorption. In nonacidotic dogs, both intact and TPTX, infusion of sodium bicarconate to induce acute alkalosis resulted in selhese data demonstrate the presence of a component of tubular calcium reabsorption situated beyond the proximal tubule, which is inhibited by chronic (but not acute) metabolic acidosis and enhanced by metabolic alkalosis (or bicarbonate infusion) independently of parathyroid hormone. PMID:480784

  10. Differential diagnosis of nongap metabolic acidosis: value of a systematic approach.

    PubMed

    Kraut, Jeffrey A; Madias, Nicolaos E

    2012-04-01

    Nongap metabolic acidosis is a common form of both acute and chronic metabolic acidosis. Because derangements in renal acid-base regulation are a common cause of nongap metabolic acidosis, studies to evaluate renal acidification often serve as the mainstay of differential diagnosis. However, in many cases, information obtained from the history and physical examination, evaluation of the electrolyte pattern (to determine if a nongap acidosis alone or a combined nongap and high anion gap metabolic acidosis is present), and examination of the serum potassium concentration (to characterize the disorder as hyperkalemic or hypokalemic in nature) is sufficient to make a presumptive diagnosis without more sophisticated studies. If this information proves insufficient, indirect estimates or direct measurement of urinary NH(4)(+) concentration, measurement of urine pH, and assessment of urinary HCO(3)(-) excretion can help in establishing the diagnosis. This review summarizes current information concerning the pathophysiology of this electrolyte pattern and the value and limitations of all of the diagnostic studies available. It also provides a systematic and cost-effective approach to the differential diagnosis of nongap metabolic acidosis.

  11. The urine osmolal gap: a clue to estimate urine ammonium in "hybrid" types of metabolic acidosis.

    PubMed

    Halperin, M L; Margolis, B L; Robinson, L A; Halperin, R M; West, M L; Bear, R A

    1988-06-01

    The urine osmolal gap is defined as the difference between measured urine osmolality and the sum of the concentrations of sodium, potassium, chloride, bicarbonate, urea and glucose. Normally, this gap is 80-100 mosmol/kg H2O. A determination of the urine osmolal gap may be useful to ascertain the etiology of metabolic acidosis which is of the mixed wide and normal plasma anion gap type ("hybrid" metabolic acidosis). For example, with "hybrid" metabolic acidosis, a low urine osmolal gap will suggest the absence of excessive organic aciduria (ketoacidosis) and the basis of the normal anion gap type of acidosis will be determined by the urine anion gap or "net charge". Where "hybrid" metabolic acidosis has occurred due to wide anion gap metabolic acidosis with loss of organic acid anion in the urine, the urine osmolal gap will be high and can be used in a semi-quantitative fashion to estimate the sum of urinary ammonium plus ketone body anion concentrations.

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

    PubMed

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

    2015-04-09

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

  13. Acute metabolic acidosis decreases muscle protein synthesis but not albumin synthesis in humans.

    PubMed

    Kleger, G R; Turgay, M; Imoberdorf, R; McNurlan, M A; Garlick, P J; Ballmer, P E

    2001-12-01

    Chronic metabolic acidosis induces negative nitrogen balance by either increased protein breakdown or decreased protein synthesis. Few data exist regarding effects of acute metabolic acidosis on protein synthesis. We investigated fractional synthesis rates (FSRs) of muscle protein and albumin, plasma concentrations of insulin-like growth factor-I (IGF-I), thyroid-stimulating hormone (TSH), and thyroid hormones (free thyroxin [fT(4)] and triiodothyronine [fT(3)]) in seven healthy human volunteers after a stable controlled metabolic period of 5 days and again 48 hours later after inducing metabolic acidosis by oral ammonium chloride intake (4.2 mmol/kg/d divided in six daily doses). Muscle and albumin FSRs were obtained by the [(2)H(5)ring]phenylalanine flooding technique. Ammonium chloride induced a significant decrease in pH (7.43 +/- 0.02 versus 7.32 +/- 0.04; P < 0.0001) and bicarbonate concentration (24.6 +/- 1.6 versus 16.0 +/- 2.7 mmol/L; P < 0.0001) within 48 hours. Nitrogen balance decreased significantly on the second day of acidosis. The FSR of muscle protein decreased (1.94 +/- 0.25 versus 1.30 +/- 0.39; P < 0.02), whereas the FSR of albumin remained constant. TSH levels increased significantly (1.1 +/- 0.5 versus 1.9 +/- 1.1 mU/L; P = 0.03), whereas IGF-I, fT(4), and fT(3) levels showed no significant change. We conclude that acute metabolic acidosis for 48 hours in humans induces a decrease in muscle protein synthesis, which contributes substantially to a negative nitrogen balance. In contrast to prolonged metabolic acidosis of 7 days, a short period of acidosis in the present study did not downregulate albumin synthesis.

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

    PubMed

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

    2011-12-01

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

  15. 5-Oxoproline as a cause of high anion gap metabolic acidosis: an uncommon cause with common risk factors.

    PubMed

    Kortmann, W; van Agtmael, M A; van Diessen, J; Kanen, B L J; Jakobs, C; Nanayakkara, P W B

    2008-09-01

    High anion gap metabolic acidosis might be caused by 5-oxoproline (pyroglutamic acid). As it is very easy to treat, it might be worth drawing attention to this uncommon and probably often overlooked diagnosis. We present three cases of high anion gap metabolic acidosis due to 5-oxoproline seen within a period of six months.

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

    PubMed

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

    2009-05-01

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

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

    PubMed

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

    1984-02-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  20. Severe lactic acidosis associated with juice of the mangosteen fruit Garcinia mangostana.

    PubMed

    Wong, Leslie P; Klemmer, Philip J

    2008-05-01

    The tropical mangosteen fruit has long been prized in Southeast Asia for its traditional healing properties. Mangosteen fruit juice is now available in the United States and marketed for its purported health benefits. We describe a case of severe lactic acidosis associated with the use of mangosteen juice as a dietary supplement.

  1. Successfully treated calcific uremic arteriolopathy: two cases of a high anion gap metabolic acidosis with intravenous sodium thiosulfate.

    PubMed

    Rein, Joshua L; Miyata, Kana N; Dadzie, Kobena A; Gruber, Steven J; Sulica, Roxana; Winchester, James F

    2014-01-01

    Calcific uremic arteriolopathy (CUA) is a rare and potentially fatal disorder of calcification involving subcutaneous small vessels and fat in patients with renal insufficiency. We describe the successful use of intravenous sodium thiosulfate (STS) for the treatment of CUA in two patients. The first case was complicated by the development of a severe anion gap metabolic acidosis, which was accompanied by a seizure. Both patients had complete wound healing within five months. Although STS should be considered in the treatment of CUA, little is known about pharmacokinetics and additional studies are required to determine dosing strategies to minimize severe potential side effects.

  2. An autopsy case of death due to metabolic acidosis after citric acid ingestion.

    PubMed

    Ikeda, Tomoya; Usui, Akihito; Matsumura, Takashi; Aramaki, Tomomi; Hosoya, Tadashi; Igari, Yui; Ohuchi, Tsukasa; Hayashizaki, Yoshie; Usui, Kiyotaka; Funayama, Masato

    2015-11-01

    A man in his 40s was found unconscious on a sofa in a communal residence for people with various disabilities. He appeared to have drunk 800 ml of undiluted citric acid from a commercial plastic bottle. The instructions on the label of the beverage specified that the beverage be diluted 20- to 30-fold before consumption. The patient was admitted to an emergency hospital with severe metabolic acidosis (pH, 6.70; HCO3(-), 3.6 mEq/L) and a low ionized calcium level (0.73 mmol/L). Although ionized calcium and catecholamines were continuously administered intravenously to correct the acidosis, the state of acidemia and low blood pressure did not improve, and he died 20 h later. Citric acid concentrations in the patient's serum drawn shortly after treatment in the hospital and from the heart at autopsy were 80.6 mg/ml and 39.8 mg/dl, respectively (normal range: 1.3-2.6 mg/dl). Autopsy revealed black discoloration of the mucosal surface of the esophagus. Microscopically, degenerated epithelium and neutrophilic infiltration in the muscle layer were observed. In daily life, drinking a large amount of concentrated citric acid beverage is rare as a cause of lethal poisoning. However, persons with mental disorders such as dementia may mistakenly drink detergent or concentrated fluids, as in our case. Family members or facility staff in the home or nursing facility must bear in mind that they should not leave such bottles in places where they are easily accessible to mentally handicapped persons.

  3. An autopsy case of death due to metabolic acidosis after citric acid ingestion.

    PubMed

    Ikeda, Tomoya; Usui, Akihito; Matsumura, Takashi; Aramaki, Tomomi; Hosoya, Tadashi; Igari, Yui; Ohuchi, Tsukasa; Hayashizaki, Yoshie; Usui, Kiyotaka; Funayama, Masato

    2015-11-01

    A man in his 40s was found unconscious on a sofa in a communal residence for people with various disabilities. He appeared to have drunk 800 ml of undiluted citric acid from a commercial plastic bottle. The instructions on the label of the beverage specified that the beverage be diluted 20- to 30-fold before consumption. The patient was admitted to an emergency hospital with severe metabolic acidosis (pH, 6.70; HCO3(-), 3.6 mEq/L) and a low ionized calcium level (0.73 mmol/L). Although ionized calcium and catecholamines were continuously administered intravenously to correct the acidosis, the state of acidemia and low blood pressure did not improve, and he died 20 h later. Citric acid concentrations in the patient's serum drawn shortly after treatment in the hospital and from the heart at autopsy were 80.6 mg/ml and 39.8 mg/dl, respectively (normal range: 1.3-2.6 mg/dl). Autopsy revealed black discoloration of the mucosal surface of the esophagus. Microscopically, degenerated epithelium and neutrophilic infiltration in the muscle layer were observed. In daily life, drinking a large amount of concentrated citric acid beverage is rare as a cause of lethal poisoning. However, persons with mental disorders such as dementia may mistakenly drink detergent or concentrated fluids, as in our case. Family members or facility staff in the home or nursing facility must bear in mind that they should not leave such bottles in places where they are easily accessible to mentally handicapped persons. PMID:26594004

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

    PubMed

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

    2016-06-01

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

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

    SciTech Connect

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

    1987-06-01

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

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

    PubMed

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

    2014-02-15

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

  7. Changes in bone sodium and carbonate in metabolic acidosis and alkalosis in the dog

    PubMed Central

    Burnell, James M.

    1971-01-01

    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. PMID:5540172

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

    PubMed Central

    Kamar, Fareed B.; McQuillan, Rory F.

    2015-01-01

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

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

    PubMed

    Kamar, Fareed B; McQuillan, Rory F

    2015-01-01

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

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

    PubMed

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

    2005-11-01

    A 5-month-old girl with distal renal tubular acidosis (RTA) and hyperammonaemia that had lasted for 12 days, despite metabolic acidosis correction, is presented in this report. The patient showed failure to thrive, poor feeding, hypotonia and vomiting crisis in absence of inborn errors of metabolism. Probably, hyperammonaemia was the result of an imbalance between the increased ammonia synthesis, in response to metabolic acidosis, and the impaired ammonia excretion, typical of distal RTA. Our case confirms that hyperammonaemia may be observed in distal RTA, mimicking an inborn error of metabolism, and it underlines that hyperammonaemia may persist several days after metabolic acidosis correction. PMID:16133056

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

    PubMed

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

    2015-12-01

    The use of metformin in chronic kidney disease (CKD) population has been intensely debated with conflicting evidence. Large population studies are needed to inform risk assessment and therapeutic decision-making. We evaluated the associations among metformin, metabolic acidosis, and CKD in a 10-year nationally representative noninstitutionalized civilian population in the United States.In this cross-sectional study, a total of 2279 diabetic adults aged 20 years or older in the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2012 were included and had measurements of serum bicarbonate, sodium, potassium, and chloride. The exposure was metformin use. The outcome was subclinical and severe metabolic acidosis defined by serum bicarbonate <23 mEq/L and anion gap > 16mEq/L and by serum bicarbonate < 20 mEq/L, respectively.The prevalence of metformin use decreased from 67.2% among CKD-1 and -2, 40.6% among CKD-3, to 1.3% among advanced CKD-4 and -5. Across CKD stages up to CKD-3b, we observed a tendency of lower levels of serum bicarbonate that was significant in metformin users with CKD-2 and CKD-3a and marginally significant with CKD-3b compared to nonmetformin users. The corresponding tendency of higher anion gap in metformin users with the estimated glomerular filtration rate >60 mL/min/1.73 m was also observed. In multiple linear regression analysis, metformin was significantly associated with decreased serum bicarbonate levels (β = -0.45, 95% CI: -0.73, -0.17) and increased serum anion gap levels (β = 0.40, 95% CI: 0.19, 0.61). The adjusted odds ratio of subclinical high anion gap and severe metabolic acidosis for metformin users was 1.68 (95% CI: 1.11, 2.55) and 1.31 (0.49, 3.47), respectively. The association between metformin and serum bicarbonate was significantly modified by CKD status. No interaction was found between metformin and CKD stages for serum anion gap and acidosis.Metformin is associated with subclinical

  12. Baking soda induced severe metabolic alkalosis in a haemodialysis patient.

    PubMed

    Solak, Yalcin; Turkmen, Kultigin; Atalay, Huseyin; Turk, Suleyman

    2009-08-01

    Metabolic alkalosis is a rare occurence in hemodialysis population compared to metabolic acidosis unless some precipitating factors such as nasogastric suction, vomiting and alkali ingestion or infusion are present. When metabolic alkalosis develops, it may cause serious clinical consequences among them are sleep apnea, resistent hypertension, dysrhythmia and seizures. Here, we present a 54-year-old female hemodialysis patient who developed a severe metabolic alkalosis due to baking soda ingestion to relieve dyspepsia. She had sleep apnea, volume overload and uncontrolled hypertension due to metabolic alkalosis. Metabolic alkalosis was corrected and the patient's clinical condition was relieved with negative-bicarbonate hemodialysis. PMID:25984015

  13. Baking soda induced severe metabolic alkalosis in a haemodialysis patient.

    PubMed

    Solak, Yalcin; Turkmen, Kultigin; Atalay, Huseyin; Turk, Suleyman

    2009-08-01

    Metabolic alkalosis is a rare occurence in hemodialysis population compared to metabolic acidosis unless some precipitating factors such as nasogastric suction, vomiting and alkali ingestion or infusion are present. When metabolic alkalosis develops, it may cause serious clinical consequences among them are sleep apnea, resistent hypertension, dysrhythmia and seizures. Here, we present a 54-year-old female hemodialysis patient who developed a severe metabolic alkalosis due to baking soda ingestion to relieve dyspepsia. She had sleep apnea, volume overload and uncontrolled hypertension due to metabolic alkalosis. Metabolic alkalosis was corrected and the patient's clinical condition was relieved with negative-bicarbonate hemodialysis.

  14. The effects of acidosis and alkalosis on the metabolism of glutamine and glutamate in renal cortex slices

    PubMed Central

    Kamm, Donald E.; Strope, Gerald L.

    1972-01-01

    Studies of the metabolism of glutamine and glutamate by renal cortex slices from acidotic, alkalotic, and control rats were performed. 88-95% of the glutamine and 104-115% of the glutamate taken up from the medium could be accounted for by the products found. Acidosis increased glutamine uptake and conversion to ammonia, CO2, glucose, lactate, pyruvate, lipid, and protein. The increase in glutamine conversion to ammonia after acidosis could be completely accounted for by the associated increase in its conversion to glucose, glutamate, lactate, and pyruvate. When glutamate metabolism was examined, acidosis did not affect substrate uptake but did increase its conversion to ammonia, glucose, lactate, CO2, and lipid. The increase in 14CO2 from U-14C-glutamine and U-14C-glutamate found with cortex slices from acidotic animals could be explained by the CO2 production calculated to be associated with the enhanced conversion of these substrates to other products during acidosis. 14CO2 production from 1.2-14C-acetate was found to be significantly increased in alkalosis rather than acidosis. These studies suggest that in the rat, the rate at which glutamine is completely oxidized in the Krebs cycle is not a factor regulating renal ammonia production. A comparison of the effects of acidbase status on glutamine and glutamate metabolism suggests that either glutamine transport or glutamine transaminase activity are significantly increased by acidosis. Images PMID:5057130

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

    PubMed

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

    2013-01-01

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

  16. Liquid chromatographic-mass spectrometric method for simultaneous determination of small organic acids potentially contributing to acidosis in severe malaria.

    PubMed

    Sriboonvorakul, Natthida; Leepipatpiboon, Natchanun; Dondorp, Arjen M; Pouplin, Thomas; White, Nicholas J; Tarning, Joel; Lindegardh, Niklas

    2013-12-15

    Acidosis is an important cause of mortality in severe falciparum malaria. Lactic acid is a major contributor to metabolic acidosis, but accounts for only one-quarter of the strong anion gap. Other unidentified organic acids have an independent strong prognostic significance for a fatal outcome. In this study, a simultaneous bio-analytical method for qualitative and quantitative assessment in plasma and urine of eight small organic acids potentially contributing to acidosis in severe malaria was developed and validated. High-throughput strong anion exchange solid-phase extraction in a 96-well plate format was used for sample preparation. Hydrophilic interaction liquid chromatography (HILIC) coupled to negative mass spectroscopy was utilized for separation and detection. Eight possible small organic acids; l-lactic acid (LA), α-hydroxybutyric acid (aHBA), β-hydroxybutyric acid (bHBA), p-hydroxyphenyllactic acid (pHPLA), malonic acid (MA), methylmalonic acid (MMA), ethylmalonic acid (EMA) and α-ketoglutaric acid (aKGA) were analyzed simultaneously using a ZIC-HILIC column with an isocratic elution containing acetonitrile and ammonium acetate buffer. This method was validated according to U.S. Food and Drug Administration guidelines with additional validation procedures for endogenous substances. Accuracy for all eight acids ranged from 93.1% to 104.0%, and the within-day and between-day precisions (i.e. relative standard deviations) were lower than 5.5% at all tested concentrations. The calibration ranges were: 2.5-2500μg/mL for LA, 0.125-125μg/mL for aHBA, 7.5-375μg/mL for bHBA, 0.1-100μg/mL for pHPLA, 1-1000μg/mL for MA, 0.25-250μg/mL for MMA, 0.25-100μg/mL for EMA, and 30-1500μg/mL for aKGA. Clinical applicability was demonstrated by analyzing plasma and urine samples from five patients with severe falciparum malaria; five acids had increased concentrations in plasma (range LA=177-1169μg/mL, aHBA=4.70-38.4μg/mL, bHBA=7.70-38.0μg/mL, pHPLA=0.900-4.30

  17. High anion gap metabolic acidosis secondary to pyroglutamic aciduria (5-oxoprolinuria): association with prescription drugs and malnutrition.

    PubMed

    Brooker, G; Jeffery, J; Nataraj, T; Sair, M; Ayling, R

    2007-07-01

    Two cases of High Anion Gap Metabolic Acidosis (HAGMA) due to pyroglutamic acid (5-oxoproline) are described. In both cases the HAGMA developed during an episode of hospital treatment, in conjunction with paracetamol and antibiotic prescription, and the surviving patient made an uneventful recovery after the drugs were withdrawn. Clinicians need to be aware of this cause for metabolic acidosis because it may be a more common metabolic disturbance in compromised patients than would be expected, and the discontinuation of drugs implicated in the aetiology is therapeutic.

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

    PubMed

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

    2012-01-15

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

  19. Multiplexed Microneedle-based Biosensor Array for Characterization of Metabolic Acidosis

    PubMed Central

    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.

    2011-01-01

    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. PMID:22265568

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

    PubMed

    Soleymanian, Tayebeh; Ghods, Ahad

    2011-11-01

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

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

    PubMed

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

    2014-03-01

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

  2. Acetaminophen-induced anion gap metabolic acidosis and 5-oxoprolinuria (pyroglutamic aciduria) acquired in hospital.

    PubMed

    Humphreys, Benjamin D; Forman, John P; Zandi-Nejad, Kambiz; Bazari, Hasan; Seifter, Julian; Magee, Colm C

    2005-07-01

    A rare cause of high anion gap acidosis is 5-oxoproline (pyroglutamic acid), an organic acid intermediate of the gamma-glutamyl cycle. Acetaminophen and several other drugs have been implicated in the development of transient 5-oxoprolinemia in adults. We report the case of a patient with lymphoma who was admitted for salvage chemotherapy. The patient subsequently developed fever and neutropenia and was administered 20.8 g of acetaminophen during 10 days. During this time, anion gap increased from 14 to 30 mEq/L (14 to 30 mmol/L) and altered mental status developed. After usual causes of high anion gap acidosis were ruled out, a screen for urine organic acids showed 5-oxoproline levels elevated at 58-fold greater than normal values. Predisposing factors in this case included renal dysfunction and sepsis. Clinicians need to be aware of this unusual cause of anion gap acidosis because it may be more common than expected, early discontinuation of the offending agent is therapeutic, and administration of N -acetylcysteine could be beneficial.

  3. A Rare Cause of Metabolic Acidosis: Fatal Transdermal Methanol Intoxication in an Infant.

    PubMed

    Sahbudak Bal, Zumrut; Can, Fulya Kamit; Anil, Ayse Berna; Bal, Alkan; Anil, Murat; Gokalp, Gamze; Yavascan, Onder; Aksu, Nejat

    2016-08-01

    Oral methanol intoxication is common, but dermal intoxication is rare. We report a previously healthy 19-month-old female infant admitted to the emergency department (ED) with vomiting and tonic-clonic seizure. On physical examination, she was comatose and presented signs of decompensated shock with Kussmaul breathing. Her left thigh was edematous, with purple coloration. Methanol intoxication was suspected due to high anion gap metabolic acidosis (pH, 6.89; HCO3, <3 meq/L) and exposure to spirit-soaked bandages (%96 methanol) for 24 hours and 3 days. The patient's serum methanol level was 20.4 mg/dL. She was treated with fomepizole and continuous venovenous hemodialysis (CVVHD) in the pediatric intensive care unit, and methanol levels decreased to 0 mg/dL after 12 hours. During follow-up, massive edema and subarachnoid hemorrhage in the occipital lobe were detected by computed tomography of the brain. The patient died after 7 days.Although methanol intoxication occurs predominantly in adults, it must be considered in children with high-anion gap metabolic acidosis. This case report demonstrates that fatal transdermal methanol intoxication can occur in children, and it is the second report in the English literature of transdermal methanol intoxication in an infant.

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

    SciTech Connect

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

    1987-01-01

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

  5. Refeeding syndrome as an unusual cause of anion gap metabolic acidosis.

    PubMed

    Singla, Manish; Perry, Alexandra; Lavery, Eric

    2012-11-01

    Refeeding syndrome is characterized by hypophosphatemia in the setting of malnutrition. It is commonly seen in patients with anorexia, alcoholism, or malignancy, and it is often a missed diagnosis. Because of the potential morbidity associated with missing the diagnosis of refeeding syndrome, it is important to monitor for this disease in any malnourished patient. We present a case of a 49-year-old male with chronic alcohol abuse who presented for alcohol detoxification and was found to have low phosphate, potassium, and magnesium on presentation, in addition to an elevated anion gap of unclear etiology. After extensive workup to evaluate the cause of his elevated anion gap and worsening of his electrolyte abnormalities despite replenishment, it was felt his symptoms were a result of refeeding syndrome. After oral intake was held and aggressive electrolyte replenishment was performed for 24 hours, the patient's anion gap closed and his electrolyte levels stabilized. This case demonstrates a unique presentation of refeeding syndrome given the patient's profound metabolic acidosis that provided a clue toward his eventual diagnosis. The standard workup for an anion gap metabolic acidosis was negative, and it was not until his refeeding syndrome had been treated that the anion gap closed.

  6. Metabolic acidosis in a patient with type 1 diabetes mellitus complicated by methanol and amitriptyline intoxication.

    PubMed

    Celik, Umit; Celik, Tamer; Avci, Akkan; Annagur, Ali; Yilmaz, Hayri Levent; Kucukosmanoglu, Osman; Topaloglu, Ali Kemal; Daglioglu, Nebile

    2009-02-01

    Diabetic ketoacidosis (DKA) is a widely known acute metabolic complication of diabetes mellitus (DM), which can be potentially fatal. It is not difficult to diagnose when a patient with DM comes with symptoms such as coma, fruity breath, hyperglycemia, acidosis, and tachypnea. If the patient has not been diagnosed with DM before, then other sicknesses characterized by an increased anion gap should be considered. A 12-year-old boy with type 1 DM and repeated earlier admissions for DKA was admitted to the emergency department in another apparent case of DKA with coma, hyperglycemia, and profound metabolic acidosis. When his condition did not improve with initial treatment, intoxication was suspected as an alternate cause of his condition. Further laboratory tests detected methanol and amitriptyline. The patient underwent hemodialysis and recovered completely. This case illustrates that a seemingly obvious medical condition can mask serious intoxication. This report is the only publication on two different entities characterized by an increased anion gap and at the end the patient has been cured completely without any complications. PMID:19106720

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

    PubMed Central

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

    2015-01-01

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

  8. Transient 5-oxoprolinuria and high anion gap metabolic acidosis: clinical and biochemical findings in eleven subjects.

    PubMed

    Pitt, J J; Hauser, S

    1998-07-01

    We describe biochemical and clinical features of 11 subjects (ages, 1.2-84 years, nine females and two males) with transient 5-oxoprolinuria (0.6-23.6 mol/mol of creatinine, reference range <0.07). A variety of conditions preceded the onset of acidosis, and all had taken acetaminophen (paracetamol), although in therapeutic amounts in most subjects. Metabolic acidosis was documented in nine subjects, and all had an increased anion gap and abnormal liver functions. 5-Oxoproline was the major urinary organic acid in five subjects, whereas the rest had more complex profiles comprising 5-oxoproline and other organic acids, such as lactate, 3-hydroxybutyrate, and 4-hydroxyphenyl lactate. The 5-oxoproline was predominantly of the L-configuration. One subject died during an acidotic episode, and the rest recovered with no apparent long-term ill effects. Urinary 5-oxoproline was within the reference range in six subjects that were re-tested after the anion gap normalized. These findings suggest that acetaminophen, in association with other unidentified factors, is involved in the development of this condition through a mechanism of depletion of liver glutathione stores.

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

    PubMed

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

    2014-11-01

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

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

    PubMed

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

    2007-08-01

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

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

    PubMed Central

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

    2016-01-01

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

  12. Neuronal expression of sodium/bicarbonate cotransporter NBCn1 (SLC4A7) and its response to chronic metabolic acidosis

    PubMed Central

    Park, Hae Jeong; Rajbhandari, Ira; Yang, Han Soo; Lee, Soojung; Cucoranu, Delia; Cooper, Deborah S.; Klein, Janet D.; Sands, Jeff M.

    2010-01-01

    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. PMID:20147654

  13. Anion gap acidosis.

    PubMed

    Ishihara, K; Szerlip, H M

    1998-01-01

    Although an anion gap at less than 20 mEq/L rarely has a defined etiology, significant elevations in the anion gap almost always signify presence of an acidosis that can be easily identified. Anion gap acidoses can be divided into those caused by lactate accumulation, ketoacid production, toxin/drugs, and uremia. Lactic acidoses caused by decreased oxygen delivery or defective oxygen utilization are associated with high mortality. The treatment of lactic acidosis is controversial. The use of bicarbonate to increase pH is rarely successful and, by generating PCO2, may worsen outcome. Ketoacidosis is usually secondary to diabetes or alcohol. Treatment is aimed at turning off ketogenesis and repairing fluid and electrolyte abnormalities. Methanol, ethylene glycol, and salicylates are responsible for the majority of toxin-induced anion gap acidoses. Both methanol and ethylene glycol are associated with severe acidoses and elevated osmolar gaps. Treatment of both is alcohol infusion to decrease formation of toxic metabolites and dialyses to remove toxins. Salicylate toxicity usually is associated with a mild metabolic acidosis and a respiratory alkalosis. Uremia is associated with a mild acidosis secondary to decreased ammonia secretion and an anion gap caused by the retention of unmeasured anions. A decrease in anion gap is caused by numerous mechanisms and thus has little clinical utility.

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

    PubMed

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

    2013-01-30

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

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

    PubMed Central

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

    2013-01-01

    This case describes the unexpected survival of an adult man who presented to the emergency department with hypovolaemic shock secondary to a splenic haemorrhage. Before surgery he had a pH 6.527, base excess (BE) −34.2 mmol/l and lactate 15.6 mmol/l. He underwent a splenectomy after which his condition stabilised. He was managed in the intensive care unit postoperatively where he required organ support including renal replacement therapy but was subsequently discharged home with no neurological or renal deficit. Although there are case reports of patients surviving such profound metabolic acidosis these have mainly been cases of near drowning or toxic alcohol ingestion. To the best of our knowledge this is the first reported case of survival after a pH of 6.5 secondary to hypovolaemic shock. PMID:23370959

  16. Severe metabolic alkalosis in pregnancy

    PubMed Central

    Frise, Charlotte; Noori, Muna

    2013-01-01

    Summary Metabolic alkalosis is uncommon in pregnancy and is most often the result of severe vomiting. If this is present at the time of delivery, transient metabolic derangement in the fetus can occur, potentially requiring additional organ support. A 22-year-old woman is described, who presented at 37 weeks gestation with a severe metabolic alkalosis, vomiting and acute renal and hepatic impairment. The investigations, management options and maternal and fetal outcome are described. PMID:27708709

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2016-05-01

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

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

    PubMed Central

    Akhenblit, Paul J; Pagel, Mark D

    2016-01-01

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

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

    PubMed

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

    2012-10-01

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

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

    PubMed

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

    2016-02-01

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

  2. Acidosis Drives the Reprogramming of Fatty Acid Metabolism in Cancer Cells through Changes in Mitochondrial and Histone Acetylation.

    PubMed

    Corbet, Cyril; Pinto, Adán; Martherus, Ruben; Santiago de Jesus, João Pedro; Polet, Florence; Feron, Olivier

    2016-08-01

    Bioenergetic preferences of cancer cells foster tumor acidosis that in turn leads to dramatic reduction in glycolysis and glucose-derived acetyl-coenzyme A (acetyl-CoA). Here, we show that the main source of this critical two-carbon intermediate becomes fatty acid (FA) oxidation in acidic pH-adapted cancer cells. FA-derived acetyl-CoA not only fuels the tricarboxylic acid (TCA) cycle and supports tumor cell respiration under acidosis, but also contributes to non-enzymatic mitochondrial protein hyperacetylation, thereby restraining complex I activity and ROS production. Also, while oxidative metabolism of glutamine supports the canonical TCA cycle in acidic conditions, reductive carboxylation of glutamine-derived α-ketoglutarate sustains FA synthesis. Concomitance of FA oxidation and synthesis is enabled upon sirtuin-mediated histone deacetylation and consecutive downregulation of acetyl-CoA carboxylase ACC2 making mitochondrial fatty acyl-CoA degradation compatible with cytosolic lipogenesis. Perturbations of these regulatory processes lead to tumor growth inhibitory effects further identifying FA metabolism as a critical determinant of tumor cell proliferation under acidosis. PMID:27508876

  3. Differing Causes of Lactic Acidosis and Deep Breathing in Cerebral Malaria and Severe Malarial Anemia May Explain Differences in Acidosis-Related Mortality

    PubMed Central

    Brand, Nathan R.; Opoka, Robert O.; Hamre, Karen E. S.

    2016-01-01

    Lactic acidosis (LA) is a marker for mortality in severe malaria, but the mechanisms that lead to LA in the different types of severe malaria and the extent to which LA-associated mortality differs by type of severe malaria are not well described. We assessed the frequency of LA in children admitted to Mulago Hospital, Kampala, Uganda with cerebral malaria (CM, n = 193) or severe malarial anemia (SMA, n = 216). LA was compared to mortality and measures of parasite biomass and sequestration (P. falciparum histidine-rich protein-2 (PfHRP2) concentration, platelet count), and to a measure of systemic tissue oxygen delivery (hemoglobin level). LA was more frequent in children with SMA than CM (SMA, 47.7%, CM, 34.2%, P = 0.006), but mortality was higher in children with CM (13.0%) than SMA (0.5%, P<0.0001). In CM, LA was associated with increased PfHRP2 concentration and decreased platelet count but was not associated with hemoglobin level. In contrast, in SMA, LA was associated with a decreased hemoglobin level, but was not associated with PfHRP2 concentration or platelet count. LA was related to mortality only in CM. In multivariable regression analysis of the effect PfHRP2 and hemoglobin levels on LA and DB, only PfHRP2 level increased risk of LA and DB in CM, while in SMA, elevated hemoglobin strongly decreased risk of LA and DB, and PfHRP2 level modestly increased risk of LA. The study findings suggest that LA in CM is due primarily to parasite sequestration, which currently has no effective adjunctive therapy, while LA in SMA is due primarily to anemia, which is rapidly corrected with blood transfusion. Differing etiologies of LA in CM and SMA may explain why LA is associated with mortality in CM but not SMA. PMID:27684745

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2015-04-01

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

  6. Repeated intoxication presenting with azotemia, elevated serum osmolal gap, and metabolic acidosis with high anion gap: differential diagnosis, management, and prognosis.

    PubMed

    Prevost, Merideth; Sun, Yijuan; Servilla, Karen S; Massie, Larry; Glew, Robert H; Tzamaloukas, Antonios H

    2012-02-01

    A man with a history of alcoholism presented on two different occasions with mental changes, clinical signs of volume depletion, elevated serum osmolal gap, metabolic acidosis with high anion gap, metabolic alkalosis, hyponatremia, and azotemia after binge drinking of only ethanol. In both episodes, the serum contained ethanol, acetone, and 2-propanol (isopropanol), but no methanol or ethylene glycol. In the first episode, the rates of excretion of acetoacetate and 3-hydroxybutyrate in the urine were greatly increased. Volume repletion was the only treatment. In both episodes, azotemia and metabolic acidosis were rapidly reversed, while modest metabolic alkalosis was noted after treatment. The triad of azotemia, elevated osmolal gap, and high anion gap metabolic acidosis, which characterizes intoxication with methanol or ethylene glycol, can also develop in alcoholic ketoacidosis (AKA), an entity with substantially different management and outcome. Finding 2-propanol in the serum of patients with AKA indicates either concomitant 2-propanol ingestion or formation of 2-propanol from acetone.

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

    NASA Technical Reports Server (NTRS)

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

    1998-01-01

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

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

    PubMed

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

    2016-02-01

    Metabolic acidosis has profound effects on vascular tone. This study investigated the in vivo effects of acute metabolic acidosis (AMA) and chronic metabolic acidosis (CMA) on hemodynamic parameters and endothelial function. CMA was induced by ad libitum intake of 1% NH4Cl for 7 days, and AMA was induced by a 3-h infusion of 6 M NH4Cl (1 mL/kg, diluted 1:10). Phenylephrine (Phe) and acetylcholine (Ach) dose-response curves were performed by venous infusion with simultaneous venous and arterial blood pressure monitoring. Plasma nitrite/nitrate (NOx) was measured by chemiluminescence. The CMA group had a blood pH of 7.15±0.03, which was associated with reduced bicarbonate (13.8±0.98 mmol/L) and no change in the partial pressure of arterial carbon dioxide (PaCO2). The AMA group had a pH of 7.20±0.01, which was associated with decreases in bicarbonate (10.8±0.54 mmol/L) and PaCO2 (47.8±2.54 to 23.2±0.74 mmHg) and accompanied by hyperventilation. Phe or ACh infusion did not affect arterial or venous blood pressure in the CMA group. However, the ACh infusion decreased the arterial blood pressure (ΔBP: -28.0±2.35 mm Hg [AMA] to -4.5±2.89 mmHg [control]) in the AMA group. Plasma NOx was normal after CMA but increased after AMA (25.3±0.88 to 31.3±0.54 μM). These results indicate that AMA, but not CMA, potentiated the Ach-induced decrease in blood pressure and led to an increase in plasma NOx, reinforcing the effect of pH imbalance on vascular tone and blood pressure control. PMID:26648089

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

    PubMed Central

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

    2015-01-01

    Metabolic acidosis has profound effects on vascular tone. This study investigated the in vivo effects of acute metabolic acidosis (AMA) and chronic metabolic acidosis (CMA) on hemodynamic parameters and endothelial function. CMA was induced by ad libitum intake of 1% NH4Cl for 7 days, and AMA was induced by a 3-h infusion of 6 M NH4Cl (1 mL/kg, diluted 1:10). Phenylephrine (Phe) and acetylcholine (Ach) dose-response curves were performed by venous infusion with simultaneous venous and arterial blood pressure monitoring. Plasma nitrite/nitrate (NOx) was measured by chemiluminescence. The CMA group had a blood pH of 7.15±0.03, which was associated with reduced bicarbonate (13.8±0.98 mmol/L) and no change in the partial pressure of arterial carbon dioxide (PaCO2). The AMA group had a pH of 7.20±0.01, which was associated with decreases in bicarbonate (10.8±0.54 mmol/L) and PaCO2 (47.8±2.54 to 23.2±0.74 mmHg) and accompanied by hyperventilation. Phe or ACh infusion did not affect arterial or venous blood pressure in the CMA group. However, the ACh infusion decreased the arterial blood pressure (ΔBP: -28.0±2.35 mm Hg [AMA] to -4.5±2.89 mmHg [control]) in the AMA group. Plasma NOx was normal after CMA but increased after AMA (25.3±0.88 to 31.3±0.54 μM). These results indicate that AMA, but not CMA, potentiated the Ach-induced decrease in blood pressure and led to an increase in plasma NOx, reinforcing the effect of pH imbalance on vascular tone and blood pressure control. PMID:26648089

  10. Sublimed (inorganic) sulfur ingestion. A cause of life-threatening metabolic acidosis with a high anion gap.

    PubMed

    Schwartz, S M; Carroll, H M; Scharschmidt, L A

    1986-07-01

    We describe a 66-year-old woman undergoing hemodialysis treatment who developed life-threatening metabolic acidosis (pH of 6.67) with a high anion gap (41 mEq/L [41 mmol/L]) and marked hyperkalemia (9.1 mEq/L [9.1 mmol/L]) after consuming sulfur. Because of an increasing number of patients with chronic renal failure and dialysis-dependent end-stage renal disease, as well as persistence of folk remedies using sulfur, recognition of the potential dangers of self-administered sulfur seems appropriate.

  11. Effects of metabolic acidosis on intracellular pH responses in multiple cell types

    PubMed Central

    Salameh, Ahlam Ibrahim; Ruffin, Vernon A.

    2014-01-01

    Metabolic acidosis (MAc), a decrease in extracellular pH (pHo) caused by a decrease in [HCO3−]o at a fixed [CO2]o, is a common clinical condition and causes intracellular pH (pHi) to fall. Although previous work has suggested that MAc-induced decreases in pHi (ΔpHi) differ among cell types, what is not clear is the extent to which these differences are the result of the wide variety of methodologies employed by various investigators. In the present study, we evaluated the effects of two sequential MAc challenges (MAc1 and MAc2) on pHi in 10 cell types/lines: primary-cultured hippocampal (HCN) neurons and astrocytes (HCA), primary-cultured medullary raphé (MRN) neurons, and astrocytes (MRA), CT26 colon cancer, the C2C12 skeletal muscles, primary-cultured bone marrow-derived macrophages (BMDM) and dendritic cells (BMDC), Ink4a/ARF-null melanocytes, and XB-2 keratinocytes. We monitor pHi using ratiometric fluorescence imaging of 2′,7′-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein while imposing MAc: lowering (pHo) from 7.4 to 7.2 by decreasing [HCO3−]o from 22 to 14 mM at 5% CO2 for 7 min. After MAc1, we return cells to the control solution for 10 min and impose MAc2. Using our definition of MAc resistance [(ΔpHi/ΔpHo) ≤ 40%], during MAc1, ∼70% of CT26 and ∼50% of C2C12 are MAc-resistant, whereas the other cell types are predominantly MAc-sensitive. During MAc2, some cells adapt [(ΔpHi/ΔpHo)2 < (ΔpHi/ΔpHo)1], particularly HCA, C2C12, and BMDC. Most maintain consistent responses [(ΔpHi/ΔpHo)2 ≅ (ΔpHi/ΔpHo)1], and a few decompensate [(ΔpHi/ΔpHo)2>(ΔpHi/ΔpHo)1], particularly HCN, C2C12, and XB-2. Thus, responses to twin MAc challenges depend both on the individual cell and cell type. PMID:25209413

  12. Effects of clinically relevant acute hypercapnic and metabolic acidosis on the cardiovascular system: an experimental porcine study

    PubMed Central

    2013-01-01

    Introduction Hypercapnic acidosis (HCA) that accompanies lung-protective ventilation may be considered permissive (a tolerable side effect), or it may be therapeutic by itself. Cardiovascular effects may contribute to, or limit, the potential therapeutic impact of HCA; therefore, a complex physiological study was performed in healthy pigs to evaluate the systemic and organ-specific circulatory effects of HCA, and to compare them with those of metabolic (eucapnic) acidosis (MAC). Methods In anesthetized, mechanically ventilated and instrumented pigs, HCA was induced by increasing the inspired fraction of CO2 (n = 8) and MAC (n = 8) by the infusion of HCl, to reach an arterial plasma pH of 7.1. In the control group (n = 8), the normal plasma pH was maintained throughout the experiment. Hemodynamic parameters, including regional organ hemodynamics, blood gases, and electrocardiograms, were measured in vivo. Subsequently, isometric contractions and membrane potentials were recorded in vitro in the right ventricular trabeculae. Results HCA affected both the pulmonary (increase in mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR)) and systemic (increase in mean arterial pressure (MAP), decrease in systemic vascular resistance (SVR)) circulations. Although the renal perfusion remained unaffected by any type of acidosis, HCA increased carotid, portal, and, hence, total liver blood flow. MAC influenced the pulmonary circulation only (increase in MPAP and PVR). Both MAC and HCA reduced the stroke volume, which was compensated for by an increase in heart rate to maintain (MAC), or even increase (HCA), the cardiac output. The right ventricular stroke work per minute was increased by both MAC and HCA; however, the left ventricular stroke work was increased by HCA only. In vitro, the trabeculae from the control pigs and pigs with acidosis showed similar contraction force and action-potential duration (APD). Perfusion with an acidic

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

    PubMed

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

    2015-07-01

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

  14. Extracorporeal treatment with high-volume continuous venovenous hemodiafiltration and charcoal-based sorbent hemoperfusion for severe metformin-associated lactic acidosis.

    PubMed

    Garg, Suneel Kumar; Singh, Omender; Deepak, Desh; Singh, Akhilesh; Yadav, Rohit; Vashist, Kirti

    2016-05-01

    We present a case of a 49-year-old female with an alleged history of ingestion of approximately 100 tablets of metformin (850 mg each). Investigations revealed severe lactic acidosis with lactate levels of 13.5 mmol/L and pH of 7.17. This indicates severe toxicity and is associated with a high mortality. Charcoal-based sorbent hemoperfusion was done as a desperate effort, as patient continued to deteriorate despite supportive care and high-volume continuous venovenous hemodiafiltration. The patient survived despite metformin-associated lactic acidosis related to severe metformin toxicity. PMID:27275079

  15. Comparison of end-tidal carbon dioxide and arterial blood bicarbonate levels in patients with metabolic acidosis referred to emergency medicine

    PubMed Central

    Taghizadieh, Ali; Pouraghaei, Mahboub; Moharamzadeh, Payman; Ala, Alireza; Rahmani, Farzad; Basiri Sofiani, Karim

    2016-01-01

    Introduction: The routine and gold standard method to diagnose of acid – base disturbance is arterial blood gas (ABG) sampling. Capnography could be used to measure the end-tidal carbon dioxide (ETCO2) levels and ETco2 has a close correlation with the PaCo2. The aim of this study was comparison the ETco2 and arterial blood bicarbonate levels in patients with metabolic acidosis. Methods: In a descriptive-analytical study that performed in Emergency Department of Emam Reza Medical Research and Training Hospital of Tabriz on patients with metabolic acidosis, ETco2 level and blood bicarbonate levels in 262 patients were evaluated. Results: Mean of ETco2 and Hco3 levels in patients with metabolic acidosis were 22.29 ± 4.15 and 12.78 ± 3.83, respectively. In all patients, the significant direct linear relationship was found between ETco2 with Hco3 (r = 0.553, P < 0.001). We had 4 groups of patients with metabolic acidosis, also there is a significant direct linear relationship between the ETCo2 and the Hco3 level of arterial blood in patients with renal failure (P < 0.001 and r = 0.551), sepsis (P < 0.001 and r = 0.431), drug toxicity (P < 0.001 and r = 0.856), and ketoacidosis (DKA) (P < 0.001 and r = 0.559). Conclusion: According to the results of this study, capnography can be used for primary diagnosis of metabolic acidosis in spontaneously breathing patients who referred to the emergency wards, however, the ABG must be considered as the gold standard tool for diagnosis and guiding the treatment. PMID:27777693

  16. Respiratory acidosis

    MedlinePlus

    ... obesity, which restricts how much the lungs can expand Obstructive sleep apnea Chronic respiratory acidosis occurs over ... Tests that may be done include: Arterial blood gas , which measures oxygen and carbon dioxide levels in ...

