Genetic heterogeneity in propionic acidemia patients with alpha-subunit defects. Identification of five novel mutations, one of them causing instability of the protein.
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The inherited metabolic disease propionic acidemia (PA) can result from mutations in either of the genes PCCA or PCCB, which encode the alpha and beta subunits, respectively, of the mitochondrial enzyme propionyl CoA-carboxylase. In this work we have analyzed the molecular basis of PCCA gene defects, studying mRNA levels and identifying putative disease causing mutations. A total of 10 different mutations, none predominant, are present in a sample of 24 mutant alleles studied. Five novel mutations are reported here for the first time. A neutral polymorphism and a variant allele present in the general population were also detected. To examine the effect of a point mutation (M348K) involving a highly conserved residue, we have carried out in vitro expression of normal and mutant PCCA cDNA and analyzed the mitochondrial import and stability of the resulting proteins. Both wild-type and mutant proteins were imported into mitochondria and processed into the mature form with similar efficiency, but the mature mutant M348K protein decayed more rapidly than did the wild-type, indicating a reduced stability, which is probably the disease-causing mechanism. (+info)
Effects of respiratory and metabolic pH changes and hypoxia on ropivacaine-induced cardiotoxicity in dogs.
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We have studied the effects of acute changes in acid-base status and hypoxia on the cardiotoxic effects of intracoronary injection of ropivacaine in anaesthetized dogs. The effects of intracoronary ropivacaine were compared when ropivacaine was administered during eucapnia and during each of another nine states in random order: hypocapnia, hypercapnia, hypoxia, metabolic alkalosis, metabolic acidosis, combined metabolic acidosis and hypocapnia, combined metabolic alkalosis and hypercapnia, combined hypoxia and hypercapnia, and combined metabolic acidosis and hypoxia. Hypocapnic alkalosis consistently reduced the cardiotoxic effects of intracoronary ropivacaine (P < 0.01). Our findings indicate that induction of hypocapnic alkalosis may provide a useful adjunct to standard resuscitative measure after inadvertent administration of amide local anaesthetic agents. (+info)
Risk factors for peripartum and postpartum stroke and intracranial venous thrombosis.
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BACKGROUND AND PURPOSE: The study goal was to identify potential risk factors for peripartum or postpartum stroke and intracranial venous thrombosis. METHODS: Data from the Healthcare Cost and Utilization Project were analyzed for the years 1993 and 1994. Observed values were weighted with poststratification discharge weights to project to the universe of all discharges from community hospitals located in the United States. Nationally representative estimates of risk were calculated on the basis of age, race, mode of delivery, income, third-party payer, hospital size, hospital ownership, hospital location (rural versus urban), hospital teaching status, census region, and presence of specific complications. Multivariate models were developed with the use of logistic regression. RESULTS: Among 1 408 015 sampled deliveries, there were 183 observed cases of peripartum stroke and 170 cases of peripartum intracranial venous thrombosis in 17 states in the United States in 1993 and 1994. There were an estimated 975 cases of stroke and 864 cases of intracranial venous thrombosis during pregnancy and the puerperium in the United States among 7 463 712 deliveries during 1993 and 1994, for estimated risks of 13.1 cases of peripartum stroke and 11.6 cases of peripartum intracranial venous thrombosis per 100 000 deliveries. Multivariate analysis showed that the following were strongly and significantly associated with both peripartum and postpartum stroke: cesarean delivery; fluid, electrolyte, and acid-base disorders; and hypertension. Covariates that were strongly and significantly associated with both peripartum and postpartum intracranial venous thrombosis included cesarean delivery, hypertension, and infections other than pneumonia and influenza. CONCLUSIONS: Pregnancy-related hypertension and cesarean delivery are important risk factors for both stroke or intracranial venous thrombosis. (+info)
Maintaining acid-base balance in organ donors.
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An abnormal blood pH may cause the loss of donor organs through harmful physiological consequences. The organ procurement coordinator must correctly analyze the acid-base abnormality and treat its cause while normalizing the blood pH. We recommend that treatment of acidemia or alkalemia be first directed toward changing parameters on the mechanical ventilator, using the Paco2 to modify blood pH. Thereafter, hydrochloric acid or sodium bicarbonate may be administered to correct the calculated metabolic acid-base deficit. The types of acidosis or alkalosis, dead space effect during mechanical ventilation, base excess, base deficit, and the appropriate evaluation of blood lactate are also discussed as related to the correction of the acid-base status throughout donor care. (+info)
Acid-base imbalance adapts without changes in cell polarity in cortical collecting ducts in premature rabbits.
