Quiz of the month. Pseudohyperkalemia and excessive K intake.
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Aged↗
Biomedical subjects
M L West
Publications and source records attributed to M L West.
Cloning and sequence analysis of the mouse genomic locus encoding the largest subunit of RNA polymerase II.
The genomic locus (RPII215) encoding the largest subunit of mouse RNA polymerase II has been cloned by low stringency hybridization to a Drosophila RPII215 probe. The mouse gene consists of 28 exons which span 30 kilobases. Analysis of the nucleotide and predicted protein sequences indicates that the protein is comprised of two domains. There is a 1500 residue amino-terminal domain which contains seven regions strikingly similar to those in the beta' subunit of Escherichia coli RNA polymerase, and a carboxyl-terminal domain comprised of 52 repeats of a 7-amino-acid consensus sequence Tyr-Ser-Pro-Thr-Ser-Pro-Ser. Among the seven highly conserved regions are a strongly basic domain consistent with a DNA-binding site and a consensus sequence characteristic of a potential zinc-binding domain. The 5' upstream region contains three tandem sequences similar to binding sites for the transcription factor SP1. Two of the introns in this gene splice at donor GC dinucleotides as opposed to previously described invariant GT sites. The identification of regions which are highly conserved as compared with bacterial and yeast RNA polymerase and other regions which are unique to the mouse protein suggests which domains of RNA polymerase large subunits are involved in aspects of transcription common to both procaryotes and eucaryotes and which are characteristic of transcription in higher organisms.
Amino Acid Sequence↗
A controlled trial of cyclophosphamide in patients with membranous glomerulonephritis.
Patients with membranous glomerulonephritis (MGN), impaired renal function and the nephrotic syndrome are at high risk of developing renal failure. Twenty-six such patients were studied with serum creatinine concentrations exceeding 135 microM, and 24-hour urine protein excretion of at least 3.5 g/day to determine the potential benefit of cyclophosphamide therapy. Cyclophosphamide (mean 1.5 mg/kg/day) was given to nine patients for 23 +/- 4 months. These patients were compared with 17 concurrent controls. The two groups did not differ in clinical or laboratory features at the time of biopsy or start of treatment or its equivalent. Six of the nine cyclophosphamide treated patients and 15 of the 17 controls had received prednisone therapy. The total follow-up was 49 +/- 10 months in the treated group and 50 +/- 6 months in the controls. At last observation, serum creatinine values exceeded 400 microM in eight controls (4 on dialysis) and in none of the treated patients. The mean serum creatinine level was significantly lower (P less than 0.02) in the treated group (173 +/- 24 microM) than in controls (433 +/- 71 0.02) in the treated group (173 +/- 24 microM) than in controls (433 +/- 71 microM). The mean serum albumin level and 24-hour urine protein excretion both improved significantly with treatment as compared with controls. There were four complete remissions, five partial remissions and no patient with persistent nephrotic syndrome after treatment. In the controls, there were no complete remissions, six partial remissions and 11 patients had persistent nephrotic syndrome (P less than 0.001). Thus, cyclophosphamide therapy appears to be of benefit in patients with MGN, the nephrotic syndrome and impaired renal function.
Adult↗
The relationship between the plasma potassium concentration and renal potassium excretion in the adrenalectomized rat.
The purpose of this study was to evaluate the renal mechanisms which lead to a high urine [K+] in adrenalectomized (ADX) rats devoid of aldosterone. By dividing the urine [K+] by the urine to plasma osmolality ratio the [K+] in the cortical collecting duct luminal fluid can be estimated; dividing this value by the plasma [K+] yields an index of the transtubular [K+] gradient (TTKG) in vivo. The TTKG was close to 7 in aldosterone deficient ADX rats while on a normal K+ diet and fell towards unity when amiloride or a low K+ diet was administered to these rats. With a longer time on a low K+ diet, the TTKG was less than 1 in ADX rats. This suggests that K+ was reabsorbed in the medullary collecting duct under these conditions. Hyperkalaemia appears to have an 'aldosterone-like' action in the cortical collecting duct in vivo in the absence of aldosterone in ADX rats. This action of hyperkalaemia permits normal K+ excretion rates despite the absence of mineralocorticoids.