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

    PubMed

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

    2016-04-01

    Low-grade metabolic acidosis (LGMA), as induced by high dietary acid load or sodium chloride (NaCl) intake, has been shown to increase bone and protein catabolism. Underlying mechanisms are not fully understood, but from clinical metabolic acidosis interactions of acid-base balance with glucocorticoid (GC) metabolism are known. We aimed to investigate GC activity/metabolism under alkaline supplementation and NaCl-induced LGMA. Eight young, healthy, normal-weight men participated in two crossover designed interventional studies. In Study A, two 10-day high NaCl diet (32 g/d) periods were conducted, one supplemented with 90 mmol KHCO3/day. In Study B, participants received a high and a low NaCl diet (31 vs. 3 g/day), each for 14 days. During low NaCl, the diet was moderately acidified by replacement of a bicarbonate-rich mineral water (consumed during high NaCl) with a non-alkalizing drinking water. In repeatedly collected 24-h urine samples, potentially bioactive-free GCs (urinary-free cortisol + free cortisone) were analyzed, as well as tetrahydrocortisol (THF), 5α-THF, and tetrahydrocortisone (THE). With supplementation of 90 mmol KHCO3, the marker of total adrenal GC secretion (THF + 5α-THF + THE) dropped (p = 0.047) and potentially bioactive-free GCs were reduced (p = 0.003). In Study B, however, GC secretion and potentially bioactive-free GCs did not exhibit the expected fall with NaCl-reduction as net acid excretion was raised by 30 mEq/d. Diet-induced acidification/alkalization affects GC activity and metabolism, which in case of long-term ingestion of habitually acidifying western diets may constitute an independent risk factor for bone degradation and cardiometabolic diseases. PMID:26349936

  18. [Metformin associates lactic acidosis].

    PubMed

    Montini, Florent; Rondeau, Eric; Peltier, Julie; Mesnard, Laurent; Jouzel, Charlotte; Ridel, Christophe

    2012-10-01

    Metformin Associates lactic acidosis (MALA) is a metabolic acidosis with higher anion gap, high levels of blood lactates and treatment by metformin. MALA is a very rare entity but is associated with high mortality (30 to 50%). The extrarenal blood purification may be necessary in emergency. Relatively good clinical tolerance contrasts with a very elevated serum lactate. There is always a trigger and hypovolemia is prevalent. MALA often occurs when its prescription is not indicated (renal failure, cardiac failure, hypovolemia, or patient aged over 80 years). Metformin must be stopped in situations of acute hypovolemia or frail patients as diuretics or blockers of the rennin-angiotensin-aldosterone system.

  19. Lactic acidosis occurrence during exercises in the smoke chamber in a 53-year-old firefighter with no significant medical history.

    PubMed

    Bronisz, Agata; Spychalska, Magdalena; Szafrańska, Małgorzata

    2014-04-01

    Lactic acidosis is a form of metabolic acidosis with a high anion gap, reduced rate of arterial blood pH under 7.35 mmol/l, and lactic acid concentration over 7 mmol/l. In the literature we can find some descriptions of the cases of lactic acidosis in patients with severe systemic diseases (cancer, acquired immunodeficiency syndrome, sepsis, diabetes with cardiovascular disease and after organ transplantations). We present the case of lactic acidosis in a patient with no chronic disease--a firefighter in whom lactic acidosis has developed during standard exercises in the smoke chamber.

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

    PubMed

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

    2016-06-01

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

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

    PubMed

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

    2013-01-01

    The question of obtaining organs from donors who died of methanol poisoning has been discussed in the medical literature for many years. The results of such transplants published so far are very optimistic. However, the possibility of permanent and significant injury to transplanted organs caused by poisons or its metabolites raises serious concerns regarding the procedure. The long-term effects of intensive treatment of poisoning need to be considered as well. Metabolic acidosis and high blood osmolality are agents with recognized damaging potential impairing organ function at cellular level. The study traced the fate of kidney transplants from 13 donors who died of methanol poisoning and one isoned with carbon monoxide. The donors group consisted of 12 men and 2 women, of mean age 49 years (SD +/- 7.93). The kidneys were transplanted 20 men and 8 women. The mean age of recipients was 50.29 years (SD +/- 12.9). At the time of admission to the Department of Toxicology all donors presented with profound metabolic acidosis and high plasma osmolality (mean 434.71 mOsm/kg H2O (SD +/- 73.29). Metabolic acidosis was treated high doses of sodium bicarbonate (mean infusion volume of was 409 ml) before the HD procedure. Blood methanol levels were between 125 and 470 mg% (mean 317.23 SD +/- 136.83). The carboxyhaemoglobin concentration of in the donor poisoned with carbon monoxide was 47.2%. Transplantation was performed after confirmation of the brain death, the period of cold ischemia (CIT) ranged from 6 to 22 hours (mean 16.06 hours; SD +/- 3.99). Kidneys have taken function immediately after transplantation in 21 recipients. In seven cases, patients required two or three HD procedures. A total of 16 dialysis were performed post-transplants. In the group of patients, the mean glomerular filtration rate (GFR) at 3 months after transplantation was 46.71 ml/min/1.73m2 (SD +/- 10.89). During the 18 months follow-up a constant upward trend to the mean GFR 50.55 was noticed. In

  2. Postnatal growth of infants of less than 1.3 kg birth weight: effects of metabolic acidosis, of caloric intake, and of calcium, sodium, and phosphate supplementation.

    PubMed

    Chance, G W; Radde, I C; Willis, D M; Roy, R N; Park, E; Ackerman, I

    1977-11-01

    Weekly increments of length, weight, head circumference, and skinfold thickness in response to a series of dietary changes were measured in 108 healthy infants who weighed less than 1.3 kg at birth. The serial manipulations included prevention of late metabolic acidosis, increased caloric intake, and calcium, sodium, and phosphorus supplementation. The study comprised four phases; the infants were divided into ten groups according to dietary regimen. AGA and SGA infants were studied separately. Growth in length was primarily influenced by a change to a formula providing a higher caloric intake and a 60:40 whey protein/casein ratio. Correction of late metabolic acidosis, sodium, and phosphorus supplementation had minor additive effects on growth in length. Increased caloric intake also influenced growth of head circumference, but only in AGA infants. Only the sodium intake was shown to influence body weight increments significantly with the range of caloric intake used in the study (132 to 160 calories/kg/day).

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

    PubMed Central

    2012-01-01

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

  4. Metabolic multianalyte microphysiometry reveals extracellular acidosis is an essential mediator of neuronal preconditioning.

    PubMed

    McKenzie, Jennifer R; Palubinsky, Amy M; Brown, Jacquelynn E; McLaughlin, Bethann; Cliffel, David E

    2012-07-18

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

  5. Acidosis activates complement system in vitro.

    PubMed Central

    Emeis, M; Sonntag, J; Willam, C; Strauss, E; Walka, M M; Obladen, M

    1998-01-01

    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. PMID:9927235

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

    PubMed

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

    2016-02-01

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

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

    PubMed

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

    2016-01-01

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

  8. Endolymphatic sac enlargement in a girl with a novel mutation for distal renal tubular acidosis and severe deafness.

    PubMed

    Nikki, Rink; Martin, Bitzan; Gus, O'Gorman; Mato, Nagel; Elena, Torban; Paul, Goodyer

    2012-01-01

    Hereditary distal renal tubular acidosis (dRTA) is caused by mutations of genes encoding subunits of the H(+)-ATPase (ATP6V0A4 and ATP6V1B1) expressed in α-intercalated cells of the distal renal tubule and in the cochlea. We report on a 2-year-old girl with distal RTA and profound speech delay which was initially misdiagnosed as autism. Genetic analysis showed compound heterozygous mutations with one known and one novel mutation of the ATP6V1B1 gene; cerebral magnetic resonance imaging (MRI) revealed bilateral enlargement of the endolymphatic sacs of the inner ear. With improved cooperation, audiometric testing showed that hearing loss was most profound on the right, where endolymphatic sac enlargement was greatest, demonstrating a clear link between the degree of deafness and the degree of inner ear abnormality. This case indicates the value of MRI for diagnosis of inner ear involvement in very young children with distal RTA. Although citrate therapy quickly corrects the acidosis and restores growth, early diagnosis of deafness is crucial so that hearing aids can be used to assist acquisition of speech and to provide enough auditory nerve stimulation to assure the affected infants remain candidates for cochlear implantation. PMID:22966473

  9. Metabolic syndrome in severe mental disorders.

    PubMed

    Ohaeri, Jude U; Akanji, Abayomi O

    2011-04-01

    The concept of metabolic syndrome in psychiatry provides a united front for confronting a series of metabolic changes that are predictive of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM), which are highly prevalent in severe mental disorders (SMDs), such as schizophrenia, bipolar disorders, and severe depression. This review attempts to answer the following questions: (1) Is there evidence of significantly increased risk of metabolic syndrome in SMDs? (2) How is this evidence explained by stress theory and functional polymorphism? (3) What role can psychopharmacology and psychosocial therapies play in minimizing the problem? We have done a historical review using related literature from Medline. Compared with the general population, metabolic syndrome is two to three times more common in SMDs. The evidence for this predates the era of antipsychotic drugs. Altered glucose metabolism and dyslipidemia seem to be integral to SMDs. However, major psychotropic drugs are associated with metabolic syndrome, because of their activity at the appetite-stimulating receptors. SMDs seem to trigger a pathogenic cycle that fuels metabolic syndrome. To explain these findings, a neural diathesis-stress model has been proposed. Furthermore, candidate genes associated with receptors for weight gain are implicated. Using metformin (≥750 mg/day) may significantly reduce metabolic risks, and the data support consideration of this intervention for psychiatric patients taking antipsychotics. The obstacles to the implementation of the available guidelines for monitoring metabolic effects and changing unhelpful lifestyles need to be overcome by making monitoring mandatory and integration of physical exercise into routine care. Drug development and genotyping for the risk factors are future solutions. PMID:20964513

  10. An investigation of the role of lactic acid production in the causation of metabolic acidosis resulting from raised intracranial pressure in rabbits.

    PubMed

    Bar, Z G; Davidson, J T

    1985-01-01

    Intracranial pressure (ICP) was acutely raised in anaesthetized rabbits by the injection of saline into the cisterna magna. The raised ICP was maintained at 200 mm Hg for 3 min after which it was allowed to return to baseline values. The profound metabolic acidosis produced (mean base deficit reaching 17.99 +/- SD 4.06 mmol/1 30 min after raised ICP) was found to be in part related to an increase in arterial blood lactate (from mean 7.04 +/- SD 3.26 mmol/l before raised ICP to mean 13.57 +/- SD 5.28 mmol/l 30 min after raised ICP). It would appear that systemic sympathetic nervous system discharge consequent upon raising ICP results in intense vasoconstriction and thus an increase in anaerobic metabolism and inorganic acid production.

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

    PubMed

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

    2003-11-01

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

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

    PubMed

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

    2003-11-01

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

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

    PubMed

    Suetrong, Bandarn; Walley, Keith R

    2016-01-01

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

  14. Severe metabolic alkalosis in the emergency department.

    PubMed

    Mennen, M; Slovis, C M

    1988-04-01

    A case of severe metabolic alkalosis (MA) resulting from ingestion of baking soda (sodium bicarbonate) is presented. On admission to the emergency department, the patient was alert and stable with an initial examination that was remarkable only for carpopedal spasm. Shortly thereafter, the patient had a sudden, unexpected cardiopulmonary arrest. Following resuscitation, without administration of sodium bicarbonate, the arterial blood gas revealed a pH of 7.73, pO2 of 51 mm Hg, and pCO2 of 52 mm Hg. After admission to the intensive care unit, the patient's MA was corrected using IV 0.25 N hydrochloric acid. The patient remained comatose as a result of severe anoxic encephalopathy and died two weeks after admission. We believe this is the first reported case of severe MA resulting in sudden cardiopulmonary arrest in a previously ambulatory patient. PMID:2833137

  15. Acidosis inhibits mineralization in human osteoblasts.

    PubMed

    Takeuchi, Shoko; Hirukawa, Koji; Togari, Akifumi

    2013-09-01

    Osteoblasts and osteoclasts maintain bone volume. Acidosis affects the function of these cells including mineral metabolism. We examined the effect of acidosis on the expression of transcription factors and mineralization in human osteoblasts in vitro. Human osteoblasts (SaM-1 cells) derived from the ulnar periosteum were cultured with α-MEM containing 50 μg/ml ascorbic acid and 5 mM β-glycerophosphate (calcifying medium). Acidosis was induced by incubating the SaM-1 cells in 10 % CO₂ (pH approximately 7.0). Mineralization, which was augmented by the calcifying medium, was completely inhibited by acidosis. Acidosis depressed c-Jun mRNA and increased osteoprotegerin (OPG) production in a time-dependent manner. Depressing c-Jun mRNA expression using siRNA increased OPG production and inhibited mineralization. In addition, depressing OPG mRNA expression with siRNA enhanced mineralization in a dose-dependent manner. Acidosis or the OPG protein strongly inhibited mineralization in osteoblasts from neonatal mice. The present study was the first to demonstrate that acidosis inhibited mineralization, depressed c-Jun mRNA expression, and induced OPG production in human osteoblasts. These results suggest that OPG is involved in mineralization via c-Jun in human osteoblasts.

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2011-01-01

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

  18. Fuel metabolism during severe rowing exercise

    SciTech Connect

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

    1986-03-01

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

  19. D-lactic acidosis in neonatal ruminants.

    PubMed

    Lorenz, Ingrid; Gentile, Arcangelo

    2014-07-01

    Metabolic acidosis in calves with neonatal diarrhea was believed to be mainly caused by the loss of bicarbonate via the intestines or the formation of L-lactate during anaerobic glycolysis after tissue hypoperfusion in dehydrated calves. Because D-lactate was not considered to be of interest in human or veterinary medicine, routine diagnostic methods targeted the detection of L-lactate only. The development of stereospecific assays for the measurement of D-lactate facilitated research. This article summarizes the available information on D-lactic metabolic acidosis in neonatal ruminants.

  20. [Metformin-associated lactic acidosis: incidence, diagnosis, prognostic factors and treatment].

    PubMed

    Vives, M; Romano, J; Stoll, E; Lafuente, A; Nagore, D; Monedero, P

    2012-05-01

    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.

  1. Protein metabolism in severe childhood malnutrition

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  2. Type B lactic acidosis associated with multiple myeloma.

    PubMed

    Sia, Patrick; Plumb, Troy J; Fillaus, Jennifer A

    2013-09-01

    We present a 58-year-old man with recurrent multiple myeloma treated with 2 autologous stem cell transplantations. He was admitted for dyspnea and found to have severe type B lactic acidosis with serum lactate level of 193.6 mg/dL. This case reviews malignancy-associated type B lactic acidosis and discusses its etiology, pathogenesis, and management.

  3. Thiamine Deficiency in a Developed Country: Acute Lactic Acidosis in Two Neonates Due to Unsupplemented Parenteral Nutrition.

    PubMed

    Salvatori, Guglielmo; Mondì, Vito; Piersigilli, Fiammetta; Capolupo, Irma; Pannone, Veronica; Vici, Carlo Dionisi; Rizzo, Cristiano; Dotta, Andrea

    2016-08-01

    Thiamine is a water-soluble vitamin implicated in several metabolic processes. Its deficiency, due to prolonged parenteral nutrition without adequate vitamin supplementation, can lead to multiorgan failure characterized by cardiovascular impairment and metabolic acidosis refractory to bicarbonate administration. Only thiamine administration allows the remission of symptoms. We report 2 preterm infants with acute thiamine deficiency due to prolonged parenteral nutrition without adequate vitamin supplementation.

  4. SDF1 induction by acidosis from principal cells regulates intercalated cell subtype distribution

    PubMed Central

    Schwartz, George J.; Gao, XiaoBo; Tsuruoka, Shuichi; Purkerson, Jeffrey M.; Peng, Hu; D’Agati, Vivette; Picard, Nicolas; Eladari, Dominique; Al-Awqati, Qais

    2015-01-01

    The nephron cortical collecting duct (CCD) is composed of principal cells, which mediate Na, K, and water transport, and intercalated cells (ICs), which are specialized for acid-base transport. There are two canonical IC forms: acid-secreting α-ICs and HCO3-secreting β-ICs. Chronic acidosis increases α-ICs at the expense of β-ICs, thereby increasing net acid secretion by the CCD. We found by growth factor quantitative PCR array that acidosis increases expression of mRNA encoding SDF1 (or CXCL12) in kidney cortex and isolated CCDs from mouse and rabbit kidney cortex. Exogenous SDF1 or pH 6.8 media increased H+ secretion and decreased HCO3 secretion in isolated perfused rabbit CCDs. Acid-dependent changes in H+ and HCO3 secretion were largely blunted by AMD3100, which selectively blocks the SDF1 receptor CXCR4. In mice, diet-induced chronic acidosis increased α-ICs and decreased β-ICs. Additionally, IC-specific Cxcr4 deletion prevented IC subtype alterations and magnified metabolic acidosis. SDF1 was transcriptionally regulated and a target of the hypoxia-sensing transcription factor HIF1α. IC-specific deletion of Hif1a produced no effect on mice fed an acid diet, as α-ICs increased and β-ICs decreased similarly to that observed in WT littermates. However, Hif1a deletion in all CCD cells prevented acidosis-induced IC subtype distribution, resulting in more severe acidosis. Cultured principal cells exhibited an HIF1α-dependent increase of Sdf1 transcription in response to media acidification. Thus, our results indicate that principal cells respond to acid by producing SDF1, which then acts on adjacent ICs. PMID:26517693

  5. Importance of metabolic monitoring systems as an early prognostic indicator in severe head injured patients.

    PubMed

    Kushi, H; Moriya, T; Saito, T; Kinoshita, K; Shibuya, T; Hayashi, N

    1999-01-01

    We have analyzed and evaluated what is the best metabolic monitoring system to determine the prognosis for maintenance of neurological function in severe head injured patients. Acute subdural hematoma (ASDH) was recognized in fifteen of 22 patients and cerebral contusion in seven in this series. Intracranial pressure (ICP), jugular venous pH and jugular bulb venous oxygen saturation (SjO2) were continuously monitored as soon as possible following stabilization. The measurement of cerebral blood flow (CBF) was carried out using a stable Xenon-computerized tomography (Xe-CT). After measuring CBF, 3% carbon dioxide (CO2) loading was conducted to determine CO2 responses (delta CBF/delta CO2). In patients who died (D), jugular venous pH showed evidence of acidosis (6.3-7.2) with delta CBF/delta CO2 < 1 and cerebral metabolic rate of oxygen (CMRO2) < 1.21 within several hours of the trauma. On the other hand, arterial pH was shown to be within the normal range. In vegetative state (VS) and severe disability (SD) patients, jugular venous pH was shown to be within normal range, with delta CBF/delta CO2 < 1 and 1.44 < CMRO2 < 1.79. In all of moderate disability (MD) and good recovery (GR) patients, jugular venous pH was shown to be within the normal range, with delta CBF/delta CO2 > 1 and 1.65 < CMRO2 < 1.85. These results suggest that jugular venous pH, CO2 response and CMRO2, were useful as early prognostic indicators in the maintenance of neurological function.

  6. Distal renal tubular acidosis that became exacerbated by proton pump inhibitor use.

    PubMed

    Okamoto, Natsumi; Nambu, Takuo; Matsuda, Yuki; Matsuo, Koji; Osaki, Keisuke; Kanai, Yugo; Ogawa, Yoshihisa; Yonemitsu, Shin; Kita, Ryuichi; Muro, Seiji; Sugawara, Akira; Oki, Shogo

    2012-01-01

    Acid-base imbalances and electrolyte disorders induced by proton pump inhibitors (PPIs) are extremely rare. However, under certain conditions, PPIs may cause metabolic acidosis or hypokalemia, probably due to an inhibitory action on the proton pump that contributes to H(+) and K(+) homeostasis in the kidney. We herein present a case of marked hypokalemia accompanied by distal renal tubular acidosis in which a PPI appeared to contribute to the pathophysiology of metabolic acidosis.

  7. Falsely normal anion gap in severe salicylate poisoning caused by laboratory interference.

    PubMed

    Jacob, Jeena; Lavonas, Eric J

    2011-09-01

    Severe salicylate poisoning is classically associated with an anion gap metabolic acidosis. However, high serum salicylate levels can cause false increase of laboratory chloride results on some analyzers. We present 2 cases of life-threatening salicylate poisoning with an apparently normal anion gap caused by an important laboratory interference. These cases highlight that the diagnosis of severe salicylism must be considered in all patients presenting with metabolic acidosis, even in the absence of an increased anion gap.

  8. Trauma triggering thyrotoxic crisis with lactic acidosis.

    PubMed

    Prosser, Jennifer S; Quan, Dan K

    2015-01-01

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

  9. Acidosis effects on insulin response during glucose tolerance tests in Jersey cows.

    PubMed

    Bigner, D R; Goff, J P; Faust, M A; Burton, J L; Tyler, H D; Horst, R L

    1996-12-01

    The effect of metabolic alkalosis and acidosis on insulin response to glucose tolerance tests was determined for cows fed a high cation diet to induce a state of metabolic acidosis. The anion diet to induce a state of metabolic acidosis. The glucose tolerance test (500 mg of glucose/kg of BW infused i.v. over 10 min) caused a rapid increase in plasma glucose and insulin concentrations. Plasma glucose concentrations were highest, and plasma insulin concentrations were lowest, during metabolic acidosis. These results suggest that insulin secretion is impaired during metabolic acidosis, which may reduce tissue uptake of glucose. Correction of metabolic acidosis by oral administration of sodium bicarbonate prior to glucose tolerance testing increased blood pH and bicarbonate concentrations and partially restored insulin response to the glucose tolerance test. Interestingly, sodium bicarbonate also caused an elevation in plasma cortisol concentrations. We concluded that glucose utilization is altered in cows with metabolic acidosis. The correction of acidosis associated with diseases such as diarrhea and ketosis may improve the therapeutic benefit of glucose infusions used to treat these diseases.

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

    PubMed

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

    2016-03-01

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

  11. Hyperammonemia in distal renal tubular acidosis: is it more common than we think?

    PubMed

    Pela, I; Seracini, D

    2007-08-01

    The hyperammonemia in distal renal tubular acidosis, previously only described in two cases, is considered an unusual occurrence. After the report published in 2005, we observed plasma ammonia levels above normal range during metabolic decompensation in two other consecutive pediatric patients suffering from distal renal tubular acidosis. The ammonia plasma levels returned to normal range after treatment with sodium bicarbonate and potassium salt. In distal renal tubular acidosis, hyperammonemia is probably the result of an imbalance between the increased ammonia synthesis, in response to metabolic acidosis, and the impaired ammonia excretion, typical of distal renal tubular acidosis. According to this physiopathological mechanism, our observation shows that hyperammonemia is not an uncommon finding in distal renal tubular acidosis, and should be included among differential diagnosis of hyperammonemia in infants and children. PMID:17722711

  12. Lactic Acidosis: Current Treatments and Future Directions.

    PubMed

    Kraut, Jeffrey A; Madias, Nicolaos E

    2016-09-01

    Mortality rates associated with severe lactic acidosis (blood pH<7.2) due to sepsis or low-flow states are high. Eliminating the triggering conditions remains the most effective therapy. Although recommended by some, administration of sodium bicarbonate does not improve cardiovascular function or reduce mortality. This failure has been attributed to both reduction in serum calcium concentration and generation of excess carbon dioxide with intracellular acidification. In animal studies, hyperventilation and infusion of calcium during sodium bicarbonate administration improves cardiovascular function, suggesting that this approach could allow expression of the positive aspects of sodium bicarbonate. Other buffers, such as THAM or Carbicarb, or dialysis might also provide base with fewer untoward effects. Examination of these therapies in humans is warranted. The cellular injury associated with lactic acidosis is partly due to activation of NHE1, a cell-membrane Na(+)/H(+) exchanger. In animal studies, selective NHE1 inhibitors improve cardiovascular function, ameliorate lactic acidosis, and reduce mortality, supporting future research into their possible use in humans. Two main mechanisms contribute to lactic acid accumulation in sepsis and low-flow states: tissue hypoxia and epinephrine-induced stimulation of aerobic glycolysis. Targeting these mechanisms could allow for more specific therapy. This Acid-Base and Electrolyte Teaching Case presents a patient with acute lactic acidosis and describes current and future approaches to treatment. PMID:27291485

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

    PubMed Central

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

    1977-01-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

    2012-01-01

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

  16. A metabolic syndrome severity score: A tool to quantify cardio-metabolic risk factors.

    PubMed

    Wiley, Joshua F; Carrington, Melinda J

    2016-07-01

    Metabolic syndrome is a cluster of cardio-metabolic risk factors and is associated with increased mortality. There is no standard, validated way to assess the severity of aggregated metabolic syndrome risk factors. Cardiovascular and diabetes risk factor data came from two studies conducted in Australia from 2006 to 2010 in adults aged 18 or above. In medication free adults, sex-specific clinical thresholds and Principal Component Analysis were used to develop a formula to calculate a metabolic syndrome severity score (MetSSS). These scores were compared to scores derived using the same process in subgroups by sex, age, medication status, and time. We also examined the MetSSS in relation to other known risk factors. In 2125 adults (57.6±14.7years of age), the MetSSS ranged from 0 to 8.7 with a mean of 2.6. There were strong correlations (.95-.99) between the MetSSS in medication free adults and the MetSSS calculated from subgroups. MetSSS predicted medication initiation for hypertension, hyperlipidemia and hyperglycemia over six months (OR=1.31, 95% CI [1.00-1.70], per MetSSS unit, p=.043). Lower education, medication prescription, history of smoking and age were associated with higher MetSSS (all p<.05). Higher physical but not mental health quality of life was associated with lower MetSSS (p<.001). A standardized formula to measure cardio-metabolic risk factor severity was constructed and demonstrated expected relations with known risk factors. The use of the MetSSS is recommended as a measure of change within individuals in cardio-metabolic risk factors and to guide treatment and management.

  17. A metabolic syndrome severity score: A tool to quantify cardio-metabolic risk factors.

    PubMed

    Wiley, Joshua F; Carrington, Melinda J

    2016-07-01

    Metabolic syndrome is a cluster of cardio-metabolic risk factors and is associated with increased mortality. There is no standard, validated way to assess the severity of aggregated metabolic syndrome risk factors. Cardiovascular and diabetes risk factor data came from two studies conducted in Australia from 2006 to 2010 in adults aged 18 or above. In medication free adults, sex-specific clinical thresholds and Principal Component Analysis were used to develop a formula to calculate a metabolic syndrome severity score (MetSSS). These scores were compared to scores derived using the same process in subgroups by sex, age, medication status, and time. We also examined the MetSSS in relation to other known risk factors. In 2125 adults (57.6±14.7years of age), the MetSSS ranged from 0 to 8.7 with a mean of 2.6. There were strong correlations (.95-.99) between the MetSSS in medication free adults and the MetSSS calculated from subgroups. MetSSS predicted medication initiation for hypertension, hyperlipidemia and hyperglycemia over six months (OR=1.31, 95% CI [1.00-1.70], per MetSSS unit, p=.043). Lower education, medication prescription, history of smoking and age were associated with higher MetSSS (all p<.05). Higher physical but not mental health quality of life was associated with lower MetSSS (p<.001). A standardized formula to measure cardio-metabolic risk factor severity was constructed and demonstrated expected relations with known risk factors. The use of the MetSSS is recommended as a measure of change within individuals in cardio-metabolic risk factors and to guide treatment and management. PMID:27095322

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

    PubMed

    Kulkarni, Manjunath

    2016-02-01

    We report a case of a 66-year-old diabetic patient who presented with muscle weakness 2 weeks after kidney transplantation. Her immunosuppressive regimen included tacrolimus, mycophenolate mofetil, and steroids. She was found to have hyperkalemia and normal anion gap metabolic acidosis. Tacrolimus levels were in therapeutic range. All other drugs such as beta blockers and trimethoprim - sulfamethoxazole were stopped. She did not respond to routine antikalemic measures. Further evaluation revealed type 4 renal tubular acidosis. Serum potassium levels returned to normal after starting sodium bicarbonate and fludrocortisone therapy. Though hyperkalemia is common in kidney transplant recipients, determining exact cause can guide specific treatment. PMID:27105603

  19. Water, acidosis, and experimental pyelonephritis

    PubMed Central

    Andriole, Vincent T.

    1970-01-01

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

  20. Severe insulin resistance alters metabolism in mesenchymal progenitor cells.

    PubMed

    Balhara, Bharti; Burkart, Alison; Topcu, Vehap; Lee, Youn-Kyoung; Cowan, Chad; Kahn, C Ronald; Patti, Mary-Elizabeth

    2015-06-01

    Donohue syndrome (DS) is characterized by severe insulin resistance due to mutations in the insulin receptor (INSR) gene. To identify molecular defects contributing to metabolic dysregulation in DS in the undifferentiated state, we generated mesenchymal progenitor cells (MPCs) from induced pluripotent stem cells derived from a 4-week-old female with DS and a healthy newborn male (control). INSR mRNA and protein were significantly reduced in DS MPC (for β-subunit, 64% and 89% reduction, respectively, P < .05), but IGF1R mRNA and protein did not differ vs control. Insulin-stimulated phosphorylation of INSR or the downstream substrates insulin receptor substrate 1 and protein kinase B did not differ, but ERK phosphorylation tended to be reduced in DS (32% decrease, P = .07). By contrast, IGF-1 and insulin-stimulated insulin-like growth factor 1 (IGF-1) receptor phosphorylation were increased in DS (IGF-1, 8.5- vs 4.5-fold increase; INS, 11- vs 6-fold; P < .05). DS MPC tended to have higher oxygen consumption in both the basal state (87% higher, P =.09) and in response to the uncoupler carbonyl cyanide-p-triflouromethoxyphenylhydrazone (2-fold increase, P =.06). Although mitochondrial DNA or mass did not differ, oxidative phosphorylation protein complexes III and V were increased in DS (by 37% and 6%, respectively; P < .05). Extracellular acidification also tended to increase in DS (91% increase, P = .07), with parallel significant increases in lactate secretion (34% higher at 4 h, P < .05). In summary, DS MPC maintain signaling downstream of the INSR, suggesting that IGF-1R signaling may partly compensate for INSR mutations. However, alterations in receptor expression and pathway-specific defects in insulin signaling, even in undifferentiated cells, can alter cellular oxidative metabolism, potentially via transcriptional mechanisms. PMID:25811318

  1. Molecular Pathophysiology of Renal Tubular Acidosis

    PubMed Central

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

    2009-01-01

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

  2. Renal tubular acidosis type 4 in pregnancy.

    PubMed

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

    2016-03-17

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

  3. 0.9% saline induced hyperchloremic acidosis.

    PubMed

    Barker, Megan E

    2015-01-01

    In the acute care setting, the type and amount of fluid administered has a significant impact on patient outcomes. In particular, 0.9% saline infusions are known to cause or exacerbate hyperchloremia. The studies presented evaluate possible complications from 0.9% saline infusions. These studies compared administration of 0.9% saline with lactated ringer or plasmalyte in the acute care setting. In each trial, the patients who were randomized to receive 0.9% saline infusions had a more severe acidosis from increased serum chloride levels. From the available data, chloride-restrictive intravenous fluid such as plasmalyte appears to reduce acid-base disturbances and improve patient outcomes.

  4. Metformin overdose, but not lactic acidosis per se, inhibits oxygen consumption in pigs

    PubMed Central

    2012-01-01

    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

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

    PubMed Central

    Yamazaki, Haruyuki; Yasumura, Rie; Wada, Kosuke

    2016-01-01

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

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

    PubMed

    Yoshioka, Hiroe; Yamazaki, Haruyuki; Yasumura, Rie; Wada, Kosuke; Kobayashi, Yoshiro

    2016-01-01

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

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

    PubMed Central

    Yamazaki, Haruyuki; Yasumura, Rie; Wada, Kosuke

    2016-01-01

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

  8. Development of diabetes-induced acidosis in the rat retina.

    PubMed

    Dmitriev, Andrey V; Henderson, Desmond; Linsenmeier, Robert A

    2016-08-01

    We hypothesized that the retina of diabetic animals would be unusually acidic due to increased glycolytic metabolism. Acidosis in tumors and isolated retina has been shown to lead to increased VEGF. To test the hypothesis we have measured the transretinal distribution of extracellular H(+) concentration (H(+)-profiles) in retinae of control and diabetic dark-adapted intact Long-Evans rats with ion-selective electrodes. Diabetes was induced by intraperitoneal injection of streptozotocin. Intact rat retinae are normally more acidic than blood with a peak of [H(+)]o in the outer nuclear layer (ONL) that averages 30 nM higher than H(+) in the choroid. Profiles in diabetic animals were similar in shape, but diabetic retinae began to be considerably more acidic after 5 weeks of diabetes. In retinae of 1-3 month diabetics the difference between the ONL and choroid was almost twice as great as in controls. At later times, up to 6 months, some diabetics still demonstrated abnormally high levels of [H(+)]o, but others were even less acidic than controls, so that the average level of acidosis was not different. Greater variability in H(+)-profiles (both between animals and between profiles recorded in one animal) distinguished the diabetic retinae from controls. Within animals, this variability was not random, but exhibited regions of higher and lower H(+). We conclude that retinal acidosis begins to develop at an early stage of diabetes (1-3 months) in rats. However, it does not progress, and the acidity of diabetic rat retina was diminished at later stages (3-6 months). Also the diabetes-induced acidosis has a strongly expressed local character. As result, the diabetic retinas show much wider variability in [H(+)] distribution than controls. pH influences metabolic and neural processes, and these results suggest that local acidosis could play a role in the pathogenesis of diabetic retinopathy. PMID:27262608

  9. Anoxia and Acidosis Tolerance of the Heart in an Air-Breathing Fish (Pangasianodon hypophthalmus).

    PubMed

    Joyce, William; Gesser, Hans; Bayley, Mark; Wang, Tobias

    2015-01-01

    Air breathing has evolved repeatedly in fishes and may protect the heart during stress. We investigated myocardial performance in the air-breathing catfish Pangasianodon hypophthalmus, a species that can withstand prolonged exposure to severe hypoxia and acidosis. Isometric ventricular preparations were exposed to anoxia, lactic acidosis, hypercapnic acidosis, and combinations of these treatments. Ventricular preparations were remarkably tolerant to anoxia, exhibiting an inotropic reduction of only 40%, which fully recovered during reoxygenation. Myocardial anoxia tolerance was unaffected by physiologically relevant elevations of bicarbonate concentration, in contrast to previous results in other fishes. Both lactic acidosis (5 mM; pH 7.10) and hypercapnic acidosis (10% CO2; pH 6.70) elicited a biphasic response, with an initial and transient decrease in force followed by overcompensation above control values. Spongy myocardial preparations were significantly more tolerant to hypercapnic acidosis than compact myocardial preparations. While ventricular preparations were tolerant to the isolated effects of anoxia and acidosis, their combination severely impaired myocardial performance and contraction kinetics. This suggests that air breathing may be a particularly important myocardial oxygen source during combined anoxia and acidosis, which may occur during exercise or environmental stress. PMID:26658412

  10. A patient with foot ulcer and severe metabolic alkalosis.

    PubMed

    John, Ruby Samuel; Simoes, Sonia; Reddi, Alluru S

    2012-01-01

    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

  11. A patient with foot ulcer and severe metabolic alkalosis.

    PubMed

    John, Ruby Samuel; Simoes, Sonia; Reddi, Alluru S

    2012-01-01

    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.

  12. Changes in intermediary metabolism in severe surgical illness.

    PubMed

    Wolfe, R R; Martini, W Z

    2000-06-01

    Under normal circumstances there is a reciprocal relation between the availability of free fatty acids (FFAs) and glucose in plasma. In the fasted state, FFAs predominate in both availability and the relative contribution to energy production, whereas the same is true for glucose in the fed state. The extent of glucose oxidation is directly determined by its availability, whereas FFAs are normally available well in excess of their rate of oxidation. The rate of FFA oxidation is determined by the rate of transfer into the mitochondria via the carnitine palmitoyltransferase (CPT) enzyme system, which in turn is regulated by the metabolism of glucose. With critical illness the stress response involves mobilization of both plasma glucose and FFAs simultaneously in both the fed and fasted states. In the situation of excess availability of substrates, the metabolism of glucose limits the oxidation of FFAs, thereby channeling those fatty acids into triglyceride (TG) stores in the muscle and the liver. The high FFA concentrations and increased tissue TG stores can limit glucose clearance from the blood, thereby contributing to the development of hyperglycemia. Also, the excessive metabolism of glucose can result in lacticacidemia and can contribute to the depletion of muscle glutamine. The nutritional treatment of such patients must account for these underlying metabolic responses to avoid amplifying potentially detrimental responses to the excess availability of substrates already present in the fasting state. PMID:10773115

  13. Severe malnutrition and metabolic complications of HIV-infected children in the antiretroviral era: clinical care and management in resource-limited settings.

    PubMed

    Musoke, Philippa M; Fergusson, Pamela

    2011-12-01

    More than 2 million children globally are living with HIV infection and >90% of these reside in sub-Saharan Africa. Severe acute malnutrition (SAM) remains a major problem for HIV-infected children who live in resource-limited settings (RLS), and SAM is an important risk factor for mortality. SAM in HIV-infected children is associated with complications including electrolyte disorders, micronutrient deficiencies, and severe infections, which contribute to the high mortality. Access to antiretroviral therapy (ART) has significantly improved the survival of HIV-infected children, although the response to ART of children with SAM remains undocumented in the literature. Immune and virologic responses to ART in RLS are similar to those of infected children in resource-rich settings, but delays in initiation of therapy have led to a high early mortality. Antiretroviral drug toxicities have been described in children who receive therapy and may affect their quality of life and long-term survival. Metabolic complications of ART include lipodystrophy, dyslipidemia, lactic acidosis, insulin resistance, and osteopenia. These complications have been well described in adults and children from developed countries, but data from RLS are limited, and these complications may be compounded by SAM. In this article we review the epidemiology, clinical presentation, and complications of SAM in HIV-infected children and the metabolic complications of HIV-infected children in the era of ART, and discuss future research priorities for RLS.

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

    PubMed

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

    2015-08-01

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

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

    PubMed Central

    Haloob, Imad; de Zoysa, Janak R

    2016-01-01

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

  16. The acidosis of cholera. Contributions of hyperproteinemia, lactic acidemia, and hyperphosphatemia to an increased serum anion gap.

    PubMed

    Wang, F; Butler, T; Rabbani, G H; Jones, P K

    1986-12-18

    To study the metabolic acidosis that occurs during the diarrhea of cholera, we examined the serum anion gap in 21 patients with hypovolemic shock due to Vibrio cholerae infection. Measurements of serum electrolytes, as well as divalent cations and the anionic contributions of serum proteins, lactate, phosphate, and serum creatinine, were made at the time of admission, after rehydration, and during convalescence. At the time of admission, the mean serum concentration of sodium was 134.8 mmol (meq) per liter, that of chloride was 103.2 mmol per liter, and that of bicarbonate was 11.4 mmol per liter; the mean anion gap was 20.2 mmol per liter. The mean serum creatinine concentration was 2.48 mg per deciliter. The low serum bicarbonate level and the high serum anion gap were corrected by rehydration. The increased serum anion gap was caused by hyperproteinemia, lactic acidemia, and hyperphosphatemia, with anionic contributions to the rise in anion gap estimated as protein, 5.5 meq per liter; lactate, 2.5 meq per liter; and phosphate, 2.5 meq per liter. The hyperproteinemia was attributed to dehydration, the lactic acidemia to shock, and the hyperphosphatemia to acidosis and transient renal failure. The mean concentrations of serum calcium and magnesium were slightly elevated but did not affect the increased anion gap. These results indicate that severe cholera causes acidosis with relatively little change in serum chloride but an increased serum anion gap. The acidosis is more profound than would be expected on the basis of stool losses of bicarbonate, because of superimposed lactic acidemia and renal failure.

  17. Low-flow CO2 removal integrated into a renal-replacement circuit can reduce acidosis and decrease vasopressor requirements

    PubMed Central

    2013-01-01

    Introduction Lung-protective ventilation in patients with ARDS and multiorgan failure, including renal failure, is often paralleled with a combined respiratory and metabolic acidosis. We assessed the effectiveness of a hollow-fiber gas exchanger integrated into a conventional renal-replacement circuit on CO2 removal, acidosis, and hemodynamics. Methods In ten ventilated critically ill patients with ARDS and AKI undergoing renal- and respiratory-replacement therapy, effects of low-flow CO2 removal on respiratory acidosis compensation were tested by using a hollow-fiber gas exchanger added to the renal-replacement circuit. This was an observational study on safety, CO2-removal capacity, effects on pH, ventilator settings, and hemodynamics. Results CO2 elimination in the low-flow circuit was safe and was well tolerated by all patients. After 4 hours of treatment, a mean reduction of 17.3 mm Hg (−28.1%) pCO2 was observed, in line with an increase in pH. In hemodynamically instable patients, low-flow CO2 elimination was paralleled by hemodynamic improvement, with an average reduction of vasopressors of 65% in five of six catecholamine-dependent patients during the first 24 hours. Conclusions Because no further catheters are needed, besides those for renal replacement, the implementation of a hollow-fiber gas exchanger in a renal circuit could be an attractive therapeutic tool with only a little additional trauma for patients with mild to moderate ARDS undergoing invasive ventilation with concomitant respiratory acidosis, as long as no severe oxygenation defects indicate ECMO therapy. PMID:23883472

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

    PubMed

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

    2014-09-01

    Renal involvement in Sjogren's syndrome (SS) is not uncommon and may precede other complaints. Tubulointerstitial nephritis is the most common renal disease in SS and may lead to renal tubular acidosis (RTA), which in turn may cause osteomalacia. Nevertheless, osteomalacia rarely occurs as the first manifestation of a renal tubule disorder due to SS. We herewith describe a 43-year-old woman who was admitted to our hospital for weakness, lumbago and inability to walk. X-ray of the long bones showed extensive demineralization of the bones. Laboratory investigations revealed chronic kidney disease with serum creatinine of 2.3 mg/dL and creatinine clearance of 40 mL/min, hypokalemia (3.2 mmol/L), hypophosphatemia (0.4 mmol/L), hypocalcemia (2.14 mmol/L) and hyperchloremic metabolic acidosis (chlorine: 114 mmol/L; alkaline reserve: 14 mmol/L). The serum alkaline phosphatase levels were elevated. The serum levels of 25-hydroxyvitamin D and 1,25-dihydroxy vitamin D were low and borderline low, respectively, and the parathyroid hormone level was 70 pg/L. Urinalysis showed inappropriate alkaline urine (urinary PH: 7), glycosuria with normal blood glucose, phosphaturia and uricosuria. These values indicated the presence of both distal and proximal RTA. Our patient reported dryness of the mouth and eyes and Schirmer's test showed xerophthalmia. An accessory salivary gland biopsy showed changes corresponding to stage IV of Chisholm and Masson score. Kidney biopsy showed diffuse and severe tubulo-interstitial nephritis with dense lymphoplasmocyte infiltrates. Sicca syndrome and renal interstitial infiltrates indicated SS as the underlying cause of the RTA and osteomalacia. The patient received alkalinization, vitamin D (Sterogyl ®), calcium supplements and steroids in an initial dose of 1 mg/kg/day, tapered to 10 mg daily. The prognosis was favorable and the serum creatinine level was 1.7 mg/dL, calcium was 2.2 mmol/L and serum phosphate was 0.9 mmol/L. PMID:25193912

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

    PubMed

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

    2014-09-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  2. In vitro metabolism of cannabigerol in several mammalian species.

