Cyclosporin-A nephrotoxicity and acute cellular rejection in renal transplant recipients: correlation between radionuclide and histologic findings

Serial radionuclide studies using both Tc-99m DTPA (perfusion) and I-131 hippuran (tubular function) were correlated with histologic findings in 25 patients with renal transplants. These cases included 15 cases of cyclosporin-A nephrotoxicity (CsA-NT) and ten cases of acute cellular rejection that were retrospectively selected on the basis of biopsy findings and favorable clinical response to therapy specific for each of these conditions. The serial radionuclide studies enabled the correct diagnosis in 12 of 15 cases of CsA-NT and eight of ten cases of acute rejection. Posttherapy radionuclide studies, furthermore, demonstrated improvement consistent with clinical response. In all cases, the radionuclide results were available at least 24 hours before biopsy findings. These results indicate that serial radionuclide studies evaluating interval changes in both perfusion and tubular function are of significant value in the diagnosis and follow-up of CsA-NT and acute cellular rejection in transplant recipients. This initial experience suggests a sensitivity of 80%.     

The effect of inhibition of mitochondrial energy metabolism on the transient inward current of isolated guinea-pig ventricular myocytes

Delayed afterdepolarizations (DADs) might underlie ischemic or reperfusion arrhythmias (Ferrier et al., 1985; Coetzee and Opie, 1987). These DADs are the result of a transient inward current iti, which is caused by instability of the intracellular level of free Ca2+ (Cai) due to an oscillatory release of Ca from the sarcoplasmic reticulum (Kass et al., 1978). DADs are known to be abolished by hypoxia and by metabolic inhibition (Di Gennaro et al., 1987; Coetzee and Opie, 1987), which could be caused by a number of different mechanisms: (1) The large increase of potassium conductance associated with metabolic inhibition (Vleugels et al., 1980; Isenberg et al., 1983) could prevent iti from causing a marked depolarization, and would thus "mask" the DADS. (2) Although metabolic inhibition will eventually result in an increase of Cai, a temporary decrease could initially take place, thereby minimizing the Ca instability. Two mechanisms are known which might produce such an effect: Firstly, the shortening of the action potential which occurs during metabolic inhibition will markedly reduce the time during which Ca channels remain open, thereby causing a diminished total Ca influx during the action potential (Isenberg et al., 1983; Noma and Shibasaki, 1985; Kakei et al., 1985). Secondly, a direct reduction of iCa by a decrease in ATP concentration, described by Irisawa and Kokubun (1983), could also contribute to a decreased Ca load. (3) Metabolic inhibitors could possibly interfere with the cycling of Ca between different compartments within the cell, thereby altering the temporal variation in Cai, and thus influencing iti.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adrenaline and the plateau phase of the cardiac action potential

Summary Conduction block in heart cells by K⁺ rich, or Na⁺ depleted solutions can be overcome by adrenaline. In order to explain this phenomenon, the effect of adrenaline on the membrane resting and action potentials of cow Purkinje fibers was measured at various extracellular concentrations of Na⁺, K⁺ and Ca⁺⁺, in the presence of tetrodotoxin, Mn⁺⁺ and beta-receptor antagonists.It was found that adrenaline specifically increases the amplitude and duration of the plateau phase of the cardiac action potential. Plateu-like action potentials, without preceding Na⁺-spike, can be generated and conducted in an all-or-nothing way. In K⁺ rich solutions and under the influence of adrenaline, the depolarization proceeds in two steps. The first step corresponds to the Na⁺-spike. The second step or secondary depolarization corresponds to the plateau; it was not modified by changes of the membrane potential between –85 and –55 mV, or by reduction of extracellular Na⁺ ions, but was specifically blocked by Mn⁺⁺ ions and beta-receptor antagonists. Its amplitude increased by 17 mV for a tenfold change in extracellular Ca⁺⁺. Tetrodotoxin preferentially blocked the Na⁺-spike, but also slowed the rate of potential change during the secondary depolarization.The simplest explanation for the observed phenomena can be found in an increase of Ca⁺⁺ inward current under the influence of adrenaline. The existence of an inward Na⁺⁺ current, different in characteristics from the Na⁺ conductance during the fast upstroke, cannot be ruled out. Some data are in accord with a decrease in K⁺ conductance.     