Adrenalectomy↗
Renal potassium handling during states of low aldosterone bio-activity: a method to differentiate renal and non-renal causes.
The purpose of this study was to examine renal potassium handling in patients with low aldosterone bio-activity. The patients with a normal renal response to aldosterone were identified by finding both a low plasma aldosterone concentration during hyperkalaemia and a transtubular potassium concentration gradient (TTKG) in the cortical distal nephron of 6 or greater within 4 h after the administration of a physiologic dose of mineralocorticoid hormone. In contrast, patients with a primary renal potassium excretion defect represent a heterogeneous population. In some, the TTKG rose when a pharmacologic but not a physiologic dose of mineralocorticoid was given; others had little renal response to the administration of this hormone. Furthermore, this renal response may be delayed and require more than 24 h to become manifest.
Adrenal Gland Diseases↗
Does the kidney 'escape' from the kaliuretic action of mineralocorticoids?
The purpose of this study was to determine if there are renal mechanisms which limit the magnitude of potassium loss during mineralocorticoid-induced hypokalemia. To study the renal effects of mineralocorticoids in vivo, the 'cortical distal nephron' transtubular [K] gradient (TTKG) was calculated by dividing the urine [K] by the urine to plasma osmolality ratio; this in turn was divided by the arterial plasma [K]. Hypokalemia (2.6 +/- 0.1 mM) was induced in rabbits by the daily administration of 5 mg deoxycorticosterone acetate (DOCA) for 9-13 days. Infusion of a K-free isotonic solution into these rabbits resulted in more severe hypokalemia (1.6 +/- 0.1 mM) and a TTKG of 4.3 +/- 0.3. The subsequent infusion of a 60-mM K-containing solution elevated the plasma [K] to 5.1 +/- 0.1 mM and was associated with a significant rise in the TTKG to 5.9 +/- 0.4 (p less than 0.05). A K-free solution was then infused to lower the plasma [K]; when the plasma [K] fell below 4 mM, the TTKG decreased to 4.4 +/- 0.3 (p less than 0.05), and was equal to the preinfusion value. Thus, DOCA-induced hypokalemia diminishes renal K excretion by two mechanisms: first, the lower value for the denominator of the TTKG (the plasma [K]) results in a lower luminal [K] at a given TTKG. Second, the TTKG fell during hypokalemia and thereby decreased the luminal [K] in the cortical distal nephron. Hence the urinary K excretion rate was diminished to a greater extent than that predicted from the fall in the plasma [K] despite continuing mineralocorticoid action.
Animals↗
Is urea formation regulated primarily by acid-base balance in vivo?
Large quantities of ammonium and bicarbonate are produced each day from the metabolism of dietary protein. It has recently been proposed that urea synthesis is regulated by the need to remove this large load of bicarbonate. The purpose of these experiments was to test whether the primary function of ureagenesis in vivo is to remove ammonium or bicarbonate. The first series of rats were given a constant acid load as hydrochloric acid or ammonium chloride; individual rats received a constant nitrogen load at a time when their plasma acid-base status ranged from normal (pH 7.4, 28 mM HCO3) to severe metabolic acidosis (pH 6.9, 6 mM HCO3). Urea plus ammonium excretions and the blood urea, glutamine, and ammonium concentrations were monitored with time. Within the constraints of non-steady-state conditions, the rate of urea synthesis was constant and the plasma glutamine and ammonium concentrations also remained constant; thus it appears that the rate of urea synthesis was not primarily regulated by the acid-base status of the animal in vivo over a wide range of plasma ammonium concentrations. In quantitative terms, the vast bulk of the ammonium load was converted to urea over 80 min; only a small quantity of ammonium appeared as circulating glutamine or urinary ammonium. Urea synthesis was proportional to the nitrogen load. A second series of rats received sodium bicarbonate; urea synthesis was not augmented by a bicarbonate load. We conclude from these studies that the need to dispose of excess bicarbonate does not primarily determine the rate of ureagenesis in vivo. The data support the classical view that ureagenesis is controlled by the quantity of ammonium to be removed.