    PubMed

    Harvey, D J; Brown, N K

    1990-09-01

    Microsomal incubations were prepared from the livers of male mice, rats, cats, guinea-pigs, hamsters and gerbils and both male and female rabbits and were incubated with cannabigerol (CBG), a constituent of marihuana. Metabolites were extracted with ethyl acetate, concentrated by chromatography on Sephadex LH-20 and examined as trimethylsilyl (TMS) and (2H9)TMS derivatives by gas chromatography/mass spectrometry. Structural elucidation was aided by hydrogenation of the metabolites to tetrahydro derivatives. Similar metabolites were produced by each of the species but the ratios of the individual compounds differed considerably. Twelve metabolites were identified. The major metabolites were monohydroxy compounds with the hydroxyl group at C-8', C-9', C-4' or at one of any position of the pentyl chain. Reduction of the delta-6' double bond was prominent in the cat to give 8'-hydroxy-6',7'-dihydro-CBG. The other major metabolic route was epoxidation of this double bond and hydrolysis to give 6',7'-dihydroxy-6',7'-dihydro-CBG. Although epoxidation of the other double bond was detected, the resulting metabolite was present in low concentration and hydrolysis was not observed. The mass spectral fragmentation of CBG and its metabolites was dominated by formation of the tropylium ion by cleavage of the C-1'--C-2' bond and by ions formed by cleavage of the C-3'--C-4' and C-4'--C-5' bonds. In addition, compounds containing hydroxylation at C-1"--C-4" (pentyl chain) gave rise to the same abundant diagnostic ions that have been observed for corresponding metabolites of other cannabinoids. PMID:2224182

  3. The Roles of Acidosis in Osteoclast Biology

    PubMed Central

    Yuan, Feng-Lai; Xu, Ming-Hui; Li, Xia; Xinlong, He; Fang, Wei; Dong, Jian

    2016-01-01

    The adverse effect of acidosis on the skeletal system has been recognized for almost a century. Although the underlying mechanism has not been fully elucidated, it appears that acidosis acts as a general stimulator of osteoclasts derived from bone marrow precursors cells and enhances osteoclastic resorption. Prior work suggests that acidosis plays a significant role in osteoclasts formation and activation via up-regulating various genes responsible for its adhesion, migration, survival and bone matrix degradation. Understanding the role of acidosis in osteoclast biology may lead to development of novel therapeutic approaches for the treatment of diseases related to low bone mass. In this review, we aim to discuss the recent investigations into the effects of acidosis in osteoclast biology and the acid-sensing molecular mechanism. PMID:27445831

  4. Early and Sustained Changes in Bone Metabolism After Severe Burn Injury.

    PubMed

    Muschitz, Gabriela Katharina; Schwabegger, Elisabeth; Kocijan, Roland; Baierl, Andreas; Moussalli, Hervé; Fochtmann, Alexandra; Nickl, Stefanie; Tinhofer, Ines; Haschka, Judith; Resch, Heinrich; Rath, Thomas; Pietschmann, Peter; Muschitz, Christian

    2016-04-01

    This study investigated serum burnover marker in male patients after severe burn injury. Ongoing changes suggest alterations in bone metabolism with a likely adverse influence on bone quality and structure. PMID:26789778

  5. Distal renal tubular acidosis associated with concurrent leptospirosis in a dog.

    PubMed

    Martinez, Stephen A; Hostutler, Roger A

    2014-01-01

    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

  6. Fluconazole and acetazolamide in the treatment of ectopic Cushing's syndrome with severe metabolic alkalosis

    PubMed Central

    Aberer, Felix; Stiegler, Claudia; R Pieber, Thomas; Obermayer-Pietsch, Barbara; Pilz, Stefan

    2015-01-01

    Summary Cushing's syndrome (CS) due to ectopic ACTH production accounts for about 10% of all types of CS and is frequently associated with metabolic alkalosis. Treatment of CS involves surgical resection and/or medical therapy to control hypercortisolism. We present the case of an 80-year-old woman affected by CS due to an unknown cause. The patient had severe metabolic alkalosis with refractory hypokalemia. To treat the underlying CS, fluconazole was initiated due to unavailability of ketoconazole. In spite of markedly decreasing cortisol levels, metabolic alkalosis persisted. Treatment of metabolic alkalosis with acetazolamide was thus initiated and pH levels successfully lowered. This case report shows that hypercortisolism can be effectively treated with fluconazole in cases where ketoconazole is unavailable or not tolerated and that persistent severe metabolic alkalosis caused by glucocorticoid excess can be safely and successfully treated with acetazolamide. Learning points Hypercortisolism can be effectively treated with fluconazole where ketoconazole is unavailable or not tolerated.Glucocorticoid excess can cause severe metabolic alkalosis.Persistent severe metabolic alkalosis can be safely and successfully treated with acetazolamide. PMID:26380091

  7. Disorders of fructose metabolism.

    PubMed

    Froesch, E R

    1976-11-01

    There are fundamental differences between the metabolic fate of fructose and of glucose. Whereas the metabolism of glucose is controlled by hormones such as insulin, fructose uptake and phosphorylation in the liver occurs independently of hormones and its ultimate metabolic fate is unpredictable. Essential fructosuria, a harmless inherited anomaly of fructose metabolism, is the least harmful of the disorders of fructose metabolism. Hereditary fructose intolerance and fructose-1,6-diphosphatase deficiency are discussed in greater detail with regard to biochemical abnormalities and clinical aspects. HFI is most serious in bottle-fed infants who cannot reject their sucrose-containing diet. Patients with HFI will have no clinical symptoms if kept on a fructose-free diet. In contrast, patients with fructose-1,6-diphosphatase deficiency can tolerate frucose. However, severe infections precipitate attacks of hypoglycaemia and lactic acidosis.

  8. Respiratory muscle strength and muscle endurance are not affected by acute metabolic acidemia.

    PubMed

    Nizet, Tessa A C; Heijdra, Yvonne F; van den Elshout, Frank J J; van de Ven, Marjo J T; Bosch, Frank H; Mulder, Paul H; Folgering, Hans Th M

    2009-11-01

    Respiratory muscle fatigue in asthma and chronic obstructive lung disease (COPD) contributes to respiratory failure with hypercapnia, and subsequent respiratory acidosis. Therapeutic induction of acute metabolic acidosis further increases the respiratory drive and, therefore, may diminish ventilatory failure and hypercapnia. On the other hand, it is known that acute metabolic acidosis can also negatively affect (respiratory) muscle function and, therefore, could lead to a deterioration of respiratory failure. Moreover, we reasoned that the impact of metabolic acidosis on respiratory muscle strength and respiratory muscle endurance could be more pronounced in COPD patients as compared to asthma patients and healthy subjects, due to already impaired respiratory muscle function. In this study, the effect of metabolic acidosis was studied on peripheral muscle strength, peripheral muscle endurance, airway resistance, and on arterial carbon dioxide tension (PaCO(2)). Acute metabolic acidosis was induced by administration of ammonium chloride (NH(4)Cl). The effect of metabolic acidosis was studied on inspiratory and expiratory muscle strength and on respiratory muscle endurance. Effects were studied in a randomized, placebo-controlled cross-over design in 15 healthy subjects (4 male; age 33.2 +/- 11.5 years; FEV(1) 108.3 +/- 16.2% predicted), 14 asthma patients (5 male; age 48.1 +/- 16.1 years; FEV(1) 101.6 +/- 15.3% predicted), and 15 moderate to severe COPD patients (9 male; age 62.8 +/- 6.8 years; FEV(1) 50.0 +/- 11.8% predicted). An acute metabolic acidemia of BE -3.1 mmol x L(-1) was induced. Acute metabolic acidemia did not significantly affect strength or endurance of respiratory and peripheral muscles, respectively. In all subjects airway resistance was significantly decreased after induction of metabolic acidemia (mean difference -0.1 kPa x sec x L(-1) [95%-CI: -0.1 - -0.02]. In COPD patients PaCO(2) was significantly lowered during metabolic acidemia (mean

  9. Emerging Drugs and Indications for Cardio-Metabolic Disorders in People with Severe Mental Illness.

    PubMed

    Kouidrat, Youssef; Amad, Ali; De Hert, Marc

    2015-01-01

    Patients with severe mental illnesses, such as schizophrenia and bipolar disorder, are at increased risk of developing metabolic disorders including obesity, diabetes, and dyslipidemia. All of these comorbidities increase the risk of cardiovascular disease and mortality. Different approaches, including diet and lifestyle modifications, behavioral therapy and switching antipsychotic agents, have been proposed to manage these metabolic abnormalities. However, these interventions may be insufficient, impractical or fail to counteract the metabolic dysregulation. Consequently, a variety of pharmacological agents such as antidiabetic drugs, have been studied in an attempt to reverse the weight gain and metabolic abnormalities evident in these patients. Despite a significant effect, many of these treatments are used off-label. This qualitative review focuses on pharmacological agents that could offer significant benefits in the management of cardio-metabolic disorders associated with serious mental illness. PMID:26088113

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

    PubMed

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

    2013-01-01

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

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

    PubMed

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

    2009-11-01

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

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

    PubMed

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

    2009-11-01

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

  13. LACTIC ACIDOSIS: A RARE MANIFESTATION OF SYNTHETIC MARIJUANA INTOXICATION.

    PubMed

    Antill, T; Jakkoju, A; Dieguez, J; Laskhmiprasad, L

    2015-01-01

    Synthetic cannabinoids are designer drugs that mimic the effect of cannabis, which has become popular with young drug users. These drugs have a similar chemical structure and pharmacologic effects as marijuana, but seem to be more potent. These substances have been banned by the US Drug Enforcement Agency in 2010. Prior to 2010, these drugs were perceived as "safer" by the general population. Synthetic cannabinoids cause effects similar to marijuana making the subjects euphoric. However, they act as full, rather than partial, agonist at the receptor sites causing more severe side effects such as severe agitation, seizures, acute renal failure, and lactic acidosis.

  14. LACTIC ACIDOSIS: A RARE MANIFESTATION OF SYNTHETIC MARIJUANA INTOXICATION.

    PubMed

    Antill, T; Jakkoju, A; Dieguez, J; Laskhmiprasad, L

    2015-01-01

    Synthetic cannabinoids are designer drugs that mimic the effect of cannabis, which has become popular with young drug users. These drugs have a similar chemical structure and pharmacologic effects as marijuana, but seem to be more potent. These substances have been banned by the US Drug Enforcement Agency in 2010. Prior to 2010, these drugs were perceived as "safer" by the general population. Synthetic cannabinoids cause effects similar to marijuana making the subjects euphoric. However, they act as full, rather than partial, agonist at the receptor sites causing more severe side effects such as severe agitation, seizures, acute renal failure, and lactic acidosis. PMID:27159480

  15. [Regional vasoactive and metabolic therapy of patients with severe cranio-cerebral traumas].

    PubMed

    Lapshin, V N; Shakh, B N; Teplov, V M; Smirnov, D B

    2012-01-01

    In patients with severe cranio-cerebral traumas an investigation was performed of the efficiency of using vasoactive therapy in complex treatment directed to earlier recovery of the microcirculatory blood flow and aerobic metabolism in ischemic parts of the brain. PMID:22880433

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

    SciTech Connect

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

    1986-09-01

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

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

    PubMed

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

    2015-11-01

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

  18. An evaluation of parameters for the detection of subclinical rumen acidosis in dairy herds.

    PubMed

    Enemark, J M D; Jørgensen, R J; Kristensen, N B

    2004-11-01

    An observational study was conducted in six Danish dairy herds. A specially designed stomach tube was compared to the rumenocentesis technique as part of the monitoring of rumen pH. In contrast to a previous study, the use of the stomach tube appeared to reduce saliva contamination. However, correlation with the rumenocentesis technique was poor ( r = 0.33; p = 0.019) and a linear model could only partly explain variations between either results. The presence of subclinical rumen acidosis (SRA) was evidenced in one herd only, as judged by results obtained by the rumenocentesis technique. The present study revealed some limitations of the rumenocentesis technique in small or medium-sized herds due to difficulties in selecting sufficient numbers of cows in the respective groups at risk. The finding of two apparently clinical normal cows with rumen pH values below 5.0 leads to the consideration that such fluctuations may be temporary and at least does not give rise to clinical symptoms. However, the long-term effect of such fluctuations is not known. In general, primiparous cows seemed more prone to low ruminal pH values (< 6.0), higher ruminal concentrations of short-chain fatty acids, and possibly to metabolic acidosis, than were multiparous cows. Ruminal propionate was the most precise predictor of rumen pH, whereas milk fat percentage varied greatly between lactational groups. Blood lactate dehydrogenase (LDH), beta-hydroxybutyrate (BHB) and fructosamine as well as urine phosphorus excretion and renal net acid-base excretion (NABE) were related to ruminal acid load, but were not predictive of rumen pH. Monitoring of dairy herds for SRA should be performed routinely and employ several diagnostic tools (rumenocentesis, renal NABE determination) as well as specific knowledge of herd management and feeding routines.

  19. Mitochondrial complex I mutations in Caenorhabditis elegans produce cytochrome c oxidase deficiency, oxidative stress and vitamin-responsive lactic acidosis.

    PubMed

    Grad, Leslie I; Lemire, Bernard D

    2004-02-01

    Mitochondrial dysfunction, with an estimated incidence of 1 in 10 000 live births, is among the most common genetically determined conditions. Missense mutations in the human NDUFV1 gene, which encodes the 51 kDa active site subunit of the NADH-ubiquinone oxidoreductase or complex I, can lead to severe neurological disorders. Owing to the rare and often sporadic nature of mitochondrial disorders, the mechanisms of pathogenesis of most mutations remain poorly understood. We have generated transgenic strains of Caenorhabditis elegans that express disease-causing mutations in the nuo-1 gene, the C. elegans homolog of the NDUFV1 gene. The transgenic strains demonstrate hallmark features of complex I dysfunction such as lactic acidosis and decreased NADH-dependent mitochondrial respiration. They are also hypersensitive to exogenous oxidative stress, suggesting that cellular defense mechanisms against reactive oxygen species are already taxed by an endogenous stress. The lactic acidosis induced by the NDUFV1 mutations could be partially corrected with the vitamins riboflavin and thiamine or with sodium dichloroacetate, an activator of the pyruvate dehydrogenase complex, resulting in significant increases in animal fitness. Surprisingly, cytochrome c oxidase activity and protein levels were reduced, establishing a connection between complexes I and IV. Our results indicate that complex I mutations exert their pathogenic effects in multiple ways: by impeding the metabolism of NADH, by increasing the production of reactive oxygen species, and by interfering with the function or assembly of other mitochondrial respiratory chain components.

  20. Metformin-Associated Lactic Acidosis in a Patient with Normal Renal Function.

    PubMed

    Omar, Ahmed; Ellen, Ruth; Sorisky, Alexander

    2016-08-01

    We report a case of metformin-associated lactic acidosis (MALA) in the setting of normal renal function and review the relevant medical literature. A 77-year-old female diagnosed with type 2 diabetes mellitus previously treated with insulin and gliclazide MR was started on metformin. A few weeks later, she was found to have lactic acidosis. Renal function was normal, and no severe underlying illness was identified. Metformin was discontinued, and lactate levels normalized within 4 days, suggesting metformin was a reversible precipitant of the lactic acidosis. MALA can occur in the absence of renal impairment, systemic hypoperfusion or severe liver disease. A possible mechanism is a genetically determined alteration in metformin pharmacokinetics. Metformin is beneficial and safe in patients with normal renal function, but the development of MALA, although rare, should be kept in mind to prevent potentially life-threatening toxicity. PMID:27197687

  1. Ruminal acidosis in feedlot: from aetiology to prevention.

    PubMed

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

    2014-01-01

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

  2. Ruminal Acidosis in Feedlot: From Aetiology to Prevention

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2013-01-01

    Acidic tissue microenvironment commonly exists in inflammatory diseases, tumors, ischemic organs, sickle cell disease, and many other pathological conditions due to hypoxia, glycolytic cell metabolism and deficient blood perfusion. However, the molecular mechanisms by which cells sense and respond to the acidic microenvironment are not well understood. GPR4 is a proton-sensing receptor expressed in endothelial cells and other cell types. The receptor is fully activated by acidic extracellular pH but exhibits lesser activity at the physiological pH 7.4 and minimal activity at more alkaline pH. To delineate the function and signaling pathways of GPR4 activation by acidosis in endothelial cells, we compared the global gene expression of the acidosis response in primary human umbilical vein endothelial cells (HUVEC) with varying level of GPR4. The results demonstrated that acidosis activation of GPR4 in HUVEC substantially increased the expression of a number of inflammatory genes such as chemokines, cytokines, adhesion molecules, NF-κB 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-κB 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

  4. Severe metabolic alkalosis due to baking soda ingestion: case reports of two patients with unsuspected antacid overdose.

    PubMed

    Fitzgibbons, L J; Snoey, E R

    1999-01-01

    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

  5. Severe metabolic alkalosis due to baking soda ingestion: case reports of two patients with unsuspected antacid overdose.

    PubMed

    Fitzgibbons, L J; Snoey, E R

    1999-01-01

    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.

  6. [The effect of subclinical and acute ante partum acidosis in cows on the course of pregnancy with regard to the steroid hormone profile].

    PubMed

    Raś, A; Janowski, T; Zduńczyk, S

    1996-08-01

    Experiment 1: In a field experiment in 19 of 87 cows being in day 260-265 of pregnancy subclinical metabolic acidosis was found. The control group included 10 healthy cows in the same stage of pregnancy. Blood samples from cows of both groups were collected once daily until day 2 post partum for determination of oestrogens, progesterone and cortisol. Dystocia was found in four and retained placenta in three cows having acidosis. These cows had lower oestrogens and markedly higher cortisol and progesterone concentrations during parturition. Course of pregnancy and delivery in control cows an without any difficulties and hormonal profiles in these cows were typical. Experiment 2: On day 265 of pregnancy experimental acute acidosis was evoked in five cows and five other cows served as control. Sampling of blood was the same as in experiment 1. Acidosis caused on day 269 in two cows premature birth with retained placenta. Moreover concentrations of studied steroids were atypical. In three other cows with acidosis course of pregnancy and delivery was without any trouble. Only cortisol was increased while progesterone and oestrogen values were in agreement with concentrations of control cows. Data suggest that metabolic acidosis can cause dystocia, premature birth and retained placenta. Furthermore, acidosis clearly affects the profile of steroid hormones. PMID:9012018

  7. Metabolite mapping reveals severe widespread perturbation of multiple metabolic processes in Huntington's disease human brain.

    PubMed

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

    2016-09-01

    Huntington's disease (HD) is a genetically-mediated neurodegenerative disorder wherein the aetiological defect is a mutation in the Huntington's gene (HTT), which alters the structure of the huntingtin protein (Htt) through lengthening of its polyglutamine tract, thus initiating a cascade that ultimately leads to premature death. However, neurodegeneration typically manifests in HD only in middle age, and mechanisms linking the causative mutation to brain disease are poorly understood. Brain metabolism is severely perturbed in HD, and some studies have indicated a potential role for mutant Htt as a driver of these metabolic aberrations. Here, our objective was to determine the effects of HD on brain metabolism by measuring levels of polar metabolites in regions known to undergo varying degrees of damage. We performed gas-chromatography/mass spectrometry-based metabolomic analyses in a case-control study of eleven brain regions in short post-mortem-delay human tissue from nine well-characterized HD patients and nine matched controls. In each patient, we measured metabolite content in representative tissue-samples from eleven brain regions that display varying degrees of damage in HD, thus identifying the presence and abundance of 63 different metabolites from several molecular classes, including carbohydrates, amino acids, nucleosides, and neurotransmitters. Robust alterations in regional brain-metabolite abundances were observed in HD patients: these included changes in levels of small molecules that play important roles as intermediates in the tricarboxylic-acid and urea cycles, and amino-acid metabolism. Our findings point to widespread disruption of brain metabolism and indicate a complex phenotype beyond the gradient of neuropathologic damage observed in HD brain. PMID:27267344

  8. Metabolomic profiling reveals severe skeletal muscle group-specific perturbations of metabolism in aged FBN rats.

    PubMed

    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

    2014-06-01

    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 × Brown 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

  9. [Self-treatment with baking soda can lead to severe metabolic alkalosis].

    PubMed

    Jensen, Sara; Skriver, Signe

    2014-12-15

    This case report describes a 66-year-old man, previously healthy besides mild hypertension. He ingested a self-made folk remedy consisting of baking soda and water against acid reflux in dosages that resulted in severe metabolic alkalosis (pH 7.8). Diagnosing and treating MA is easy and cheap, but if the condition is not treated, consequences can be severe. The challenge is to uncover patients' use of non prescription medications and folk remedies in the diagnostic process. Having this information it is possible to prevent MA in both high- and low-risk patients. PMID:25497637

  10. [Self-treatment with baking soda can lead to severe metabolic alkalosis].

    PubMed

    Jensen, Sara; Skriver, Signe

    2014-12-15

    This case report describes a 66-year-old man, previously healthy besides mild hypertension. He ingested a self-made folk remedy consisting of baking soda and water against acid reflux in dosages that resulted in severe metabolic alkalosis (pH 7.8). Diagnosing and treating MA is easy and cheap, but if the condition is not treated, consequences can be severe. The challenge is to uncover patients' use of non prescription medications and folk remedies in the diagnostic process. Having this information it is possible to prevent MA in both high- and low-risk patients.

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

    PubMed

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

    2015-10-01

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

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

    PubMed

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

    2015-10-01

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

  13. Gas exchange theory and the lactic acidosis (anaerobic) threshold.

    PubMed

    Wasserman, K; Beaver, W L; Whipp, B J

    1990-01-01

    The physiological requirements of performing exercise above the anaerobic threshold are considerably more demanding than for lower work rates. Lactic acidosis develops at a metabolic rate that is specific to the individual and the task being performed. Although numerous pyruvate-dependent mechanisms can lead to an elevated blood lactate, the increase in lactate during muscular exercise is accompanied by an increase in lactate/pyruvate ratio (i.e., increased NADH/NAD ratio). This is typically caused by an inadequate O2 supply to the mitochondria. Thus, the anaerobic threshold can be considered to be an important assessment of the ability of the cardiovascular system to supply O2 at a rate adequate to prevent muscle anaerobiosis during exercise testing. In this paper, we demonstrate, with statistical justification, that the pattern of arterial lactate and lactate/pyruvate ratio increase during exercise evidences threshold dynamics rather than the continuous exponential increase proposed by some investigators. The pattern of change in arterial bicarbonate (HCO3-) and pulmonary gas exchange supports this threshold concept. To estimate the anaerobic threshold by gas exchange methods, we measure CO2 output (VCO2) as a continuous function of O2 uptake (VO2) (V-slope analysis) as work rate is increased. The break-point in this plot reflects the obligate buffering of increasing lactic acid production by HCO3-. The anaerobic threshold measured by the V-slope analysis appears to be a sensitive index of the development of metabolic acidosis even in subjects in whom other gas exchange indexes are insensitive, owing to irregular breathing, reduced chemoreceptor sensitivity, impaired respiratory mechanics, or all of these occurrences.

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

    PubMed

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

    2014-08-01

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

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

    PubMed

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

    2014-08-01

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

  16. Genetic background of uric acid metabolism in a patient with severe chronic tophaceous gout.

    PubMed

    Petru, Lenka; Pavelcova, Katerina; Sebesta, Ivan; Stiburkova, Blanka

    2016-09-01

    Hyperuricemia depends on the balance of endogenous production and renal excretion of uric acid. Transporters for urate are located in the proximal tubule where uric acid is secreted and extensively reabsorbed: secretion is principally ensured by the highly variable ABCG2 gene. Enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) plays a central role in purine metabolism and its deficiency is an X-linked inherited metabolic disorder associated with clinical manifestations of purine overproduction. Here we report the case of a middle-aged man with severe chronic tophaceous gout with a poor response to allopurinol and requiring repeated surgical intervention. We identified the causal mutations in the HPRT1 gene, variant c.481G>T (p.A161S), and in the crucial urate transporter ABCG2, a heterozygous variant c.421C>A (p.Q141K). This case shows the value of an analysis of the genetic background of serum uric acid. PMID:27288985

  17. Mineral metabolism disturbances are associated with the presence and severity of calcific aortic valve disease*

    PubMed Central

    Yang, Zhen-kun; Ying, Chen; Zhao, Hong-yan; Fang, Yue-hua; Chen, Ying; Shen, Wei-feng

    2015-01-01

    Objective: We investigated whether disturbance of calcium and phosphate metabolism is associated with the presence and severity of calcific aortic valve disease (CAVD) in patients with normal or mildly impaired renal function. Methods: We measured serum levels of calcium, phosphate, alkaline phosphatase (AKP), intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (25-OHD), and biomarkers of bone turnover in 260 consecutive patients with normal or mildly impaired renal function and aortic valve sclerosis (AVSc) (n=164) or stenosis (AVS) (n=96) and in 164 age- and gender-matched controls. Logistic regression models were used to determine the association of mineral metabolism parameters with the presence and severity of CAVD. Results: Stepwise increases were observed in serum levels of calcium, phosphate, AKP, and iPTH from the control group to patients with AVS, and with reverse changes for 25-OHD levels (all P<0.001). Similarly, osteocalcin, procollagen I N-terminal peptide, and β-isomerized type I collagen C-telopeptide breakdown products were significantly increased stepwise from the control group to patients with AVS (all P<0.001). In patients with AVS, serum levels of iPTH were positively, in contrast 25-OHD levels were negatively, related to trans-aortic peak flow velocity and mean pressure gradient. After adjusting for relevant confounding variables, increased serum levels of calcium, phosphate, AKP, and iPTH and reduced serum levels of 25-OHD were independently associated with the presence and severity of CAVD. Conclusions: This study suggests an association between mineral metabolism disturbance and the presence and severity of CAVD in patients with normal or mildly impaired renal function. Abnormal bone turnover may be a potential mechanism. PMID:25990053

  18. Morning cortisol levels and glucose metabolism parameters in moderate and severe obstructive sleep apnea patients.

    PubMed

    Bozic, Josko; Galic, Tea; Supe-Domic, Daniela; Ivkovic, Natalija; Ticinovic Kurir, Tina; Valic, Zoran; Lesko, Josip; Dogas, Zoran

    2016-09-01

    Obstructive sleep apnea (OSA) has been associated with dysregulation of the hypothalamic-pituitary-adrenal axis and alterations in glucose metabolism with increased risk for type 2 diabetes. The aim of the current study was to compare morning plasma cortisol levels and glucose metabolism parameters between moderate (apnea-hypopnea index (AHI): 15-30 events/h) and severe OSA patients (AHI >30 events/h), with respective controls. A total of 56 male OSA patients, 24 moderate (AHI = 21.1 ± 5.3) and 32 severe (AHI = 49.7 ± 18.1), underwent a full-night polysomnography, oral glucose tolerance test (OGTT), and measurement of morning plasma cortisol levels. These groups were compared to 20 matched subjects in a control group. Morning plasma cortisol levels were statistically lower in severe OSA group than in moderate OSA and control groups (303.7 ± 93.5 vs. 423.9 ± 145.1 vs. 417.5 ± 99.8 pmol/L, P < 0.001). Significant negative correlations were found between morning plasma cortisol levels and AHI (r = -0.444, P = 0.002), as well as oxygen desaturation index (r = -0.381, P = 0.011). Fasting plasma glucose (5.0 ± 0.5 vs. 5.4 ± 0.7 vs. 4.9 ± 0.6 mmol/L, P = 0.009) was higher in the severe OSA group compared to moderate OSA and controls. Homeostasis model assessment insulin resistance (HOMA-IR) was higher in the severe OSA group compared to moderate OSA and controls (4.6 ± 3.7 vs. 2.7 ± 2.0 and 2.2 ± 1.8, respectively, P = 0.006). In conclusion, our study showed that morning plasma cortisol levels measured at 8 a.m. were significantly lower in severe OSA patients than those in moderate OSA group and controls. Morning plasma cortisol levels showed a negative correlation with AHI and oxygen desaturation index. Additionally, this study confirmed the evidence of glucose metabolism impairment in moderate and severe OSA patients, with more pronounced effect in the severe OSA patients group. PMID:27000083

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

    PubMed Central

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

    2016-01-01

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

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

    SciTech Connect

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

    1985-08-01

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

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

    PubMed Central

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

    1982-01-01

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

  2. Lactic Acidosis Induced by Linezolid Mimics Symptoms of an Acute Intracranial Bleed: A Case Report and Literature Review

    PubMed Central

    Zuccarini, Nichole Suzzanne; Yousuf, Tariq; Wozniczka, Daniel; Rauf, Anis Abdul

    2016-01-01

    Lactic acidosis is common and most often associated with disturbed acid-base balance. Rarely, it can be a life-threatening medication side effect. Hence, determining the etiology of lactic acidosis early in patients is paramount in choosing the correct therapeutic intervention. Although lactic acidosis as an adverse drug reaction of linezolid is a well-recognized and documented clinical entity, the occurrence of such mimicking an acute intracranial bleed has not been reported to our knowledge. The following case is presented as an example of such an occurrence. A 67-year-old woman presented to the emergency department for lethargy, nausea and syncope. The head CT did not demonstrate any bleeding or mass effect, but lab results were significant for elevated lactic acid. The patient recently underwent left total hip replacement surgery, which was complicated by a methicillin-resistant Staphylococcus aureus (MRSA) infection. She received 6 weeks of oral linezolid therapy. And upon learning that key part of her history, the linezolid was discontinued. Her lactic acid rapidly normalized and she was discharged home. Several publications demonstrate that linezolid induces lactic acidosis by disrupting crucial mitochondrial functions. It is essential that clinicians are aware that linezolid can cause lactic acidosis. And, the important reminder is that adverse drug reactions can often mimic common diseases. If it is not recognized early, ominous clinical consequences may occur. In conclusion, linezolid should be suspected and included in the differential diagnosis if lactic acidosis exists with an uncommon clinical picture. PMID:27635182

  3. Lactic Acidosis Induced by Linezolid Mimics Symptoms of an Acute Intracranial Bleed: A Case Report and Literature Review

    PubMed Central

    Zuccarini, Nichole Suzzanne; Yousuf, Tariq; Wozniczka, Daniel; Rauf, Anis Abdul

    2016-01-01

    Lactic acidosis is common and most often associated with disturbed acid-base balance. Rarely, it can be a life-threatening medication side effect. Hence, determining the etiology of lactic acidosis early in patients is paramount in choosing the correct therapeutic intervention. Although lactic acidosis as an adverse drug reaction of linezolid is a well-recognized and documented clinical entity, the occurrence of such mimicking an acute intracranial bleed has not been reported to our knowledge. The following case is presented as an example of such an occurrence. A 67-year-old woman presented to the emergency department for lethargy, nausea and syncope. The head CT did not demonstrate any bleeding or mass effect, but lab results were significant for elevated lactic acid. The patient recently underwent left total hip replacement surgery, which was complicated by a methicillin-resistant Staphylococcus aureus (MRSA) infection. She received 6 weeks of oral linezolid therapy. And upon learning that key part of her history, the linezolid was discontinued. Her lactic acid rapidly normalized and she was discharged home. Several publications demonstrate that linezolid induces lactic acidosis by disrupting crucial mitochondrial functions. It is essential that clinicians are aware that linezolid can cause lactic acidosis. And, the important reminder is that adverse drug reactions can often mimic common diseases. If it is not recognized early, ominous clinical consequences may occur. In conclusion, linezolid should be suspected and included in the differential diagnosis if lactic acidosis exists with an uncommon clinical picture.

  4. Lactic Acidosis Induced by Linezolid Mimics Symptoms of an Acute Intracranial Bleed: A Case Report and Literature Review.

    PubMed

    Zuccarini, Nichole Suzzanne; Yousuf, Tariq; Wozniczka, Daniel; Rauf, Anis Abdul

    2016-10-01

    Lactic acidosis is common and most often associated with disturbed acid-base balance. Rarely, it can be a life-threatening medication side effect. Hence, determining the etiology of lactic acidosis early in patients is paramount in choosing the correct therapeutic intervention. Although lactic acidosis as an adverse drug reaction of linezolid is a well-recognized and documented clinical entity, the occurrence of such mimicking an acute intracranial bleed has not been reported to our knowledge. The following case is presented as an example of such an occurrence. A 67-year-old woman presented to the emergency department for lethargy, nausea and syncope. The head CT did not demonstrate any bleeding or mass effect, but lab results were significant for elevated lactic acid. The patient recently underwent left total hip replacement surgery, which was complicated by a methicillin-resistant Staphylococcus aureus (MRSA) infection. She received 6 weeks of oral linezolid therapy. And upon learning that key part of her history, the linezolid was discontinued. Her lactic acid rapidly normalized and she was discharged home. Several publications demonstrate that linezolid induces lactic acidosis by disrupting crucial mitochondrial functions. It is essential that clinicians are aware that linezolid can cause lactic acidosis. And, the important reminder is that adverse drug reactions can often mimic common diseases. If it is not recognized early, ominous clinical consequences may occur. In conclusion, linezolid should be suspected and included in the differential diagnosis if lactic acidosis exists with an uncommon clinical picture. PMID:27635182

  5. Treatment of Severe Metabolic Alkalosis with Continuous Renal Replacement Therapy: Bicarbonate Kinetic Equations of Clinical Value.

    PubMed

    Yessayan, Lenar; Yee, Jerry; Frinak, Stan; Kwon, David; Szamosfalvi, Balazs

    2015-01-01

    Concomitant severe metabolic alkalosis, hypernatremia, and kidney failure pose a therapeutic challenge. Hemodialysis to correct azotemia and abnormal electrolytes results in rapid correction of serum sodium, bicarbonate, and urea but presents a risk for dialysis disequilibrium and brain edema. We describe a patient with Zollinger-Ellison syndrome with persistent encephalopathy, severe metabolic alkalosis (highest bicarbonate 81 mEq/L), hypernatremia (sodium 157 mEq/L), and kidney failure despite 30 hours of intravenous crystalloids and proton pump inhibitor. We used continuous renal replacement therapy (RRT) with delivered hourly urea clearance of ~3 L/hour (24 hour sustained low efficiency dialysis with regional citrate anticoagulation protocol at blood flow rate 60 ml/min and dialysate flow rate 400 ml/min). To mitigate a pronounced decrease in plasma osmolality while removing urea from this hypernatremic patient, dialysate sodium was set to start at 155 mEq/L then at 150 mEq/L after 6 hours. Serum bicarbonate, urea, and sodium were slowly corrected over 26 hours. This case demonstrates how to regulate and predict the systemic bicarbonate level using single pool kinetic modeling during convective or diffusive RRT. Kinetic modeling provides a valuable tool for systemic blood pH control in future combined use of extracorporeal CO2 removal and continuous RRT systems.

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

    PubMed

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

    2009-12-14

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

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

    PubMed Central

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

    2016-01-01

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

  8. Severe hypokalemia, metabolic alkalosis and hypertension in a 54 year old male with ectopic ACTH syndrome: a case report.

    PubMed

    Martínez-Valles, Miguel Angel; Palafox-Cazarez, Asael; Paredes-Avina, Jose Antonio

    2009-01-01

    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

  9. Severe hypokalemia, metabolic alkalosis and hypertension in a 54 year old male with ectopic ACTH syndrome: a case report

    PubMed Central

    Palafox-Cazarez, Asael; Paredes-Avina, Jose Antonio

    2009-01-01

    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

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

    PubMed Central

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

    2015-01-01

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

  11. Distal Renal Tubular Acidosis and Calcium Nephrolithiasis

    NASA Astrophysics Data System (ADS)

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

    2008-09-01

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

  12. Crassulacean acid metabolism under severe light limitation: a matter of plasticity in the shadows?

    PubMed

    Ceusters, Johan; Borland, Anne M; Godts, Christof; Londers, Elsje; Croonenborghs, Sarah; Van Goethem, Davina; De Proft, Maurice P

    2011-01-01

    Despite the increased energetic costs of CAM compared with C(3) photosynthesis, it is hypothesized that the inherent photosynthetic plasticity of CAM allows successful acclimation to light-limiting conditions. The present work sought to determine if CAM presented any constraints to short and longer term acclimation to light limitation and to establish if and how metabolic and photosynthetic plasticity in the deployment of the four phases of CAM might facilitate acclimation to conditions of deep shade. Measurements of leaf gas exchange, organic acids, starch and soluble sugar (glucose, fructose, and sucrose) contents were made in the leaves of the constitutive CAM bromeliad Aechmea 'Maya' over a three month period under severe light limitation. A. 'Maya' was not particularly tolerant of severe light limitation in the short term. A complete absence of net CO(2) uptake and fluctuations in key metabolites (i.e. malate, starch or soluble sugars) indicated a dampened metabolism whilst cell death in the most photosynthetically active leaves was attributed to an over-acidification of the cytoplasm. However, in the longer term, plasticity in the use of the different phases of gas exchange and different storage carbohydrate pools, i.e. a switch from starch to sucrose as the major carbohydrate source, ensured a positive carbon balance for this CAM species under extremely low levels of irradiance. As such, co-ordinated plasticity in the use of C(3) and C(4) carboxylases and different carbohydrate pools together with an increase in the abundance of light-harvesting complexes, appear to underpin the adaptive radiation of the energetically costly CAM pathway within light-limiting environments such as wet cloud forests and shaded understoreys of tropical forests.

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

    PubMed

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

    2016-03-01

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

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

    NASA Astrophysics Data System (ADS)

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

    1985-02-01

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

  15. Purine nucleoside metabolism in the erythrocytes of patients with adenosine deaminase deficiency and severe combined immunodeficiency.

    PubMed Central

    Agarwal, R P; Crabtree, G W; Parks, R E; Nelson, J A; Keightley, R; Parkman, R; Rosen, F S; Stern, R C; Polmar, S H

    1976-01-01

    Deficiency of erythrocytic and lymphocytic adenosine deaminase (ADA) occurs in some patients with severe combined immunodeficiency disease (SCID). SCID with ADA deficiency is inherited as an autosomal recessive trait. ADA is markedly reduced or undetectable in affected patients (homozygotes), and approximately one-half normal levels are found in individuals heterozygous for ADA deficiency. The metabolism of purine nucleosides was studied in erythrocytes from normal individuals, four ADA-deficiency patients, and two heterozygous individuals. ADA deficiency in intake erythrocytes was confirmed by a very sensitive ammonia-liberation technique. Erythrocytic ADA activity in three heterozygous individuals (0.07,0.08, and 0.14 mumolar units/ml of packed cells) was between that of the four normal controls (0.20-0.37 mumol/ml) and the ADA-deficient patients (no activity). In vitro, adenosine was incorporated principally into IMP in the heterozygous and normal individuals but into the adenosine nucleotides in the ADa-deficient patients. Coformycin (3-beta-D-ribofuranosyl-6,7,8-trihydroimidazo[4,5-4] [1,3] diazepin-8 (R)-ol), a potent inhibitor of ADA, made possible incorporation of adenosine nucleotides in the ADA-deficient patients... PMID:947948

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

    PubMed Central

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

    2015-01-01

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

  17. Metabolic crisis in severely head-injured patients: is ischemia just the tip of the iceberg?

    PubMed

    Carre, Emilie; Ogier, Michael; Boret, Henry; Montcriol, Ambroise; Bourdon, Lionel; Jean-Jacques, Risso

    2013-10-11

    Ischemia and metabolic crisis are frequent post-traumatic secondary brain insults that negatively influence outcome. Clinicians commonly mix up these two types of insults, mainly because high lactate/pyruvate ratio (LPR) is the common marker for both ischemia and metabolic crisis. However, LPR elevations during ischemia and metabolic crisis reflect two different energetic imbalances: ischemia (Type 1 LPR elevations with low oxygenation) is characterized by a drastic deprivation of energetic substrates, whereas metabolic crisis (Type 2 LPR elevations with normal or high oxygenation) is associated with profound mitochondrial dysfunction but normal supply of energetic substrates. The discrimination between ischemia and metabolic crisis is crucial because conventional recommendations against ischemia may be detrimental for patients with metabolic crisis. Multimodal monitoring, including microdialysis and brain tissue oxygen monitoring, allows such discrimination, but these techniques are not easily accessible to all head-injured patients. Thus, a new "gold standard" and adapted medical education are required to optimize the management of patients with metabolic crisis.

  18. Severe pulmonary hypertension is associated with altered right ventricle metabolic substrate uptake.

    PubMed

    Graham, Brian B; Kumar, Rahul; Mickael, Claudia; Sanders, Linda; Gebreab, Liya; Huber, Kendra M; Perez, Mario; Smith-Jones, Peter; Serkova, Natalie J; Tuder, Rubin M

    2015-09-01

    In severe pulmonary hypertension (SPH), prior studies have shown an increase in right ventricle (RV) uptake of glucose, but it is unclear whether there is a change in the relative utilization of fatty acids. We hypothesized that in the RV in SPH, as in left ventricular (LV) failure, there is altered substrate utilization, with increased glucose uptake and decreased fatty acid uptake. SPH was induced in rats by treatment with the VEGF receptor inhibitor SU5416 and 3 wk of hypoxia (10% FiO2 ), followed by an additional 4 wk of normoxia (SU-Hx group). Control rats were treated with carboxymethylcellulose vehicle and 7 wk of normoxia (CMC-Nx group). The rodents then underwent positron emission tomography with sequential administration of two radiotracers, 2-deoxy-2-[(18)F]fluoroglucose ((18)F-FDG) and 14-(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid ((18)F-FTHA), analogs of glucose and fatty acid, respectively. Five CMC-Nx and 3 SU-Hx rats completed the entire experimental protocol. In the RV, there was a mild increase in (18)F-FDG uptake (1.35-fold, P = 0.085) and a significant decrease in (18)F-FTHA uptake (-2.1-fold, P < 0.05) in the SU-Hx rats relative to the CMC-Nx rats. In the LV, SU-Hx rats had less uptake of both radiotracers compared with CMC-Nx rats. Less RV fatty acid uptake in SPH was corroborated by decreased fatty acid transporters and enzymes in the RV tissue, and specifically a decrease in lipoprotein lipase. In the RV in rats with SPH, there is a major shift in metabolic substrate preference, largely due to decreased fatty acid uptake. PMID:26115672

  19. Severe pulmonary hypertension is associated with altered right ventricle metabolic substrate uptake

    PubMed Central

    Kumar, Rahul; Mickael, Claudia; Sanders, Linda; Gebreab, Liya; Huber, Kendra M.; Perez, Mario; Smith-Jones, Peter; Serkova, Natalie J.; Tuder, Rubin M.

    2015-01-01

    In severe pulmonary hypertension (SPH), prior studies have shown an increase in right ventricle (RV) uptake of glucose, but it is unclear whether there is a change in the relative utilization of fatty acids. We hypothesized that in the RV in SPH, as in left ventricular (LV) failure, there is altered substrate utilization, with increased glucose uptake and decreased fatty acid uptake. SPH was induced in rats by treatment with the VEGF receptor inhibitor SU5416 and 3 wk of hypoxia (10% FiO2), followed by an additional 4 wk of normoxia (SU-Hx group). Control rats were treated with carboxymethylcellulose vehicle and 7 wk of normoxia (CMC-Nx group). The rodents then underwent positron emission tomography with sequential administration of two radiotracers, 2-deoxy-2-[18F]fluoroglucose (18F-FDG) and 14-(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (18F-FTHA), analogs of glucose and fatty acid, respectively. Five CMC-Nx and 3 SU-Hx rats completed the entire experimental protocol. In the RV, there was a mild increase in 18F-FDG uptake (1.35-fold, P = 0.085) and a significant decrease in 18F-FTHA uptake (−2.1-fold, P < 0.05) in the SU-Hx rats relative to the CMC-Nx rats. In the LV, SU-Hx rats had less uptake of both radiotracers compared with CMC-Nx rats. Less RV fatty acid uptake in SPH was corroborated by decreased fatty acid transporters and enzymes in the RV tissue, and specifically a decrease in lipoprotein lipase. In the RV in rats with SPH, there is a major shift in metabolic substrate preference, largely due to decreased fatty acid uptake. PMID:26115672

  20. Lower than predicted resting metabolic rate is associated with severely impaired cardiorespiratory fitness in obese individuals.

    PubMed

    Miller, Wendy M; Spring, Thomas J; Zalesin, Kerstyn C; Kaeding, Kaylee R; Nori Janosz, Katherine E; McCullough, Peter A; Franklin, Barry A

    2012-03-01

    Obese individuals have reduced cardiorespiratory fitness as compared with leaner counterparts. Regular exercise maintains or increases fitness and lean body mass. Lean body mass, in turn, has a direct impact on resting metabolic rate (RMR). Given these relationships, we sought to evaluate the association between RMR and cardiorespiratory fitness in obese individuals. We evaluated 64 obese individuals (78% female) with direct assessment of RMR and cardiorespiratory fitness via breath-by-breath measurement of oxygen consumption and carbon dioxide production at rest and during exercise. The mean age and BMI were 47.4 ± 12.2 years and 47.2 ± 9.2 kg/m(2), respectively. The majority of subjects, 69%, had a measured RMR above that predicted by the Harris-Benedict equation. Compared with the higher RMR group, those with a lower than predicted RMR had increased BMI, with values of 52.9 vs. 44.7 kg/m(2), P = 0.001, respectively. Analysis of those demonstrating significant effort during cardiopulmonary exercise testing (peak respiratory exchange ratio ≥1.10) revealed a significantly higher peak oxygen uptake (VO(2) peak) in the higher RMR group (17.3 ± 3.5 ml/min/kg) compared with the lower RMR group (13.6 ± 1.9 ml/min/kg), P = 0.003. In summary, a lower than predicted RMR was associated with a severely reduced VO(2) peak and a higher BMI in this cohort. These data suggest that morbid obesity may be a vicious cycle of increasing BMI, reduced cardiorespiratory fitness, muscle deconditioning, and lower RMR. Collectively, these responses may, over time, exacerbate the imbalance between energy intake and expenditure, resulting in progressive increases in body weight and fat stores.

