Biomedical subjects
Publications and source records attributed to T J Stokes.
Hippocrates noted that bubbles in urine were associated with kidney disease. We examined changes in surface tension responsible for bubble formation in urine, to investigate whether surface tension could be a more accurate and continuous linear predictor of 24-h proteinuria than currently available tests on spot urine.
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Over 170 years after Richard Bright and a century after Ernest H. Starling, the development, location, and severity of edema in patients with renal impairment continue to baffle the predictions of most nephrologists. While much of the phenomenon can be explained by levels of serum proteins, or hydrostatic pressures, there are stunning exceptions well known to any practicing nephrologist. Some of the derangement is undoubtedly due to unmeasured but well-known variables, such as membrane permeability; however, other factors such as free entropy of plasma are also clearly involved. The study of other polyelectrolyte colloids, similar to plasma proteins, for industrial purposes has led to the identification of various phenomena such as counterion condensation that can result in loss of entropy and consequently osmotic pressure. Variables known to result in a loss of free entropy, such as pH, oxidation products and ligand binding, are discussed. Older equations developed by van't Hoff and Donnan might require replacement by newer mathematical models such as the nonlinear Poisson-Boltzmann equation or the Monte Carlo simulator. Attempts to restore free entropy to plasma would be a more physiological treatment of edema than diuretic use. Implications are noted for future drug development to treat edema.
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The effect of delay in thrombectomy of occluded hemodialysis accesses was examined to determine whether a critical period exists during which a salvage procedure was more likely to be successful. A total of 1,126 vascular access surgeries between January 1, 1989, and December 31, 1994, were analyzed. No period of delay in thrombectomy was found when it was possible to say with certainty that an access could not be salvaged, although success was greatest in the first 48 h. Autogenous fistulas were less likely to be salvaged and surgery was unlikely to be successful if performed later than the day of thrombosis. However, grafts were likely to undergo successful thrombectomy even 3 days after thrombosis. Overall when the delay was more than 3 weeks after thrombosis, a new access was more likely to be constructed than the thrombosed access was to be successfully declotted.
A periodicity has been observed in thrombotic events that occur in a variety of vascular beds. There also has been a recent suggestion that there is an increased failure of hemodialysis vascular accesses due to thrombosis during the summer months. We reviewed the last 949 episodes of vascular access thrombosis and found no seasonal pattern, but a weekly pattern was noted that corresponded to the patients' dialysis schedule. That pattern was apparently due to our technique of observation and not due to any intrinsic periodicity in the thrombosis itself. We find no evidence to support the belief in any intrinsic periodicity in hemodialysis vascular access thrombosis and since the thrombotic event itself is usually asymptomatic, any accurate assessment of a diurnal or circumseptan pattern is not possible under ordinary clinical conditions.
We examined the effects of hand dominance and the patients' stated preference of the sleeping position on the survival of vascular accesses for hemodialysis in different locations. Analysis was made of vascular access survival times after 1, 126 vascular access surgeries performed between January 1, 1989, and December 31, 1994. We found that hand dominance and access site were not related to any survival differences in patients with autogenous fistulas, but thigh grafts on both sides had greater survival than arm grafts. The preferential side for sleeping similarly did not seem to affect access survival, but patients who stated a sleep preference on the side opposite their vascular graft tended to have longer access survival time.
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The role of atrial peptide in humans with chronic renal insufficiency is uncertain. Therefore, the effects of synthetic atrial peptide (atriopeptin III, 24 amino acids) infusion on renal function and solute excretion were examined in 16 subjects with chronic renal insufficiency of diverse etiologies. After a two-hour baseline period, atrial peptide was infused for four hours in doses ranging from 0.005 to 0.1 micrograms/kg/min. When all doses were combined, absolute and fractional excretions of sodium increased significantly from baseline values (130 +/- 15 to 231 +/- 28 microEq/min and 3.57 +/- 0.57 to 6.03 +/- 1.26%, respectively, P less than 0.05). Significant increases in urinary excretion of chloride, calcium, and phosphorus were also seen during atrial peptide infusion. Increased absolute and fractional phosphorus excretion persisted during the two-hour postinfusion period, while excretion of other solutes returned to baseline. Glomerular filtration rate (GFR) increased by greater than 20% in five of 16 subjects. Two subjects with severe renal insufficiency (GFR = 9 and 12 mL/min) had no apparent response to atrial peptide infusion. Subjects receiving doses of 0.05 and 0.1 microgram/kg/min had significant falls of mean arterial pressure by the last hour of infusion. A dose-dependent effect of atrial peptide on sodium excretion was suggested, but not statistically significant. No apparent dose-dependent effect was seen on GFR or other solute excretions. Despite the presence of chronic renal insufficiency, atrial peptide increased renal solute excretion in most subjects. The demonstration that atrial peptide retains its diuretic and natriuretic effect in the presence of renal insufficiency supports the hypothesis that atrial peptide plays an important adaptive role in sodium homeostasis of the failing kidney.