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It has been demonstrated that intercalated cells (ICs) change their cellular composition in acid stimuli in adult rabbits but not fully explained in developing rabbits. To clarify the mechanisms of adaptation in acid-base imbalance in collecting ducts in developing rabbit kidneys, we examined the cellular composition of cortical collecting ducts (CCDs) in 4-week-old rabbits. In the control group, the ratio of ICs to total CCD cells and that of peanut agglutinin (PNA) non-binding ICs to total ICs were 37.2 +/- 7.2% and 40.3 +/- 3.1%, respectively. By contrast, inconsistent with adult reports, in the acidotic group, these ratios were 38.4 +/- 5.1% and 41.9 +/- 1.7%, respectively, similar to the control group. The urinary pH in the control group was 8.20 +/- 0.14, while that in acidemia was 4.98 +/- 0.33 (p < 0.01). These data indicated that cellular remodeling of ICs in the acidotic state is less important for adaptation in the 4-week-old rabbit. Another mechanism, employing an acid-base related protein, might be playing an important role during development for acid base imbalance. (+info)
Venous pH can safely replace arterial pH in the initial evaluation of patients in the emergency department.
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OBJECTIVE: This study aims to determine the extent of correlation of arterial and venous pH with a view to identifying whether venous samples can be used as an alternative to arterial values in the clinical management of selected patients in the emergency department. METHODS: This prospective study of patients who were deemed by their treating doctor to require an arterial blood gas analysis to determine their ventilatory or acid-base status, compared pH on an arterial and a venous sample taken as close to simultaneously as possible. Data were analysed using Pearson correlation and bias (Bland-Altman) methods. RESULTS: Two hundred and forty six patients were entered into the study; 196 with acute respiratory disease and 50 with suspected metabolic derangement. The values of pH on arterial and venous samples were highly correlated (r=0.92) with an average difference between the samples of -0.4 units. There was also a high level of agreement between the methods with the 95% limits of agreement being -0.11 to +0.04 units. CONCLUSION: Venous pH estimation shows a high degree of correlation and agreement with the arterial value, with acceptably narrow 95% limits of agreement. Venous pH estimation is an acceptable substitute for arterial measurement and may reduce risks of complications both for patients and health care workers. (+info)
Rat proximal NHE3 adapts to chronic acid-base disorders but not to chronic changes in dietary NaCl intake.
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In the proximal tubule, the apical Na(+)/H(+) exchanger identified as NHE3 mediates most NaCl and NaHCO(3) absorption. The purpose of this study was to analyze the long-term regulation of NHE3 during alkalosis induced by dietary NaHCO(3) loading and changes in NaCl intake. Sprague-Dawley rats exposed to a low-NaCl, high-NaCl, or NaHCO(3) diet for 6 days were studied. Renal cortical apical membrane vesicles (AMV) were prepared from treated and normal rats. Na(+)/H(+) exchange was assayed as the initial rate of (22)Na(+) uptake in the presence of an outward H(+) gradient. (22)Na(+) uptake measured in the presence of high-dose 5-(N-ethyl-N-isopropyl) amiloride was not different among models. Changes in NaCl intake did not affect NHE3 activity, whereas NaHCO(3) loading inhibited (22)Na(+) uptake by 30%. AMV NHE3 protein abundance assessed by Western blot analysis was unaffected during changes in NaCl intake. During NaHCO(3) loading, NHE3 protein abundance was decreased by 65%. We conclude that proximal NHE3 adapts to chronic metabolic acid-base disorders but not to changes in dietary NaCl intake. (+info)
Cerebrospinal fluid and arterial lactate, pyruvate and acid-base balance in patients with intracranial hemorrhages.
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Lactate and pyruvate concentrations and acid-base balance in cerebrospinal fluid (CSF) and arterial blood were determined in patients with intracranial hemorrhages (28 subarachnoid hemorrhages and 15 intracerebral hemorrhages). A greater increase in CSF lactate and lactate-pyruvate ratio (L/P ratio) was observed in patients with impairment of consciousness, focal neurological deficits, poor prognosis, or CSF pressures higher than 300 mm H2O. A combination of CSF lactate greater than 2.5 mM per liter, L/P ration above 20, bicarbonate less than 20.4 mEq per liter, pH below 7.276, or arterial PCO2 below 31.5 mm Hg seems to indicate poor prognosis from intracranial hemorrhage. The mechanism of hyperventilation in acute cerebrovascular diseases and of CSF pH regulation in acid-base disturbances was also discussed. (+info)