  1. Severe hypoglycemic encephalopathy due to hypoallergenic formula in an infant.

    PubMed

    Ogawa, Erika; Ishige, Mika; Takahashi, Yuno; Kodama, Hiroko; Fuchigami, Tatsuo; Takahashi, Shori

    2016-08-01

    A 7-month-old girl was brought to hospital due to vomiting. Upon admission, she was in a convulsive state and stupor with extremely low blood glucose. Head computed tomography showed brain edema, and comprehensive treatment for acute encephalopathy was initiated immediately. Severe hypoglycemia, metabolic acidosis, elevation of ammonia and serum transaminases and creatine kinase suggested metabolic decompensation. Infusion of a high-glucose solution containing vitamins, biotin, and l-carnitine resolved the metabolic crisis quickly, but brain damage was irreversible. She was found to have been fed exclusively on a hypoallergenic formula (HF) for 7 months, although she was found later to be non-allergic. Evidence of inborn metabolic diseases was absent, therefore biotin deficiency and carnitine deficiency were concluded to be a consequence of reliance on a HF for a prolonged period. Health-care professionals should warn parents of the consequences of using HF. PMID:27324861

  2. Near-fatal persistent anion- and osmolal-gap acidosis due to massive gamma-butyrolactone/ethanol intoxication.

    PubMed

    Heytens, Luc; Neels, Hugo; Van Regenmortel, Niels; van den Brink, Wim; Henckes, Manu; Schouwers, Sofie; Dockx, Greet; Crunelle, Cleo L

    2015-03-01

    We report a case of an ethanol and massive gamma-butyrolactone (GBL) intoxication, the precursor of the recreational drug gamma-hydroxybutyric acid (GHB), resulting in life-threatening metabolic acidosis (pH 6.5) with a highly increased anion- and osmolal gap. Rapid analysis using gas chromatography revealed a GHB plasma concentration of 4400 mg/L, far above the upper limit concentration of 1000 mg/L found in adult fatalities attributed to GBL. Full recovery was established following supportive treatment including haemodialysis. This is the first report of a combined ethanol/GBL intoxication as a cause of high serum anion- and osmolal-gap metabolic acidosis.

  3. Anesthetic management of a patient with sustained severe metabolic alkalosis and electrolyte abnormalities caused by ingestion of baking soda.

    PubMed

    Soliz, Jose; Lim, Jeffrey; Zheng, Gang

    2014-01-01

    The use of alternative medicine is prevalent worldwide. However, its effect on intraoperative anesthetic care is underreported. We report the anesthetic management of a patient who underwent an extensive head and neck cancer surgery and presented with a severe intraoperative metabolic alkalosis from the long term ingestion of baking soda and other herbal remedies. PMID:25180100

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

    PubMed

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

    2014-12-01

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

  5. Anesthetic management of a patient with sustained severe metabolic alkalosis and electrolyte abnormalities caused by ingestion of baking soda.

    PubMed

    Soliz, Jose; Lim, Jeffrey; Zheng, Gang

    2014-01-01

    The use of alternative medicine is prevalent worldwide. However, its effect on intraoperative anesthetic care is underreported. We report the anesthetic management of a patient who underwent an extensive head and neck cancer surgery and presented with a severe intraoperative metabolic alkalosis from the long term ingestion of baking soda and other herbal remedies.

  6. Anesthetic Management of a Patient with Sustained Severe Metabolic Alkalosis and Electrolyte Abnormalities Caused by Ingestion of Baking Soda

    PubMed Central

    Lim, Jeffrey

    2014-01-01

    The use of alternative medicine is prevalent worldwide. However, its effect on intraoperative anesthetic care is underreported. We report the anesthetic management of a patient who underwent an extensive head and neck cancer surgery and presented with a severe intraoperative metabolic alkalosis from the long term ingestion of baking soda and other herbal remedies. PMID:25180100

  7. Genetics Home Reference: renal tubular acidosis with deafness

    MedlinePlus

    ... a disorder characterized by kidney (renal) problems and hearing loss. The kidneys normally filter fluid and waste products ... In people with renal tubular acidosis with deafness , hearing loss caused by changes in the inner ear (sensorineural ...

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

    MedlinePlus

    ... HIV medicines. All HIV medicines in the nucleoside reverse transcriptase inhibitor (NRTI) drug class may cause lactic acidosis, but ... some HIV medicines. HIV medicines in the nucleoside reverse transcriptase inhibitor (NRTI) drug class can cause the body to ...

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

    ERIC Educational Resources Information Center

    Rodriguez-Soriano, J.; And Others

    1975-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2015-09-01

    Complex III deficiency due to a MT-CYB mutation has been reported in patients with myopathy. Here, we describe a 15-year-old boy who presented with metabolic acidosis, ketotic hypoglycemia and carnitine deficiency. Electron transport chain analysis and mitochondrial DNA sequencing on muscle tissue lead to the eventual diagnosis of complex III deficiency. This case demonstrates the critical role of muscle biopsies in a myopathy work-up, and the clinical efficacy of supplement therapy. PMID:26937408

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

    PubMed Central

    Morvan, Daniel

    2013-01-01

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

  14. Severe dietary lysine restriction affects growth and body composition and hepatic gene expression for nitrogen metabolism in growing rats.

    PubMed

    Kim, J; Lee, K S; Kwon, D-H; Bong, J J; Jeong, J Y; Nam, Y S; Lee, M S; Liu, X; Baik, M

    2014-02-01

    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

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

    ClinicalTrials.gov

    2016-08-15

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

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

    PubMed Central

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

    2015-01-01

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

  17. [Severe accidental hypothermia in an elderly woman].

    PubMed

    Knobel, B; Mikhlin, A

    2001-11-01

    Profound hypothermia (core temperature of less than 28 degrees C) is a life threatening state and a medical emergency associated with a high mortality rate. The prognosis depends on underlying diseases, advanced or very early age, the duration prior to treatment, the degree of hemodynamic deterioration, and especially, the methods of treatment, including active external or internal rewarming. This is a case study of an 80-year-old female patient with severe accidental hypothermia (core temperature 27 degrees C). She was found in her home lying immobile on the cold floor after a fall. The patient was in a profound coma with cardiocirculatory collapse, and the medical staff treating her was inclined to pronounce her deceased. On her arrival at the hospital, she was resuscitated, put on a respirator and actively warmed. Very severe metabolic disorders were found, including a marked metabolic acidosis composed of diabetic ketoacidosis (she had suffered from insulin treated type 2 diabetes mellitus) and lactic acidosis with a very high anion gap (42) and a hyperosmotic state (blood glucose 1202 mg/dl). There were pathognomonic electrocardiographic abnormalities, J-wave of Osborn and prolonged repolarization. Slow atrial fibrillation with a ventricular response of 30 bpm followed by a nodal rhythm of 12 bpm and reversible cardiac arrest were recorded. The pulse and blood pressure were unobtainable. Despite the successful resuscitation and hemodynamic and cognitive improvement, rhabdomyolysis (CKP 6580 u/L), renal failure and hepatic damage developed. She was extubated and treated with intravenous fluids containing dopamine, bicarbonate, insulin and antibiotics. Her medical condition gradually improved, and she was discharged clear minded, functioning very well and independent. Renal and liver tests returned eventually to normal limits. Progressive bradycardia, hypotension and death due to ventricular fibrillation or asystole commonly occur during severe hypothermia

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

    Mitrophanov, Alexander Y.; Rosendaal, Frits R.

    2015-01-01

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

  20. Lactic acidosis complicating treatment of ketosis of labour.

    PubMed Central

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

    1975-01-01

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

  1. Bone and metabolic complications of urinary diversions.

    PubMed

    Cano Megías, Marta; Muñoz Delgado, Eva Golmayo

    2015-02-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-09-01

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

  4. Acidosis counteracts the negative inotropic effect of K+ on ventricular muscle strips from the toad Bufo marinus.

    PubMed

    Andersen, Johnnie Bremholm; Gesser, Hans; Wang, Tobias

    2004-01-01

    Strenuous activity is associated with acidosis, increased extracellular potassium concentration ([K+]o), and elevated levels of circulating catecholamines. Acidosis and elevated [K+]o are normally considered harmful to cardiac function, and a high sympathetic tone on the heart may lead to arrhythmia. During activity, however, the heart must be able to increase rate and strength of contraction. While the individual effects of [K+]o, acidosis, and adrenaline on contractile properties of cardiac muscle have been characterized for some ectothermic species, less information is available on their interactions. Here we examine the isolated and combined effects of [K+]o, acidosis, and adrenaline on ventricular muscle strips from the toad Bufo marinus. This study showed that increased [K+]o significantly reduced twitch force, while lactic acid significantly increased twitch force and more than counteracted the negative inotropic effects of elevated [K+]o. There was no inotropic effect of Na-lactate (neutralized lactic acid), which suggests that lactic acid stimulated twitch force through reduced pH and not by serving as a substrate. Adrenaline had a positive effect on twitch force in all preparations. Irrespective of treatment, twitch force decreased as stimulation rate increased. During high [K+]o, there was a severe reduction in maximal frequency of toad ventricular strips that was not alleviated by lactic acidosis and/or adrenaline, which suggests that high [K+]o influences twitch force and maximal rate by different mechanisms. In vivo levels of lactic acid, [K+]o, adrenaline, and heart rate previously observed during forced activity in Bufo did not significantly affect the contractile properties of heart muscle strips in vitro. Thus, although [K+]o significantly decreased twitch force, this detrimental effect was more than counteracted by the positive inotropic effect of lactic acid and adrenaline.

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

    PubMed Central

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

    2008-01-01

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

  6. Putrescine Catabolism is a Metabolic Response to Several Stresses in Escherichia coli

    PubMed Central

    Schneider, Barbara L.; Hernandez, V. James; Reitzer, Larry

    2013-01-01

    Summary Genes whose products degrade arginine and ornithine, precursors of putrescine synthesis, are activated by either regulators of the nitrogen-regulated (Ntr) response or σS-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 β-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 σS-RNA polymerase, and Nac, an Ntr regulator, enhanced the σS-dependent transcription. Since Nac activation via σS-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 σS 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 σS-dependent expression indicates that polyamine catabolism is a core metabolic response to stress. PMID:23531166

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

    SciTech Connect

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

    1990-04-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  9. Glucose metabolism and thermogenesis during glucose and insulin infusion in severely underweight patients.

    PubMed

    Gallen, I W; Macdonald, I A; Allison, S P

    1992-01-01

    This study investigates the effects of gross loss of body weight on glucose disposal (GD), storage (GS), oxidation (GO), and the thermogenic response (TR) during hyperinsulinemic euglycemic glucose infusion in 9 underweight but nourished patients (UP) and in 3 of the patients after weight gain (WGP). In UP, baseline metabolic rate (MR) was 4.1 +/- 0.2 kJ/min and respiratory exchange ratio (RER) 0.97 +/- 0.02. During the final 30 minutes of hyperinsulinemia MR rose by 0.32 +/- 0.07 kJ/min (p less than .01) and RER rose to 1.09 +/- 0.03 (p less than .01). GD was 61 +/- 3 mumol/kg per minute, GO 35 +/- 1 mumol/kg per minute, and GS 26 +/- 4 mumol/kg per minute. The energy cost of glucose storage as glycogen was 0.15 kJ/min, and as lipid was 0.2 kJ/min. In WGP baseline MR was 4.5 +/- 0.4 kJ/min and RER was 0.91 +/- 0.03. During hyperinsulinemia MR rose by 0.63 +/- 0.2 kJ/min, RER rose to 0.93 +/- 0.02, GD was 53 +/- 4 mumol/kg per minute, GO was 30 +/- 3 mumol/kg per minute, and GS was 23 +/- 1 mumol/kg per minute. The energy cost for this glucose storage was 0.22 kJ/min. Therefore, during hyperinsulinemia in UP, GD, and TR are similar, but GO is greater and GS is less than previously reported in healthy subjects. However, this TR is entirely accounted for by the energy cost of glucose storage with no evidence of facultative thermogenesis. In WGP, all responses were similar to those in healthy subjects, and the TR was in excess of that required of the energy cost of glucose storage.

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

    SciTech Connect

    Peek, K.E.H.

    1988-01-01

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

  11. Metabolism

    MedlinePlus

    Metabolism refers to all the physical and chemical processes in the body that convert or use energy, ... Tortora GJ, Derrickson BH. Metabolism. In: Tortora GJ, Derrickson BH. Principles of Anatomy and Physiology . 14th ed. Hoboken, NJ: John H Wiley and Sons; 2013: ...

  12. Acidosis, magnesium and acetylsalicylic acid: Effects on thrombin

    NASA Astrophysics Data System (ADS)

    Borisevich, Nikolaj; Loznikova, Svetlana; Sukhodola, Aleksandr; Halets, Inessa; Bryszewska, Maria; Shcharbin, Dzmitry

    2013-03-01

    Thrombin, an enzyme from the hydrolase family, is the main component of the blood coagulation system. In ischemic stroke it acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin forming blood clots in the brain. It has been found to phosphoresce at room temperature in the millisecond and microsecond ranges. The phosphorescence of thrombin was studied under physiological conditions, in acidosis (decrease of pH from 8.0 to 5.0) and on the addition of salts (magnesium sulfate and sodium chloride) and of acetylsalicylic acid, and its connection with thrombin function is discussed. Acidosis significantly increased the internal dynamics of thrombin. We propose that lactate-acidosis plays a protective role in stroke, preventing the formation of clots. The addition of NaCl and MgSO4 in different concentrations increased the internal dynamics of thrombin. Also, the addition of MgSO4 decreased thrombin-induced platelet aggregation. However, magnesium sulfate and acetylsalicylic acid in the therapeutic concentrations used for treatment of ischemic stroke had no effect on thrombin internal dynamics. The data obtained will help to elucidate the conformational stability of thrombin under conditions modulating lactate-acidosis and in the presence of magnesium sulfate.

  13. Acidosis, magnesium and acetylsalicylic acid: effects on thrombin.

    PubMed

    Borisevich, Nikolaj; Loznikova, Svetlana; Sukhodola, Aleksandr; Halets, Inessa; Bryszewska, Maria; Shcharbin, Dzmitry

    2013-03-01

    Thrombin, an enzyme from the hydrolase family, is the main component of the blood coagulation system. In ischemic stroke it acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin forming blood clots in the brain. It has been found to phosphoresce at room temperature in the millisecond and microsecond ranges. The phosphorescence of thrombin was studied under physiological conditions, in acidosis (decrease of pH from 8.0 to 5.0) and on the addition of salts (magnesium sulfate and sodium chloride) and of acetylsalicylic acid, and its connection with thrombin function is discussed. Acidosis significantly increased the internal dynamics of thrombin. We propose that lactate-acidosis plays a protective role in stroke, preventing the formation of clots. The addition of NaCl and MgSO(4) in different concentrations increased the internal dynamics of thrombin. Also, the addition of MgSO(4) 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.

  14. Controversies involving hypercapnic acidosis in acute respiratory distress syndrome.

    PubMed

    Nardelli, Liliane; Rocco, Patricia Rieken Macedo; Garcia, Cristiane Sousa Nascimento Baez

    2009-12-01

    Acute respiratory distress syndrome is characterized by a diffuse inflammatory reaction of lung parenchyma induced by a direct insult to the alveolar epithelium (pulmonary acute respiratory distress syndrome) or an indirect lesion through the vascular endothelium (extrapulmonary acute respiratory distress syndrome). The main therapeutic strategy for acute respiratory distress syndrome is the ventilatory support. However, mechanical ventilation can worsen lung injury. In this context, a protective ventilatory strategy with low tidal volume has been proposed. The use of low tidal volume reduced the mortality rate of acute respiratory distress syndrome patients, but result in hypercapnic acidosis. The current article presents a review of literature on the effects of permissive hypercapnia in acute respiratory distress syndrome. To that end, we carried out a systematic review of scientific literature based on established criteria for documental analysis including clinical and experimental articles, using as data bases MedLine, LILACS, SciELO, PubMed, Cochrane. Hypercapnic acidosis has been considered by some authors as a modulator of the inflammatory process of acute respiratory distress syndrome. However, clinical and experimental studies on the effects of hypercapnic acidosis have shown controversial results. Therefore it is important to better elucidate the role of hypercapnic acidosis in acute respiratory distress syndrome.

  15. Metformin-associated lactic acidosis: Current perspectives on causes and risk.

    PubMed

    DeFronzo, Ralph; Fleming, G Alexander; Chen, Kim; Bicsak, Thomas A

    2016-02-01

    Although metformin has become a drug of choice for the treatment of type 2 diabetes mellitus, some patients may not receive it owing to the risk of lactic acidosis. Metformin, along with other drugs in the biguanide class, increases plasma lactate levels in a plasma concentration-dependent manner by inhibiting mitochondrial respiration predominantly in the liver. Elevated plasma metformin concentrations (as occur in individuals with renal impairment) and a secondary event or condition that further disrupts lactate production or clearance (e.g., cirrhosis, sepsis, or hypoperfusion), are typically necessary to cause metformin-associated lactic acidosis (MALA). As these secondary events may be unpredictable and the mortality rate for MALA approaches 50%, metformin has been contraindicated in moderate and severe renal impairment since its FDA approval in patients with normal renal function or mild renal insufficiency to minimize the potential for toxic metformin levels and MALA. However, the reported incidence of lactic acidosis in clinical practice has proved to be very low (<10 cases per 100,000 patient-years). Several groups have suggested that current renal function cutoffs for metformin are too conservative, thus depriving a substantial number of type 2 diabetes patients from the potential benefit of metformin therapy. On the other hand, the success of metformin as the first-line diabetes therapy may be a direct consequence of conservative labeling, the absence of which could have led to excess patient risk and eventual withdrawal from the market, as happened with earlier biguanide therapies. An investigational delayed-release metformin currently under development could potentially provide a treatment option for patients with renal impairment pending the results of future studies. This literature-based review provides an update on the impact of renal function and other conditions on metformin plasma levels and the risk of MALA in patients with type 2 diabetes.

  16. Oxidative stress parameters and their correlation with clinical, metabolic and polysomnographic parameters in severe obstructive sleep apnea syndrome

    PubMed Central

    Asker, Selvi; Asker, Muntecep; Sarikaya, Eren; Sunnetcioglu, Aysel; Aslan, Mehmet; Demir, Halit

    2015-01-01

    The aim of the present study was to assess the levels of oxidative stress markers, catalase (CAT), glutathione peroxidase (GPX) and malondialdehyde (MDA) in severe OSAS and to investigate any correlation between oxidative stress markers and clinical, metabolic and polysomnographic parameters. A total of 30 patients with severe OSAS and 30 healthy controls were included in this cross-sectional, clinical study. Demographic data, polysomnographic, biochemical and clinical indices as well as serum levels of CAT, MDA and GPX were measured and compared in OSAS and control groups. Furthermore, OSAS patients with and without pulmonary hypertension (PHT) were evaluated in terms of levels of CAT, MDA and GPX. Patients with severe OSAS exhibited significantly lower serum levels of CAT (P<0.001) and GPX (P<0.001). Serum MDA levels were remarkably higher in OSAS group (P<0.001). Correlation analysis revealed that levels of CAT and GPX were correlated with apnea-hypopnea index and there was a correlation between serum levels of MDA and CRP. Severe OSAS patients with and without PHT did not reveal any differences for CAT (P=0.789), MDA (P=0.805) and GPX levels (P=0.281). Our results have shown that oxidative stress markers significantly changed in patients with severe OSAS. This information is noteworthy because documentation of the role of oxidative stress in OSAS may have important implications regarding diagnosis, monitoring, treatment and prognosis. PMID:26379962

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

    SciTech Connect

    Swenson, E.R.

    1986-06-01

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

  18. Immunization with a Streptococcus bovis vaccine administered by different routes against lactic acidosis in sheep.

    PubMed

    Shu, Q; Gill, H S; Leng, R A; Rowe, J B

    2000-05-01

    Streptococcus bovis is an important lactic acid bacterium in the rumen, which contributes to the development of lactic acidosis. This study was designed to test the efficacy of immunization with S. bovis primed either intramuscularly (i.m.) or intraperitoneally (i.p. ) against lactic acidosis. Forty-five wethers were allocated to three treatment groups. Two groups were injected with a S. bovis vaccine by either the i.m. or i.p. route for primary immunization; both groups were further immunized by the same route(s) (oral and/or i.m.) for boosters. The third group was not immunized (control). Antibody concentrations were measured in saliva prior to and following animals being fed a grain diet, and also in the rumen fluid, before the animals were suddenly introduced to a grain diet. The average antibody concentration in the animals of the i.m. group was higher than the i.p. group (P< 0.05). The antibody concentration in the rumen fluid of immunized sheep was higher than the control animals (P< 0.01). The difference in the rumen fluid antibody concentration between the i.m. and i.p. groups was not statistically significant (P> 0.05). In the i.m. group, there was a significantly greater feed intake, higher rumen pH, lower diarrhoea scores, and less increase in blood packed cell volume following grain feeding than in the animals of the control group. The severity of diarrhoea and the increase of blood packed cell volume in the animals of the i. p. group were also less than in the animals of the control group. The results suggest that the risk of lactic acidosis can be reduced by immunization against S. bovis, and that the immunization primed i. m. is more effective than the immunization primed i.p.

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

    PubMed

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

    2015-04-01

    lambs' ADG was more than 2-fold greater than the PFTN controls. These results indicate that HS markedly alters the energetics of weight gain during growth and that the effects of HS are dependent on the severity of the heat load. PMID:26020185

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

    PubMed

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

    2015-04-01

    lambs' ADG was more than 2-fold greater than the PFTN controls. These results indicate that HS markedly alters the energetics of weight gain during growth and that the effects of HS are dependent on the severity of the heat load.

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

    PubMed Central

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

    2016-01-01

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

  2. Fluid replacements after squash: an analysis of the effects of several fluid regimens on exercise-related metabolic changes.

    PubMed

    MacGowan, G A; Ryan, R; O'Donovan, D; Tempany, K; Kinsella, A; Horgan, J H

    1994-01-01

    We studied the effects of several fluid replacements taken after squash on exercise-related metabolic responses. 12 subjects played 5 games and after each game were assigned one of the following, receiving a different one each time: (1) no fluid replacement, or 500 ml of (2) water, (3) electrolyte solution, (4) glucose solution or (5) a glucose/electrolyte 'sports' drink. Circulating levels of lactate, free fatty acids, glucose, potassium, sodium and plasma osmolality were measured at rest and at 5, 15, 30 and 60 min after games. There were significant changes over time for all measured variables (p < 0.001). The only effect of these drinks was by the glucose-containing drinks, which resulted in significant elevation of blood glucose levels (p < 0.001); no effects on circulating electrolyte levels were demonstrated. In conclusion, while fluid replacements may increase glucose levels, electrolyte levels are not affected by drinks which are commonly used after squash.

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

    PubMed Central

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

    2014-01-01

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

  4. [Multiple calcium oxalate stone formation in a patient with glycogen storage disease type I (von Gierke's disease) and renal tubular acidosis type I: a case report].

    PubMed

    Kanematsu, A; Segawa, T; Kakehi, Y; Takeuchi, H

    1993-07-01

    A case of multiple urinary stones in a patient with glycogen storage disease type 1 (GSD-1) is reported. In spite of the presence of hyperuricemia, these stones did not consist of uric acid, but mainly of calcium oxalate. Laboratory studies revealed distal renal tubular acidosis and hypocitraturia, but no significant abnormality in calcium metabolism. We discussed the mechanism of calcium stone formation in our case, and its prophylactic treatment by oral administration of citrate compound. PMID:8362684

  5. Complement and contact activation in term neonates after fetal acidosis

    PubMed Central

    Sonntag, J.; Wagner, M.; Strauss, E.; Obladen, M.

    1998-01-01

    AIMS—To evaluate complement and contact activation after fetal acidosis.
METHODS—Fifteen term neonates with hypoxic-ischaemic encephalopathy after umbilical arterial pH < 7.10 were compared with 15 healthy neonates with umbilical arterial pH > 7.20. Determinations of the complement function and C1-inhibitor activity were performed as kinetic tests 22-28 hours after birth. C1q, C1-inhibitor, and factor B concentrations were determined by radial immunodiffusion and those of C3a, C5a, and factor XIIa by enzyme immunoabsorbent assay.
RESULTS—Median complement function (46 vs 73 %), C1q (4.3 vs 9.1 mg/dl), and factor B (5.2 vs 7.7 mg/dl) decreased after fetal acidosis. The activated split products C3a (260 vs 185 µg/l), C5a (5.0 vs 0.6 µg/l), and factor XIIa (3.2 vs 1.3 µg/l) increased in the neonates after fetal acidosis. No differences were found in the concentration and activity of C1-inhibitor.
CONCLUSIONS—Complement and contact activation occurred in the newborns with hypoxic-ischaemic encephalopathy. Activation of these systems generates mediators which can trigger inflammation and tissue injury.

 PMID:9577283

  6. Sequential changes in the metabolic response in severely septic patients during the first 23 days after the onset of peritonitis.

    PubMed Central

    Plank, L D; Connolly, A B; Hill, G L

    1998-01-01

    OBJECTIVE: To quantify the sequential changes in metabolic response occurring in patients with severe sepsis after the onset of peritonitis. SUMMARY BACKGROUND DATA: Understanding the changes in energy expenditure and body composition is essential for the optimal management of severely septic patients; however, they have not been quantified in the context of modern surgical care. METHODS: Twelve patients with severe sepsis secondary to peritonitis (median APACHE II score = 21.5) had measurements of energy expenditure and body composition as soon as they were hemodynamically stable and 5, 10, and 21 days later. Sequential measurements of acute-phase proteins and cytokine responses were also made. RESULTS: Resting energy expenditure rose to 49% above predicted and remained elevated throughout the study period. Total energy expenditure was 1.25 x resting energy expenditure. Body fat was oxidized when energy intake was insufficient to achieve energy balance. There was a positive fluid balance of 12.5 1 over the first 2 days after onset of sepsis; thereafter, body water changes closely paralleled body weight changes and were largely accounted for by changes in extracellular water. During the 21 -day study period, there was a loss of 1.21 kg (13%) of total body protein. During the first 10 days, 67% of the protein lost came from skeletal muscle, but after this time it was predominantly from viscera. Intracellular potassium levels were low but did not deteriorate further after hemodynamic stability had been reached. There was a reprioritization of hepatic protein synthesis that was obligatory and independent of changes in total body protein. The cytokine responses demonstrated the complexity, redundancy, and overlap of mediators. CONCLUSIONS: The period of hypermetabolism in severely septic patients is similar to that previously described, but the fluid changes are larger and the protein loss is greater. Protein loss early on is predominantly from muscle, thereafter from

  7. Human anion exchanger1 mutations and distal renal tubular acidosis.

    PubMed

    Yenchitsomanus, Pa-thai

    2003-09-01

    The human anion exchanger 1 (AE1 or SLC4A1) gene encodes anion exchanger 1 (or band 3) protein in erythrocytes and in alpha-intercalated cells of the kidney. Thus, AE1 mutations show pleiotrophic effects resulting in two distinct and seemingly unrelated defects, an erythrocyte abnormality and distal renal tubular acidosis (dRTA). Southeast Asian ovalocytosis (SAO), a well-known red blood cell (RBC) defect, which is widespread in Southeast Asian regions, is caused by AE1 mutation due to a deletion of 27 base pairs in codons 400-408 (delta400-408) leading to an in-frame 9 amino-acid loss in the protein. Co-existence of SAO and dRTA is usually not seen in the same individual. However, the two conditions can co-exist as the result of compound heterozygosities between delta400-408 and other mutations. The reported genotypes include delta400-408/G701D, delta400-408/R602H, delta400-408/deltaV850, and delta400-408/A858D. The presence of dRTA, with or without RBC abnormalities, may occur from homozygous or compound heterozygous conditions of recessive AE1 mutations (eg G701D/G701D, V488M/V488M, deltaV850/deltaV850, deltaV850/A858D, G701D/S773P) or heterozygous dominant AE1 mutations (eg R598H, R589C, R589S, S613F, R901X). Codon 589 of this gene seems to be a 'mutational hot-spot' since repeated mutations at this codon occurring in different ethnic groups and at least two de novo (R589H and R589C) mutations have been observed. Therefore, AE1 mutations can result in both recessive and dominant dRTA, possibly depending on the position of the amino acid change in the protein. As several mutant AE1 proteins still maintain a significant anion transport function but are defective in targeting to the cell surface, impaired intracellular trafficking of the mutant AE1 is an important molecular mechanism involved in the pathogenesis of dRTA associated with AE1 mutations. PMID:15115146

  8. Metabolism of platelet activating factor (PAF) and lyso-PAF in polymorphonuclear granulocytes from severely burned patients.

    PubMed

    Schönfeld, W; Kasimir, S; Köller, M; Erbs, G; Müller, F E; König, W

    1990-12-01

    We studied the metabolism of 3H-platelet activating factor (PAF) and lyso-PAF in human polymorphonuclear granulocytes (PMN) from severely burned patients (n = 6) on days 1, 5, 9, 15, and 25 post-trauma. All patients suffered from a severe burn trauma of more than 30% total body surface area. Stimulation of PMN in healthy donors (n = 10) with the Ca-ionophore resulted in the conversion of 3H-lyso-PAF into PAF (18 +/- 2% of total radioactivity) and alkyl-acyl-glycero-phosphorylcholine (alkyl-acyl-GPC, 50 +/- 6%). In burned patients a significantly reduced formation of 3H-PAF was observed between days 1 and 15 post-trauma (day 9: 1 +/- 1%, p less than 0.0001). This pattern was normalized again in patients (n = 5) who survived the trauma after septic periods and was observed during the second week post-trauma. In one patient who succumbed to his injuries a sustained inhibition of PAF formation was observed up to his death. The decreased formation of PAF correlated weakly with the appearance of immature granulocytes within the analyzed cell fraction (ratio of immature cells versus PAF-formation, r = -0.55, p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2258972

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

    SciTech Connect

    Lonien, J.; Schwender, J.

    2009-11-01

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

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

    PubMed

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

    2015-12-01

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

  11. Renal tubular acidosis type II associated with vitamin D deficiency presenting as chronic weakness.

    PubMed

    Ali, Yaseen; Parekh, Amila; Baig, Mirza; Ali, Taseen; Rafiq, Tazeen

    2014-08-01

    Chronic vitamin D deficiency, though common in the elderly, is often under diagnosed and when progressing to renal tubular acidosis type II (RTA 2) can cause several simultaneous electrolyte imbalances that may present with weakness and pain as chief symptoms. We present such a case that after months of evaluation and symptomatic treatment did not lead to an effective establishment of the etiology causing chronic weakness and body pain in an elderly female patient. Eventually, after a careful review of the patient's history, repeat physical examinations, laboratory data evaluation, and diagnostic testing led to the establishment of the diagnosis of proximal RTA 2 associated with vitamin D deficiency, which caused the patient to develop several remarkable secondary electrolyte imbalances such as hypokalemia, hypocalcemia, hypophosphatemia, acidemia, hyperparathyroidism, with weakness and body pain.

  12. Renal tubular acidosis type II associated with vitamin D deficiency presenting as chronic weakness

    PubMed Central

    Parekh, Amila; Baig, Mirza; Ali, Taseen; Rafiq, Tazeen

    2014-01-01

    Chronic vitamin D deficiency, though common in the elderly, is often under diagnosed and when progressing to renal tubular acidosis type II (RTA 2) can cause several simultaneous electrolyte imbalances that may present with weakness and pain as chief symptoms. We present such a case that after months of evaluation and symptomatic treatment did not lead to an effective establishment of the etiology causing chronic weakness and body pain in an elderly female patient. Eventually, after a careful review of the patient’s history, repeat physical examinations, laboratory data evaluation, and diagnostic testing led to the establishment of the diagnosis of proximal RTA 2 associated with vitamin D deficiency, which caused the patient to develop several remarkable secondary electrolyte imbalances such as hypokalemia, hypocalcemia, hypophosphatemia, acidemia, hyperparathyroidism, with weakness and body pain. PMID:25343024

  13. Effect of UV-B Radiation (290-320nm) on the Nitrogen Metabolism of Several Marine Diatoms.

    PubMed

    Döhler, G

    1985-04-01

    The marine diatoms Bellerochea yucatanensis, Biddulphia sinensis, Ditylum brightwellii, Lauderia annulata and Thalassiosira rotula were grown for 2 days under different levels of UV-B radiation (439, 717, and 1230J · m (-2) ·d(-1)). UV-B stress depressed the growth rates of all species. A low UV-B dose (439 J · m (-2) · d (-1), weighted), usually caused a slight increase in biomass production (dry weight} in comparison to nontreated cells. Enhanced UV-B reduced the dry matter productivity of all diatoms. All marine diatoms exposed to UV-B showed a diminution of protein and pigment content (chlorophyll a, chlorophyll c(1) + C(2), and carotenoids). Algae grown in 20 %o or 35 %o salt concentrations were more sensitive to UV-B radiation than those grown in 45%o. S. The effect of higher UV-B dose (717J · m (-2) · d(-1), weighted) upon the pools of free amino acids was species-dependent. Aspartate and asparagine levels were reduced in all diatoms. A marked increase in glutamine levels was found in Bellerochea, Biddulphia, Ditylum and Lauderia. Thalassiosira cells exposed to UV-B showed a significant increase in glutamate levels and a reduction of glutamine levels. (15)N and (14)C incorporation into several amino acids was reduced by exposure to UV-B. The results are discussed with reference to the inhibition of the enzymes for carbon and nitrogen metabolism. PMID:23196172

  14. ENDOCRINE AND METABOLIC ALTERATIONS MAY UNDERLIE MORTALITY OF SEVERE SEPSIS AND SEPTIC SHOCK PATIENTS ADMITTED TO ICU.

    PubMed

    Ameen, Abdelbadee; Abdel Rehim, Marwa; Shaaban, Yasser Hassan

    2016-04-01

    The study evaluated endocrinal and metabolic response to sepsis and its applicability for the prediction of outcome of septic patients. Patients were 39 adult with severe infections and within 24 h after onset or suspected clinical tissue hypoperfusion. At enrollment patients were evaluated for acute physiology and chronic health evaluation II score (APACHE II) and Glasgow Coma Scale (GCS). Global hemodynamic parameters including systolic blood pressure (SBP), heart rate (HR) and central venous pressure (CVP) were recorded and monitored. All patients were managed at ICU due to Surviving Sepsis Campaign guidelines. ELISA estimated serum copeptin, macrophage migration inhibitory factor (MIF) and total cortisol (TC) and blood lactate levels. Study outcome was survival rate via 28 days (28-D SR) and best predictor for it. The results showed that 22 patients passed total hospital stay uneventfully for a total survival rate of 56.4%. Seventeen patients died; 10 during ICU stay and 7 during word stay. At admission serum markers levels were significantly higher in survivors and non-survivors compared to controls and in non-survivors compared to survivors. Survival showed negative significant correlation with age, high blood lactate and serum copeptin, TC and MIF levels. Survival showed positive significant correlation with SBP, CVP and urine output. ROC curve and Regression analyses defined high at admission serum copeptin and blood lactate levels as significant predictors for mortality of septic patients. PMID:27363046

  15. A Fatal Case of Metformin-associated Lactic Acidosis.

    PubMed

    Ozeki, Toshikazu; Kawato, Rui; Watanabe, Mitsuru; Minatoguchi, Shun; Murai, Yukari; Ryuge, Akihiro; Takasugi, Koji; Hamada, Takuya; Oyama, Yukako; Nomura, Atsushi; Tomino, Tatsuhito; Shimizu, Hideaki; Fujita, Yoshiro

    2016-01-01

    A 72-year-old woman with a history of type 2 diabetes mellitus was brought to the ER with metformin-associated lactic acidosis. She received continuous hemofiltration and hemodialysis, but the laboratory analyses showed no improvement. She died 11 hours after admission. Metformin is minimally bound to proteins and is readily dialyzable, but a prolonged period of dialysis is required, because metformin has a very large distribution volume and is distributed to multiple compartments. The peak blood metformin level was 432 mg/L in this case, which is one of the highest metformin concentrations ever reported, and eight hours of hemodialysis were not sufficient to reduce the serum level.

  16. Renal histology and immunopathology in distal renal tubular acidosis.

    PubMed

    Feest, T G; Lockwood, C M; Morley, A R; Uff, J S

    1978-11-01

    Renal biospy studies are reported from 10 patients with distal renal tubular acidosis (DRTA). On the biopsies from 6 patients who had associated immunological abnormalities immunofluorescent studies for immunoglobulins, complement, and fibrin were performed. Interstitial cellular infiltration and fibrosis were common findings in patients with and without immunological abnormalities, and were usually associated with nephrocalcinosis and/or recurrent urinary infection. No immune deposits were demonstrated in association with the renal tubules. This study shows that DRTA in immunologically abnormal patients is not caused by tubular deposition of antibody or immune complexes. The possibility of cell mediated immune damage is discussed.

  17. Bench-to-bedside review: Oxygen debt and its metabolic correlates as quantifiers of the severity of hemorrhagic and post-traumatic shock

    PubMed Central

    Rixen, Dieter; Siegel, John H

    2005-01-01

    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 correlates, namely base deficit and lactate, as indices of shock severity and adequacy of volume resuscitation. Relevant studies in the medical literature were identified using Medline and Cochrane Library searches. Findings in both experimental animals (dog/pig) and humans suggest that oxygen debt or its metabolic correlates may be more useful quantifiers of hemorrhagic shock than estimates of blood loss, volume replacement, blood pressure, or heart rate. This is evidenced by the oxygen debt/probability of death curves for the animals, and by the consistency of lethal dose (LD)25,50 points for base deficit across all three species. Quantifying human post-traumatic shock based on base deficit and adjusting for Glasgow Coma Scale score, prothrombin time, Injury Severity Score and age is demonstrated to be superior to anatomic injury severity alone or in combination with Trauma and Injury Severity Score. The data examined in this review indicate that estimates of oxygen debt and its metabolic correlates should be included in studies of experimental shock and in the management of patients suffering from hemorrhagic shock. PMID:16277731

  18. Tumor cell metabolism

    PubMed Central

    Romero-Garcia, Susana; Lopez-Gonzalez, Jose Sullivan; B´ez-Viveros, José Luis; Aguilar-Cazares, Dolores

    2011-01-01

    Cancer is a genetic disease that is caused by mutations in oncogenes, tumor suppressor genes and stability genes. The fact that the metabolism of tumor cells is altered has been known for many years. However, the mechanisms and consequences of metabolic reprogramming have just begun to be understood. In this review, an integral view of tumor cell metabolism is presented, showing how metabolic pathways are reprogrammed to satisfy tumor cell proliferation and survival requirements. In tumor cells, glycolysis is strongly enhanced to fulfill the high ATP demands of these cells; glucose carbons are the main building blocks in fatty acid and nucleotide biosynthesis. Glutaminolysis is also increased to satisfy NADPH regeneration, whereas glutamine carbons replenish the Krebs cycle, which produces metabolites that are constantly used for macromolecular biosynthesis. A characteristic feature of the tumor microenvironment is acidosis, which results from the local increase in lactic acid production by tumor cells. This phenomenon is attributed to the carbons from glutamine and glucose, which are also used for lactic acid production. Lactic acidosis also directs the metabolic reprogramming of tumor cells and serves as an additional selective pressure. Finally, we also discuss the role of mitochondria in supporting tumor cell metabolism. PMID:22057267

  19. Metabolic studies of transient tyrosinemia in premature infants

    NASA Technical Reports Server (NTRS)

    Fernbach, S. A.; Summons, R. E.; Pereira, W. E.; Duffield, A. M.

    1975-01-01

    The recently developed technique of gas chromatography-mass spectrometry supported by computer has considerably improved the analysis of physiologic fluids. This study attempted to demonstrate the value of this system in the investigation of metabolite patterns in urine in two metabolic problems of prematurity, transient tyrosinemia and late metabolic acidosis. Serial 24-hr urine specimens were analyzed in 9 infants. Transient tyrosinemia, characterized by 5- 10-fold increases over basal excretion of tyrosine, p-hydroxyphenyllactate, and p-hydroxyphenylpyruvate in urine, was noted in five of the infants. Late metabolic acidosis was seen in four infants, but bore no relation to transient tyrosinemia.

  20. [Ketoacidotic diabetic metabolic dysregulation: pathophysiology, clinical aspects, diagnosis and therapy].

    PubMed

    Kaufmann, P; Smolle, K H; Fleck, S; Lueger, A

    1994-01-01

    When glucose utilisation is impaired due to decreased insulin effect, ketones are produced by the liver from free fatty acids to supply an alternate source of energy. This adaptation may be associated with severe metabolic acidosis and tends to occur in patients with type I (insulin-dependent) diabetes mellitus. In addition, hypovolemia is an almost invariable finding with marked hypoglycemia and is primarily induced by the associated glucosuria. Ketoacidosis stimulates both the central and peripheral chemoreceptors controlling respiration, resulting in alveolar hyperventilation (Kussmaul's respiration). With the ensuing fall in pCO2 the patient tries to raise the extracellular pH. A fruity odor of acetone on the patient's breath sometimes suggests that ketoacidosis is present. The classical triad of symptoms associated with hyperglycemia are polyuria, polydipsia, and weight loss. Circulatory insufficiency with hypotension is not uncommon due to the marked fluid loss and acidemia. In more severely affected patients, neurologic abnormalities may be seen, including lethargy, seizures or coma. Some patients also have marked vomiting and abdominal pain. The history and physical examination may provide important clues to the presence of uncontrolled diabetes mellitus. Once suspected, the diagnosis can be easily confirmed by measuring the plasma glucose concentration. Glucosuria and ketonuria can be semiquantitatively detected with reagent sticks. Blood gas analysis and anion gap give objective information as to the severity of the metabolic acidosis. Therapy must be directed toward each of the metabolic disturbances: hyperosmolality, ketoacidosis, hypovolemia and potassium, and phosphate depletion. The mainstays of therapy are the administration of low-dose insulin and volume repletion.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8171867

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

    PubMed

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

    2016-01-01

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

  2. Pre-treatment evaluation of 5-fluorouracil degradation rate: association of poor and ultra-rapid metabolism with severe toxicity in a colorectal cancer patients cohort

    PubMed Central

    Mazzuca, Federica; Borro, Marina; Botticelli, Andrea; Mazzotti, Eva; Marchetti, Luca; Gentile, Giovanna; La Torre, Marco; Lionetto, Luana; Simmaco, Maurizio; Marchetti, Paolo

    2016-01-01

    Despite the wide use of 5-fluorouracil-based chemotherapy, development of severe toxicity that follow the treatment is not a rare event. The efforts to establish pretreatment tools for toxicity prediction, led to the development of various pharmacogenetic and biochemical assays, mainly targeted to assess the activity level of dihydropyrimidine dehydrogenase (DPD), the main metabolizing enzyme for 5-fluorouracil. Using peripheral blood mononuclear cells, we developed a biochemical assay, that is not limited to the evaluation of DPD activity, but determines the net result of all the enzymatic transformation of 5FU, in terms of the amount of drug consumed by the cells in a time unit. This parameter, named 5-fluorauracil degradation rate, presents a normal distribution inside the population and highlight the presence of an ultra-rapid metabolizers class of subjects, besides the expected poor metabolizers class. Here we will show that, in a colorectal cancer patient cohort, both poor and ultra-rapid metabolizers have significantly increased the risk of developing severe toxicity (grade3–4). Patient stratification depending on the individual 5-fluorouracil degradation rate allows to identify a 10% of the overall population at high risk of developing severe toxicity, compared to the 1.3% (as assessed in the Italian population) identified by the most commonly employed pharmacogenetic test, including the DPD polymorphism IVS14+1G>A. PMID:26967565

  3. Nineteen-year follow-up of a patient with severe glutathione synthetase deficiency.

    PubMed

    Atwal, Paldeep S; Medina, Casey R; Burrage, Lindsay C; Sutton, V Reid

    2016-07-01

    Glutathione synthetase deficiency is a rare autosomal recessive disorder resulting in low levels of glutathione and an increased susceptibility to oxidative stress. Patients with glutathione synthetase deficiency typically present in the neonatal period with hemolytic anemia, metabolic acidosis and neurological impairment. Lifelong treatment with antioxidants has been recommended in an attempt to prevent morbidity and mortality associated with the disorder. Here, we present a 19-year-old female who was diagnosed with glutathione synthetase deficiency shortly after birth and who has been closely followed in our metabolic clinic. Despite an initial severe presentation, she has had normal intellectual development and few complications of her disorder with a treatment regimen that includes polycitra (citric acid, potassium citrate and sodium citrate), vitamin C, vitamin E and selenium.

  4. A fatal outcome of complicated severe diabetic ketoacidosis in a 11-year-old girl.

    PubMed

    Severinski, Srećko; Butorac Ahel, Ivona; Ovuka, Aleksandar; Verbić, Arijan

    2016-08-01

    Diabetic ketoacidosis (DKA) is a complex metabolic state characterized by hyperglycemia, metabolic acidosis and ketonuria. Cerebral edema is the most common rare complication of DKA in children. The objective of the study was to emphasize the importance of careful evaluation and monitoring for signs and symptoms of cerebral edema in all children undergoing treatment for DKA. We present a case of 11-year-old girl with a history of diabetes mellitus type I (T1DM) who presented with severe DKA complicated by hypovolemic shock, cerebral edema and hematemesis. Considering the fact that complications of DKA are rare and require a high index of clinical suspicion, early recognition and treatment are crucial for avoiding permanent damage.