Acid-Base Equilibrium↗
Development of a test to evaluate the transtubular potassium concentration gradient in the cortical collecting duct in vivo.
The purpose of these investigations was to develop a noninvasive test to estimate the transtubular potassium concentration gradient (TTKG) and thereby aldosterone action in the late distal convoluted tubule and the cortical collecting duct in patients with disorders of potassium excretion. Experiments were performed in rats under conditions where the ratio of urine to renal venous potassium concentration could reflect this TTKG. A large furosemide-induced diuresis ensured that sodium delivery was adequate and minimized the change in water content during transit through the medullary collecting duct (equal osmolality and TF/P inulin at the base and the tip of the medullary collecting duct). There was no significant potassium reabsorption nor secretion during transit through the medulla as shown by micropuncture and microcatheterization. Thus the potassium concentration in the urine should mirror that in the lumen at the major nephron sites of potassium secretion. The potassium concentration in the renal vein provides the simplest estimate of the cortical peritubular potassium concentration (the mean renal A-V difference for potassium was 1.2 mM); with a very high fractional excretion of potassium, an adjustment can be made to the arterial potassium concentration to correct for the potassium extracted. If the urine/plasma potassium concentration ratio were a quantitative reflection, then the transepithelial potential difference (TEPD) would be close to -40 mV in normal rats. The TTKG fell to unity when amiloride was given, consistent with an abolition of the apparent TEPD in vivo by this drug. Similar results were obtained in non-diuretic rats. The clinical implications of these findings are discussed.
Aldosterone↗
New clinical approach to evaluate disorders of potassium excretion.
A new clinical approach to patients with disorders of potassium excretion is reported. This approach uses a urinary index, the ratio of potassium concentrations in the urine to vein after adjusting the urine potassium concentration for medullary water abstraction. This index provides a semiquantitative assessment of the apparent transtubular potassium concentration gradient (TTKG) in the major distal nephron segment where potassium is secreted. Three clinical situations are presented where the use of this index provided a better indication of the renal action of mineralocorticoids than did the traditional approach; in each case, the presence of mineralocorticoids was known as drugs with this action were administered. We emphasize that use of this index is restricted to situations where the urine is not hypotonic and distal nephron sodium delivery is not limiting for potassium secretion (greater than 25 mM, twice the sodium concentration required for maximum potassium transport at this nephron site).
Desoxycorticosterone↗
Can marked hyperglycemia occur without ketosis?
The significance of ketosis in this syndrome has been evaluated from several viewpoints. With respect to acid-base considerations (pH, anion gap), ketosis was not very significant. However, with respect to sustained hyperglycemia, the combustion of less glucose than normal by the brain is critical and it is likely that ketone body metabolism plays an important role in this regard. This point can be underscored by a quantitative example. First, assume that the maximum rate of new glucose production in a fasted subject is less than 100 g of glucose per day. Second, since the brain will burn 100 g of glucose per day in a non-ketotic subject, it follows that, even in the absence of glucosuria, there will be a net daily consumption of glucose. Since the hyperglycemic individual has only an extra 100 or so g of glucose, it follows that the blood glucose concentration would approach the renal threshold in several days in the absence of ketosis. Recall that this is a minimum estimate because glucose oxidation in other organs and glucosuria will remove an additional quantity of glucose. Hyperglycemia can only be maintained in the absence of glucose intake if there is a reduced rate of glucose metabolism in the brain. The brain can diminish its rate of glucose catabolism by several mechanisms, including a diminished metabolic rate in the brain and/or the consumption of non-glucose fuels (free fatty acids or beta-hydroxybutyrate) by this organ.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetone↗
The sensitivity of a peer-nomination technique in assessing changes in children's social behavior: a case study.