Interchromosomal duplications of the adrenoleukodystrophy locus: a phenomenon of pericentromeric plasticity

A 9.7 kb segment encompassing exons 7-10 of the adrenoleukodystrophy (ALD) locus of the X chromosome has duplicated to specific locations near the pericentromeric regions of human chromosomes 2p11,10p11, 16p11 and 22q11. Comparative sequence analysis reveals 92-96% nucleotide identity, indicating that the autosomal ALD paralogs arose relatively recently during the course of higher primate evolution (5-10 million years ago). Analysis of sequences flanking the duplication region identifies the presence of an unusual GCTTTTTGC repeat which may be a sequence-specific integration site for the process of pericentromeric- directed transposition. The breakpoint sequence and phylogenetic analysis predict a two-step transposition model, in which a duplication from Xq28 to pericentromeric 2p11 occurred once, followed by a rapid distribution of a larger duplicon cassette among the pericentromeric regions. In addition to facilitating more effective mutation detection among ALD patients, these findings provide further insight into the molecular basis underlying a pericentromeric-directed mechanism for non- homologous interchromosomal exchange.      

The effect of raised pH on pacemaker activity and ionic currents in cardiac purkinje fibers

1. Cardiac Purkinje fibers exposed to alkaline solutions (pH 8 to 9.5) show an increase in rate of diastolic depolarization, eventually resulting in induction of spontaneous activity or an increase of the spontaneous firing rate.
2. The voltage-clamp analysis of the transmembrane currents in pH 9–9.5 shows: i) a shift in the depolarizing direction of the activation (s∞) and time constants (τ _s ) curve of the \(i_{{\text{K}}_{\text{2}} }\) current, ii) a small increase in the maximal value of the fully activated \(i_{{\text{K}}_{\text{2}} }\) current, iii) no significant change of background current in the pacemaker region of membrane potentials.
3. The effect of NH₄Cl was studied as a means to vary intracellular pH. In the presence of Tris buffer the addition of 5 mM NH₄Cl resulted in i) a shift in the depolarizing direction and a decrease in slope of the activation curve of the \(i_{{\text{K}}_{\text{2}} }\) current, ii) a shift in the depolarizing direction of the time-constants curve together with an increase in the maximum value of τ _s , iii) an increase in the maximum value of the fully activated \(i_{{\text{K}}_{\text{2}} }\) current and a depolarizing shift of the reversal potential, similar to the effect of addition of K_c. In the presence of CO₂?HCO₃ buffer the addition of NH₄Cl had no significant effect on the kinetics of the \(i_{{\text{K}}_{\text{2}} }\) current. Since intracellular pH is only affected by NH₄Cl in the presence of Tris buffer, the results suggest that intracellular alkalinization is responsible for the change in \(i_{{\text{K}}_{\text{2}} }\) kinetics.
4. Based on the findings with NH₄Cl it is suggested that perfusion with Tris buffered alkaline solutions not only affects net negative surface charges on the outside but also and to a larger extent increases negative surface charges on the inside of the cell membrane.

     

Effects of the enantiomers of disopyramide and its major metabolite on the electrophysiological characteristics of the guinea-pig papillary muscle