  5. 19-Year Follow-up of A Patient With Severe Glutathione Synthetase Deficiency

    PubMed Central

    Atwal, Paldeep S.; Medina, Casey R.; Burrage, Lindsay C.; Sutton, V. Reid

    2016-01-01

    Glutathione synthetase deficiency is a rare autosomal recessive disorder resulting in low levels of glutathione and an increased susceptibility to oxidative stress. Patients with glutathione synthetase deficiency typically present in the neonatal period with hemolytic anemia, metabolic acidosis and neurological impairment. Lifelong treatment with antioxidants has been recommended in an attempt to prevent morbidity and mortality associated with the disorder. Here we present a 19-year-old female who was diagnosed with glutathione synthetase deficiency shortly after birth and who has been closely followed in our metabolic clinic. Despite an initial severe presentation, she has had normal intellectual development and few complications of her disorder with a treatment regimen that includes polycitra (citric acid, potassium citrate and sodium citrate), vitamin C, vitamin E and selenium. PMID:26984560

  6. A fatal outcome of complicated severe diabetic ketoacidosis in a 11-year-old girl.

    PubMed

    Severinski, Srećko; Butorac Ahel, Ivona; Ovuka, Aleksandar; Verbić, Arijan

    2016-08-01

    Diabetic ketoacidosis (DKA) is a complex metabolic state characterized by hyperglycemia, metabolic acidosis and ketonuria. Cerebral edema is the most common rare complication of DKA in children. The objective of the study was to emphasize the importance of careful evaluation and monitoring for signs and symptoms of cerebral edema in all children undergoing treatment for DKA. We present a case of 11-year-old girl with a history of diabetes mellitus type I (T1DM) who presented with severe DKA complicated by hypovolemic shock, cerebral edema and hematemesis. Considering the fact that complications of DKA are rare and require a high index of clinical suspicion, early recognition and treatment are crucial for avoiding permanent damage. PMID:27226096

  7. Liquid extracorporeal carbon dioxide removal: use of THAM (tris-hydroxymethyl aminomethane) coupled to hemofiltration to control hypercapnic acidosis in a porcine model of protective mechanical ventilation

    PubMed Central

    Tapia, Pablo; Lillo, Felipe; Soto, Dagoberto; Escobar, Leslie; Simon, Felipe; Hernández, Karina; Alegría, Leyla; Bruhn, Alejandro

    2016-01-01

    A promising approach to facilitate protective mechanical ventilation is the use of extracorporeal CO2 removal techniques. Several strategies based on membrane gas exchangers have been developed. However, these techniques are still poorly available. The goal of this study was to assess the efficacy and safety of THAM infusion coupled to hemofiltration for the management of hypercapnic acidosis. A severe respiratory acidosis was induced in seven anesthetized pigs. Five of them were treated with THAM 8-mmol·kg-1·h-1 coupled to hemofiltration (THAM+HF group) at 100 mL·kg-1·h-1. After 18-hours of treatment the THAM infusion was stopped but hemofiltration was kept on until 24-hours. The 2 other animals were treated with THAM but without hemofiltration. After 1-hour of treatment in THAM+HF, PaCO2 rapidly decreased from a median of 89.0 (IQR) (80.0, 98.0) to 71.3 (65.8, 82.0) mmHg (P<0.05), while pH increased from 7.12 (7.01, 7.15) to 7.29 (7.27, 7.30) (P<0.05). Thereafter PaCO2 remained stable between 60-70 mmHg, while pH increased above 7.4. After stopping THAM at 18 hours of treatment a profound rebound effect was observed with severe hypercapnic acidosis. The most important side effect we observed was hyperosmolality, which reached a maximum of 330 (328, 332) mOsm·kg H2O-1 at T18. The animals treated only with THAM developed severe hypercapnia, despite the fact that pH returned to normal values, and died after 12 hours. Control-group had an uneven evolution until the end of the experiment. A combined treatment with THAM coupled to hemofiltration may be an effective treatment to control severe hypercapnic acidosis.

  8. Liquid extracorporeal carbon dioxide removal: use of THAM (tris-hydroxymethyl aminomethane) coupled to hemofiltration to control hypercapnic acidosis in a porcine model of protective mechanical ventilation.

    PubMed

    Tapia, Pablo; Lillo, Felipe; Soto, Dagoberto; Escobar, Leslie; Simon, Felipe; Hernández, Karina; Alegría, Leyla; Bruhn, Alejandro

    2016-01-01

    A promising approach to facilitate protective mechanical ventilation is the use of extracorporeal CO2 removal techniques. Several strategies based on membrane gas exchangers have been developed. However, these techniques are still poorly available. The goal of this study was to assess the efficacy and safety of THAM infusion coupled to hemofiltration for the management of hypercapnic acidosis. A severe respiratory acidosis was induced in seven anesthetized pigs. Five of them were treated with THAM 8-mmol·kg(-1)·h(-1) coupled to hemofiltration (THAM+HF group) at 100 mL·kg(-1)·h(-1). After 18-hours of treatment the THAM infusion was stopped but hemofiltration was kept on until 24-hours. The 2 other animals were treated with THAM but without hemofiltration. After 1-hour of treatment in THAM+HF, PaCO2 rapidly decreased from a median of 89.0 (IQR) (80.0, 98.0) to 71.3 (65.8, 82.0) mmHg (P<0.05), while pH increased from 7.12 (7.01, 7.15) to 7.29 (7.27, 7.30) (P<0.05). Thereafter PaCO2 remained stable between 60-70 mmHg, while pH increased above 7.4. After stopping THAM at 18 hours of treatment a profound rebound effect was observed with severe hypercapnic acidosis. The most important side effect we observed was hyperosmolality, which reached a maximum of 330 (328, 332) mOsm·kg H2O(-1) at T18. The animals treated only with THAM developed severe hypercapnia, despite the fact that pH returned to normal values, and died after 12 hours. Control-group had an uneven evolution until the end of the experiment. A combined treatment with THAM coupled to hemofiltration may be an effective treatment to control severe hypercapnic acidosis.

  9. Intracellular pH during "chemical hypoxia" in cultured rat hepatocytes. Protection by intracellular acidosis against the onset of cell death.

    PubMed Central

    Gores, G J; Nieminen, A L; Wray, B E; Herman, B; Lemasters, J J

    1989-01-01

    The relationships between extracellular pH (pHo), intracellular pH (pHi), and loss of cell viability were evaluated in cultured rat hepatocytes after ATP depletion by metabolic inhibition with KCN and iodoacetate (chemical hypoxia). pHi was measured in single cells by ratio imaging of 2',7'-biscarboxy-ethyl-5,6-carboxyfluorescein (BCECF) fluorescence using multiparameter digitized video microscopy. During chemical hypoxia at pHo of 7.4, pHi decreased from 7.36 to 6.33 within 10 min. pHi remained at 6.1-6.5 for 30-40 min (plateau phase). Thereafter, pHi began to rise and cell death ensued within minutes, as evidenced by nuclear staining with propidium iodide and coincident leakage of BCECF from the cytoplasm. An acidic pHo produced a slightly greater drop in pHi, prolonged the plateau phase of intracellular acidosis, and delayed the onset of cell death. Inhibition of Na+/H+ exchange also prolonged the plateau phase and delayed cell death. In contrast, monensin or substitution of gluconate for Cl- in buffer containing HCO3- abolished the pH gradient across the plasma membrane and shortened cell survival. The results indicate that intracellular acidosis after ATP depletion delays the onset of cell death, whereas reduction of the degree of acidosis accelerates cell killing. We conclude that intracellular acidosis protects against hepatocellular death from ATP depletion, a phenomenon that may represent a protective adaptation against hypoxic and ischemic stress. Images PMID:2536397

  10. Effects of increased red cell mass on subclinical tissue acidosis in hyaline membrane disease.

    PubMed Central

    La Gamma, E F; Krauss, A; Auld, P A

    1996-01-01

    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. PMID:8949689

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

    PubMed

    Leitz, T

    1987-07-01

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

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

    SciTech Connect

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

    1989-01-01

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

  13. Two major QTLs and several others relate to factors of metabolic syndrome in the family blood pressure program.

    PubMed

    Kraja, Aldi T; Rao, Dabeeru C; Weder, Alan B; Cooper, Richard; Curb, J David; Hanis, Craig L; Turner, Stephen T; de Andrade, Mariza; Hsiung, Chao Agnes; Quertermous, Thomas; Zhu, Xiaofeng; Province, Michael A

    2005-10-01

    Genome-wide variance components linkage analysis was performed on 4 latent factors underlying metabolic syndrome derived from 10 risk factors. The latent factors represent obesity and insulin, blood pressure, lipids and insulin, and central obesity. The metabolic syndrome factor scores were derived in 4 ethnic groups recruited in 3 Networks of the Family Blood Pressure Program: GENOA (blacks, Hispanics, and whites), HyperGEN (blacks and whites), SAPPHIRe (Asians). Heritabilities of metabolic syndrome factors ranged from 66% for obesity and insulin to 11% for blood pressure factor. We observed higher heritabilities for obesity and insulin, and lipids and insulin, whereas those for blood pressure and central obesity were smaller. Linkage analysis detected two major quantitative trait loci. One of them linked to the obesity and insulin factor with a lod score of 3.94 (P=0.00001, marker GATA11A06, D18S53, 41.24 cM) at marker positions linkage (lod 4.71, at 46.84 cM at 1-cM-apart distances linkage), located on chromosome 18p11.21 in GENOA black. The other linked to the blood pressure factor with a lod score of 3.22 (P=0.000059, marker GATA49C09, D17S1290, 82 cM) at marker positions linkage (lod 3.56, at 84.63 cM for 1 cM apart distances linkage) located on chromosome 17q23.1 in Hispanics. These quantitative trait loci, together with 4 additional ones with lod scores >2.5, and 30 additional ones with lod score >1.7, offer hope for dissecting the genetic architecture of metabolic syndrome with beneficial implications for molecular diagnosis, prognosis, and in potential medical intervention.

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

    PubMed Central

    2010-01-01

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

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

    PubMed

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

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

  16. [Effect of carbostimulin on metabolism in rats with deep burns].

    PubMed

    Stogniĭ, N A; Zhurbin, G I; Sushkova, V V; Kul'baka, V S; Gulyĭ, M F

    1981-01-01

    It is established that at early stages of the burn disease (deep burn of III-B degree, 20% of body surface) in rats there appears metabolic acidosis, the content of urea increases in the liver and blood serum, a pronounced hydration of the liver and muscles is observed in the burn zone. Administration per os of carbostimulin just a day after burn removes symptoms of metabolic acidosis. When the preparation is fed to rats during 7 days after burn the intensity of radioactive label incorporation into proteins, lipid and glycogen of the liver as well as in proteins and lipids of kidneys and spleen increases. PMID:7256958

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

    PubMed Central

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

    2016-01-01

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

  18. Antisense repression of cytosolic phosphoglucomutase in potato (Solanum tuberosum) results in severe growth retardation, reduction in tuber number and altered carbon metabolism.

    PubMed

    Fernie, Alisdair R; Tauberger, Eva; Lytovchenko, Anna; Roessner, Ute; Willmitzer, Lothar; Trethewey, Richard N

    2002-02-01

    The aim of this work was to investigate the role of cytosolic phosphoglucomutase (PGM; EC 5.4.2.2) in the regulation of carbohydrate metabolism. Many in vitro studies have indicated that PGM plays a central role in carbohydrate metabolism; however, until now the importance of this enzyme in plants has not been subject to reverse-genetics investigations. With this intention we cloned the cytosolic isoform of potato PGM (StcPGM) and expressed this in the antisense orientation under the control of the CaMV 35 S promoter in potato plants. We confirmed that these plants contained reduced total PGM activity and that loss in activity was due specifically to a reduction in cytosolic PGM activity. These plants were characterised by a severe phenotype: stunted aerial growth combined with limited root growth and a reduced tuber yield. Analysis of the metabolism of these lines revealed that leaves of these plants were inhibited in sucrose synthesis whereas the tubers exhibited decreased levels of sucrose and starch as well as decreased levels of glycolytic intermediates but possessed unaltered levels of adenylates. Furthermore, a broader metabolite screen utilising GC-MS profiling revealed that these lines contained altered levels of several intermediates of the TCA cycle and of amino acids. In summary, we conclude that cytosolic PGM plays a crucial role in the sucrose synthetic pathway within the leaf and in starch accumulation within the tuber, and as such is important in the maintenance of sink-source relationships.

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

    PubMed Central

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

    2015-01-01

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

  20. Mechanisms of adaptation to chronic respiratory acidosis in the rabbit proximal tubule.

    PubMed Central

    Krapf, R

    1989-01-01

    The hyperbicarbonatemia of chronic respiratory acidosis is maintained by enhanced bicarbonate reabsorption in the proximal tubule. To investigate the cellular mechanisms involved in this adaptation, cell and luminal pH were measured microfluorometrically using (2",7')-bis(carboxyethyl)-(5,6)-carboxyfluorescein in isolated, microperfused S2 proximal convoluted tubules from control and acidotic rabbits. Chronic respiratory acidosis was induced by exposure to 10% CO2 for 52-56 h. Tubules from acidotic rabbits had a significantly lower luminal pH after 1-mm perfused length (7.03 +/- 0.09 vs. 7.26 +/- 0.06 in controls, perfusion rate = 10 nl/min). Chronic respiratory acidosis increased the initial rate of cell acidification (dpHi/dt) in response to luminal sodium removal by 63% and in response to lowering luminal pH (7.4-6.8) by 69%. Chronic respiratory acidosis also increased dpHi/dt in response to peritubular sodium removal by 63% and in response to lowering peritubular pH by 73%. In conclusion, chronic respiratory acidosis induces a parallel increase in the rates of the luminal Na/H antiporter and the basolateral Na/(HCO3)3 cotransporter. Therefore, the enhanced proximal tubule reabsorption of bicarbonate in chronic respiratory acidosis may be, at least in part, mediated by a parallel adaptation of these transporters. PMID:2537851

  1. Medullary nephrocalcinosis, distal renal tubular acidosis and polycythaemia in a patient with nephrotic syndrome

    PubMed Central

    2012-01-01

    Background Medullary nephrocalcinosis and distal renal tubular acidosis are closely associated and each can lead to the other. These clinical entities are rare in patients with nephrotic syndrome and polycythaemia is an unusual finding in such patients. We describe the presence of medullary nephrocalcinosis, distal renal tubular acidosis and polycythaemia in a patient with nephrotic syndrome due to minimal change disease. Proposed mechanisms of polycythaemia in patients with nephrotic syndrome and distal renal tubular acidosis include, increased erythropoietin production and secretion of interleukin 8 which in turn stimulate erythropoiesis. Case presentation A 22 year old Sri Lankan Sinhala male with nephrotic syndrome due to minimal change disease was investigated for incidentally detected polycythaemia. Investigations revealed the presence of renal tubular acidosis type I and medullary nephrocalcinosis. Despite extensive investigation, a definite cause for polycythaemia was not found in this patient. Treatment with potassium and bicarbonate supplementation with potassium citrate led to correction of acidosis thereby avoiding the progression of nephrocalcinosis and harmful effects of chronic acidosis. Conclusion The constellation of clinical and biochemical findings in this patient is unique but the pathogenesis of erythrocytosis is not clearly explained. The proposed mechanisms for erythrocytosis in other patients with proteinuria include increased erythropoietin secretion due to renal hypoxia and increased secretion of interleukin 8 from the kidney. This case illustrates that there may exist hitherto unknown connections between tubular and glomerular dysfunction in patients with nephrotic syndrome. PMID:22834973

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

    PubMed Central

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

    2014-01-01

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

  3. Neural Correlates of the Severity of Cocaine, Heroin, Alcohol, MDMA and Cannabis Use in Polysubstance Abusers: A Resting-PET Brain Metabolism Study

    PubMed Central

    Moreno-López, Laura; Stamatakis, Emmanuel A.; Fernández-Serrano, Maria José; Gómez-Río, Manuel; Rodríguez-Fernández, Antonio; Pérez-García, Miguel; Verdejo-García, Antonio

    2012-01-01

    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. PMID:22768136

  4. Localization of a Gene for Autosomal Recessive Distal Renal Tubular Acidosis with Normal Hearing (rdRTA2) to 7q33-34

    PubMed Central

    Karet, Fiona E.; Finberg, Karin E.; Nayir, Ahmet; Bakkaloglu, Aysin; Ozen, Seza; Hulton, Sally A.; Sanjad, Sami A.; Al-Sabban, Essam A.; Medina, Juan F.; Lifton, Richard P.

    1999-01-01

    Summary Failure of distal nephrons to excrete excess acid results in the “distal renal tubular acidoses” (dRTA). Early childhood features of autosomal recessive dRTA include severe metabolic acidosis with inappropriately alkaline urine, poor growth, rickets, and renal calcification. Progressive bilateral sensorineural hearing loss (SNHL) is evident in approximately one-third of patients. We have recently identified mutations in ATP6B1, encoding the B-subunit of the collecting-duct apical proton pump, as a cause of recessive dRTA with SNHL. We now report the results of genetic analysis of 13 kindreds with recessive dRTA and normal hearing. Analysis of linkage and molecular examination of ATP6B1 indicated that mutation in ATP6B1 rarely, if ever, accounts for this phenotype, prompting a genomewide linkage search for loci underlying this trait. The results strongly supported linkage with locus heterogeneity to a segment of 7q33-34, yielding a maximum multipoint LOD score of 8.84 with 68% of kindreds linked. The LOD-3 support interval defines a 14-cM region flanked by D7S500 and D7S688. That 4 of these 13 kindreds do not support linkage to rdRTA2 and ATP6B1 implies the existence of at least one additional dRTA locus. These findings establish that genes causing recessive dRTA with normal and impaired hearing are different, and they identify, at 7q33-34, a new locus, rdRTA2, for recessive dRTA with normal hearing. PMID:10577919

  5. Energy metabolic disorder is a major risk factor in severe influenza virus infection: Proposals for new therapeutic options based on animal model experiments.

    PubMed

    Kido, Hiroshi; Indalao, Irene L; Kim, Hyejin; Kimoto, Takashi; Sakai, Satoko; Takahashi, Etsuhisa

    2016-09-01

    Severe influenza is characterized by cytokine storm and multiorgan failure. Influenza patients with underlying diseases show a rapid progression in disease severity. The major mechanism that underlies multiorgan failure during the progressive stage of infection, particularly in patients with underlying risk factors, is mitochondrial energy crisis. The relationship between the factors that determine infection severity, such as influenza virus, cytokines, cellular trypsin as a hemagglutinin processing protease for viral multiplication, accumulation of metabolic intermediates and ATP crisis in mitochondria, is termed the "influenza virus-cytokine-trypsin" cycle. This occurs during the initial stages of infection, and is interconnected with the "metabolic disorders-cytokine" cycle in the middle to late phase of infection. Experiments using animal models have highlighted the complex relationship between these two cycles. New treatment options have been proposed that target the ATP crisis and multiorgan failure during the late phase of infection, rather than antiviral treatments with neuraminidase inhibitors that work during the initial phase. These options are (i) restoration of glucose oxidation in mitochondria by diisopropylamine dichloroacetate, which inhibits infection-induced pyruvate dehydrogenase kinase 4 activity, and (ii) restoration of long-chain fatty acid oxidation in mitochondria by l-carnitine and bezafibrate, an agonist of peroxisome proliferation-activated receptors-β/δ, which transcriptionally upregulates carnitine palmitoyltransferase II. The latter is particularly effective in patients with influenza-associated encephalopathy who have thermolabile and short half-life compound variants of carnitine palmitoyltransferase II. PMID:27566378

  6. Antioxidant and metabolic impairment result in DNA damage in arsenic-exposed individuals with severe dermatological manifestations in Eastern India.

    PubMed

    Maiti, Smarajit; Chattopadhyay, Sandip; Deb, Bimal; Samanta, Tanmoy; Maji, Gurupada; Pan, Bappaditya; Ghosh, Amar; Ghosh, Debidas

    2012-05-01

    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 μg/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.

  7. [Brachial artery endothelial function in teenagers with obesity depending on severity of clinical, trophological and metabolic disorders].

    PubMed

    Maskova, G S; Chernaia, N L; Nagornova, E Iu; Fomina, O V; Byteva, T A

    2014-01-01

    We carried out complex examination of 68 adolescents aged 11-17 years with primary obesity which in addition to assessment of clinical-anamnestic, laboratory data and functional parameters of cardiovascular system included registration of reaction of brachial artery endothelium to reactive hyperemia. Vascular endothelial dysfunction (VED) was found in 66% of obese teenagers. Obesity in adolescents with VED was characterized by aggravated course with higher fat mass index (36.8 +/- 4.39%) and prevalence of hypothalamic (42%) and metabolic (8.8%) syndromes. Stable arterial hypertension (AH) found in 37% of examined adolescents was 1.5 times more often registered in those with VED. We distinguished 4 groups of adolescents with various degree of risk of development of cardiovascular disorders: with stable AH and VED (group I), with stable AH and normal function of vascular endothelium (group II), with normal or labile arterial pressure with VED (group III), with normal or labile arterial pressure with normal function of vascular endothelium. It is expedient to supplement examination of obese adolescents with assessment of the state of vascular endothelium aiming at determination of degree of risk of development of atherosclerosis and/or stable AH.

  8. G418-mediated ribosomal read-through of a nonsense mutation causing autosomal recessive proximal renal tubular acidosis

    PubMed Central

    Azimov, Rustam; Abuladze, Natalia; Sassani, Pakan; Newman, Debra; Kao, Liyo; Liu, Weixin; Orozco, Nicholas; Ruchala, Piotr; Pushkin, Alexander; Kurtz, Ira

    2008-01-01

    Autosomal recessive proximal renal tubular acidosis is caused by mutations in the SLC4A4 gene encoding the electrogenic sodium bicarbonate cotransporter NBCe1-A. The mutations that have been characterized thus far result in premature truncation, mistargeting, or decreased function of the cotransporter. Despite bicarbonate treatment to correct the metabolic acidosis, extrarenal manifestations persist, including glaucoma, cataracts, corneal opacification, and mental retardation. Currently, there are no known therapeutic approaches that can specifically target mutant NBCe1-A proteins. In the present study, we tested the hypothesis that the NBCe1-A-Q29X mutation can be rescued in vitro by treatment with aminoglycoside antibiotics, which are known for their ability to suppress premature stop codons. As a model system, we cloned the NBCe1-A-Q29X mutant into a vector lacking an aminoglycoside resistance gene and transfected the mutant cotransporter in HEK293-H cells. Cells transfected with the NBCe1-A-Q29X mutant failed to express the cotransporter because of the premature stop codon. Treatment of the cells with G418 significantly increased the expression of the full-length cotransporter, as assessed by immunoblot analysis. Furthermore, immunocytochemical studies demonstrated that G418 treatment induced cotransporter expression on the plasma membrane whereas in the absence of G418, NBCe1-A-Q29X was not expressed. In HEK293-H cells transfected with the NBCe1-A-Q29X mutant not treated with G418, NBCe1-A-mediated flux was not detectable. In contrast, in cells transfected with the NBCe1-A-Q29X mutant, G418 treatment induced Na+- and HCO3−-dependent transport that did not differ from wild-type NBCe1-A function. G418 treatment in mock-transfected cells was without effect. In conclusion, G418 induces ribosomal read-through of the NBCe1-A-Q29X mutation in HEK293-H cells. These findings represent the first evidence that in the presence of the NBCe1-A-Q29X mutation that causes

  9. Twenty-four hour metabolic rate measurements utilized as a reference to evaluate several prediction equations for calculating energy requirements in healthy infants

    PubMed Central

    2011-01-01

    Background To date, only short-duration metabolic rate measurements of less than four hours have been used to evaluate prediction equations for calculating energy requirements in healthy infants. Therefore, the objective of this analysis was to utilize direct 24-hour metabolic rate measurements from a prior study to evaluate the accuracy of several currently used prediction equations for calculating energy expenditure (EE) in healthy infants. Methods Data from 24-hour EE, resting (RMR) and sleeping (SMR) metabolic rates obtained from 10 healthy infants, served as a reference to evaluate 11 length-weight (LWT) and weight (WT) based prediction equations. Six prediction equations have been previously derived from 50 short-term EE measurements in the Enhanced Metabolic Testing Activity Chamber (EMTAC) for assessing 24-hour EE, (EMTACEE-LWT and EMTACEE-WT), RMR (EMTACRMR-LWT and EMTACRMR-WT) and SMR (EMTACSMR-LWT and EMTACSMR-WT). The last five additional prediction equations for calculating RMR consisted of the World Health Organization (WHO), the Schofield (SCH-LWT and SCH-WT) and the Oxford (OXFORD-LWT and OXFORD-WT). Paired t-tests and the Bland & Altman limit analysis were both applied to evaluate the performance of each equation in comparison to the reference data. Results 24-hour EE, RMR and SMR calculated with the EMTACEE-WT, EMTACRMR-WT and both the EMTACSMR-LWT and EMTACSMR-WT prediction equations were similar, p = NS, to that obtained from the reference measurements. However, RMR calculated using the WHO, SCH-LWT, SCH-WT, OXFORD-LWT and OXFORD-WT prediction equations were not comparable to the direct 24-hour metabolic measurements (p < 0.05) obtained in the 10 reference infants. Moreover, the EMTACEE-LWT and EMTACRMR-LWT were also not similar (p < 0.05) to direct 24-hour metabolic measurements. Conclusions Weight based prediction equations, derived from short-duration EE measurements in the EMTAC, were accurate for calculating EE, RMR and SMR in healthy

  10. Effect of acrylamide on neurotransmitter metabolism and neuropeptide levels in several brain regions and upon circulating hormones.

    PubMed

    Ali, S F; Hong, J S; Wilson, W E; Uphouse, L L; Bondy, S C

    1983-01-01

    The effect of acute and subchronic acrylamide treatment on levels of dopamine, serotonin, and their metabolites was determined in several brain regions of the rat. Concentrations of several neuropeptides and circulating hormones were also measured. Both a single and repeated doses of acrylamide resulted in elevated levels of 5-hydroxyindolacetic acid in all regions studied (frontal cortex, striatum, hippocampus, brain stem, and hypothalamus). Changes in regional content of other monoamines were much less pronounced. Turnover studies following pargyline blockage of monoamine oxidase, suggested results were due to increased rates of serotonin turnover in acrylamide-treated rats. Changes in neuropeptide levels were only detected in the hypothalamus where a single acrylamide treatment caused elevated levels of beta-endorphin and substance P, and in frontal cortex where met-enkephalin levels were higher after repeated acrylamide injection. Such repeated injection caused a major depression in plasma levels of testosterone and prolactin.

  11. Oxidative Stress and Polymorphism of Xenobiotic-Metabolizing Enzymes in Two Patients with Severe Alpha-1-Antitrypsin Deficiency.

    PubMed

    Topic, Aleksandra; Nagorni-Obradovic, Ljudmila; Francuski, Djordje; Ljujic, Mila; Malic, Zivka; Radojkovic, Dragica

    2016-10-01

    Alpha-1-antitrypsin deficiency (AATD) and tobacco smoke play a key role in the pathogenesis of early-onset emphysema. Differences in AATD-related chronic obstructive pulmonary disease stages imply the existence of modifying factors associated with disease severity. We present two male patients with emphysema caused by severe AATD (PiZZ genotype). Both are former smokers and have epoxide hydrolase low-activity phenotype. Extremely high level of oxidative stress (high urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine), increased inflammation (high serum CRP), and GSTP1 105Val mutation were found in patient with a worse lung function and prognosis. These data provide more evidence that oxidative stress-related gene variants and inflammation are associated with worse symptoms of AATD-related emphysema. Therefore, prevention against severe stage of AATD-related emphysema would include early identification of the risk gene variants, cessation or never smoking, and treatment with anti-inflammatory and anti-oxidant drugs. Additionally, urinary 8-oxodG could be a candidate for predictive biomarker for routine assessment of the oxidative stress level in AATD patients.

  12. Cardiac and metabolic changes in long-term high fructose-fat fed rats with severe obesity and extensive intramyocardial lipid accumulation.

    PubMed

    Axelsen, Lene N; Lademann, Jacob B; Petersen, Jørgen S; Holstein-Rathlou, Niels-Henrik; Ploug, Thorkil; Prats, Clara; Pedersen, Henrik D; Kjølbye, Anne Louise

    2010-06-01

    Metabolic syndrome and obesity-related diseases are affecting more and more people in the Western world. The basis for an effective treatment of these patients is a better understanding of the underlying pathophysiology. Here, we characterize fructose- and fat-fed rats (FFFRs) as a new animal model of metabolic syndrome. Sprague-Dawley rats were fed a 60 kcal/100 kcal fat diet with 10% fructose in the drinking water. After 6, 12, 18, 24, 36, and 48 wk of feeding, blood pressure, glucose tolerance, plasma insulin, glucose, and lipid levels were measured. Cardiac function was examined by in vivo pressure volume measurements, and intramyocardial lipid accumulation was analyzed by confocal microscopy. Cardiac AMP-activated kinase (AMPK) and hepatic phosphoenolpyruvate carboxykinase (PEPCK) levels were measured by Western blotting. Finally, an ischemia-reperfusion study was performed after 56 wk of feeding. FFFRs developed severe obesity, decreased glucose tolerance, increased serum insulin and triglyceride levels, and an initial increased fasting glucose, which returned to control levels after 24 wk of feeding. The diet had no effect on blood pressure but decreased hepatic PEPCK levels. FFFRs showed significant intramyocardial lipid accumulation, and cardiac hypertrophy became pronounced between 24 and 36 wk of feeding. FFFRs showed no signs of cardiac dysfunction during unstressed conditions, but their hearts were much more vulnerable to ischemia-reperfusion and had a decreased level of phosphorylated AMPK at 6 wk of feeding. This study characterizes a new animal model of the metabolic syndrome that could be beneficial in future studies of metabolic syndrome and cardiac complications.

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

    PubMed

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

    2013-05-01

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

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

    PubMed

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

    2013-05-01

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

  15. Contribution of respiratory acidosis to diaphragmatic fatigue at exercise.

    PubMed

    Jonville, S; Delpech, N; Denjean, A

    2002-06-01

    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 sessions, 14 healthy subjects performed two cycling tests (at 60% of maximal aerobic power for 16 min), one while breathing spontaneously (mean minute ventilation (V'E) 67.9 L x min(-1)) and the other while hypoventilating voluntarily (mean V'E 53.8 L x min(-1)). Exercise was voluntarily set at a moderate power to avoid a fatiguing effect of exercise per se. As compared with spontaneous breathing (SB), voluntary hypoventilation (VHV) significantly increased mean carbon dioxide tension in arterial blood (Pa,CO2) (51 mmHg versus 41 mmHg) and significantly decreased arterial pH (7.28 versus 7.34). After 10 min of SB test, tw,Pmo was unchanged compared to the baseline value (19.1 versus 18.5 cmH2O) whereas tw,Pmo fell significantly as compared to baseline (17.1 versus 18.5 cmH2O) and to SB (17.1 versus 19.1 cmH2O) after the VHV test. The results of this study suggest that exposure to hypercapnia may impair respiratory muscle function. This impairment could be more clinically relevant in patients with chronic obstructive lung disease. PMID:12108860

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-10-01

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

  18. Increased extracellular heat shock protein 90α in severe sepsis and SIRS associated with multiple organ failure and related to acute inflammatory-metabolic stress response in children.

    PubMed

    Fitrolaki, Michaela-Diana; Dimitriou, Helen; Venihaki, Maria; Katrinaki, Marianna; Ilia, Stavroula; Briassoulis, George

    2016-08-01

    Mammalian heat-shock-protein (HSP) 90α rapidly responses to environmental insults. We examined the hypothesis that not only serum HSP72 but also HSP90α is increased in the systemic inflammatory response syndrome (SIRS), severe-sepsis (SS), and/or sepsis (S) compared to healthy children (H); we assessed HSP90α relation to (a) multiple organ system failure (MOSF) and (b) inflammatory-metabolic response and severity of illness.A total of 65 children with S, SS, or SIRS and 25 H were included. ELISA was used to evaluate extracellular HSP90α and HSP72, chemiluminescence interleukins (ILs), flow-cytometry neutrophil-CD64 (nCD64)-expression.HSP90α, along with HSP72, were dramatically increased among MOSF patients. Patients in septic groups and SIRS had elevated HSP90α compared to H (P < 0.01). HSP90α was independently related to predicted death rate and severity of illness; positively to HSP72, nCD64, ILs, length of stay, days on ventilator, and fever; negatively to HDL and LDL (P < 0.05). The HSP72 was increased in SS/S and related negatively to HDL and LDL (P < 0.05).Serum HSP90α is markedly elevated in children with severe sepsis and is associated with MOSF. Better than the HSP72, also increased in SS, SIRS, and MOSF, HSP90α is related to the inflammatory stress, fever, outcome endpoints, and predicted mortality and inversely related to the low-LDL/low-HDL stress metabolic pattern. PMID:27583886

  19. Increased extracellular heat shock protein 90α in severe sepsis and SIRS associated with multiple organ failure and related to acute inflammatory-metabolic stress response in children

    PubMed Central

    Fitrolaki, Michaela-Diana; Dimitriou, Helen; Venihaki, Maria; Katrinaki, Marianna; Ilia, Stavroula; Briassoulis, George

    2016-01-01

    Abstract Mammalian heat-shock-protein (HSP) 90α rapidly responses to environmental insults. We examined the hypothesis that not only serum HSP72 but also HSP90α is increased in the systemic inflammatory response syndrome (SIRS), severe-sepsis (SS), and/or sepsis (S) compared to healthy children (H); we assessed HSP90α relation to (a) multiple organ system failure (MOSF) and (b) inflammatory-metabolic response and severity of illness. A total of 65 children with S, SS, or SIRS and 25 H were included. ELISA was used to evaluate extracellular HSP90α and HSP72, chemiluminescence interleukins (ILs), flow-cytometry neutrophil-CD64 (nCD64)-expression. HSP90α, along with HSP72, were dramatically increased among MOSF patients. Patients in septic groups and SIRS had elevated HSP90α compared to H (P < 0.01). HSP90α was independently related to predicted death rate and severity of illness; positively to HSP72, nCD64, ILs, length of stay, days on ventilator, and fever; negatively to HDL and LDL (P < 0.05). The HSP72 was increased in SS/S and related negatively to HDL and LDL (P < 0.05). Serum HSP90α is markedly elevated in children with severe sepsis and is associated with MOSF. Better than the HSP72, also increased in SS, SIRS, and MOSF, HSP90α is related to the inflammatory stress, fever, outcome endpoints, and predicted mortality and inversely related to the low-LDL/low-HDL stress metabolic pattern. PMID:27583886

  20. Successful treatment of severe iron intoxication with gastrointestinal decontamination, deferoxamine, and hemodialysis.

    PubMed

    Gumber, Manoj R; Kute, Vivek B; Shah, Pankaj R; Vanikar, Aruna V; Patel, Himanshu V; Balwani, Manish R; Ghuge, Pramod P; Trivedi, Hargovind L

    2013-01-01

    Acute iron poisoning is a common and potentially serious problem in the pediatric population. Early recognition and treatment is crucial for a better outcome and to prevent morbidity and mortality. An 18-year-old female, who had accidental ingestion of 50 tablets of ferrous sulfate (100 mg of elemental iron per 335 mg tablet), 100 mg/kg of elemental iron, developed acute gastrointestinal and neurologic signs of toxicity and severe anion gap metabolic acidosis. The patient had received gastrointestinal decontamination, deferoxamine (DFO) infusion, and hemodialysis (HD) resulting in a decrease in serum iron concentration from 2150 to 160 mcg/dL at 24-h post-ingestion and improved mental status. Our cases demonstrate that HD may assist in decreasing serum iron concentration and improving clinical status in patients with massive overdose and life-threatening toxicity. PMID:23635030

  1. A novel heterozygous mutation in the ATP6V0A4 gene encoding the V-ATPase a4 subunit in an adult patient with incomplete distal renal tubular acidosis

    PubMed Central

    Imai, Eri; Kaneko, Shuzo; Mori, Takayasu; Okado, Tomokazu; Uchida, Shinichi; Tsukamoto, Yusuke

    2016-01-01

    A 40-year-old Japanese man who had a medical history of hypokalemic periodic paralysis 4 months prior was hospitalized to undergo a cholecystectomy. Hypokalemia, nephrocalcinosis and alkaluria suggesting distal renal tubular acidosis (dRTA) were detected, but metabolic acidosis was not evident. An ammonium chloride/furosemide–fludrocortisone/bicarbonate loading test demonstrated a remarkable disability in urinary H+ excretion. A novel heterozygous mutation in the ATP6V0A4 gene encoding the vacuolar H+-ATPase (V-ATPase) a4 subunit p.S544L was detected. Among cases of V-ATPase a4 mutations, this is the first case in which a heterozygous mutation developed to an incomplete or latent form of dRTA. PMID:27274828

  2. A novel heterozygous mutation in the ATP6V0A4 gene encoding the V-ATPase a4 subunit in an adult patient with incomplete distal renal tubular acidosis.

    PubMed

    Imai, Eri; Kaneko, Shuzo; Mori, Takayasu; Okado, Tomokazu; Uchida, Shinichi; Tsukamoto, Yusuke

    2016-06-01

    A 40-year-old Japanese man who had a medical history of hypokalemic periodic paralysis 4 months prior was hospitalized to undergo a cholecystectomy. Hypokalemia, nephrocalcinosis and alkaluria suggesting distal renal tubular acidosis (dRTA) were detected, but metabolic acidosis was not evident. An ammonium chloride/furosemide-fludrocortisone/bicarbonate loading test demonstrated a remarkable disability in urinary H(+) excretion. A novel heterozygous mutation in the ATP6V0A4 gene encoding the vacuolar H(+)-ATPase (V-ATPase) a4 subunit p.S544L was detected. Among cases of V-ATPase a4 mutations, this is the first case in which a heterozygous mutation developed to an incomplete or latent form of dRTA. PMID:27274828

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

    PubMed Central

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

    2012-01-01

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

  4. CO2 induced acute respiratory acidosis and brain tissue intracellular pH: a 31P NMR study in swine.

    PubMed

    Martoft, L; Stødkilde-Jørgensen, H; Forslid, A; Pedersen, H D; Jørgensen, P F

    2003-07-01

    High concentration carbon dioxide (CO(2)) is used to promote pre-slaughter anaesthesia in swine and poultry, as well as short-lasting surgical anaesthesia and euthanasia in laboratory animals. Questions related to animal welfare have been raised, as CO(2) anaesthesia does not set in momentarily. Carbon dioxide promotes anaesthesia by lowering the intracellular pH in the brain cells, but the dynamics of the changes in response to a high concentration of CO(2) is not known. Based on (31)P NMR spectroscopy, we describe CO(2)-induced changes in intracellular pH in the brains of five pigs inhaling 90% CO(2) in ambient air for a period of 60 s, and compare the results to changes in arterial blood pH, P(CO2), O(2) saturation and HCO(3)(-) concentration. The intracellular pH paralleled the arterial pH and P(CO2) during inhalation of CO(2); and it is suggested that the acute reaction to CO(2) inhalation mainly reflects respiratory acidosis, and not metabolic regulation as for example transmembrane fluxes of H(+)/HCO(3)(-). The intracellular pH decreased to approximately 6.7 within the 60 s inhalation period, and the situation was metabolically reversible after the end of CO(2) inhalation. The fast decrease in intracellular pH supports the conclusion that high concentration CO(2) leads to anaesthesia soon after the start of inhalation. PMID:12869287

  5. In vitro activation of complement and contact system by lactic acidosis.

    PubMed Central

    Sonntag, J; Emeis, M; Strauss, E; Obladen, M

    1998-01-01

    The activation of complement and contact systems occurs in reperfusion injuries with initial tissue hypoxia, and lactic acidosis such as mycardial infarction and birth asphyxia. The aim of our experiment was the formal proof of activation by sole lactic acidosis. Lactic acid was added to blood and plasma samples from 10 healthy volunteers. C5a and factor XIIa were measured by EIA after incubation at 37 degrees C for 1 h. Both concentrations increased (P < 0.0001 by Friedman analysis) in blood and plasma samples with increasing amount of added lactic acid. Lactic acidosis can activate C5 from the complement system and factor XII from the contact system directly, even in the absence of cellular components. PMID:9839699

  6. Angiopoietin-2 associations with the underlying infection and sepsis severity.

    PubMed

    Lymperopoulou, Korina; Velissaris, Dimitrios; Kotsaki, Antigone; Antypa, Elli; Georgiadou, Sara; Tsaganos, Thomas; Koulenti, Despina; Paggalou, Evgenia; Damoraki, Georgia; Karagiannidis, Napoleon; Orfanos, Stylianos E

    2015-05-01

    Angiopoietin-2 (Ang-2) is an important mediator in sepsis. We have previously shown that endotoxemia levels are related to the underlying infection and affect septic patients' outcome. Based on this background we now investigated if circulating Ang-2 (cAng-2) and monocyte Ang-2 expression in septic patients are associated with the underlying infection and organ failure. We measured cAng-2 in 288 septic patients (121 with sepsis, 167 with severe sepsis/septic shock) at less than 24h post study inclusion (day 1) and on days 3 and 7. Peripheral blood mononuclear cells (PBMCs) were additionally isolated; Ang-2 gene expression was estimated by means of real-time PCR. Levels of cAng-2 were higher under severe sepsis and septic shock, as compared to uncomplicated sepsis; PBMC Ang-2 copies were higher in severe sepsis. On day 1, cAng-2 and Ang-2 gene copies were greater under severe sepsis/septic shock in sufferers from all types of infections with the exception of community-acquired pneumonia and ventilator-associated pneumonia. cAng-2 increased proportionally to the number of failing organs, and was higher under metabolic acidosis and acute coagulopathy as compared to no failing organ. On day 1, copies of Ang-2 were higher in survivors, whereas cAng-2 was higher in non-survivors. In a large cohort of septic patients, cAng-2 kinetics appears associated with the underlying infection and organ failure type.

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

    PubMed Central

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

    2012-01-01

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

  8. A Rare Case of Persistent Lactic Acidosis in the ICU: Glycogenic Hepatopathy and Mauriac Syndrome

    PubMed Central

    Alvarez, George F.

    2016-01-01

    Mauriac syndrome is a rare disorder that can present with the single feature of glycogenic hepatopathy in children and adults with poorly controlled diabetes mellitus. An often underrecognized finding of glycogenic hepatopathy is lactic acidosis and hyperlactatemia. Primary treatment of glycogenic hepatopathy is improved long-term blood glucose control. Resolution of symptoms and hepatomegaly will occur with improvement in hemoglobin A1C. We present here a case of a young adult female presenting to the intensive care unit with Mauriac syndrome. This case demonstrates exacerbation of lactic acidosis in a patient with glycogenic hepatopathy treated for diabetic ketoacidosis with high dose insulin and dextrose. PMID:27699071

  9. Point of care testing for antiretroviral therapy-related lactic acidosis in resource-poor settings.

    PubMed

    Ivers, Louise C; Mukherjee, Joia S

    2006-03-21

    Lactic acidosis is a rare but potentially life-threatening complication of antiretroviral therapy (ART) and is commonly considered in the differential diagnosis of patients on ART. In the developing world, definitive diagnosis by laboratory measurement of lactate may be impossible. Point-of-care devices are available that provide simple, accurate measurements of lactic acid levels at relatively low cost. Their use in an HIV treatment programme in rural Haiti has greatly assisted clinical decision-making in patients with symptoms suggestive of lactic acidosis. PMID:16514312

  10. A Rare Case of Persistent Lactic Acidosis in the ICU: Glycogenic Hepatopathy and Mauriac Syndrome

    PubMed Central

    Alvarez, George F.

    2016-01-01

    Mauriac syndrome is a rare disorder that can present with the single feature of glycogenic hepatopathy in children and adults with poorly controlled diabetes mellitus. An often underrecognized finding of glycogenic hepatopathy is lactic acidosis and hyperlactatemia. Primary treatment of glycogenic hepatopathy is improved long-term blood glucose control. Resolution of symptoms and hepatomegaly will occur with improvement in hemoglobin A1C. We present here a case of a young adult female presenting to the intensive care unit with Mauriac syndrome. This case demonstrates exacerbation of lactic acidosis in a patient with glycogenic hepatopathy treated for diabetic ketoacidosis with high dose insulin and dextrose.

  11. Liquid extracorporeal carbon dioxide removal: use of THAM (tris-hydroxymethyl aminomethane) coupled to hemofiltration to control hypercapnic acidosis in a porcine model of protective mechanical ventilation.