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Child↗
The effect of occlusion on carbon dioxide emission from human skin.
The effect of occlusion on the carbon dioxide (CO2) emission rate (CDER) of human skin was determined. Occlusive plastic tape elevated the CDER 4.5 times (90nl/cm2/hr) over the normal CDER (20nl/cm2/hr). This increase was noted within a 3-hour period. Non-occlusive paper tape had no effect on CDER. Quantitation of the amount of CO2 under plastic tape revealed that CO2 was present at a concentration of 8-10%. Removal of the plastic tape after 24 hours allowed the CDER to return to approximately normal values within 2 hours. The mechanism by which occlusive plastic tape mediates this dramatic effect on CDER as well as the significance of elevated CO2 concentrations under occlusion are discussed.
Adult↗
The cosmology of 'Hippocrates', De Hebdomadibus.
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Greece, Ancient↗
Hearing loss in a child following neomycin irrigation. Report of a case.
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Child, Preschool↗
Quantitative analysis of glucose loss during acute therapy for hyperglycemic hyperosmolar syndrome.
Four patients with severe hyperglycemia and hyperosmolality were studied to quantitate the major mechanisms responsible for the fall in blood glucose concentration. Insulin was not administered to any of these patients during the first 15 h of therapy. In each case, there was a fall in glucose concentration due to dilution; this was quantitated by chloride space analysis and accounted for 24-34% of the fall in concentration. The size of the glucose pool decreased for two reasons. Glucosuria accounted for the majority of the reduction in the size of the glucose pool in the patients with the smallest decrease in extracellular fluid (ECF) volume [and hence the best preserved glomerular filtration rate (GFR)]. In contrast, glucosuria was a less important factor in causing glucose loss in the patients with very low GFR values. The size of the glucose pool also decreased due to glucose metabolism that did not require exogenous insulin. Thus the fall in glucose concentration in the initial therapy in patients with the hyperglycemic hyperosmolar syndrome is multifactorial and is not absolutely dependent on exogenous insulin. Furthermore, the patients grouped in this diagnostic category represent a heterogeneous population with the common features of severe hyperglycemia, hyperosmolality, and a negative or weakly reactive test for serum ketones.
Adult↗
Possible role of the intestinal P-450 enzyme system in a cyclosporine-clarithromycin interaction.
Clarithromycin is a macrolide antibiotic similar in structure to erythromycin, but suggested to have fewer drug interactions. Although a pharmacokinetic interaction between clarithromycin and cyclosporine was recently reported, its magnitude and mechanism have not been explored. A 43-year-old renal transplant recipient receiving cyclosporine was treated with clarithromycin because of pneumonia. A cyclosporine pharmacokinetic study was performed 8 days after the initiation of the clarithromycin and 14 days after stopping the drug. Clarithromycin coadministration caused an approximately 2-fold increase in the area under the whole blood concentration versus time curve of cyclosporine. The oral clearance of cyclosporine was halved by clarithromycin, but the terminal elimination rate constant decreased only 15% and mean residence time 20%. These observations suggest that clarithromycin inhibits not only the hepatic metabolism but also the intestinal metabolism of cyclosporine. Caution is advised when administering the two drugs concurrently, and additional studies are necessary to elucidate the mechanism of this interaction.
Adult↗
Binding kinetics and bioassay of RRE mRNA fragments to a peptide containing the recognition domain of HIV-1 Rev.
Surface plasmon resonance techniques have been used to examine the kinetics of binding for two RNA fragments to an RNA binding domain of HIV-1 REv. RBE3 RNA elicited an apparent dissociation constant (KD) of 121 nM while RREIIB41-79 RNA exhibited an apparent dissociation constant (KD) of 2.5 nM. The dissociation rates for both RNA fragments were comparable. However, the shorter sequence, RBE3, exhibited considerably slower association kinetics. A series of known inhibitors were assayed against these RNA' and the derived K1's were consistent with those reported in the literature, validating the method for routine inhibitor assays.
Amino Acid Sequence↗