Summary Disopyramide, a Class la antiarrhythmic drug, is clinically used as a racemic mixture; R(–)disopyramide and S(+)disopyramide. The major metabolite in man is desisopropyldisopyramide: R(–)desisopropyl-disopyramide and S(+)desisopropyldisopyramide. The effects of the four compounds were compared on the electrophysiological characteristics of the guinea-pig papillary muscle using the standard microelectrode technique. At an external K⁺ concentration of 5.4 mmol/l and a stimulation frequency of 1 Hz, S(+)disopyramide (20 mol/l) increased action potential duration (APD) by more than 18%, while it was diminished by 6% in the presence of R(–)disopyramide. Resting membrane potential amounted to –87.1 ± 0.5 mV (n = 14) and –85.6 ± 1.2 mV (n = 10), respectively. Also a small but significant difference in effect on the maximal rate of depolarization was observed, R(–)disopyramide being more potent, related with a slower recovery of the maximal rate of depolarization.The enantiomers of the metabolite appeared to be three times less potent than those of the parent drug in their effect on the maximal rate of depolarization. The characteristics of the enantiomers of the metabolite correlated with those of the parent drug: also the R(–)-enantiomer was more potent in decreasing the maximal rate of depolarization and caused more shortening of the action potential than the S(+)enantiomer.Time constants for onset and recovery of/from rate dependent block of the maximal rate of depolarization were dependent upon the external K⁺ concentration, both for the enantiomers of the parent drug and those of the metabolite. Onset slowed down while recovery accelerated when external K⁺ was increased. Time constants were lower for the metabolite.When stimulation interval was shortened, the effect on the maximal rate of depolarisation increased. Only for the metabolite statistical significant stereoselective differences were observed at all stimulation intervals. The effects on the action potential duration were dependent upon stimulation interval; for all enantiomers the action potential duration tended to be relatively (% of control) higher at short stimulation intervals than at large stimulation intervals. The effect on the maximal rate of depolarization was also voltage dependent, but no significant differences were observed between the enantiomers, for the parent drug as well as for the metabolite. Send offprint requests to N. Verbeke at the above address     

Plasma cyclic nucleotide levels in acute leukemia patients

To verify the clinical usefulness of extracellular cyclic nucleotide determination as a tumor marker, plasma cyclic AMP (cAMP) and cyclic GMP (cGMP) levels were measured in 70 normal subjects and 173 acute leukemia patients studied in different stages of their disease. Mean plasma cAMP levels were similar in leukemic and normal subjects, although in 48 patients in the active stage of the disease, first diagnosis, or relapse, the cAMP values were below the normal range, and most of these patients failed to respond to chemotherapy. Plasma cGMP levels were markedly elevated in untreated patients, normalized in all patients who attained complete remission, and increased promptly to pretreatment values in patients who relapsed, suggesting that their determination may be useful to monitor the patients' response to treatment.     

Risk factors associated with having psoriatic arthritis in patients with cutaneous psoriasis

The aim of this study was to determine if the following characteristics were associated with the presence of psoriatic arthritis in a sample of psoriasis patients: race, family history of psoriasis and psoriatic arthritis, age of onset of psoriasis, smoking, alcohol consumption and the maximum body surface area (BSA) affected by psoriasis. This was a case–control study involving 400 psoriasis patients who attended the Psoriasis and Photo‐medicine clinic in the National Skin Center of Singapore over a 1‐year period. Cases were psoriasis patients with psoriatic arthritis while controls were psoriasis patients without psoriatic arthritis. The diagnosis of psoriatic arthritis was made by rheumatologists and participants completed a self‐administered standardized questionnaire. The maximum BSA involved was determined from the case notes. Psoriatic arthritis was not significantly associated with sex, race, age of onset of psoriasis, a family history of psoriasis, smoking and alcohol consumption but was significantly associated with a family history of psoriatic arthritis (P < 0.001) and the maximum body surface involved (P = 0.05). Using multivariate analysis to control for variables, the presence of psoriatic arthritis was significantly associated with a family history of psoriatic arthritis (odds ratio [OR] = 20.5; 95% confidence interval [CI] = 2.49–169.10) and the maximum BSA involved (OR = 2.52; 95% CI = 1.33–4.75). Indian psoriatic patients were more likely to have psoriatic arthritis compared to the other races. A family history of psoriatic arthritis and a greater maximum body surface involved may be associated with having psoriatic arthritis in this study population of psoriasis patients.