    PubMed

    Tapia, Pablo; Lillo, Felipe; Soto, Dagoberto; Escobar, Leslie; Simon, Felipe; Hernández, Karina; Alegría, Leyla; Bruhn, Alejandro

    2016-01-01

    A promising approach to facilitate protective mechanical ventilation is the use of extracorporeal CO2 removal techniques. Several strategies based on membrane gas exchangers have been developed. However, these techniques are still poorly available. The goal of this study was to assess the efficacy and safety of THAM infusion coupled to hemofiltration for the management of hypercapnic acidosis. A severe respiratory acidosis was induced in seven anesthetized pigs. Five of them were treated with THAM 8-mmol·kg(-1)·h(-1) coupled to hemofiltration (THAM+HF group) at 100 mL·kg(-1)·h(-1). After 18-hours of treatment the THAM infusion was stopped but hemofiltration was kept on until 24-hours. The 2 other animals were treated with THAM but without hemofiltration. After 1-hour of treatment in THAM+HF, PaCO2 rapidly decreased from a median of 89.0 (IQR) (80.0, 98.0) to 71.3 (65.8, 82.0) mmHg (P<0.05), while pH increased from 7.12 (7.01, 7.15) to 7.29 (7.27, 7.30) (P<0.05). Thereafter PaCO2 remained stable between 60-70 mmHg, while pH increased above 7.4. After stopping THAM at 18 hours of treatment a profound rebound effect was observed with severe hypercapnic acidosis. The most important side effect we observed was hyperosmolality, which reached a maximum of 330 (328, 332) mOsm·kg H2O(-1) at T18. The animals treated only with THAM developed severe hypercapnia, despite the fact that pH returned to normal values, and died after 12 hours. Control-group had an uneven evolution until the end of the experiment. A combined treatment with THAM coupled to hemofiltration may be an effective treatment to control severe hypercapnic acidosis. PMID:27648139

  12. Liquid extracorporeal carbon dioxide removal: use of THAM (tris-hydroxymethyl aminomethane) coupled to hemofiltration to control hypercapnic acidosis in a porcine model of protective mechanical ventilation

    PubMed Central

    Tapia, Pablo; Lillo, Felipe; Soto, Dagoberto; Escobar, Leslie; Simon, Felipe; Hernández, Karina; Alegría, Leyla; Bruhn, Alejandro

    2016-01-01

    A promising approach to facilitate protective mechanical ventilation is the use of extracorporeal CO2 removal techniques. Several strategies based on membrane gas exchangers have been developed. However, these techniques are still poorly available. The goal of this study was to assess the efficacy and safety of THAM infusion coupled to hemofiltration for the management of hypercapnic acidosis. A severe respiratory acidosis was induced in seven anesthetized pigs. Five of them were treated with THAM 8-mmol·kg-1·h-1 coupled to hemofiltration (THAM+HF group) at 100 mL·kg-1·h-1. After 18-hours of treatment the THAM infusion was stopped but hemofiltration was kept on until 24-hours. The 2 other animals were treated with THAM but without hemofiltration. After 1-hour of treatment in THAM+HF, PaCO2 rapidly decreased from a median of 89.0 (IQR) (80.0, 98.0) to 71.3 (65.8, 82.0) mmHg (P<0.05), while pH increased from 7.12 (7.01, 7.15) to 7.29 (7.27, 7.30) (P<0.05). Thereafter PaCO2 remained stable between 60-70 mmHg, while pH increased above 7.4. After stopping THAM at 18 hours of treatment a profound rebound effect was observed with severe hypercapnic acidosis. The most important side effect we observed was hyperosmolality, which reached a maximum of 330 (328, 332) mOsm·kg H2O-1 at T18. The animals treated only with THAM developed severe hypercapnia, despite the fact that pH returned to normal values, and died after 12 hours. Control-group had an uneven evolution until the end of the experiment. A combined treatment with THAM coupled to hemofiltration may be an effective treatment to control severe hypercapnic acidosis. PMID:27648139

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  15. [Impact of lactic acid fermentation in the large intestine on acute lactic acidosis in cattle].

    PubMed

    Zust, J; Pestevsek, U; Vengust, A

    2000-09-01

    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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  18. Comparison of potential risks of lactic acidosis induction by biguanides in rats.

    PubMed

    Bando, Kiyoko; Ochiai, Shoko; Kunimatsu, Takeshi; Deguchi, Jiro; Kimura, Juki; Funabashi, Hitoshi; Seki, Takaki

    2010-10-01

    Lactic acidosis has been considered to be a side effect of some biguanides, after phenformin was withdrawn from the market because of its association with lactic acidosis. The potential of lactic acidosis induced by biguanides at human therapeutic exposure levels, however, has not been examined. Then, we compared the risk of lactic acid at doses providing exposure levels comparable to human therapeutic doses. Metformin and phenformin were orally administered to rats for up to 28 days, and plasma drug concentrations and blood lactic acid levels were examined. Metformin did not elevate lactic acid levels at the dose corresponding to higher systemic drug exposure than human therapeutic level, even for repeated doses. In contrast, phenformin elevated lactic acid levels at the dose corresponding to lower exposure than human therapeutic level, and sustained high levels were observed up to 24h post-dose; furthermore, these changes were enhanced by repeated doses. Direct comparison at each rat equivalent dose clearly indicated that lactic acid levels of phenformin were higher than those of metformin. These non-clinical findings suggest that metformin dose not increase lactic acid levels like phenformin does, and therefore may not increase the risk for lactic acidosis at human therapeutic exposure level.

  19. In-vitro activation of complement system by lactic acidosis in newborn and adults.

    PubMed Central

    Hecke, F; Hoehn, T; Strauss, E; Obladen, M; Sonntag, J

    2001-01-01

    INTRODUCTION: Complement activation occurs secondary to a variety of external stimuli. Lactic acidosis has been previously shown to activate the complement factors C3a and C5a. In the present investigation we examined the differential effect of lactic acidosis on anaphylatoxin levels in cord and adult blood. Furthermore we aimed to determine if the entire complement cascade could be activated by lactic acidosis. METHODS: Cord and adult blood samples (n = 20 each) were collected and incubated for one hour in either untreated condition or with the addition of lactate in two concentrations (5.5 mmol/l vs. 22 mmol/l). Following incubation, levels of C3a, C5a and sC5b-9, and blood gas parameters were determined. RESULTS: Anaphylatoxin (C3a and C5a) and sC5b-9 levels increased with the addition of lactate in a dose-dependent manner in cord and adult blood (C3a: 1 h, 5.5 mmo/l, 22 mmol/l: 418/498/622 microg/l in cord blood; 1010/1056/1381 microg/l in adult blood, p<0,05; similar results were found for C5a and sC5b-9). CONCLUSION: Lactic acidosis leads to an activation of the entire complement system in neonates and in adults. This activation is dose-dependent and more pronounced in adults as compared to neonates. PMID:11324901

  20. Disruption of Glycerol Metabolism by RNAi Targeting of Genes Encoding Glycerol Kinase Results in a Range of Phenotype Severity in Drosophila

    PubMed Central

    Wightman, Patrick J.; Jackson, George R.; Dipple, Katrina M.

    2013-01-01

    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. PMID:24039719

  1. Acidosis downregulates platelet haemostatic functions and promotes neutrophil proinflammatory responses mediated by platelets.

    PubMed

    Etulain, Julia; Negrotto, Soledad; Carestia, Agostina; Pozner, Roberto Gabriel; Romaniuk, María Albertina; D'Atri, Lina Paola; Klement, Giannoula Lakka; Schattner, Mirta

    2012-01-01

    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 αIIbβ3 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-1α 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.

  2. Outcomes of Extremely Low Birth Weight Infants with Acidosis at Birth

    PubMed Central

    Randolph, David A.; Nolen, Tracy L.; Ambalavanan, Namasivayam; Carlo, Waldemar A.; Peralta-Carcelen, Myriam; Das, Abhik; Bell, Edward F.; Davis, Alexis S.; Laptook, Abbot R.; Stoll, Barbara J.; Shankaran, Seetha; Higgins, Rosemary D.

    2014-01-01

    OBJECTIVES To test the hypothesis that acidosis at birth is associated with the combined primary outcome of death or neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants, and to develop a predictive model of death/NDI exploring perinatal acidosis as a predictor variable. STUDY DESIGN The study population consisted of ELBW infants born between 2002-2007 at NICHD Neonatal Research Network hospitals. Infants with cord blood gas data and documentation of either mortality prior to discharge or 18-22 month neurodevelopmental outcomes were included. Multiple logistic regression analysis was used to determine the contribution of perinatal acidosis, defined as a cord blood gas with a pH<7 or base excess (BE)<-12, to death/NDI in ELBW infants. In addition, a multivariable model predicting death/NDI was developed. RESULTS 3979 patients were identified of whom 249 had a cord gas pH<7 or BE<-12 mEq/L. 2124 patients (53%) had the primary outcome of death/NDI. After adjustment for confounding variables, pH<7 and BE<-12 mEq/L were each significantly associated with death/NDI (OR=2.5[1.6,4.2]; and OR=1.5[1.1,2.0], respectively). However, inclusion of pH or BE did not improve the ability of the multivariable model to predict death/NDI. CONCLUSIONS Perinatal acidosis is significantly associated with death/NDI in ELBW infants. Perinatal acidosis is infrequent in ELBW infants, however, and other factors are more important in predicting death/NDI. PMID:24554564

  3. Early Cerebral Hemodynamic, Metabolic, and Histological Changes in Hypoxic–Ischemic Fetal Lambs during Postnatal Life

    PubMed Central

    Rey-Santano, Carmen; Mielgo, Victoria E.; Gastiasoro, Elena; Murgia, Xabier; Lafuente, Hector; Ruiz-del-Yerro, Estibaliz; Valls-i-Soler, Adolf; Hilario, Enrique; Alvarez, Francisco J.

    2011-01-01

    The hemodynamic, metabolic, and biochemical changes produced during the transition from fetal to neonatal life may be aggravated if an episode of asphyxia occurs during fetal life. The aim of the study was to examine regional cerebral blood flow (RCBF), histological changes, and cerebral brain metabolism in preterm lambs, and to analyze the role of oxidative stress in the first hours of postnatal life following severe fetal asphyxia. Eighteen chronically instrumented newborn lambs were randomly assigned to either a control group or the hypoxic–ischemic (HI) group, in which case fetal asphyxia was induced just before delivery. All the animals were maintained on intermittent positive pressure ventilation for 3 h after delivery. During the HI insult, the injured group developed acidosis, hypoxia, hypercapnia, lactic acidosis, and tachycardia (relative to the control group), without hypotension. The intermittent positive pressure ventilation transiently improved gas exchange and cardiovascular parameters. After HI injury and during ventilatory support, there continued to be an increased RCBF in inner regions among the HI group, but no significant differences were detected in cortical flow compared to the control group. Also, the magnitude of the increase in TUNEL positive cells (apoptosis) and antioxidant enzymes, and decrease of ATP reserves was significantly greater in the brain regions where the RCBF was not higher. In conclusion, our findings identify early metabolic, histological, and hemodynamic changes involved in brain damage in premature asphyxiated lambs. Such changes have been described in human neonates, so our model could be useful to test the safety and the effectiveness of different neuroprotective or ventilation strategies applied in the first hours after fetal HI injury. PMID:21960958

  4. Blueberries and Metabolic Syndrome

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

    Herrero, Óscar; Planelló, Rosario; Morcillo, Gloria

    2015-06-01

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

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

    PubMed

    Herrero, Óscar; Planelló, Rosario; Morcillo, Gloria

    2015-06-01

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

  8. Effects of two kinds of underwear on metabolic heat production during 60 min recovery after 30 min severe exercise in the cold.

    PubMed

    Ha, M; Tokura, H; Gotoh, J; Holmér, I

    1998-09-01

    The purpose of this study is to investigate the thermophysiological significance of hydrophilic and hydrophobic properties of underwear materials under the influences of profuse sweating produced during severe exercise in the cold. Two kinds of underwear were used: two layers of cotton underwear with two-piece long-sleeved shirt and full-trousers (C), and two layers of polypropylene underwear with two-piece long-sleeved shirt and full-trousers (P). In addition, the subject put on a two-piece ski suit of 100% polyester including 100% polyester padding. Eight adult females volunteered as subjects in this study. The test was performed in a climatic chamber at an ambient air temperature of 2 degrees C and an air velocity of 0.26 m.s-1. The subject exercised on a cycle ergometer at an intensity of 65% maximal oxygen uptake for 30 min and followed by 60 min recovery. The major findings are summarized as follows: 1) The fall of rectal temperature tended to be greater in P during the recovery. 2) The absolute humidity of innermost layer and middle layer was significantly higher in C than in P during the recovery, but the absolute humidity of middle layer and outermost layer was significantly higher in P than in C during the exercise. 3) Clothing microclimate temperature of innermost at back was significantly higher in C during the exercise and recovery. 4) Metabolic heat production for last 30 min during recovery was significantly higher in P. 5) The degree of skin wettedness sensation and sweating sensation for whole body was significantly higher in P during the exercise. It was concluded that the slower evaporation behavior by absorbing of underwear material in the clothing system has a beneficial influence on thermophysiological responses during severe exercise and its recovery in the cold, although the differences were very small.

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

    PubMed Central

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

    2014-01-01

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

  10. Testosterone protects female embryonic heart H9c2 cells against severe metabolic stress by activating estrogen receptors and up-regulating IES SUR2B.

    PubMed

    Ballantyne, Thomas; Du, Qingyou; Jovanović, Sofija; Neemo, Andrew; Holmes, Robert; Sinha, Sharabh; Jovanović, Aleksandar

    2013-02-01

    A recent clinical study demonstrated that a testosterone supplementation improves functional capacity in elderly female patients suffering from heart failure. These findings prompted us to consider possible mechanisms of testosterone-induced cardioprotection in females. To address this question we have used a pure female population of rat heart embryonic H9c2 cells. Pre-treatment of cells with testosterone for 24h significantly increased survival of H9c2 cells exposed to 2,4-dinitrophenol (DNP), an inhibitor of oxidative phosphorylation. These cells expressed low level of androgen receptors and the effect of testosterone was not modified by hydroxyflutamide, an antagonist of androgen receptor. In contrast, cyclohexamide, an inhibitor of protein biosynthesis, and tamoxifene, a partial agonist of estrogen receptors, abolished cardioprotection afforded by testosterone. In addition, finasteride, an inhibitor of 5α-reductase, and anastrazole, an inhibitor of α-aromatase, also blocked testosterone-induced cytoprotection. Real time RT-PCR revealed that testosterone did not regulate the expression of nine subunits and accessory proteins of sarcolemmal ATP-sensitive K(+) (K(ATP)) channels. On the other hand, testosterone, as well as 17β-estradiol, up-regulated a putative mitochondrial K(ATP) channel subunit, mitochondrial sulfonylurea receptor 2B intraexonics splice variant (IES SUR2B), without affecting expression of IES SUR2A. Tamoxifene inhibited testosterone-induced up-regulation of IES SUR2B without affecting IES SUR2A. In conclusion, this study has shown that testosterone protect female embryonic heart H9c2 cells against severe metabolic stress by its conversion into metabolites that activate estrogen receptors and up-regulate IES SUR2B.

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

    PubMed Central

    2012-01-01

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

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

    PubMed Central

    2012-01-01

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

  13. A patient with Graves' disease who survived despite developing thyroid storm and lactic acidosis

    PubMed Central

    2010-01-01

    A 56-year-old woman with Graves' disease presented with the complaints of diarrhea and palpitations. Physical examination and laboratory data revealed hypothermia and signs of mild hyperthyroidism, heart failure, hepatic dysfunction with jaundice, hypoglycemia, and lactic acidosis. The patient was diagnosed as having developed the complication of thyroid storm in the absence of marked elevation of the thyroid hormone levels, because of the potential hepatic and cardiac dysfunctions caused by heavy alcohol drinking. A year later, after successful treatment, the patient remains well without any clinical evidence of heart failure or hepatic dysfunction. Thyroid storm associated with lactic acidosis and hypothermia is a serious condition and has rarely been reported. Prompt treatment is essential even if the serum thyroid hormone levels are not markedly elevated. We present a report about this patient, as her life could eventually be saved. PMID:20731531

  14. Prevalence and severity of disordered mineral metabolism in patients with chronic kidney disease: A study from a tertiary care hospital in India

    PubMed Central

    Vikrant, Sanjay; Parashar, Anupam

    2016-01-01

    Background: Disordered mineral metabolism is common complications of chronic kidney disease (CKD). However, there are limited data on the pattern of these disturbances in Indian CKD population. Materials and Methods: This was a prospective observational study of CKD-mineral and bone disorder (CKD-MBD) over a period of 3 years. The biochemical markers of CKD-MBD, namely, calcium, phosphorus, alkaline phosphatase, intact parathyroid hormone (iPTH), and 25-hydoxyvitamin Vitamin D3 (25OHD), were measured in newly diagnosed CKD Stage 3–5 and prevalent CKD Stage 5D adult patients. Results: A total of 462 patients of CKD Stage 3–5D were studied. The frequency of various biochemical abnormalities was hypocalcemia (23.8%), hypercalcemia (5.4%), hypophosphatemia (2.8%), hyperphosphatemia (55.4%), raised alkaline phosphatase (56.9%), secondary hyperparathyroidism (82.7%), and hypoparathyroidism (1.5%). 25OHD was done in 335 (72.5%) patients and 90.4% were found to have Vitamin D deficiency. About 70.6% of the patients had iPTH levels were above kidney disease outcomes quality initiative (KDOQI) target range. Nondiabetic CKD as compared to diabetic CKD had a higher alkaline phosphatase (P = 0.016), a higher iPTH (P = 0.001) a higher proportion of patients with iPTH above KDOQI target range (P = 0.09), and an elevated alkaline phosphatase (P = 0.004). The 25OHD levels were suggestive of severe Vitamin D deficiency in 33.7%, Vitamin D deficiency in 45.4%, and Vitamin D insufficiency in 11.3% patients. There was a significant positive correlation between iPTH with alkaline phosphatase (r = 0.572, P = 0.001), creatinine (r = 0.424, P = 0.001), and phosphorus (r = 0.241, P = 0.001) and a significant negative correlation with hemoglobin (r = −0.325, 0.001), age (r = −0.169, P = 0.002), and 25OHD (r = −0.126, P = 0.021). On multivariate logistic regression analysis, an elevated alkaline phosphatase was a significant predictor of hyperparathyroidism (odds ratio 9.7, 95

  15. Metabolic resuscitation in sepsis: a necessary step beyond the hemodynamic?

    PubMed Central

    de Lima, Lúcio Flávio Peixoto

    2016-01-01

    Despite the advances made in monitoring and treatment of sepsis and septic shock, many septic patients ultimately develop multiple organ dysfunction (MODS) and die, suggesting that other players are involved in the pathophysiology of this syndrome. Mitochondrial dysfunction occurs early in sepsis and has a central role in MODS development. MODS severity and recovery of mitochondrial function have been associated with survival. In recent clinical and experimental investigations, mitochondrion-target therapy for sepsis and septic shock has been suggested to reduce MODS severity and mortality. This intervention, which might be named “metabolic resuscitation”, would lead to improved mitochondrial activity afforded by pharmacological and nutritional agents. Of particular interest in this therapeutic strategy is thiamine, a water-soluble vitamin that plays an essential role in cellular energy metabolism. Critical illness associated with hypermetabolic states may predispose susceptible individuals to the development of thiamine deficiency, which is not usually identified by clinicians as a source of lactic acidosis. The protective effects of thiamine on mitochondrial function may justify supplementation in septic patients at risk of deficiency. Perspectives of supplementation with other micronutrients (ascorbic acid, tocopherol, selenium and zinc) and potential metabolic resuscitators [coenzyme Q10 (CoQ10), cytochrome oxidase (CytOx), L-carnitine, melatonin] to target sepsis-induced mitochondrial dysfunction are also emerging. Metabolic resuscitation may probably be a safe and effective strategy in the treatment of septic shock in the future. However, until then, preliminary investigations should be replicated in further researches for confirmation. Better identification of groups of patients presumed to benefit clinically by a certain intervention directed to “mitochondrial resuscitation” are expected to increase driven by genomics and metabolomics. PMID:27501325

  16. Metabolic resuscitation in sepsis: a necessary step beyond the hemodynamic?

    PubMed

    Leite, Heitor Pons; de Lima, Lúcio Flávio Peixoto

    2016-07-01

    Despite the advances made in monitoring and treatment of sepsis and septic shock, many septic patients ultimately develop multiple organ dysfunction (MODS) and die, suggesting that other players are involved in the pathophysiology of this syndrome. Mitochondrial dysfunction occurs early in sepsis and has a central role in MODS development. MODS severity and recovery of mitochondrial function have been associated with survival. In recent clinical and experimental investigations, mitochondrion-target therapy for sepsis and septic shock has been suggested to reduce MODS severity and mortality. This intervention, which might be named "metabolic resuscitation", would lead to improved mitochondrial activity afforded by pharmacological and nutritional agents. Of particular interest in this therapeutic strategy is thiamine, a water-soluble vitamin that plays an essential role in cellular energy metabolism. Critical illness associated with hypermetabolic states may predispose susceptible individuals to the development of thiamine deficiency, which is not usually identified by clinicians as a source of lactic acidosis. The protective effects of thiamine on mitochondrial function may justify supplementation in septic patients at risk of deficiency. Perspectives of supplementation with other micronutrients (ascorbic acid, tocopherol, selenium and zinc) and potential metabolic resuscitators [coenzyme Q10 (CoQ10), cytochrome oxidase (CytOx), L-carnitine, melatonin] to target sepsis-induced mitochondrial dysfunction are also emerging. Metabolic resuscitation may probably be a safe and effective strategy in the treatment of septic shock in the future. However, until then, preliminary investigations should be replicated in further researches for confirmation. Better identification of groups of patients presumed to benefit clinically by a certain intervention directed to "mitochondrial resuscitation" are expected to increase driven by genomics and metabolomics. PMID:27501325

  17. Metabolic resuscitation in sepsis: a necessary step beyond the hemodynamic?

    PubMed

    Leite, Heitor Pons; de Lima, Lúcio Flávio Peixoto

    2016-07-01

    Despite the advances made in monitoring and treatment of sepsis and septic shock, many septic patients ultimately develop multiple organ dysfunction (MODS) and die, suggesting that other players are involved in the pathophysiology of this syndrome. Mitochondrial dysfunction occurs early in sepsis and has a central role in MODS development. MODS severity and recovery of mitochondrial function have been associated with survival. In recent clinical and experimental investigations, mitochondrion-target therapy for sepsis and septic shock has been suggested to reduce MODS severity and mortality. This intervention, which might be named "metabolic resuscitation", would lead to improved mitochondrial activity afforded by pharmacological and nutritional agents. Of particular interest in this therapeutic strategy is thiamine, a water-soluble vitamin that plays an essential role in cellular energy metabolism. Critical illness associated with hypermetabolic states may predispose susceptible individuals to the development of thiamine deficiency, which is not usually identified by clinicians as a source of lactic acidosis. The protective effects of thiamine on mitochondrial function may justify supplementation in septic patients at risk of deficiency. Perspectives of supplementation with other micronutrients (ascorbic acid, tocopherol, selenium and zinc) and potential metabolic resuscitators [coenzyme Q10 (CoQ10), cytochrome oxidase (CytOx), L-carnitine, melatonin] to target sepsis-induced mitochondrial dysfunction are also emerging. Metabolic resuscitation may probably be a safe and effective strategy in the treatment of septic shock in the future. However, until then, preliminary investigations should be replicated in further researches for confirmation. Better identification of groups of patients presumed to benefit clinically by a certain intervention directed to "mitochondrial resuscitation" are expected to increase driven by genomics and metabolomics.

  18. Prognosis of alcohol-associated lactic acidosis in critically ill patients: an 8-year study

    PubMed Central

    Yang, Chun-Chieh; Chan, Khee-Siang; Tseng, Kuei-Ling; Weng, Shih-Feng

    2016-01-01

    Lactic acidosis is common in critical care; by contrast, a subtype called alcohol-associated lactic acidosis (AALA) is rarely encountered. The primary purpose of this study was to determine the prognosis of AALA in critically ill patients and the second aim was to determine whether the survival was associated to the peak blood lactate concentration. An 8-year retrospective analysis of adult patients admitted to the intensive care unit (ICU) with AALA between January 2007 and December 2014 was considered in a tertiary care hospital. In total, 23 patients were analyzed and the median peak blood lactate level was 15.9 mmol/L. Only 2 patients (8.7%) presented peak blood lactate levels <10 mmol/L. In this study, 21 patients survived from ICU and hospital, the mortality rate was 8.7%. The result indicted the survival of AALA was not associated with peak blood lactate concentration although survivors still had a better lactate clearance rate per hour than non-survivors. Moreover, AALA patients with coexisting sepsis presenting higher lactate clearance rate and shorter lactate clearance time than those of AALA patients with solely sepsis-related lactic acidosis. PMID:27748410

  19. Diabetes Stimulates Osteoclastogenesis by Acidosis-Induced Activation of Transient Receptor Potential Cation Channels

    PubMed Central

    Reni, Carlotta; Mangialardi, Giuseppe; Meloni, Marco; Madeddu, Paolo

    2016-01-01

    Patients with type 1 diabetes have lower bone mineral density and higher risk of fractures. The role of osteoblasts in diabetes-related osteoporosis is well acknowledged whereas the role of osteoclasts (OCLs) is still unclear. We hypothesize that OCLs participate in pathological bone remodeling. We conducted studies in animals (streptozotocin-induced type 1 diabetic mice) and cellular models to investigate canonical and non-canonical mechanisms underlying excessive OCL activation. Diabetic mice show an increased number of active OCLs. In vitro studies demonstrate the involvement of acidosis in OCL activation and the implication of transient receptor potential cation channel subfamily V member 1 (TRPV1). In vivo studies confirm the establishment of local acidosis in the diabetic bone marrow (BM) as well as the ineffectiveness of insulin in correcting the pH variation and osteoclast activation. Conversely, treatment with TRPV1 receptor antagonists re-establishes a physiological OCL availability. These data suggest that diabetes causes local acidosis in the BM that in turn increases osteoclast activation through the modulation of TRPV1. The use of clinically available TRPV1 antagonists may provide a new means to combat bone problems associated with diabetes. PMID:27468810

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  3. The effect of acidosis on the interval-force relation and mechanical restitution in ferret papillary muscle.

    PubMed

    McCall, E; Orchard, C H

    1991-01-01

    1. The effect of a respiratory acidosis on the interval-force relation and on mechanical restitution was investigated in ferret papillary muscles. 2. Acidosis (pH 6.85) decreased developed force over a range of stimulation frequencies (1.0.06 Hz); the percentage decrease was greatest at the lowest stimulation frequencies. Qualitatively similar effects of acidosis on developed force were observed in the presence of the sarcoplasmic reticulum (SR) inhibitor ryanodine. 3. Mechanical restitution curves were constructed by interpolating extra-systoles at different test intervals following a train of steady-state beats. Mechanical restitution in ferret papillary muscle was triphasic: an initial, rapid, exponential increase in force with test intervals to 2 s, a further increase with test intervals between 60 and 90 s and then a slow decline, with a plateau at about 30 min (0.33 Hz, 30 degrees C). 4. Acidosis slowed the initial phase of mechanical restitution. The degree of slowing depended on the steady-state stimulation frequency, being greatest at low frequencies. 5. Inhibition of the SR abolished the initial phase of mechanical restitution, suggesting that this phase depends on Ca2+ release from the SR. 6. The strength of the first contraction after the extra-systole varied inversely with the size of the extra-systole under all conditions studied. 7. It is concluded that acidosis may inhibit the SR by altering the time required for Ca2+ recycling between contractions. This effect may alter Ca2+ release from the SR during acidosis, and may underlie the mechanical alternans (the alternation of small and large contractions) that can occur during acidosis.

  4. Japanese cases of acute onset diabetic ketosis without acidosis in the absence of glutamic acid decarboxylase autoantibody.

    PubMed

    Iwasaki, Yorihiro; Hamamoto, Yoshiyuki; Kawasaki, Yukiko; Ikeda, Hiroki; Honjo, Sachiko; Wada, Yoshiharu; Koshiyama, Hiroyuki

    2010-04-01

    We report consecutive Japanese patients presented with acute onset diabetic ketosis who had negative glutamic acid decarboxylase autoantibody (GADAb) to clarify the clinical characteristics of them. A total of consecutive 1,296 in-patients with newly diagnosed diabetes mellitus, who were admitted to our center from April 2003 to October 2008, were analyzed. Among them, 17 patients who presented with acute onset diabetic ketosis without acidosis, and found to be negative for GADAb, were included. They showed male preponderance (n = 15). Ten patients had history of excessive ingestion of sugar-containing soft drink. Patients who successfully withdrew insulin therapy by 6 months (n = 7) showed significantly higher insulin secretion capacity and higher body mass index at the time of diagnosis than those who continued insulin therapy at least for 6 months (n = 10). These findings suggest that some of Japanese patients who presented with acute onset diabetic ketosis and negative for GADAb share several clinical characteristics with atypical type 2 diabetes such as ketosis-prone diabetes and "soft-drink ketosis," but others do not. PMID:20960264

  5. Novel AE1 mutations in recessive distal renal tubular acidosis. Loss-of-function is rescued by glycophorin A.

    PubMed

    Tanphaichitr, V S; Sumboonnanonda, A; Ideguchi, H; Shayakul, C; Brugnara, C; Takao, M; Veerakul, G; Alper, S L

    1998-12-15

    The AE1 gene encodes band 3 Cl-/HCO3- exchangers that are expressed both in the erythrocyte and in the acid-secreting, type A intercalated cells of the kidney. Kidney AE1 contributes to urinary acidification by providing the major exit route for HCO3- across the basolateral membrane. Several AE1 mutations cosegregate with dominantly transmitted nonsyndromic renal tubular acidosis (dRTA). However, the modest degree of in vitro hypofunction exhibited by these dRTA-associated mutations fails to explain the disease phenotype in light of the normal urinary acidification associated with the complete loss-of-function exhibited by AE1 mutations linked to dominant spherocytosis. We report here novel AE1 mutations linked to a recessive syndrome of dRTA and hemolytic anemia in which red cell anion transport is normal. Both affected individuals were triply homozygous for two benign mutations M31T and K56E and for the loss-of-function mutation, G701D. AE1 G701D loss-of-function was accompanied by impaired trafficking to the Xenopus oocyte surface. Coexpression with AE1 G701D of the erythroid AE1 chaperonin, glycophorin A, rescued both AE1-mediated Cl- transport and AE1 surface expression in oocytes. The genetic and functional data both suggest that the homozygous AE1 G701D mutation causes recessively transmitted dRTA in this kindred with apparently normal erythroid anion transport. PMID:9854053

  6. Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy.

    PubMed

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

    2014-12-01

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

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

    PubMed Central

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

    2014-01-01

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

  8. The effects of subacute ruminal acidosis on sodium bicarbonate-supplemented water intake for lactating dairy cows.

    PubMed

    Cottee, G; Kyriazakis, I; Widowski, T M; Lindinger, M I; Cant, J P; Duffield, T F; Osborne, V R; McBride, B W

    2004-07-01

    Four multiparous ruminally fistulated Holstein dairy cows were used in an 8-wk experiment utilizing a repeated measures block design to determine the effects of subacute ruminal acidosis (SARA) on supplemented water intake. Animals were subjected to SARA, which was induced by replacing 25% of the ad libitum intake of the total mixed ration (dry matter basis) with 50:50 wheat:barley pellets utilizing a grain challenge model. Cows had free choice from 2 water bowls. One bowl contained water with sodium bicarbonate (SB) supplemented at 2.5 g/L. The other bowl contained unsupplemented water. Ruminal pH was monitored continuously during the trial using indwelling pH probes. The induction of SARA reduced daily mean ruminal pH and increased the duration when ruminal pH was below 6. The total mixed ration intake by the cows decreased during the SARA periods. The overall preference for SB-supplemented water did not change, as the preference ratio was similar during the control and SARA periods. During the period of greatest ruminal pH depression, total water intake was higher during the SARA periods than during the control periods. During SARA, there was no difference in the preference of a SB water source to unsupplemented water. During the period of day with the most severe ruminal pH depression, the lactating dairy cows subjected to SARA increased their total water intake. PMID:15328239

  9. Japanese cases of acute onset diabetic ketosis without acidosis in the absence of glutamic acid decarboxylase autoantibody.

    PubMed

    Iwasaki, Yorihiro; Hamamoto, Yoshiyuki; Kawasaki, Yukiko; Ikeda, Hiroki; Honjo, Sachiko; Wada, Yoshiharu; Koshiyama, Hiroyuki

    2010-04-01

    We report consecutive Japanese patients presented with acute onset diabetic ketosis who had negative glutamic acid decarboxylase autoantibody (GADAb) to clarify the clinical characteristics of them. A total of consecutive 1,296 in-patients with newly diagnosed diabetes mellitus, who were admitted to our center from April 2003 to October 2008, were analyzed. Among them, 17 patients who presented with acute onset diabetic ketosis without acidosis, and found to be negative for GADAb, were included. They showed male preponderance (n = 15). Ten patients had history of excessive ingestion of sugar-containing soft drink. Patients who successfully withdrew insulin therapy by 6 months (n = 7) showed significantly higher insulin secretion capacity and higher body mass index at the time of diagnosis than those who continued insulin therapy at least for 6 months (n = 10). These findings suggest that some of Japanese patients who presented with acute onset diabetic ketosis and negative for GADAb share several clinical characteristics with atypical type 2 diabetes such as ketosis-prone diabetes and "soft-drink ketosis," but others do not.

  10. Thiamine Deficiency in Tropical Pediatrics: New Insights into a Neglected but Vital Metabolic Challenge

    PubMed Central

    Hiffler, Laurent; Rakotoambinina, Benjamin; Lafferty, Nadia; Martinez Garcia, Daniel

    2016-01-01

    In humans, thiamine is a micronutrient prone to depletion that may result in severe clinical abnormalities. This narrative review summarizes current knowledge on thiamine deficiency (TD) and bridges the gap between pathophysiology and clinical presentation by integrating thiamine metabolism at subcellular level with its function to vital organs. The broad clinical spectrum of TD is outlined, with emphasis on conditions encountered in tropical pediatric practice. In particular, TD is associated with type B lactic acidosis and classic forms of beriberi in children, but it is often unrecognized. Other severe acute conditions are associated with hypermetabolism, inducing a functional TD. The crucial role of thiamine in infant cognitive development is also highlighted in this review, along with analysis of the potential impact of TD in refeeding syndrome during severe acute malnutrition (SAM). This review aims to increase clinical awareness of TD in tropical settings where access to diagnostic tests is poor, and advocates for an early therapeutic thiamine challenge in resource-limited settings. Moreover, it provides evidence for thiamine as treatment in critical conditions requiring metabolic resuscitation, and gives rationale to the consideration of increased thiamine supplementation in therapeutic foods for malnourished children. PMID:27379239

  11. Thiamine Deficiency in Tropical Pediatrics: New Insights into a Neglected but Vital Metabolic Challenge.

    PubMed

    Hiffler, Laurent; Rakotoambinina, Benjamin; Lafferty, Nadia; Martinez Garcia, Daniel

    2016-01-01

    In humans, thiamine is a micronutrient prone to depletion that may result in severe clinical abnormalities. This narrative review summarizes current knowledge on thiamine deficiency (TD) and bridges the gap between pathophysiology and clinical presentation by integrating thiamine metabolism at subcellular level with its function to vital organs. The broad clinical spectrum of TD is outlined, with emphasis on conditions encountered in tropical pediatric practice. In particular, TD is associated with type B lactic acidosis and classic forms of beriberi in children, but it is often unrecognized. Other severe acute conditions are associated with hypermetabolism, inducing a functional TD. The crucial role of thiamine in infant cognitive development is also highlighted in this review, along with analysis of the potential impact of TD in refeeding syndrome during severe acute malnutrition (SAM). This review aims to increase clinical awareness of TD in tropical settings where access to diagnostic tests is poor, and advocates for an early therapeutic thiamine challenge in resource-limited settings. Moreover, it provides evidence for thiamine as treatment in critical conditions requiring metabolic resuscitation, and gives rationale to the consideration of increased thiamine supplementation in therapeutic foods for malnourished children.

  12. Thiamine Deficiency in Tropical Pediatrics: New Insights into a Neglected but Vital Metabolic Challenge.

    PubMed

    Hiffler, Laurent; Rakotoambinina, Benjamin; Lafferty, Nadia; Martinez Garcia, Daniel

    2016-01-01

    In humans, thiamine is a micronutrient prone to depletion that may result in severe clinical abnormalities. This narrative review summarizes current knowledge on thiamine deficiency (TD) and bridges the gap between pathophysiology and clinical presentation by integrating thiamine metabolism at subcellular level with its function to vital organs. The broad clinical spectrum of TD is outlined, with emphasis on conditions encountered in tropical pediatric practice. In particular, TD is associated with type B lactic acidosis and classic forms of beriberi in children, but it is often unrecognized. Other severe acute conditions are associated with hypermetabolism, inducing a functional TD. The crucial role of thiamine in infant cognitive development is also highlighted in this review, along with analysis of the potential impact of TD in refeeding syndrome during severe acute malnutrition (SAM). This review aims to increase clinical awareness of TD in tropical settings where access to diagnostic tests is poor, and advocates for an early therapeutic thiamine challenge in resource-limited settings. Moreover, it provides evidence for thiamine as treatment in critical conditions requiring metabolic resuscitation, and gives rationale to the consideration of increased thiamine supplementation in therapeutic foods for malnourished children. PMID:27379239

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

    PubMed

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

    2012-06-21

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

  14. The importance of hyporheic sediment respiration in several mid-order Michigan rivers: Comparison between methods in estimates of lotic metabolism

    USGS Publications Warehouse

    Uzarski, D.G.; Stricker, C.A.; Burton, T.M.; King, D. K.; Steinman, A.D.

    2004-01-01

    Metabolism was measured in four Michigan streams, comparing estimates made using a flow-through chamber designed to include the hyporheic zone to a 20 cm depth and a traditional closed chamber that enclosed to a 5 cm depth. Mean levels of gross primary productivity and community respiration were consistently greater in the flow-through chamber than the closed chamber in all streams. Ratios of productivity to respiration (P/R) were consistently greater in the closed chambers than the flow-through chambers. P/R ratios were consistently <1 in all streams when estimated with flow-through chambers, suggesting heterotrophic conditions. Maintenance of stream ecosystem structure and function therefore is dependent on subsidies either from the adjacent terrestrial system or upstream sources. Our results suggest that stream metabolism studies that rely on extrapolation of closed chambers to the whole reach will most likely underestimate gross primary productivity and community respiration.

  15. Cadmium toxicity in diazotrophic Anabaena spp. adjudged by hasty up-accumulation of transporter and signaling and severe down-accumulation of nitrogen metabolism proteins.

    PubMed

    Singh, Prashant Kumar; Shrivastava, Alok Kumar; Chatterjee, Antra; Pandey, Sarita; Rai, Snigdha; Singh, Shilpi; Rai, L C

    2015-09-01

    Present study demonstrates interspecies variation in proteome and survival strategy of three Anabaena species i.e., Anabaena L31, Anabaena sp. PCC 7120 and Anabaena doliolum subjected to respective LC50 doses of Cd at 0, 1, 3, 5 and 7day intervals. The proteome coverage with 452 differentially accumulated proteins unveiled species and time specific expression and interaction network of proteins involved in important cellular functions. Statistical analysis of protein abundance across Cd-treated proteomes clustered their co-expression pattern into four groups viz., (i) early (days 1 and 3) accumulated proteins, (ii) proteins up-accumulated for longer duration, (iii) late (days 5 and 7) accumulated proteins, and (iv) mostly down-accumulated proteins. Appreciable growth of Cd treated A L31 over other two species may be ascribed to proteins contained in the first and second groups (belonging to energy and carbohydrate metabolism (TK, G6-PI, PGD, FBA, PPA, ATP synthase)), sulfur metabolism (GR, GST, PGDH, PAPS reductase, GDC-P, and SAM synthetase), fatty acid metabolism (AspD, PspA, SQD-1), phosphorous metabolism (PhoD, PstB and SQD1), molecular chaperones (Gro-EL, FKBP-type peptidylprolyl isomerase), and antioxidative defense enzymes (SOD-A, catalase). Anabaena sp. PCC 7120 harboring proteins largely from the third group qualified as a late accumulator and A. doliolum housing majority of proteins from the fourth group emerged as the most sensitive species. Thus early up-accumulation of transporter and signaling category proteins and drastic reduction of nitrogen assimilation proteins could be taken as a vital indicator of cadmium toxicity in Anabaena spp. This article is part of a Special Issue entitled: Proteomics in India.

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

    SciTech Connect

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

    2015-07-01

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

  17. [A 38 years old female with inflammatory myofibroblastic tumor and lactic acidosis].

    PubMed

    Gorham, J; Liberale, G; Haydar, H Nasser; De Saint Aubain, N; Meert, A P

    2016-01-01

    Inflammatory myofibroblastic tumors (IMT) are rare tumors. They were originally described in the lung, but they have been now observed in many others locations, mainly abdominal and pelvic. These tumors are usually benign but their recurrent nature and the presence of an abnormality of chromosome band 2p23 in some of them, suggest that some lesions form a true tumor entity. Surgical excision as complete as possible is the gold standard treatment. We report the case of a 38 years old female, who presented a recurrent metastasizing inflammatory myofibroblastic tumor causing lactic acidosis and other biological abnormalities such as hypercalcemia, hypoalbuminemia, hypoglycemia, disseminated intravascular coagulation and inflammatory syndrome. PMID:27487696

  18. Central Diabetes Insipidus, Central Hypothyroidism, Renal Tubular Acidosis and Dandy-Walker Syndrome: New Associations

    PubMed Central

    Alafif, MM; Aljaid, SS; Al-Agha, AE

    2015-01-01

    Dandy-Walker syndrome (DWS) is a rare brain malformation involving the cerebellum, and the fluid filled spaces around it, usually detected during the antenatal period or the early infancy. Clinically, it is characterized by mental retardation, developmental delay as well as cerebellar ataxia. It has been frequently associated with other conditions such as congenital heart diseases, primary hypothyroidism, and other disorders of the central nervous, gastrointestinal, genitourinary, and orthopedic systems. In this report, we describe a 3-month-old Saudi boy with the rare association of DWS with central diabetes insipidus, congenital central hypothyroidism, and type-2 renal tubular acidosis. PMID:25861538

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

    PubMed Central

    Peppicelli, Silvia; Bianchini, Francesca; Calorini, Lido

    2015-01-01

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

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

    PubMed

    Peppicelli, Silvia; Bianchini, Francesca; Calorini, Lido

    2015-01-01

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

  1. Identification of hibernating myocardium: a comparison between dobutamine echocardiography and study of perfusion and metabolism in patients with severe left ventricular dysfunction.

    PubMed

    Mariani, M A; Palagi, C; Donatelli, F; Mengozzi, G; Biadi, O; Vanoli, G; Landoni, C; Paolini, G; Lucignani, G; Fazio, F

    1995-01-01

    The distinction between fibrotic and viable myocardium is a key issue in patients with coronary artery disease and left ventricular dysfunction. Metabolic imaging with positron emission tomography (PET) and labeled tracers, along with the study of myocardial perfusion, is now available to identify hibernating myocardium. However, PET imaging of myocardial metabolism is a high-cost and time-consuming technique, and requires an on-site cyclotron. The aim of this study is to test the reliability of dobutamine echocardiography (DE) compared with PET imaging, for the identification of hibernating myocardium. In 16 patients, scheduled for myocardial revascularization, left ventricular shapes were divided in eight segments both for echocardiographic and nuclear study evaluation. All patients underwent a technetium 99m MIBI single-photon emission tomography stress-rest study of perfusion, a fluorine-18-labeled deoxyglucose (FDG(/PET study of metabolism, and a DE test (baseline, at a 5 micrograms/kg/min infusion of dobutamine for 8 minutes and at a 10 micrograms/kg/min dose for additional 8 minutes). Neither myocardial ischemia nor arrhythmia occurred during the DE test. Baseline echocardiograms showed 90 segments with wall motion abnormalities: wall motion impairment was decreased or reversed in 33 of 90 segments; it remained unchanged in 57 of 90 segments. In 32 of 33 segments considered viable on the basis of DE and in 21 of 57 segments with unchanged kinesis, some degree of FDG was detected. Thus, sensitivity and specificity of DE compared with nuclear studies was 60% and 97% respectively. Moreover, a good correlation and agreement (kappa = 0.51) between DE and the presence of FDG were found. We conclude that DE is a safe and reliable test for the screening of hibernating myocardium in patients with chronic coronary artery disease and left ventricular dysfunction.