The present studies demonstrate that endogenous levels of atrial peptide are significantly elevated in the plasma of rats with bilateral ureteral obstruction (BUO) compared with control rats or rats with unilateral ureteral obstruction. The contribution of endogenous atrial peptide to the natriuresis and diuresis that follows release of BUO was examined by the intravenous infusion of heparin with or without the exogenous administration of atrial peptide. Infusion of heparin, which binds atrial peptide and interferes with its biological effect, decreased the natriuresis and diuresis observed after release of BUO. Heparin administration also markedly blunted the natriuresis and diuresis observed after exogenous administration of atrial peptide following release of BUO in rats. In contrast, heparin administration did not decrease the natriuresis and diuresis seen in the experimental kidney after relief of unilateral ureteral obstruction. The finding of increased plasma levels of atrial peptide in rats with bilateral ureteral obstruction together with the decrease in diuresis and natriuresis observed with the administration of heparin after release of BUO in these animals indicate that endogenous levels of atrial peptide contribute to the natriuresis and diuresis that occur after release of BUO in rats.
There is evidence that guanine nucleotide-sensitive (G) proteins intervene in the activation of adenylate cyclase by parathyroid hormone (PTH). Furthermore, recent studies suggest that G proteins may be involved in the activation by PTH of phospholipase C, with subsequent elevation of diacylglycerol, inositol trisphosphate, and intracellular calcium. Since G proteins may be involved in both transduction systems postulated to mediate the actions of PTH, the present studies were performed to evaluate the influence of pertussis toxin, which prevents receptor-mediated activation of G proteins, on the effects of PTH in opossum kidney (OK) cells. In OK cell membranes, pertussis toxin catalyzed the adenosine diphosphate (ADP) ribosylation of a protein with a molecular weight of 41 kd on SDS-PAGE. Cholera toxin catalyzed the ribosylation of two proteins of molecular weight 52 and 45 kd. Pretreatment of the cells with pertussis toxin abolished the labelling of this 41 kd protein, confirming the access of the toxin into the cells and the presence of pertussis toxin-sensitive substrates. The ribosylation of the cholera toxin substrates was unaffected by pertussis toxin pretreatment of the cells. Treatment of OK cells with pertussis toxin did not change the basal levels of cyclic AMP, but increased the levels of cyclic AMP in response to bPTH 1-34 from 355 +/- 17 to 449 +/- 20 pmoles cyclic AMP per 5 minutes per culture. These results were consistent with the inactivation of an inhibitory G protein. Furthermore, PTH-stimulated cyclic AMP generation was inhibited by norepinephrine from 362 +/- 10 to 228 +/- 18 pmole cyclic AMP per 5 minutes per culture.(ABSTRACT TRUNCATED AT 250 WORDS)
Four hemodialysis patients receiving deferoxamine for metal overload had fatal rhinocerebral rhizopus infections. Serious fungal infections are not commonly seen in patients on dialysis, and none of these patients had the usual risk factors for rhizopus infection. Deferoxamine is being used with increased frequency in dialysis patients for aluminum and iron overload states. We propose that there is a link between the deferoxamine therapy and this unusual infection. Deferoxamine may serve as a specific growth factor for Rhizopus species or may alter host immune function. We suggest searching for fungal organisms in patients with unexplained illnesses receiving deferoxamine.
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Atriopeptin III is natriuretic, diuretic, and phosphaturic in the intact dog and relaxes vascular and nonvascular smooth muscle in vitro. The mechanism of the renal effects of atriopeptin remains ill defined but may include hemodynamic alterations and/or direct tubular effects. Since many peptide hormones act through changes in cyclic nucleotide formation, we examined the effect of synthetic atriopeptins on cAMP and cGMP accumulation in isolated glomeruli and proximal tubules from normal dog kidney. Synthetic atriopeptin produced a dose-related increase in cGMP in glomeruli with a Kact of 200 +/- 19 nM and a maximal activity of 64.1 +/- 6.3 pmol cGMP X mg prot-1 X 5 min-1. In the presence of 4 mM Mn2+ Kact was reduced to 19 +/- 2 nM with no change in maximal cGMP production (66.2 +/- 11.8 pmol cGMP X mg prot-1 X 5 min-1). Atriopeptin (1 microM) did not increase cGMP accumulation above basal levels in proximal tubule segments. The cAMP production of neither glomeruli nor proximal tubules was stimulated by atriopeptin. These studies demonstrate a dose-dependent stimulation of guanylate cyclase by atriopeptin in glomeruli but not in proximal tubule segments. In addition, atriopeptin neither stimulates nor inhibits cAMP accumulation in glomeruli or proximal tubules. These data suggest a major role for the renal effects of atriopeptin at the glomerular level, possibly through hemodynamic effects or changes in the glomerular ultrafiltration coefficient.(ABSTRACT TRUNCATED AT 250 WORDS)
In many systems, perturbations of membrane architecture by changes of lipid and phospholipid composition have been shown to alter the activity of membrane-bound enzymes. The present studies examined the effect of benzyl alcohol, an agent that has been shown to increase membrane fluidity, on the parathyroid hormone (PTH)-sensitive adenylate cyclase system of canine kidney. Benzyl alcohol progressively increased basal adenylate cyclase activity up to fourfold and maximal enzyme activity in the presence of PTH, GTP, guanylimidodiphosphate, and sodium fluoride by four- to sixfold. In the presence of 20 mM Mn2+ (no Mg2+), conditions under which enzyme activity is devoid of influence of guanine nucleotides or hormones, benzyl alcohol was without effect. PTH binding was increased by 25% in the presence of benzyl alcohol without a change in binding affinity. Fluorescent polarization studies using diphenylhexatriene showed a decrease in fluorescence anisotropy in the presence of benzyl alcohol. The results suggest that benzyl alcohol facilitates the interaction of the components of the adenylate cyclase system, presumably by increasing membrane fluidity. Alterations of membrane fluidity may be a potent means of regulating hormone sensitive adenylate cyclase activity.