  2. Important Role of FTO in the Survival of Rare Panresistant Triple-Negative Inflammatory Breast Cancer Cells Facing a Severe Metabolic Challenge

    PubMed Central

    Singh, Balraj; Kinne, Hannah E.; Milligan, Ryan D.; Washburn, Laura J.; Olsen, Mark; Lucci, Anthony

    2016-01-01

    We have previously shown that only 0.01% cells survive a metabolic challenge involving lack of glutamine in culture medium of SUM149 triple-negative Inflammatory Breast Cancer cell line. These cells, designated as SUM149-MA for metabolic adaptability, are resistant to chemotherapeutic drugs, and they efficiently metastasize to multiple organs in nude mice. We hypothesized that obesity-related molecular networks, which normally help in cellular and organismal survival under metabolic challenges, may help in the survival of MA cells. The fat mass and obesity-associated protein FTO is overexpressed in MA cells. Obesity-associated cis-acting elements in non-coding region of FTO regulate the expression of IRX3 gene, thus activating obesity networks. Here we found that IRX3 protein is significantly overexpressed in MA cells (5 to 6-fold) as compared to the parental SUM149 cell line, supporting our hypothesis. We also obtained evidence that additional key regulators of energy balance such as ARID5B, IRX5, and CUX1 P200 repressor could potentially help progenitor-like TNBC cells survive in glutamine-free medium. MO-I-500, a pharmacological inhibitor of FTO, significantly (>90%) inhibited survival and/or colony formation of SUM149-MA cells as compared to untreated cells or those treated with a control compound MO-I-100. Curiously, MO-I-500 treatment also led to decreased levels of FTO and IRX3 proteins in the SUM149 cells initially surviving in glutamine-free medium as compared to MO-I-100 treatment. Interestingly, MO-I-500 treatment had a relatively little effect on cell growth of either the SUM149 or SUM149-MA cell line when added to a complete medium containing glutamine that does not pose a metabolic challenge. Importantly, once selected and cultured in glutamine-free medium, SUM149-MA cells were no longer affected by MO-I-500 even in Gln-free medium. We conclude that panresistant MA cells contain interconnected molecular networks that govern developmental status and

  3. Important Role of FTO in the Survival of Rare Panresistant Triple-Negative Inflammatory Breast Cancer Cells Facing a Severe Metabolic Challenge.

    PubMed

    Singh, Balraj; Kinne, Hannah E; Milligan, Ryan D; Washburn, Laura J; Olsen, Mark; Lucci, Anthony

    2016-01-01

    We have previously shown that only 0.01% cells survive a metabolic challenge involving lack of glutamine in culture medium of SUM149 triple-negative Inflammatory Breast Cancer cell line. These cells, designated as SUM149-MA for metabolic adaptability, are resistant to chemotherapeutic drugs, and they efficiently metastasize to multiple organs in nude mice. We hypothesized that obesity-related molecular networks, which normally help in cellular and organismal survival under metabolic challenges, may help in the survival of MA cells. The fat mass and obesity-associated protein FTO is overexpressed in MA cells. Obesity-associated cis-acting elements in non-coding region of FTO regulate the expression of IRX3 gene, thus activating obesity networks. Here we found that IRX3 protein is significantly overexpressed in MA cells (5 to 6-fold) as compared to the parental SUM149 cell line, supporting our hypothesis. We also obtained evidence that additional key regulators of energy balance such as ARID5B, IRX5, and CUX1 P200 repressor could potentially help progenitor-like TNBC cells survive in glutamine-free medium. MO-I-500, a pharmacological inhibitor of FTO, significantly (>90%) inhibited survival and/or colony formation of SUM149-MA cells as compared to untreated cells or those treated with a control compound MO-I-100. Curiously, MO-I-500 treatment also led to decreased levels of FTO and IRX3 proteins in the SUM149 cells initially surviving in glutamine-free medium as compared to MO-I-100 treatment. Interestingly, MO-I-500 treatment had a relatively little effect on cell growth of either the SUM149 or SUM149-MA cell line when added to a complete medium containing glutamine that does not pose a metabolic challenge. Importantly, once selected and cultured in glutamine-free medium, SUM149-MA cells were no longer affected by MO-I-500 even in Gln-free medium. We conclude that panresistant MA cells contain interconnected molecular networks that govern developmental status and

  4. Draft Genome Sequence of Lactobacillus delbrueckii Strain #22 Isolated from a Patient with Short Bowel Syndrome and Previous d-Lactic Acidosis and Encephalopathy.

    PubMed

    Domann, Eugen; Fischer, Florence; Glowatzki, Fabian; Fritzenwanker, Moritz; Hain, Torsten; Zechel-Gran, Silke; Giffhorn-Katz, Susanne; Neubauer, Bernd A

    2016-01-01

    d-Lactic acidosis with associated encephalopathy caused by overgrowth of intestinal lactic acid bacteria is a rarely diagnosed neurological complication of patients with short bowel syndrome. Here, we report the draft genome sequence of Lactobacillus delbrueckii strain #22 isolated from a patient with short bowel syndrome and previous d-lactic acidosis/encephalopathy. PMID:27469967

  5. Draft Genome Sequence of Lactobacillus delbrueckii Strain #22 Isolated from a Patient with Short Bowel Syndrome and Previous d-Lactic Acidosis and Encephalopathy

    PubMed Central

    Fischer, Florence; Glowatzki, Fabian; Fritzenwanker, Moritz; Hain, Torsten; Zechel-Gran, Silke; Giffhorn-Katz, Susanne; Neubauer, Bernd A.

    2016-01-01

    d-Lactic acidosis with associated encephalopathy caused by overgrowth of intestinal lactic acid bacteria is a rarely diagnosed neurological complication of patients with short bowel syndrome. Here, we report the draft genome sequence of Lactobacillus delbrueckii strain #22 isolated from a patient with short bowel syndrome and previous d-lactic acidosis/encephalopathy. PMID:27469967

  6. A Case of Myopathy, Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS) Syndrome with Intracardiac Thrombus [corrected].

    PubMed

    Joo, Jung-Chul; Seol, Myung Do; Yoon, Jin Won; Lee, Young Soo; Kim, Dong-Keun; Choi, Yong Hoon; Ahn, Hyo Seong; Cho, Wook Hyun

    2013-03-01

    Myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a multisystem clinical syndrome manifested by mitochondrial myopathy, encephalopathy, lactic acidosis and recurrent stroke-like episodes. A 27-year-old female with MELAS syndrome presented with cerebral infarction. Echocardiography revealed a thrombus attached to the apex of the hypertrophied left ventricle, with decreased systolic function. The embolism of the intracardiac thrombus might have been the cause of stroke. There should be more consideration given to the increased possibility of intracardiac thrombus formation when a MELAS patient with cardiac involvement is encountered.

  7. Impact of subacute ruminal acidosis (SARA) adaptation on rumen microbiota in dairy cattle using pyrosequencing.

    PubMed

    Mao, S Y; Zhang, R Y; Wang, D S; Zhu, W Y

    2013-12-01

    The objective of this study was to evaluate the changes in bacterial populations in the rumen of dairy cattle following adaptation to subacute ruminal acidosis (SARA) using 16S rRNA gene pyrosequencing. Rumen contents were collected from four cattle adapted to either a 40% (control diet, COD) or 70% (SARA induction diet, SAID) concentrate feeds. DNA was extracted from each of the samples. Bacterial 16S rRNA genes of ruminal DNA extracts were PCR amplified with 2 bar coded primer sets and sequenced by 454 pyrosequencing. At a high taxonomic level, the percentage of Proteobacteria and Bacteroidetes were reduced by SAID feeding, whereas Firmicutes and Actinobacteria were more abundant in the SAID than in the COD group. At the genus level, as compared with the COD group, the abundances of Prevotella, Treponema, Anaeroplasma, Papillibacter, Acinetobacter and unclassified populations including unclassified Lentisphaerae, and unclassified bacteria were lower (P < 0.05), while the percentages of Ruminococcus, Atopobium, unclassified Clostridiales and Bifidobacterium were increased (P < 0.05) in the SAID group. Feeding of SAID reduced (P < 0.001) the diversity of the rumen microbial community. Taken together, our findings provide a comprehensive picture of current knowledge of the community structure of the rumen bacterial ecosystem during SARA, and enhance our understanding about the ruminal microbial ecology that may be useful in the prevention of ruminal acidosis.

  8. [Higher Brain Dysfunction in Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS)].

    PubMed

    Ichikawa, Hiroo

    2016-02-01

    Stroke-like episodes are one of the cardinal features of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and occur in 84-99% of the patients. The affected areas detected on neuroimaging do not have classical vascular distribution, and involve predominantly the temporal, parietal and occipital lobes. Thus, the neurological symptoms including higher brain dysfunction correlate with this topographical distribution. In association with the occipital lobe involvement, the most frequent symptom is cortical blindness. Other symptoms have been occasionally reported in case reports: visual agnosia, prosopagnosia, cortical deafness, auditory agnosia, topographical disorientation, various types of aphasia, hemispatial neglect, and so on. On the other hand, cognitive decline associated with more diffuse brain impairment rather than with focal stroke-like lesions has been postulated. This condition is also known as mitochondrial dementia. Domains of cognitive dysfunction include abstract reasoning, verbal memory, visual memory, language (naming and fluency), executive or constructive functions, attention, and visuospatial function. Cognitive functions and intellectual abilities may decline from initially minimal cognitive impairment to dementia. To date, the neuropsychological and neurologic impairment has been reported to be associated with cerebral lactic acidosis as estimated by ventricular spectroscopic lactate levels. PMID:26873235

  9. [Higher Brain Dysfunction in Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS)].

    PubMed

    Ichikawa, Hiroo

    2016-02-01

    Stroke-like episodes are one of the cardinal features of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and occur in 84-99% of the patients. The affected areas detected on neuroimaging do not have classical vascular distribution, and involve predominantly the temporal, parietal and occipital lobes. Thus, the neurological symptoms including higher brain dysfunction correlate with this topographical distribution. In association with the occipital lobe involvement, the most frequent symptom is cortical blindness. Other symptoms have been occasionally reported in case reports: visual agnosia, prosopagnosia, cortical deafness, auditory agnosia, topographical disorientation, various types of aphasia, hemispatial neglect, and so on. On the other hand, cognitive decline associated with more diffuse brain impairment rather than with focal stroke-like lesions has been postulated. This condition is also known as mitochondrial dementia. Domains of cognitive dysfunction include abstract reasoning, verbal memory, visual memory, language (naming and fluency), executive or constructive functions, attention, and visuospatial function. Cognitive functions and intellectual abilities may decline from initially minimal cognitive impairment to dementia. To date, the neuropsychological and neurologic impairment has been reported to be associated with cerebral lactic acidosis as estimated by ventricular spectroscopic lactate levels.

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

    PubMed Central

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

    2013-01-01

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

  11. Evidence that the Severity of Depletion of Inorganic Phosphate Determines the Severity of the Disturbance of Adenine Nucleotide Metabolism in the Liver and Renal Cortex of the Fructose-Loaded Rat

    PubMed Central

    Morris, R. Curtis; Nigon, Kathleen; Reed, Elizabeth B.

    1978-01-01

    To test the hypothesis that in both the liver and renal cortex of the fructose-loaded rat, severity of depletion of inorganic phosphate (Pi), and not the magnitude of accumulation of fructose-1-phosphate (F-1-P), determines the severity of the dose-dependent reduction of ATP, we intraperitoneally injected fed rats with fructose, 20 and 40 μmol/g, alone, and at the higher load, in combination with (a) sodium phosphate, 20 μmol/g, administered shortly beforehand or subsequently or, (b) adenosine, 2 μmol/g, administered beforehand. The following observations were made: (a) With fructose loading alone, at the higher load, both Pi and total adenine nucleotides (TAN) were reduced by one third in the renal cortex and (as previously observed) by two thirds in the liver; and at either load, the reduction of ATP (and TAN) and the accumulation of F-1-P were less severe in the renal cortex than in the liver. (b) Prior phosphate loading largely prevented the reductions of ATP and TAN in the renal cortex and significantly attenuated them in the liver, yet doubled the renal cortical accumulation of F-1-P. (c) Adenosine loading substantially attenuated the reductions of ATP, TAN, and Pi only in the renal cortex. (d) ATP varied directly with Pi (P < 0.001, r = 0.98) in the domain of control and reduced values of Pi taken from both liver and renal cortex. (e) As judged from tissue and plasma concentrations of fructose and glucose, and tissue concentrations of fructose-6-phosphate and glucose-6-phosphate, the rate at which the renal cortex and liver converted fructose to glucose was much lower at the higher fructose load. (f) Prior phosphate loading prevented this decrease in rate in the renal cortex and attenuated it in the liver; adenosine loading attenuated it only in the renal cortex. We conclude that in both the renal cortex of the fructose-loaded rat: (a) Depletion of Pi is critical to the causation of the reductions in both ATP and TAN and, at the higher fructose load, of a

  12. Clinical approach to inherited metabolic disorders in neonates.

    PubMed

    Saudubray, J M; Narcy, C; Lyonnet, L; Bonnefont, J P; Poll The, B T; Munnich, A

    1990-01-01

    Most inborn errors of intermediary metabolism presenting in the neonatal period fall schematically into three clinical categories: (1) those which lead to a neurological distress 'intoxication type' with a symptom-free interval, vomiting, comas, hypertonia, abnormal movements and frequent humoral disturbances (organic acidaemias, congenital urea cycle defects); (2) those which lead to a neurological distress 'energy deficiency' type. Frequent symptoms in this group include hyperlactacidaemia, severe hypotonia, cardiomyopathy, failure to thrive and malformations (congenital lactic acidaemias, fatty acid oxidation defects, peroxysomal disorders); (3) those which present evidence of liver dysfunction and hepatomegaly (glycogenesis, neoglucogenesis defects, galactosaemia, fructosaemia, tyrosinaemia type I). According to these three major clinical presentations and according to the proper use of few screening tests (blood gases, glucose, ammonia, lactic acid, electrolytes, acetest), we propose a method of diagnosis which groups these children into five schematical syndromes: type I MSUD; type II organic acidaemias; type III; congenital lactic acidosis; type IVa, urea cycle defects; type IVb, non-ketotic hyperglycinaemia, sulfite oxidase deficiency, peroxisomal disorders; type V liver dysfunctions. Once the above classification has been made, sophisticated and specific investigations can be planned (amino acid chromatography, organic acid chromatography, enzymatic studies, etc).

  13. Traumatic rhabdomyolysis from severe beating--experience of volume diuresis in 200 patients.

    PubMed

    Knottenbelt, J D

    1994-08-01

    Fluid loading with balanced salt solution (BSS) was carried out in 200 patients with extensive soft tissue injuries from severe beatings. Urinary volume and dipstick specific gravity testing were used to monitor renal function with administration of furosemide for persistent oliguria. Acute intrinsic renal failure (AIRF) occurred in 21 patients (10.5%) and five patients died (2.5%); two of hyperkalemia, two of sepsis and one of multiple organ failure. Significantly increased rates of AIRF and death were associated with injury-admission intervals of more than 12 hours, severe metabolic acidosis, low initial hemoglobin, heavy pigmenturia, and high serum creatine kinase (CK) levels. An increased serum creatinine/BUN ratio was noted in four of the five patients who died. An average of 7.5 L fluids was needed in non-AIRF patients to achieve adequate diuresis with a mean positive fluid balance of 4.7 L. No patient without pigmenturia developed AIRF. Balanced salt solution volume diuresis supplemented with furosemide as necessary appears to be safe and effective in preventing AIRF in soft tissue injuries sustained in beatings. PMID:8064919

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The purpose of this study was to investigate variability among individual cows for their susceptibility to ruminal acidosis (RA) pre- and postpartum, and determine whether this variability was related to differences in their ruminal bacterial community composition (BCC). Variability in susceptibilit...

  15. The Role of Plasma and Urine Metabolomics in Identifying New Biomarkers in Severe Newborn Asphyxia: A Study of Asphyxiated Newborn Pigs following Cardiopulmonary Resuscitation

    PubMed Central

    Sachse, Daniel; Solevåg, Anne Lee; Berg, Jens Petter; Nakstad, Britt

    2016-01-01

    Background Optimizing resuscitation is important to prevent morbidity and mortality from perinatal asphyxia. The metabolism of cells and tissues is severely disturbed during asphyxia and resuscitation, and metabolomic analyses provide a snapshot of many small molecular weight metabolites in body fluids or tissues. In this study metabolomics profiles were studied in newborn pigs that were asphyxiated and resuscitated using different protocols to identify biomarkers for subject characterization, intervention effects and possibly prognosis. Methods A total of 125 newborn Noroc pigs were anesthetized, mechanically ventilated and inflicted progressive asphyxia until asystole. Pigs were randomized to resuscitation with a FiO2 0.21 or 1.0, different duration of ventilation before initiation of chest compressions (CC), and different CC to ventilation ratios. Plasma and urine samples were obtained at baseline, and 2 h and 4 h after return of spontaneous circulation (ROSC, heart rate > = 100 bpm). Metabolomics profiles of the samples were analyzed by nuclear magnetic resonance spectroscopy. Results Plasma and urine showed severe metabolic alterations consistent with hypoxia and acidosis 2 h and 4 h after ROSC. Baseline plasma hypoxanthine and lipoprotein concentrations were inversely correlated to the duration of hypoxia sustained before asystole occurred, but there was no evidence for a differential metabolic response to the different resuscitation protocols or in terms of survival. Conclusions Metabolic profiles of asphyxiated newborn pigs showed severe metabolic alterations. Consistent with previously published reports, we found no evidence of differences between established and alternative resuscitation protocols. Lactate and pyruvate may have a prognostic value, but have to be independently confirmed. PMID:27529347

  16. Attainment and Maintenance of Normal Stature with Alkali Therapy in Infants and Children with Classic Renal Tubular Acidosis

    PubMed Central

    McSherry, Elisabeth; Morris, R. Curtis

    1978-01-01

    Growth was evaluated in a group of 10 infants and children with familial or idiopathic classic renal tubular acidosis in whom alkali therapy was initiated at ages ranging from 8 days to 9.5 yr and administered at dosage schedules documented to sustain correction of acidosis in at least four prolonged observation periods on the Pediatric Clinical Research Ward. When alkali therapy was begun, six patients (four infants and two children) were stunted (height <2.5 SD below mean). Of the four who were not, two infants were too young (<2 wk of age) to have become stunted, and two children had been documented earlier to be nonacidotic. At the start of alkali therapy, the heights of the patients correlated inversely with the maximal possible duration of prior acidosis. With sustained alkali therapy: (a) each patient attained and maintained normal stature; (b) the mean height of the 10 patients increased from the 1.4±4 to the 37.0±33 percentile (of a normal age- and sex-matched population); (c) the mean height reached the 69th percentile in the eight patients whose heights could be analyzed according to parental prediction (Tanner technique); (d) the rate of growth increased two- to threefold, and normal heights were attained within 6 mo of initiating alkali therapy in the stunted infants and within 3 yr in the stunted children; (e) the height attained correlated inversely with the maximal possible duration of acidosis (before alkali therapy) only in those patients in whom alkali therapy was started after 6 mo of age, and not in those treated earlier. The amount of alkali required to sustain correction of acidosis increased substantially during the course of treatment in each patient. The maximal alkali requirement ranged from 4.8 to 14.1 meq/kg per day, and in each patient its amount was determined principally by the magnitude of renal bicarbonate wasting. Images PMID:621287

  17. When should MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis?

    PubMed

    Lorenzoni, Paulo José; Werneck, Lineu Cesar; Kay, Cláudia Suemi Kamoi; Silvado, Carlos Eduardo Soares; Scola, Rosana Herminia

    2015-11-01

    Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a rare mitochondrial disorder. Diagnostic criteria for MELAS include typical manifestations of the disease: stroke-like episodes, encephalopathy, evidence of mitochondrial dysfunction (laboratorial or histological) and known mitochondrial DNA gene mutations. Clinical features of MELAS are not necessarily uniform in the early stages of the disease, and correlations between clinical manifestations and physiopathology have not been fully elucidated. It is estimated that point mutations in the tRNALeu(UUR) gene of the DNAmt, mainly A3243G, are responsible for more of 80% of MELAS cases. Morphological changes seen upon muscle biopsy in MELAS include a substantive proportion of ragged red fibers (RRF) and the presence of vessels with a strong reaction for succinate dehydrogenase. In this review, we discuss mainly diagnostic criterion, clinical and laboratory manifestations, brain images, histology and molecular findings as well as some differential diagnoses and current treatments.

  18. Toxigenic and metabolic causes of ketosis and ketoacidotic syndromes.

    PubMed

    Cartwright, Martina M; Hajja, Waddah; Al-Khatib, Sofian; Hazeghazam, Maryam; Sreedhar, Dharmashree; Li, Rebecca Na; Wong-McKinstry, Edna; Carlson, Richard W

    2012-10-01

    Ketoacidotic syndromes are frequently encountered in acute care medicine. This article focuses on ketosis and ketoacidotic syndromes associated with intoxications, alcohol abuse, starvation, and certain dietary supplements as well as inborn errors of metabolism. Although all of these various processes are characterized by the accumulation of ketone bodies and metabolic acidosis, there are differences in the mechanisms, clinical presentations, and principles of therapy for these heterogeneous disorders. Pathophysiologic mechanisms that account for these disorders are presented, as well as guidance regarding identification and management.

  19. Regulation of intracellular pH in cnidarians: response to acidosis in Anemonia viridis.

    PubMed

    Laurent, Julien; Venn, Alexander; Tambutté, Éric; Ganot, Philippe; Allemand, Denis; Tambutté, Sylvie

    2014-02-01

    The regulation of intracellular pH (pHi) is a fundamental aspect of cell physiology that has received little attention in studies of the phylum Cnidaria, which includes ecologically important sea anemones and reef-building corals. Like all organisms, cnidarians must maintain pH homeostasis to counterbalance reductions in pHi, which can arise because of changes in either intrinsic or extrinsic parameters. Corals and sea anemones face natural daily changes in internal fluids, where the extracellular pH can range from 8.9 during the day to 7.4 at night. Furthermore, cnidarians are likely to experience future CO₂-driven declines in seawater pH, a process known as ocean acidification. Here, we carried out the first mechanistic investigation to determine how cnidarian pHi regulation responds to decreases in extracellular and intracellular pH. Using the anemone Anemonia viridis, we employed confocal live cell imaging and a pH-sensitive dye to track the dynamics of pHi after intracellular acidosis induced by acute exposure to decreases in seawater pH and NH₄Cl prepulses. The investigation was conducted on cells that contained intracellular symbiotic algae (Symbiodinium sp.) and on symbiont-free endoderm cells. Experiments using inhibitors and Na⁺-free seawater indicate a potential role of Na⁺/H⁺ plasma membrane exchangers (NHEs) in mediating pHi recovery following intracellular acidosis in both cell types. We also measured the buffering capacity of cells, and obtained values between 20.8 and 43.8 mM per pH unit, which are comparable to those in other invertebrates. Our findings provide the first steps towards a better understanding of acid-base regulation in these basal metazoans, for which information on cell physiology is extremely limited. PMID:24256552

  20. Prevalence and consequences of subacute ruminal acidosis in German dairy herds

    PubMed Central

    2013-01-01

    Background The prevalence and the clinical consequences of subacute ruminal acidosis (SARA) in dairy cows are still poorly understood. In order to evaluate the prevalence of SARA, 26 German dairy farms were included in a field study. In each herd, between 11 and 14 lactating dairy cows were examined for their ruminal pH using rumenocentesis. Milk production data and farm management characteristics were recorded. Each farm was scored for lameness prevalence among lactating animals, and body condition score was recorded three times four to five weeks apart in all animals examined. Farms were grouped on basis of ruminal pH and compared for lameness, body condition, milk production parameters and style of management. Animals were grouped on basis of their measured ruminal pH and compared accordingly for milk production parameters and body condition score. Results Of 315 cows examined, 63 individuals (20%) exhibited a ruminal pH of ≤ 5.5 at time of rumenocentesis. Of 26 farms examined, eleven farms had three or more of their cows experiencing a ruminal pH of ≤ 5.5 and were classified as likely experiencing subacute ruminal acidosis. These farms tended to be bigger than the others and offered less lying space to the lactating cows. There was no clear tendency regarding lameness. Among individual cows, animals with a low ruminal pH of ≤ 5.5 were found to be in significantly poorer body condition than animals with higher pH values (p < 0,05). Conclusions The study shows 11 out of 26 of herds likely experiencing SARA. Bigger herds tend to be at a higher risk for SARA, while individuals with low ruminal pH tend to be lower in body condition. The study points to the importance of management in preventing SARA. PMID:23805878

  1. Myocardial contractility recovery during hypercapnic acidosis: its dissociation from recovery in pHi by ryanodine.

    PubMed

    Pérez, N G; Mattiazzi, A R; Camilion de Hurtado, M C; Cingolani, H E

    1995-01-01

    Myocardial contractility falls quickly during respiratory acidosis but if acidosis is maintained a slow gradual return towards control state is detected. In cat papillary muscle, changes in developed tension (DT) during isometric contractions (pacing rate 0.2 Hz) and intracellular pH (pHi) were continuously monitored before and during hypercapnia to study the contribution of pHi recovery to the recovery of contractility. On exposure to hypercapnia (extracellular pH [pHo] = 6.90) DT fell to 50.33 +/- 2.20% of control and pHi decreased from 7.21 +/- 0.05 to 6.90 +/- 0.02. After 30 mins of hypercapnia DT recovered to 64.66 +/- 4.05% of control, but no significant recovery in pHi was detected. Intracellular sodium concentration slowly rose to 61.05 +/- 23.79% over basal level 10 mins after the onset of hypercapnia and it remained elevated for 10 mins before gradually returning to control levels. When pHo was kept at 7.40 during hypercapnia by increasing sodium bicarbonate concentration, DT recovered to 79.11 +/- 6.94% of control after 30 mins of hypercapnia, while a significant recovery of pHi (0.12 +/- 0.02 pH units) was detected. Low extracellular sodium concentration diminished contractility recovery during hypercapnia without changing the initial decrease in DT. 5-[N-ethyl-N-isopropyl] amiloride (EIPA) (5 microM) increased the initial fall in DT to 34.33 +/- 8.68% of control and abolished the recovery. Sarcoplasmic reticulum (SR) inhibition by ryanodine (0.5 microM) markedly reduced the recovery of contractility without altering the recovery in pHi.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7656191

  2. Regulation of intracellular pH in cnidarians: response to acidosis in Anemonia viridis.

    PubMed

    Laurent, Julien; Venn, Alexander; Tambutté, Éric; Ganot, Philippe; Allemand, Denis; Tambutté, Sylvie

    2014-02-01

    The regulation of intracellular pH (pHi) is a fundamental aspect of cell physiology that has received little attention in studies of the phylum Cnidaria, which includes ecologically important sea anemones and reef-building corals. Like all organisms, cnidarians must maintain pH homeostasis to counterbalance reductions in pHi, which can arise because of changes in either intrinsic or extrinsic parameters. Corals and sea anemones face natural daily changes in internal fluids, where the extracellular pH can range from 8.9 during the day to 7.4 at night. Furthermore, cnidarians are likely to experience future CO₂-driven declines in seawater pH, a process known as ocean acidification. Here, we carried out the first mechanistic investigation to determine how cnidarian pHi regulation responds to decreases in extracellular and intracellular pH. Using the anemone Anemonia viridis, we employed confocal live cell imaging and a pH-sensitive dye to track the dynamics of pHi after intracellular acidosis induced by acute exposure to decreases in seawater pH and NH₄Cl prepulses. The investigation was conducted on cells that contained intracellular symbiotic algae (Symbiodinium sp.) and on symbiont-free endoderm cells. Experiments using inhibitors and Na⁺-free seawater indicate a potential role of Na⁺/H⁺ plasma membrane exchangers (NHEs) in mediating pHi recovery following intracellular acidosis in both cell types. We also measured the buffering capacity of cells, and obtained values between 20.8 and 43.8 mM per pH unit, which are comparable to those in other invertebrates. Our findings provide the first steps towards a better understanding of acid-base regulation in these basal metazoans, for which information on cell physiology is extremely limited.

  3. Genetic Variation in Iron Metabolism Is Associated with Neuropathic Pain and Pain Severity in HIV-Infected Patients on Antiretroviral Therapy

    PubMed Central

    Kallianpur, Asha R.; Jia, Peilin; Ellis, Ronald J.; Zhao, Zhongming; Bloss, Cinnamon; Wen, Wanqing; Marra, Christina M.; Hulgan, Todd; Simpson, David M.; Morgello, Susan; McArthur, Justin C.; Clifford, David B.; Collier, Ann C.; Gelman, Benjamin B.; McCutchan, J. Allen; Franklin, Donald; Samuels, David C.; Rosario, Debralee; Holzinger, Emily; Murdock, Deborah G.; Letendre, Scott; Grant, Igor

    2014-01-01

    HIV sensory neuropathy and distal neuropathic pain (DNP) are common, disabling complications associated with combination antiretroviral therapy (cART). We previously associated iron-regulatory genetic polymorphisms with a reduced risk of HIV sensory neuropathy during more neurotoxic types of cART. We here evaluated the impact of polymorphisms in 19 iron-regulatory genes on DNP in 560 HIV-infected subjects from a prospective, observational study, who underwent neurological examinations to ascertain peripheral neuropathy and structured interviews to ascertain DNP. Genotype-DNP associations were explored by logistic regression and permutation-based analytical methods. Among 559 evaluable subjects, 331 (59%) developed HIV-SN, and 168 (30%) reported DNP. Fifteen polymorphisms in 8 genes (p<0.05) and 5 variants in 4 genes (p<0.01) were nominally associated with DNP: polymorphisms in TF, TFRC, BMP6, ACO1, SLC11A2, and FXN conferred reduced risk (adjusted odds ratios [ORs] ranging from 0.2 to 0.7, all p<0.05); other variants in TF, CP, ACO1, BMP6, and B2M conferred increased risk (ORs ranging from 1.3 to 3.1, all p<0.05). Risks associated with some variants were statistically significant either in black or white subgroups but were consistent in direction. ACO1 rs2026739 remained significantly associated with DNP in whites (permutation p<0.0001) after correction for multiple tests. Several of the same iron-regulatory-gene polymorphisms, including ACO1 rs2026739, were also associated with severity of DNP (all p<0.05). Common polymorphisms in iron-management genes are associated with DNP and with DNP severity in HIV-infected persons receiving cART. Consistent risk estimates across population subgroups and persistence of the ACO1 rs2026739 association after adjustment for multiple testing suggest that genetic variation in iron-regulation and transport modulates susceptibility to DNP. PMID:25144566

  4. [The intracellular metabolism of neutrophils under different forms of ischemic heart disease].

    PubMed

    Kratnov, A E

    2012-12-01

    The article deals with the results of study of the intracellular metabolism of neutrophils in 96 patients including 56 (58.3%) patients with ischemic heart disease. It is established that in patients with ischemic heart disease as compared with patients without ischemic heart disease occurs the increase of neutrophils producing of active forms of oxygen against the background of decrease of intracellular activity of catalase and increase of concentration of lactate in phagocytes. Under severing of ischemic heart disease from unstable stenocardia to cardiac infarction the activation of oxygen-depending metabolism of neutrophils conditioned by increase of concentration of immune complexes circulating in blood was not compensated by increasing of intracellular activity of enzymes of system of antioxidant defense. The maximum activation of NAD(F)N-oxidase of neutrophils (production of superoxide anion-radical) was detected in patients with cardiac infarction with Q-wave. This condition was accompanied by maximal increase of concentration of lactate in phagocytes up to twice higher exceed the level of indicators in patients without ischemic heart disease. It can be assumed that in conditions of acute hypoxia occurring under myocardium ischemia in patients with ischemic heart disease, the lactate production increases in neutrophils hence the triggering of development of intracellular acidosis, impact of oxygen-depending factors and phagocytes destruction.

  5. Embryonic phenotype, β-carotene and retinoid metabolism upon maternal supplementation of β-carotene in a mouse model of severe vitamin A deficiency

    PubMed Central

    Wassef, L.; Spiegler, E.; Quadro, L.

    2013-01-01

    We investigated the effect of β-carotene (bC) supplementation during pregnancy in a mouse model of severe vitamin A deficiency, i.e. Lrat−/−Rbp−/− dams maintained on a vitamin A-deficient diet during gestation. bC, a provitamin A carotenoid, can be enzymatically cleaved to form vitamin A for use by the developing embryo. We found that an acute supplementation (13.5 days post coitum, dpc) of bC to Lrat−/−Rbp−/− dams on a vitamin A-deficient diet activated transcriptional mechanisms in the developing tissues to maximize the utilization of bC provided to the dams. Nevertheless, these regulatory mechanisms are inefficient under this regimen, as the embryonic phenotype was not improved. We further investigated the effect of a repeated supplementation of bC during a crucial developmental period (6.5–9.5 dpc) on the above-mentioned mouse model. This treatment improved the embryonic abnormalities, as 40% of the embryos showed a normal phenotype. In addition, analysis of retinoic acid-responsive genes, such as Cyp26a1 in these embryos suggests that bC cleavage results in the production of retinoic acid which then can be used by the embryo. Taken together, these in vivo studies show that bC can be used as a source of vitamin A for severely vitamin A-deficient mammalian embryos. PMID:23871845

  6. Profiling genetic variation along the androgen biosynthesis and metabolism pathways implicates several single nucleotide polymorphisms and their combinations as prostate cancer risk factors.

    PubMed

    Mononen, Nina; Seppälä, Eija H; Duggal, Priya; Autio, Ville; Ikonen, Tarja; Ellonen, Pekka; Saharinen, Juha; Saarela, Janna; Vihinen, Mauno; Tammela, Teuvo L J; Kallioniemi, Olli; Bailey-Wilson, Joan E; Schleutker, Johanna

    2006-01-15

    Several candidate genes along androgen pathway have been suggested to affect prostate cancer risk but no single gene seems to be overwhelmingly important for a large fraction of the patients. In this study, we first screened for variants in candidate genes and then chose to explore the association between 18 variants and prostate cancer risk by genotyping DNA samples from unselected (n = 847) and familial (n = 121) prostate cancer patients and population controls (n = 923). We identified a novel single nucleotide polymorphism (SNP) in the CYP19A1 gene, T201M, with a mild significant association with prostate cancer [odds ratio (OR), 2.04; 95% confidence interval (95% CI), 1.03-4.03; P = 0.04]. Stratified analysis revealed that this risk was most apparent in patients with organ-confined (T(1)-T(2)) and low-grade (WHO grade 1) tumors (OR, 5.42; 95% CI, 2.33-12.6; P < 0.0001). In contrast, CYP17A1 -34T>C alteration was associated with moderate to poorly differentiated (WHO grade 2-3) organ-confined disease (OR, 1.42; 95% CI, 1.09-1.83; P = 0.007). We also tested a multigenic model of prostate cancer risk by calculating the joint effect of CYP19A1 T201M with five other common SNPs. Individuals carrying both the CYP19A1 and KLK3 -252A>G variant alleles had a significantly increased risk for prostate cancer (OR, 2.87; 95% CI, 1.10-7.49; P = 0.03). In conclusion, our results suggest that several SNPs along the androgen pathway, especially in CYP19A1 and CYP17A1, may influence prostate cancer development and progression. These genes may have different contributions to distinct clinical subsets as well as combinatorial effects in others illustrating that profiling and joint analysis of several genes along each pathway may be needed to understand genetic contributions to prostate cancer etiology.

  7. The central role of chloride in the metabolic acid-base changes in canine parvoviral enteritis.

    PubMed

    Burchell, Richard K; Schoeman, Johan P; Leisewitz, Andrew L

    2014-04-01

    The acid-base disturbances in canine parvoviral (CPV) enteritis are not well described. In addition, the mechanisms causing these perturbations have not been fully elucidated. The purpose of the present study was to assess acid-base changes in puppies suffering from CPV enteritis, using a modified strong ion model (SIM). The hypothesis of the study was that severe acid-base disturbances would be present and that the SIM would provide insights into pathological mechanisms, which have not been fully appreciated by the Henderson-Hasselbalch model. The study analysed retrospective data, obtained from 42 puppies with confirmed CPV enteritis and 10 healthy control dogs. The CPV-enteritis group had been allocated a clinical score, to allow classification of the data according to clinical severity. The effects of changes in free water, chloride, l-lactate, albumin and phosphate were calculated, using a modification of the base excess algorithm. When the data were summated for each patient, and correlated to each individual component, the most important contributor to the metabolic acid-base changes, according to the SIM, was chloride (P<0.001). Severely-affected animals tended to demonstrate hypochloraemic alkalosis, whereas mildly-affected puppies had a hyperchloraemic acidosis (P=0.007). In conclusion, the acid-base disturbances in CPV enteritis are multifactorial and complex, with the SIM providing information in terms of the origin of these changes.

  8. Correlation analysis of hypothalamic mRNA levels of appetite regulatory neuropeptides and several metabolic parameters in 28-day-old layer chickens.

    PubMed

    Honda, Kazuhisa; Saneyasu, Takaoki; Aoki, Koji; Shimatani, Tomohiko; Yamaguchi, Takuya; Kamisoyama, Hiroshi

    2015-05-01

    Various lines of evidence suggest that appetite-related neuropeptides in the hypothalamus are regulated by adiposity signals such as leptin and insulin in mammals. In the present study, we examined age-dependent changes in the weight of abdominal fat and hypothalamic mRNA levels of neuropeptide Y (NPY, an orexigenic neuropeptide) and proopiomelanocortin (POMC, a precursor of anorexigenic neuropeptides) in growing chickens at 7, 14, 21 and 28 days of age. Hypothalamic NPY mRNA levels were significantly (P < 0.05) decreased after 14 days of age, whereas hypothalamic POMC mRNA levels were significantly (P < 0.05) increased at 28 days of age. The percentage of abdominal fat was significantly increased after 14 days of age in chickens. We next examined the correlation of hypothalamic NPY and POMC mRNA levels and several parameters at 28 days of age. There were no significant correlations between hypothalamic mRNA levels of NPY or POMC and the percentage of abdominal fat. These findings suggest that the gene expressions of NPY and POMC do not depend on adiposity in chickens, at least in 28-day-old layer chickens.

  9. Re-engineering Cytochrome P450 2B11dH for Enhanced Metabolism of Several Substrates Including the Anti-cancer Prodrugs Cyclophosphamide and Ifosfamide

    PubMed Central

    Sun, Ling; Chen, Chong S.; Waxman, David J.; Liu, Hong; Halpert, James R.; Kumar, Santosh

    2007-01-01

    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 μM). I209A also demonstrated enhanced selectivity for testosterone 16β-hydroxylation over 16α-hydroxylation. In contrast, V183L showed a 4-fold increased kcat for 7-benzyloxyresorufin debenzylation and a 4.7-fold increased kcat/Km for testosterone 16α-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. PMID:17254539

  10. Comprehensive review on lactate metabolism in human health.

    PubMed

    Adeva-Andany, M; López-Ojén, M; Funcasta-Calderón, R; Ameneiros-Rodríguez, E; Donapetry-García, C; Vila-Altesor, M; Rodríguez-Seijas, J

    2014-07-01

    Metabolic pathways involved in lactate metabolism are important to understand the physiological response to exercise and the pathogenesis of prevalent diseases such as diabetes and cancer. Monocarboxylate transporters are being investigated as potential targets for diagnosis and therapy of these and other disorders. Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. Pyruvate may be either oxidized to carbon dioxide producing energy or transformed into glucose. Pyruvate oxidation requires oxygen supply and the cooperation of pyruvate dehydrogenase, the tricarboxylic acid cycle, and the mitochondrial respiratory chain. Enzymes of the gluconeogenesis pathway sequentially convert pyruvate into glucose. Congenital or acquired deficiency on gluconeogenesis or pyruvate oxidation, including tissue hypoxia, may induce lactate accumulation. Both obese individuals and patients with diabetes show elevated plasma lactate concentration compared to healthy subjects, but there is no conclusive evidence of hyperlactatemia causing insulin resistance. Available evidence suggests an association between defective mitochondrial oxidative capacity in the pancreatic β-cells and diminished insulin secretion that may trigger the development of diabetes in patients already affected with insulin resistance. Several mutations in the mitochondrial DNA are associated with diabetes mellitus, although the pathogenesis remains unsettled. Mitochondrial DNA mutations have been detected in a number of human cancers. d-lactate is a lactate enantiomer normally formed during glycolysis. Excess d-lactate is generated in diabetes, particularly during diabetic ketoacidosis. d-lactic acidosis is typically associated with small bowel resection. PMID:24929216

  11. Comprehensive review on lactate metabolism in human health.

    PubMed

    Adeva-Andany, M; López-Ojén, M; Funcasta-Calderón, R; Ameneiros-Rodríguez, E; Donapetry-García, C; Vila-Altesor, M; Rodríguez-Seijas, J

    2014-07-01

    Metabolic pathways involved in lactate metabolism are important to understand the physiological response to exercise and the pathogenesis of prevalent diseases such as diabetes and cancer. Monocarboxylate transporters are being investigated as potential targets for diagnosis and therapy of these and other disorders. Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. Pyruvate may be either oxidized to carbon dioxide producing energy or transformed into glucose. Pyruvate oxidation requires oxygen supply and the cooperation of pyruvate dehydrogenase, the tricarboxylic acid cycle, and the mitochondrial respiratory chain. Enzymes of the gluconeogenesis pathway sequentially convert pyruvate into glucose. Congenital or acquired deficiency on gluconeogenesis or pyruvate oxidation, including tissue hypoxia, may induce lactate accumulation. Both obese individuals and patients with diabetes show elevated plasma lactate concentration compared to healthy subjects, but there is no conclusive evidence of hyperlactatemia causing insulin resistance. Available evidence suggests an association between defective mitochondrial oxidative capacity in the pancreatic β-cells and diminished insulin secretion that may trigger the development of diabetes in patients already affected with insulin resistance. Several mutations in the mitochondrial DNA are associated with diabetes mellitus, although the pathogenesis remains unsettled. Mitochondrial DNA mutations have been detected in a number of human cancers. d-lactate is a lactate enantiomer normally formed during glycolysis. Excess d-lactate is generated in diabetes, particularly during diabetic ketoacidosis. d-lactic acidosis is typically associated with small bowel resection.

  12. Role of interleukin 1 and tumor necrosis factor on energy metabolism in rabbits

    SciTech Connect

    Tredget, E.E.; Yu, Y.M.; Zhong, S.; Burini, R.; Okusawa, S.; Gelfand, J.A.; Dinarello, C.A.; Young, V.R.; Burke, J.F.

    1988-12-01

    A study of the combined effects of intravenous infusion of the recombinant cytokines beta-interleukin 1 (IL-1) and alpha-tumor necrosis factor (TNF) on energy substrate metabolism in awake, conditioned, adult rabbits was performed. After a 2-h basal or control period, 48-h fasted rabbits were administered TNF and IL-1 as a bolus (5 micrograms/kg) followed by a continuous intravenous infusion (25 ng.kg-1.min-1) for 3 h. Significant increases in plasma lactate (P less than 0.01), glucose (P less than 0.01), and triglycerides (P less than 0.05) occurred during the combined infusion of IL-1 and TNF, whereas neither cytokine alone had no effect. There was a 33% increase in the rate of glucose appearance (P less than 0.05), but glucose clearance was not altered compared with the control period. Glucose oxidation increased during the combined cytokine infusion period and glucose recycling increased by 600% (P less than 0.002). Lactic acidosis and decreased oxygen consumption, as a result of the cytokine infusions, indicated development of anaerobic glycolytic metabolism. A reduction in the activity state of hepatic mitochondrial pyruvate dehydrogenase (65 vs. 82% in control animals, P less than 0.05) was consistent with the observed increase in anaerobic glycolysis. Thus the combined infusion of IL-1 and TNF in rabbits produces metabolic manifestations seen in severe injury and sepsis in human patients and, as such, may account for the profound alterations of energy metabolism seen in these conditions.

  13. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome mimicking herpes simplex encephalitis on imaging studies.

    PubMed

    Gieraerts, Christopher; Demaerel, Philippe; Van Damme, Philip; Wilms, Guido

    2013-01-01

    We present a case in which mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome mimicked the clinical and radiological signs of herpes simplex encephalitis. In a patient with subacute encephalopathy, on computed tomography and magnetic resonance imaging, lesions were present in both temporal lobes extending to both insular regions with sparing of the lentiform nuclei and in both posterior straight and cingulate gyri. Final diagnosis of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome was based on biochemical investigations on cerebrospinal fluid, electromyogram, muscle biopsy, and genetic analysis. On diffusion-weighted imaging, diffusion restriction was present in some parts of the lesions but not throughout the entire lesions. We suggest that this could be an important sign in the differential diagnosis with herpes simplex encephalitis.

  14. Acidosis is a key regulator of osteoblast ecto-nucleotidase pyrophosphatase/phosphodiesterase 1 (NPP1) expression and activity.

    PubMed

    Orriss, Isabel R; Key, Michelle L; Hajjawi, Mark O R; Millán, José L; Arnett, Timothy R

    2015-12-01

    Previous work has shown that acidosis prevents bone nodule formation by osteoblasts in vitro by inhibiting mineralisation of the collagenous matrix. The ratio of phosphate (Pi ) to pyrophosphate (PPi ) in the bone microenvironment is a fundamental regulator of bone mineralisation. Both Pi and PPi , a potent inhibitor of mineralisation, are generated from extracellular nucleotides by the actions of ecto-nucleotidases. This study investigated the expression and activity of ecto-nucleotidases by osteoblasts under normal and acid conditions. We found that osteoblasts express mRNA for a number of ecto-nucleotidases including NTPdase 1-6 (ecto-nucleoside triphosphate diphosphohydrolase) and NPP1-3 (ecto-nucleotide pyrophosphatase/phosphodiesterase). The rank order of mRNA expression in differentiating rat osteoblasts (day 7) was Enpp1 > NTPdase 4 > NTPdase 6 > NTPdase 5 >  alkaline phosphatase > ecto-5-nucleotidase > Enpp3 > NTPdase 1 > NTPdase 3 > Enpp2 > NTPdase 2. Acidosis (pH 6.9) upregulated NPP1 mRNA (2.8-fold) and protein expression at all stages of osteoblast differentiation compared to physiological pH (pH 7.4); expression of other ecto-nucleotidases was unaffected. Furthermore, total NPP activity was increased up to 53% in osteoblasts cultured in acid conditions (P < 0.001). Release of ATP, one of the key substrates for NPP1, from osteoblasts, was unaffected by acidosis. Further studies showed that mineralised bone formation by osteoblasts cultured from NPP1 knockout mice was increased compared with wildtypes (2.5-fold, P < 0.001) and was partially resistant to the inhibitory effect of acidosis. These results indicate that increased NPP1 expression and activity might contribute to the decreased mineralisation observed when osteoblasts are exposed to acid conditions.

  15. Metabolic bone diseases in kidney transplant recipients.

    PubMed

    Zhang, Rubin; Chouhan, Kanwaljit K

    2012-10-01

    Metabolic bone disease after kidney transplantation has a complex pathophysiology and heterogeneous histology. Pre-existing renal osteodystrophy may not resolve completely, but continue or evolve into a different osteodystrophy. Rapid bone loss immediately after transplant can persist, at a lower rate, for years to come. These greatly increase the risk of bone fracture and vertebral collapse. Each patient may have multiple risk factors of bone loss, such as steroids usage, hypogonadism, persistent hyperparathyroidism (HPT), poor allograft function, metabolic acidosis, hypophosphatemia, vitamin D deficiency, aging, immobility and chronic disease. Clinical management requires a comprehensive approach to address the underlying and ongoing disease processes. Successful prevention of bone loss has been shown with vitamin D, bisphosphonates, calcitonin as well as treatment of hypogonadism and HPT. Novel approach to restore the normal bone remodeling and improve the bone quality may be needed in order to effectively decrease bone fracture rate in kidney transplant recipients. PMID:24175250

  16. Inhibition of the oxygen sensor PHD2 in the liver improves survival in lactic acidosis by activating the Cori cycle.

    PubMed

    Suhara, Tomohiro; Hishiki, Takako; Kasahara, Masataka; Hayakawa, Noriyo; Oyaizu, Tomoko; Nakanishi, Tsuyoshi; Kubo, Akiko; Morisaki, Hiroshi; Kaelin, William G; Suematsu, Makoto; Minamishima, Yoji Andrew

    2015-09-15

    Loss of prolyl hydroxylase 2 (PHD2) activates the hypoxia-inducible factor-dependent hypoxic response, including anaerobic glycolysis, which causes large amounts of lactate to be released from cells into the circulation. We found that Phd2-null mouse embryonic fibroblasts (MEFs) produced more lactate than wild-type MEFs, as expected, whereas systemic inactivation of PHD2 in mice did not cause hyperlacticacidemia. This unexpected observation led us to hypothesize that the hypoxic response activated in the liver enhances the Cori cycle, a lactate-glucose carbon recycling system between muscle and liver, and thereby decreases circulating lactate. Consistent with this hypothesis, blood lactate levels measured after a treadmill or lactate tolerance test were significantly lower in Phd2-liver-specific knockout (Phd2-LKO) mice than in control mice. An in vivo (13)C-labeled lactate incorporation assay revealed that the livers of Phd2-LKO mice produce significantly more glucose derived from (13)C-labeled lactate than control mice, suggesting that blockade of PHD2 in the liver ameliorates lactic acidosis by activating gluconeogenesis from lactate. Phd2-LKO mice were resistant to lactic acidosis induced by injection of a lethal dose of lactate, displaying a significant elongation of survival. Moreover, oral administration of a PHD inhibitor improved survival in an endotoxin shock mice model. These data suggest that PHD2 is a potentially novel drug target for the treatment of lactic acidosis, which is a serious and often fatal complication observed in some critically ill patients.

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

    PubMed Central

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

    2014-01-01

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

  18. Metabolism of octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine by Clostridium bifermentans strain HAW-1 and several other H2-producing fermentative anaerobic bacteria.

    PubMed

    Zhao, Jian-Shen; Paquet, Louise; Halasz, Annamaria; Manno, Dominic; Hawari, Jalal

    2004-08-01

    Several H2-producing fermentative anaerobic bacteria including Clostridium, Klebsiella and Fusobacteria degraded octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) (36 microM) to formaldehyde (HCHO) and nitrous oxide (N2O) with rates ranging from 5 to 190 nmol h(-1)g [dry weight] of cells(-1). Among these strains, C. bifermentans strain HAW-1 grew and transformed HMX rapidly with the detection of the two key intermediates the mononitroso product and methylenedinitramine. Its cellular extract alone did not seem to degrade HMX appreciably, but degraded much faster in the presence of H2, NADH or NADPH. The disappearance of HMX was concurrent with the release of nitrite without the formation of the nitroso derivative(s). Results suggest that two types of enzymes were involved in HMX metabolism: one for denitration and the second for reduction to the nitroso derivative(s).

  19. Pathophysiological evaluation of subacute ruminal acidosis (SARA) by continuous ruminal pH monitoring

    PubMed Central

    2016-01-01

    Abstract Evaluation of the radio‐transmission pH‐measurement system for monitoring the ruminal pH and subacute ruminal acidosis (SARA) in cattle is described. This is done in order to reveal the possible application of this system for detection and pathophysiological research of SARA by continuous ruminal pH measurement. The possibility of using this system for assessment of the ruminal pH in SARA cattle, and the presence of negative correlation between the ruminal pH and ruminal temperature in heathy and SARA cattle were determined. In addition, the 16S rRNA gene pyrosequencing analysis showed that the ruminal microbial community was simpler in SARA cattle, and the bacterial numbers in SARA cattle were lower than those in healthy hay‐fed cattle. Concentrate feeding might have reduced the diversity of the ruminal microbial community. Changes in the ruminal microbial community of SARA cattle might be related to the changes in ruminal pH followed by the decrease in the number of some bacteria. Continuous monitoring of the ruminal pH using the radio‐transmission pH‐measurement system would be applied for detection and prevention of SARA in the field and pathophysiological research of SARA, including ruminal zymology and bacteriology, which have been determined previously by sampling of the ruminal fluid and measuring of ruminal pH. PMID:26279060

  20. Lactic acidosis, potassium, and the heart rate deflection point in professional road cyclists

    PubMed Central

    Lucia, A; Hoyos, J; Santalla, A; Perez, M; Carvajal, A; Chicharro, J

    2002-01-01

    Objective: To determine the influence of lactic acidosis, the Bohr effect, and exercise induced hyperkalaemia on the occurrence of the heart rate deflection point (HRDP) in elite (professional) cyclists. Methods: Sixteen professional male road cyclists (mean (SD) age 26 (1) years) performed a ramp test on a cycle ergometer (workload increases of 5 W/12 s, averaging 25 W/min). Heart rate (HR), gas exchange parameters, and blood variables (lactate, pH, P50 of the oxyhaemoglobin dissociation curve, and K+) were measured during the tests. Results: A HRDP was shown in 56% of subjects at about 88% of their maximal HR (HRDP group; n = 9) but was linear in the rest (No-HRDP group; n = 7). In the HRDP group, the slope of the HR-workload regression line above the HRDP correlated inversely with levels of K+ at the maximal power output (r = -0.67; p<0.05). Conclusions: The HRDP phenomenon is associated, at least partly, with exercise induced hyperkalaemia. PMID:11916893

  1. Treatment options for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome.

    PubMed

    Santa, Kristin M

    2010-11-01

    Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a rare neurodegenerative disease caused by the decreased ability of cells to produce sufficient energy in the form of adenosine 5'-triphosphate. Although it is one of the most common maternally inherited mitochondrial disorders, its exact incidence is unknown. Caused most frequently by an A-to-G point mutation at the 3243 position in the mitochondrial DNA, MELAS syndrome has a broad range of clinical manifestations and a highly variable course. The classic neurologic characteristics include encephalopathy, seizures, and stroke-like episodes. In addition to its neurologic manifestations, MELAS syndrome exhibits multisystem effects including cardiac conduction defects, diabetes mellitus, short stature, myopathy, and gastrointestinal disturbances. Unfortunately, no consensus guidelines outlining standard drug regimens exist for this syndrome. Many of the accepted therapies used in treating MELAS syndrome have been identified through a small number of clinical trials or isolated case reports. Currently, the drugs most often used include antioxidants and various vitamins aimed at minimizing the demands on the mitochondria and supporting and maximizing their function. Some of the most frequently prescribed agents include coenzyme Q(10), l-arginine, B vitamins, and levocarnitine. Although articles describing MELAS syndrome are available, few specifically target education for clinical pharmacists. This article will provide pharmacists with a practical resource to enhance their understanding of MELAS syndrome in order to provide safe and effective pharmaceutical care.

  2. Pathophysiological evaluation of subacute ruminal acidosis (SARA) by continuous ruminal pH monitoring.

    PubMed

    Sato, Shigeru

    2016-02-01

    Evaluation of the radio-transmission pH-measurement system for monitoring the ruminal pH and subacute ruminal acidosis (SARA) in cattle is described. This is done in order to reveal the possible application of this system for detection and pathophysiological research of SARA by continuous ruminal pH measurement. The possibility of using this system for assessment of the ruminal pH in SARA cattle, and the presence of negative correlation between the ruminal pH and ruminal temperature in heathy and SARA cattle were determined. In addition, the 16S rRNA gene pyrosequencing analysis showed that the ruminal microbial community was simpler in SARA cattle, and the bacterial numbers in SARA cattle were lower than those in healthy hay-fed cattle. Concentrate feeding might have reduced the diversity of the ruminal microbial community. Changes in the ruminal microbial community of SARA cattle might be related to the changes in ruminal pH followed by the decrease in the number of some bacteria. Continuous monitoring of the ruminal pH using the radio-transmission pH-measurement system would be applied for detection and prevention of SARA in the field and pathophysiological research of SARA, including ruminal zymology and bacteriology, which have been determined previously by sampling of the ruminal fluid and measuring of ruminal pH.

  3. Molecular Connections between Cancer Cell Metabolism and the Tumor Microenvironment

    PubMed Central

    Justus, Calvin R.; Sanderlin, Edward J.; Yang, Li V.

    2015-01-01

    Cancer cells preferentially utilize glycolysis, instead of oxidative phosphorylation, for metabolism even in the presence of oxygen. This phenomenon of aerobic glycolysis, referred to as the “Warburg effect”, commonly exists in a variety of tumors. Recent studies further demonstrate that both genetic factors such as oncogenes and tumor suppressors and microenvironmental factors such as spatial hypoxia and acidosis can regulate the glycolytic metabolism of cancer cells. Reciprocally, altered cancer cell metabolism can modulate the tumor microenvironment which plays important roles in cancer cell somatic evolution, metastasis, and therapeutic response. In this article, we review the progression of current understandings on the molecular interaction between cancer cell metabolism and the tumor microenvironment. In addition, we discuss the implications of these interactions in cancer therapy and chemoprevention. PMID:25988385

  4. A reliable, practical, and economical protocol for inducing diarrhea and severe dehydration in the neonatal calf.

    PubMed

    Walker, P G; Constable, P D; Morin, D E; Drackley, J K; Foreman, J H; Thurmon, J C

    1998-07-01

    Fifteen healthy, colostrum-fed, male dairy calves, aged 2 to 7 d were used in a study to develop a diarrhea protocol for neonatal calves that is reliable, practical, and economical. After instrumentation and recording baseline data, diarrhea and dehydration were induced by administering milk replacer [16.5 mL/kg of body weight (BW), PO], sucrose (2 g/kg in a 20% aqueous solution, p.o.), spironolactone and hydrochlorothiazide (1 mg/kg, PO) every 8 h, and furosemide (2 mg/kg, i.m., q6h). Calves were administered sucrose and diuretic agents for 48 h to induce diarrhea and severe dehydration. Clinical changes after 48 h were severe watery diarrhea, severe depression, and marked dehydration (mean, 14% BW loss). Cardiac output, stroke volume, mean central venous pressure, plasma volume, thiocyanate space, blood pH and bicarbonate concentration, base excess, serum chloride concentration, and fetlock temperature were decreased. Plasma lactate concentration, hematocrit, and serum potassium, creatinine, phosphorus, total protein and albumin concentrations were increased. This non-infectious calf diarrhea protocol has a 100% response rate, while providing a consistent and predictable hypovolemic state with diarrhea that reflects most of the clinicopathologic changes observed in osmotic/maldigestive diarrhea caused by infection with rotavirus, coronavirus or cryptosporidia. Limitations of the protocol, when compared to infectious diarrhea models, include failure to induce a severe metabolic acidosis, absence of hyponatremia, renal instead of enteric loss of chloride, renal as well as enteric loss of free water, absence of profound clinical depression and suspected differences in the morphologic and functional effect on intestinal epithelium. Despite these differences, the sucrose/diuretic protocol should be useful in the initial screening of new treatment modalities for calf diarrhea. To confirm their efficacy, the most effective treatment methods should then be examined in

  5. A reliable, practical, and economical protocol for inducing diarrhea and severe dehydration in the neonatal calf.

    PubMed Central

    Walker, P G; Constable, P D; Morin, D E; Drackley, J K; Foreman, J H; Thurmon, J C

    1998-01-01

    Fifteen healthy, colostrum-fed, male dairy calves, aged 2 to 7 d were used in a study to develop a diarrhea protocol for neonatal calves that is reliable, practical, and economical. After instrumentation and recording baseline data, diarrhea and dehydration were induced by administering milk replacer [16.5 mL/kg of body weight (BW), PO], sucrose (2 g/kg in a 20% aqueous solution, p.o.), spironolactone and hydrochlorothiazide (1 mg/kg, PO) every 8 h, and furosemide (2 mg/kg, i.m., q6h). Calves were administered sucrose and diuretic agents for 48 h to induce diarrhea and severe dehydration. Clinical changes after 48 h were severe watery diarrhea, severe depression, and marked dehydration (mean, 14% BW loss). Cardiac output, stroke volume, mean central venous pressure, plasma volume, thiocyanate space, blood pH and bicarbonate concentration, base excess, serum chloride concentration, and fetlock temperature were decreased. Plasma lactate concentration, hematocrit, and serum potassium, creatinine, phosphorus, total protein and albumin concentrations were increased. This non-infectious calf diarrhea protocol has a 100% response rate, while providing a consistent and predictable hypovolemic state with diarrhea that reflects most of the clinicopathologic changes observed in osmotic/maldigestive diarrhea caused by infection with rotavirus, coronavirus or cryptosporidia. Limitations of the protocol, when compared to infectious diarrhea models, include failure to induce a severe metabolic acidosis, absence of hyponatremia, renal instead of enteric loss of chloride, renal as well as enteric loss of free water, absence of profound clinical depression and suspected differences in the morphologic and functional effect on intestinal epithelium. Despite these differences, the sucrose/diuretic protocol should be useful in the initial screening of new treatment modalities for calf diarrhea. To confirm their efficacy, the most effective treatment methods should then be examined in

  6. The effects of active dried and killed dried yeast on subacute ruminal acidosis, ruminal fermentation, and nutrient digestibility in beef heifers.

    PubMed

    Vyas, D; Uwizeye, A; Mohammed, R; Yang, W Z; Walker, N D; Beauchemin, K A

    2014-02-01

    , irrespective of its viability, in reducing the severity of SARA. However, further studies are required to evaluate the importance of yeast viability for other dietary conditions, particularly when the risk of acidosis is high.

  7. Rare mutation in the SLC26A3 transporter causes life-long diarrhoea with metabolic alkalosis.

    PubMed

    Abou Ziki, Maen D; Verjee, Mohamud A

    2015-01-01

    SLC26A3, a chloride/bicarbonate transporter mainly expressed in the intestines, plays a pivotal role in chloride absorption. We present a 23-year-old woman with a history of congenital chloride diarrhoea (CCD) and renal transplant who was admitted for rehydration and treatment of acute kidney injury after she presented with an acute diarrhoeal episode. Laboratory investigations confirmed metabolic alkalosis and severe hypochloraemia, consistent with her underlying CCD. This contrasts with most other forms of diarrhoea, which are normally associated with metabolic acidosis. Genetic testing was offered and revealed a homozygous non-sense mutation in SLC26A3 (Gly-187-Stop). This loss-of-function mutation results in bicarbonate retention in the blood and chloride loss into the intestinal lumen. Symptomatic management with daily NaCl and KCl oral syrups was supplemented with omeprazole therapy. The loss of her own kidneys is most likely due to crystal-induced nephropathy secondary to chronic volume contraction and chloride depletion. This case summarises the pathophysiology and management of CCD. PMID:25568271

  8. Rare mutation in the SLC26A3 transporter causes life-long diarrhoea with metabolic alkalosis.

    PubMed

    Abou Ziki, Maen D; Verjee, Mohamud A

    2015-01-07

    SLC26A3, a chloride/bicarbonate transporter mainly expressed in the intestines, plays a pivotal role in chloride absorption. We present a 23-year-old woman with a history of congenital chloride diarrhoea (CCD) and renal transplant who was admitted for rehydration and treatment of acute kidney injury after she presented with an acute diarrhoeal episode. Laboratory investigations confirmed metabolic alkalosis and severe hypochloraemia, consistent with her underlying CCD. This contrasts with most other forms of diarrhoea, which are normally associated with metabolic acidosis. Genetic testing was offered and revealed a homozygous non-sense mutation in SLC26A3 (Gly-187-Stop). This loss-of-function mutation results in bicarbonate retention in the blood and chloride loss into the intestinal lumen. Symptomatic management with daily NaCl and KCl oral syrups was supplemented with omeprazole therapy. The loss of her own kidneys is most likely due to crystal-induced nephropathy secondary to chronic volume contraction and chloride depletion. This case summarises the pathophysiology and management of CCD.

  9. Cellular metabolism and disease: what do metabolic outliers teach us?

    PubMed Central

    DeBerardinis, Ralph J.; Thompson, Craig B.

    2012-01-01

    An understanding of metabolic pathways based solely on biochemistry textbooks would underestimate the pervasive role of metabolism in essentially every aspect of biology. It is evident from recent work that many human diseases involve abnormal metabolic states – often genetically programmed – that perturb normal physiology and lead to severe tissue dysfunction. Understanding these metabolic outliers is now a crucial frontier in disease-oriented research. This review discusses the broad impact of metabolism in cellular function, how modern concepts of metabolism can inform our understanding of common diseases like cancer, and considers the prospects of developing new metabolic approaches to disease treatment. PMID:22424225

  10. UPLC/ESI-MS/MS-based determination of metabolism of several new illicit drugs, ADB-FUBINACA, AB-FUBINACA, AB-PINACA, QUPIC, 5F-QUPIC and α-PVT, by human liver microsome.

    PubMed

    Takayama, Takahiro; Suzuki, Mayu; Todoroki, Kenichiro; Inoue, Koichi; Min, Jun Zhe; Kikura-Hanajiri, Ruri; Goda, Yukihiro; Toyo'oka, Toshimasa

    2014-06-01

    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 α-pyrrolidinovalerothiophenone (α-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 α-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. PMID:24861751

  11. Targeting the Metabolic Microenvironment of Tumors

    PubMed Central

    Bailey, Kate M.; Wojtkowiak, Jonathan W.; Hashim, Arig Ibrahim; Gillies, Robert J.

    2013-01-01

    The observation of aerobic glycolysis by tumor cells in 1924 by Otto Warburg, and subsequent innovation of imaging glucose uptake by tumors in patients with PET-CT has incited a renewed interest in the altered metabolism of tumors. As tumors grow in situ, a fraction of it is further away from their blood supply, leading to decreased oxygen concentrations (hypoxia), which induces the hypoxia response pathways of HIF1α, mTOR and UPR. In normal tissues, these responses mitigate hypoxic stress and induce neo-angiogenesis. In tumors, these pathways are dysregulated and lead to decreased perfusion and exacerbation of hypoxia as a result of immature and chaotic blood vessels. Hypoxia selects for a glycolytic phenotype and resultant acidification of the tumor microenvironment, facilitated by upregulation of proton transporters. Acidification selects for enhanced metastatic potential and reduced drug efficacy through ion trapping. In this review, we provide a comprehensive summary of pre-clinical and clinical drugs under development for targeting aerobic glycolysis, acidosis, hypoxia and hypoxia-response pathways. Hypoxia and acidosis can be manipulated, providing further therapeutic benefit for cancers that feature these common phenotypes. PMID:22959024

  12. Phosphate Binding with Sevelamer Preserves Mechanical Competence of Bone Despite Acidosis in Advanced Experimental Renal Insufficiency

    PubMed Central

    Jokihaara, Jarkko; Pörsti, Ilkka H.; Sievänen, Harri; Kööbi, Peeter; Kannus, Pekka; Niemelä, Onni; Turner, Russell T.; Iwaniec, Urszula T.; Järvinen, Teppo L. N.

    2016-01-01

    Introduction Phosphate binding with sevelamer can ameliorate detrimental histomorphometric changes of bone in chronic renal insufficiency (CRI). Here we explored the effects of sevelamer-HCl treatment on bone strength and structure in experimental CRI. Methods Forty-eight 8-week-old rats were assigned to surgical 5/6 nephrectomy (CRI) or renal decapsulation (Sham). After 14 weeks of disease progression, the rats were allocated to untreated and sevelamer-treated (3% in chow) groups for 9 weeks. Then the animals were sacrificed, plasma samples collected, and femora excised for structural analysis (biomechanical testing, quantitative computed tomography). Results Sevelamer-HCl significantly reduced blood pH, and final creatinine clearance in the CRI groups ranged 30%-50% of that in the Sham group. Final plasma phosphate increased 2.4- to 2.9-fold, and parathyroid hormone 13- to 21-fold in CRI rats, with no difference between sevelamer-treated and untreated animals. In the femoral midshaft, CRI reduced cortical bone mineral density (-3%) and breaking load (-15%) (p<0.05 for all versus Sham), while sevelamer increased bone mineral density (+2%) and prevented the deleterious changes in bone. In the femoral neck, CRI reduced bone mineral density (-11%) and breaking load (-10%), while sevelamer prevented the decrease in bone mineral density (+6%) so that breaking load did not differ from controls. Conclusions In this model of stage 3–4 CRI, sevelamer-HCl treatment ameliorated the decreases in femoral midshaft and neck mineral density, and restored bone strength despite prevailing acidosis. Therefore, treatment with sevelamer can efficiently preserve mechanical competence of bone in CRI. PMID:27658028

  13. Progress in Diagnosing Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episodes

    PubMed Central

    Wang, Ying-Xin; Le, Wei-Dong

    2015-01-01

    Objective: Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a progressive, multisystem affected mitochondrial disease associated with a number of disease-related defective genes. MELAS has unpredictable presentations and clinical course, and it can be commonly misdiagnosed as encephalitis, cerebral infarction, or brain neoplasms. This review aimed to update the diagnosis progress in MELAS, which may provide better understanding of the disease nature and help make the right diagnosis as well. Data Sources: The data used in this review came from published peer review articles from October 1984 to October 2014, which were obtained from PubMed. The search term is “MELAS”. Study Selection: Information selected from those reported studies is mainly based on the progress on clinical features, blood biochemistry, neuroimaging, muscle biopsy, and genetics in diagnosing MELAS. Results: MELAS has a wide heterogeneity in genetics and clinical manifestations. The relationship between mutations and phenotypes remains unclear. Advanced serial functional magnetic resonance imaging (MRI) can provide directional information on this disease. Muscle biopsy has meaningful value in diagnosing MELAS, which shows the presence of ragged red fibers and mosaic appearance of cytochrome oxidase negative fibers. Genetic studies have reported that approximately 80% of MELAS cases are caused by the mutation m.3243A>G of the mitochondrial transfer RNA (Leu (UUR)) gene (MT-TL1). Conclusions: MELAS involves multiple systems with variable clinical symptoms and recurrent episodes. The prognosis of MELAS patients depends on timely diagnosis. Therefore, overall diagnosis of MELAS should be based on the maternal inheritance family history, clinical manifestation, and findings from serial MRI, muscle biopsy, and genetics. PMID:26112726

  14. Glucose metabolism derangements in adults with the MELAS m.3243A>G mutation.

    PubMed

    El-Hattab, Ayman W; Emrick, Lisa T; Hsu, Jean W; Chanprasert, Sirisak; Jahoor, Farook; Scaglia, Fernando; Craigen, William J

    2014-09-01

    The m.3243A>G mutation in the mitochondrial gene MT-TL1 leads to a wide clinical spectrum ranging from asymptomatic carriers to MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) at the severe end. Diabetes mellitus (DM) occurs in mitochondrial diseases, with the m.3243A>G mutation being the most common mutation associated with mitochondrial DM. The pathogenesis of mitochondrial DM remains largely unknown, with previous studies suggesting that impaired insulin secretion is the major factor. In this study we used stable isotope infusion techniques to assess glucose metabolism in vivo and under physiological conditions in 5 diabetic and 11 non-diabetic adults with the m.3243A>G mutation and 10 healthy adult controls. Our results revealed increased glucose production due to increased gluconeogenesis in both diabetic and non-diabetic subjects with the m.3243A>G mutation. In addition, diabetic subjects demonstrated insulin resistance and relative insulin deficiency, resulting in an inability to increase glucose oxidation which can explain the development of DM in these subjects. Non-diabetic subjects showed normal insulin sensitivity; and therefore, they were able to increase their glucose oxidation rate. The ability to increase glucose utilization can act as a compensatory mechanism that explains why these subjects do not have DM despite the higher rate of glucose production. These results suggest that increased gluconeogenesis is not enough to cause DM and the occurrence of combined insulin resistance and relative insulin deficiency are needed to develop DM in individuals with the m.3243A>G mutation. Therefore, multiple defects in insulin and glucose metabolism are required for DM to occur in individuals with mitochondrial diseases. The results of this study uncover previously undocumented alterations in glucose metabolism in individuals with the m.3243A>G mutation that contribute significantly to our understanding of the pathogenesis

  15. Sustained metabolic scope.

    PubMed Central

    Peterson, C C; Nagy, K A; Diamond, J

    1990-01-01

    Sustained metabolic rates (SusMR) are time-averaged metabolic rates that are measured in free-ranging animals maintaining constant body mass over periods long enough that metabolism is fueled by food intake rather than by transient depletion of energy reserves. Many authors have suggested that SusMR of various wild animal species are only a few times resting (basal or standard) metabolic rates (RMR). We test this conclusion by analyzing all 37 species (humans, 31 other endothermic vertebrates, and 5 ectothermic vertebrates) for which SusMR and RMR had both been measured. For all species, the ratio of SusMR to RMR, which we term sustained metabolic scope, is less than 7; most values fall between 1.5 and 5. Some of these values, such as those for Tour de France cyclists and breeding birds, are surely close to sustainable metabolic ceilings for the species studied. That is, metabolic rates higher than 7 times RMR apparently cannot be sustained indefinitely. These observations pose several questions: whether the proximate physiological causes of metabolic ceilings reside in the digestive tract's ability to process food or in each tissue's metabolic capacity; whether ceiling values are independent of the mode of energy expenditure; whether ceilings are set by single limiting physiological capacities or by coadjusted clusters of capacities (symmorphosis); what the ultimate evolutionary causes of metabolic ceilings are; and how metabolic ceilings may limit animals' reproductive effort, foraging behavior, and geographic distribution. PMID:2315323

  16. Metabolic Panel

    MedlinePlus

    A metabolic panel is a group of tests that measures different chemicals in the blood. These tests are usually ... kidneys and liver. There are two types: basic metabolic panel (BMP) and comprehensive metabolic panel (CMP). The ...

  17. Metabolic neuropathies

    MedlinePlus

    Neuropathy - metabolic ... can be caused by many different things. Metabolic neuropathy may be caused by: A problem with the ... one of the most common causes of metabolic neuropathies. People who are at the highest risk for ...

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

    PubMed Central

    Katnik, Christopher; Cuevas, Javier

    2014-01-01

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

  19. Non-specific inhibition of ischemia- and acidosis-induced intracellular calcium elevations and membrane currents by α-phenyl-N-tert-butylnitrone, butylated hydroxytoluene and trolox.

    PubMed

    Katnik, Christopher; Cuevas, Javier

    2014-02-27

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

  20. Hemostatic resuscitation for massive hemorrhage with warm fresh whole blood in a patient with severe blunt trauma.

    PubMed

    Liu, Yuan-Hao; Chao, Chia-Sheng; Chang, Yee-Phoung; Chin, Hsien-Kuo

    2014-10-01

    A 24-year-old male Navy soldier was struck on the left thigh by a ruptured cable and was subsequently thrown into the sea. Initial evaluation showed an Injury Severity Score of 34. Core body temperature was 34.1°C. Laboratory data included a hemoglobin level of 4.5 g/dL and a hematocrit of 13.3%. Prothrombin time was prolonged (>100 seconds), international normalized ratio was elevated (9.99), and partial thromboplastin time was elevated (>180 seconds). The patient was treated for hypothermia, coagulopathy, and metabolic acidosis during resuscitation. The patient was transfused with 16,320 mL of blood during the first 24 hours following the accident, including 4500 mL (18 units) of warm fresh whole blood (WFWB) donated by the patient's military colleagues. The patient was successfully resuscitated, and the injured leg was salvaged. Component therapy can afford replacement of specific deficiencies or requirements, decrease the risk of transfusion-transmitted infectious diseases, and improve resource utilization. However, a protocol of early transfusion with WFWB should be considered during resuscitation following massive hemorrhage in specific conditions such as battle fields or urgent situations. PMID:25300438

  1. Lactic acidosis in vivo: testing the link between lactate generation and H+ accumulation in ischemic mouse muscle

    PubMed Central

    Marcinek, David J.; Kushmerick, Martin J.

    2010-01-01

    The link between lactate generation and cellular acidosis has been questioned based on the possibility of H+ generation, independent of lactate production during glycolysis under physiological conditions. Here we test whether glycolytic H+ generation matches lactate production over a physiological pH and lactate range using ischemia applied to the hindlimb of a mouse. We measured the H+ generation and ATP level in vivo using 31P-magnetic resonance spectroscopy and chemically determined intracellular lactate level in the hindlimb muscles. No significant change was found in ATP content by chemical analysis (P > 0.1), in agreement with the stoichiometric decline in phosphocreatine (20.2 ± 1.2 mM) vs. rise in Pi (18.7 ± 2.0 mM), as measured by 31P-magnetic resonance spectroscopy. A substantial drop in pH from 7.0 to 6.7 and lactate accumulation to 25 mM were found during 25 min of ischemia. The rise in H+ generation closely agreed with the accumulation of lactate, as shown by a close correlation with a slope near identity (0.98; r2 = 0.86). This agreement between glycolytic H+ production and elevation of lactate is confirmed by an analysis of the underlying reactions involved in glycolysis in vivo and supports the concept of lactic acidosis under conditions that substantially elevate lactate and drop pH. However, this link is expected to fail with conditions that deplete phosphocreatine, leading to net ATP hydrolysis and nonglycolytic H+ generation. Thus both direct measurements and an analysis of the stoichiometry of glycolysis in vivo support lactate acidosis as a robust concept for physiological conditions of the muscle cell. PMID:20133437

  2. Intoxication with over-the-counter antitussive medication containing dihydrocodeine and chlorpheniramine causes generalized convulsion and mixed acidosis.

    PubMed

    Murao, Satoshi; Manabe, Hiroaki; Yamashita, Tetsuji; Sekikawa, Takashi

    2008-01-01

    We report a 35-year-old man who was referred to our hospital with generalized convulsion and mixed acidosis presumably caused by abuse of SS-BRON tablets, an over-the-counter (OTC) antitussive medication sold in Japan. These tablets contain dihydrocodeine phosphate, methylephedrine, chlorpheniramine, and caffeine. Although it is difficult to discern which component caused these symptoms, it seems that dihydrocodeine phosphate or methylephedrine was involved in the addiction to SS-BRON and chlorpheniramine may have caused the generalized convulsion. It should be recognized that an OTC antitussive, which is quite easy to obtain, can be abused and subsequently induce serious intoxication.

  3. Inhalational sevoflurane in severe bronchial obstruction unresponsive to multipharmacologic therapy: a case report

    PubMed Central

    Weber, Thomas

    2012-01-01

    Introduction: Bronchial asthma with respiratory failure is a challenge for the intensivist as mechanical ventilation is often difficult due to bronchoconstriction and air-trapping. We describe a case of severe asthma with respiratory acidosis in a 10-year-old patient unresponsive to multipharmacologic broncholytic therapy. Only the initiation of sevoflurane inhalation resolved severe bronchoconstriction and dynamic hyperinflation, leading to complete recovery. Case presentation: A 10-year-old Caucasian boy was intubated and mechanically ventilated due to an asthmatic attack. Bronchoconstriction and dynamic hyperinflation were severe while multipharmacological broncholytic therapy was unsuccessful. Inhalation with sevoflurane via an anaesthesia machine was the key intervention leading to gradual resolving of severe hypercapnia and respiratory acidosis. Furthermore bilateral pupil dilation occurred during hypercapnia, but no intracranial pathology could be detected. The patient made an uneventful recovery. To our knowledge this is the first case where hypercapnia and respiratory acidosis were so profound and long lasting yet the patient survived without any damage. Conclusions: Inhalational anaesthetics must be considered as an early treatment option in ventilated asthmatic patients with bronchial obstruction unresponsive to conventional therapy even though their administration in intensive care units may be difficult. PMID:24358829

  4. Severe Weather

    ERIC Educational Resources Information Center

    Forde, Evan B.

    2004-01-01

    Educating the public about safety issues related to severe weather is part of the National Oceanic and Atmospheric Administration's (NOAA) mission. This article deals with a poster entitled, "Severe Weather," that has been created by NOAA to help educate the public about hazardous weather conditions. The four types of severe weather highlighted in…

  5. Severe Weather

    ERIC Educational Resources Information Center

    Forde, Evan B.

    2004-01-01

    Educating the public about safety issues related to severe weather is part of the National Oceanic and Atmospheric Administration's (NOAA) mission. This month's insert, Severe Weather, has been created by NOAA to help educate the public about hazardous weather conditions. The four types of severe weather highlighted in this poster are hurricanes,…

  6. Standardized treatment of severe methanol poisoning with ethanol and hemodialysis

    SciTech Connect

    Ekins, B.R.; Rollins, D.E.; Duffy, D.P.; Gregory, M.C.

    1985-03-01

    Seven patients with methanol poisoning were treated with ethanol, hemodialysis and supportive measures. The interval between ingestion and initiation of ethanol therapy varied from 3 to 67 hours and from ingestion to dialysis from 9 to 93 hours. All patients survived, but one had permanent visual impairment. A 10% ethanol solution administered intravenously is a safe and effective antidote for severe methanol poisoning. Ethanol therapy is recommended when plasma methanol concentrations are higher than 20 mg per dl, when ingested doses are greater than 30 ml and when there is evidence of acidosis or visual abnormalities in cases of suspected methanol poisoning. 13 references, 1 figure, 2 table.

  7. Induction of Subacute Ruminal Acidosis Affects the Ruminal Microbiome and Epithelium.

    PubMed

    McCann, Joshua C; Luan, Shaoyu; Cardoso, Felipe C; Derakhshani, Hooman; Khafipour, Ehsan; Loor, Juan J

    2016-01-01

    Subacute ruminal acidosis (SARA) negatively impacts the dairy industry by decreasing dry matter intake, milk production, profitability, and increasing culling rate and death loss. Six ruminally cannulated, lactating Holstein cows were used in a replicated incomplete Latin square design to determine the effects of SARA induction on the ruminal microbiome and epithelium. Experimental periods were 10 days with days 1-3 for ad libitum intake of control diet, followed by 50% feed restriction on day 4, and ad libitum access on day 5 to the basal diet or the basal diet with an additional 10% of a 50:50 wheat/barley pellet. Based on subsequent ruminal pH, cows were grouped (SARA grouping; SG) as Non-SARA or SARA based on time <5.6 pH (0 and 3.4 h, respectively). Ruminal samples were collected on days 1 and 6 of each period prior to feeding and separated into liquid and solid fractions. Microbial DNA was extracted for bacterial analysis using 16S rRNA gene paired-end sequencing on the MiSeq Illumina platform and quantitative PCR (qPCR). Ruminal epithelium biopsies were taken on days 1 and 6 before feeding. Quantitative RT-PCR was used to determine gene expression in rumen epithelium. Bray-Curtis similarity indicated samples within the liquid fraction separated by day and coincided with an increased relative abundance of genera Prevotella, Ruminococcus, Streptococcus, and Lactobacillus on day 6 (P < 0.06). Although Firmicutes was the predominant phyla in the solid fraction, a SG × day interaction (P < 0.01) indicated a decrease on day 6 for SARA cows. In contrast, phylum Bacteroidetes increased on day 6 (P < 0.01) for SARA cows driven by greater genera Prevotella and YRC22 (P < 0.01). Streptococcus bovis and Succinivibrio dextrinosolvens populations tended to increase on day 6 but were not affected by SG. In ruminal epithelium, CLDN1 and CLDN4 expression increased on day 6 (P < 0.03) 24 h after SARA induction and a tendency for a SG × day interaction (P < 0.10) was

  8. Acidosis and blockade of orthodromic responses caused by anoxia in rat hippocampal slices at different temperatures.

    PubMed Central

    Krnjević, K; Walz, W

    1990-01-01

    1. Interstitial pH (pHo) and field responses (to stratum radiatum stimulation) were recorded simultaneously with double-barrelled microelectrodes in the CA1 region of hippocampal slices from Sprague-Dawley rats. 2. Both the relative acidity and amplitude of field responses increased with depth, reaching a maximum near the centre of the slice. When the temperature was raised from 22 to 37 degrees C, this pHo gradient was greater than 2 times steeper, but the field responses were much diminished. 3. Standard anoxic tests (substituting 95% N2 + 5% CO2 for 95% O2 + 5% CO2, for 2 min) tended to reduce pHo and population spikes, but these effects were highly temperature sensitive: at approximately 22 degrees C the blocking rate was only 12.3 +/- 4.6% and delta pHo -0.018 +/- 0.0157 units, both per minute; corresponding changes at 34-35 degrees C were 67.6 +/- 11.9% and -0.065 +/- 0.0046 units per minute. Highly significant linear correlations between rates of block and delta pHo gave a mean slope of 90.4 +/- 17.6% per 0.1 unit of acid change. 4. Anoxia caused similar temperature-dependent increases in acidity in stratum pyramidale and radiatum, but in the latter field responses (EPSPs) were much less depressed after 2 min of anoxia. 5. When slices were superfused with acid medium (low [HCO3-]), much greater reductions in pHo were needed to depress responses, giving a mean slope of 17.7% per 0.1 pH unit. 6. In glucose-free medium, there was a slow alkaline shift in pHo (0.13 +/- 0.036 units); population spikes and the acid transients evoked by anoxia disappeared. 7. It was concluded that acidosis cannot be the immediate cause of the similar depressions of postsynaptic excitability seen during anoxia and hypoglycaemia. 8. In further tests, DL-p-hydroxyphenyl-lactic acid, a blocker of lactate transport, failed to diminish acid transients evoked by anoxia, indicating that these are not mediated principally by lactate transport. PMID:2352175

  9. Induction of Subacute Ruminal Acidosis Affects the Ruminal Microbiome and Epithelium

    PubMed Central

    McCann, Joshua C.; Luan, Shaoyu; Cardoso, Felipe C.; Derakhshani, Hooman; Khafipour, Ehsan; Loor, Juan J.

    2016-01-01

    Subacute ruminal acidosis (SARA) negatively impacts the dairy industry by decreasing dry matter intake, milk production, profitability, and increasing culling rate and death loss. Six ruminally cannulated, lactating Holstein cows were used in a replicated incomplete Latin square design to determine the effects of SARA induction on the ruminal microbiome and epithelium. Experimental periods were 10 days with days 1–3 for ad libitum intake of control diet, followed by 50% feed restriction on day 4, and ad libitum access on day 5 to the basal diet or the basal diet with an additional 10% of a 50:50 wheat/barley pellet. Based on subsequent ruminal pH, cows were grouped (SARA grouping; SG) as Non-SARA or SARA based on time <5.6 pH (0 and 3.4 h, respectively). Ruminal samples were collected on days 1 and 6 of each period prior to feeding and separated into liquid and solid fractions. Microbial DNA was extracted for bacterial analysis using 16S rRNA gene paired-end sequencing on the MiSeq Illumina platform and quantitative PCR (qPCR). Ruminal epithelium biopsies were taken on days 1 and 6 before feeding. Quantitative RT-PCR was used to determine gene expression in rumen epithelium. Bray–Curtis similarity indicated samples within the liquid fraction separated by day and coincided with an increased relative abundance of genera Prevotella, Ruminococcus, Streptococcus, and Lactobacillus on day 6 (P < 0.06). Although Firmicutes was the predominant phyla in the solid fraction, a SG × day interaction (P < 0.01) indicated a decrease on day 6 for SARA cows. In contrast, phylum Bacteroidetes increased on day 6 (P < 0.01) for SARA cows driven by greater genera Prevotella and YRC22 (P < 0.01). Streptococcus bovis and Succinivibrio dextrinosolvens populations tended to increase on day 6 but were not affected by SG. In ruminal epithelium, CLDN1 and CLDN4 expression increased on day 6 (P < 0.03) 24 h after SARA induction and a tendency for a SG × day interaction (P < 0.10) was

  10. A single mild episode of subacute ruminal acidosis does not affect ruminal barrier function in the short term.

    PubMed

    Penner, G B; Oba, M; Gäbel, G; Aschenbach, J R

    2010-10-01

    Twenty-four German Merino sheep (72.3±10.1 kg of body weight) were fed an all-hay diet and assigned to either the subacute ruminal acidosis (SARA) treatment (n=17) or sham treatment (n=7). The SARA sheep were orally dosed with a 2.2 M glucose solution to supply 5 g of glucose/kg of body weight, whereas sham sheep received an equal volume of water. Ruminal pH was measured for 48 h before and 3 h after the oral dose. Sheep were then killed and ruminal epithelia from the ventral sac were mounted in Ussing chambers. The serosal-to-mucosal flux rate of partially (3)H-labeled mannitol (J(mannitol-SM)), an indicator of barrier function, was measured while epithelia were exposed to 3 sequential in vitro measurement periods lasting 1 h each. The measurement periods consisted of baseline, challenge, and recovery periods and were interspersed by 30-min periods for treatment equilibration. Baseline conditions were pH 6.1 (mucosal solution) and pH 7.4 (serosal solution) with a bilateral osmolarity of 293 mOsm/L. During the challenge period, the mucosal side of the epithelia was exposed to either an acidotic challenge (pH 5.2, osmolarity 293 mOsm/L) or an osmotic challenge (pH 6.1, osmolarity 450 mOsm/L); a third group served as control (pH 6.1, osmolarity 293 mOsm/L). The mucosal buffer solution was replaced for the recovery period. In vivo, sheep on the SARA treatment had lower mean (5.77 vs. 6.67) and nadir (5.48 vs. 6.47) ruminal pH for the 3h following the oral drench compared with sham sheep, indicating the successful induction of SARA with the oral glucose dose. Despite the marked reduction in pH in vivo, induction of SARA had no detectable effects on the baseline measurements of J(mannitol-SM), tissue conductance (G(t)), and short-circuit current (I(sc)) in vitro. However, reducing mucosal pH to 5.2 in vitro had negative effects on epithelial barrier function in the recovery period, including increased J(mannitol-SM), increased G(t), and decreased I(sc). The osmotic

  11. Lactate metabolism: a new paradigm for the third millennium

    PubMed Central

    Gladden, L B

    2004-01-01

    For much of the 20th century, lactate was largely considered a dead-end waste product of glycolysis due to hypoxia, the primary cause of the O2 debt following exercise, a major cause of muscle fatigue, and a key factor in acidosis-induced tissue damage. Since the 1970s, a ‘lactate revolution’ has occurred. At present, we are in the midst of a lactate shuttle era; the lactate paradigm has shifted. It now appears that increased lactate production and concentration as a result of anoxia or dysoxia are often the exception rather than the ru