Biomedical subjects
Publications and source records attributed to J Alvarez.
In order to study the expression of the major subunit of neurofilaments (NFs), rat brain poly(A)+ RNA was purified by three different procedures and was injected in Xenopus laevis oocytes. This system was able to translate efficiently the 200 kDa NF subunit as shown by a dot-blot immunoassay and by immunoprecipitation of labeled NF polypeptides.
A 51-year-old woman with advanced rheumatoid arthritis developed a Goodpasture's syndrome during treatment with penicillamine and carbimazole. Circulating antiglomerular basement membrane antibodies (anti-GBM) were present. Renal biopsy showed focal necrotizing glomerulonephritis with crescents, and HLA typing showed the presence of DR3 and DR4. The patient responded dramatically to pulse methylprednisolone and cyclophosphamide, with both clinical remission and disappearance of anti-GBM antibodies.
A child developed steroid-responsive nephrotic syndrome at the age of 3 years. 6 years later, he developed insulin-dependent diabetes mellitus. At this time renal biopsy disclosed minimal-change disease. After multiple relapses requiring cyclophosphamide or repeated courses of steroid therapy, a second renal biopsy, 5 years after the first, revealed early diabetic changes with associated exudative lesions. The nephrotic syndrome remains responsive to steroids and cyclophosphamide, and the patient maintains an increased glomerular filtration rate and normal blood pressure 3.5 years afterwards. His HLA typing showed DR4 and DR7. Since DR4 and DR7 are associated with diabetes and minimal-change disease, respectively, we speculate that he could carry the genetic predisposition for the development of both diseases.
A 37-year-old diabetic patient with end-stage renal disease on maintenance dialysis developed widely disseminated tuberculosis. Tuberculosis was associated with hypercalcemia, inappropriately elevated serum levels of 1,25(OH)2D3, and consistently suppressed serum levels of iPTH. This case provides additional evidence that in granulomatous diseases extrarenal synthesis of 1,25(OH)2D3 may occur.
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Several lipophilic calmodulin antagonists (phenotiazines, butyrophenones and diphenylbutylpiperidines) inhibited Ca2+-induced loss of KC1 from human red cells. However, the Ki values for this effect did not bear good correlation with the Ki values reported for well-known calmodulin-dependent systems. In addition, the inhibition was strongly dependent on the haematocrit and valinomycin-induced KC1 fluxes were also affected. Added calmodulin did not have any effect on Ca2+-dependent 86Rb uptake by inside-out vesicles derived from red cell membranes whereas stimulation of Ca2+-dependent ATPase was apparent. Lipophilic anticalmodulins at high doses had all kinds of effects on 86Rb uptake by inside-out vesicles: increase, decrease or no change of the fraction of activated vesicles reached at submaximal Ca2+ concentrations, with or without modification of the relative rate of 86Rb uptake. The hydrophylic compound 48/80 decreased the fraction of activated vesicles reached at submaximal Ca2+ concentrations without affecting the relative rate of 86Rb uptake, but this effect took place only at concentrations 10-fold higher than the reported Ki for calmodulin-dependent systems. These results suggest that Ca2+-dependent K+ channels of red cells are not regulated by calmodulin.
The calibers and microtubular content of axons were studied in normal and regenerating fibers of the sural nerve from 17 to 122 days after a lesion of the sciatic nerve of young adult rats. During this period (70-175 days of age), the cross-sectional area of control myelinated axons almost doubled but that of nonmedullated axons did not change. In regenerating nerves, after 122 days of recovery, the cross-sectional area of myelinated fibers was still 38% below that of the normal side. In contrast, the regenerating nonmedullated population was richer in fine (less than 0.2 micron2) and in coarse (greater than 0.9 micron2) fibers than on the control side; the cross-sectional area averages were 0.50 and 0.54-0.70 micron 2 for the normal and regenerating populations, respectively. The microtubular density of normal 3-micron myelinated fibers averaged 24.0 microtubules/micron2. In regenerating fibers of the same size the density varied between 19.2 and 23.2 microtubules/micron2. Microtubular density values of normal and regenerating fibers were not statistically different. In nonmedullated fibers, the microtubular content (expressed as microtubular density or number of microtubules per axon) correlated with the caliber of the fiber. In these correlations, only minor differences were observed between regenerating and uninjured fibers. Our results indicate that nonmedullated fibers terminate their radial growth well before myelinated fibers do, and that axonal microtubular content correlates with the local size of the fiber and is largely insensitive to regeneration.
The caliber and microtubular content of growing axons were assessed with the electron microscope in the sural nerve of the rat from birth until the age of 63 days (young adult). The caliber of both nonmedullated and myelinated fibers increased throughout the period of observation. At birth, nonmedullated fibers smaller than 0.2 micron2 represented 69% of the population; at day 63 less than 7% were that small. Irrespective of the age of the rat, the number of microtubule profiles of nonmedullated fibers increased with the cross-sectional area of the axon although their packing decreased. In myelinated fibers of a given caliber, the packing of microtubules increased with time, and by day 63 the density had reached its final value. In nonmedullated fibers of a given caliber, a similar trend was observed after day 31; i.e., fibers showed a small but consistent increase in density. However, before that, and in contrast to myelinated fibers, nonmedullated fibers of defined calibers exhibited a transient increase in the microtubular density. Notwithstanding, during the history of an individual fiber the packing of its microtubules may decrease continuously until stabilizing, because the developing fiber is increasing its caliber and hence decreasing its microtubular density. In the 5-day-old rats, the caliber spectra of myelinated and nonmedullated axons overlapped in the 0.49-0.83 micron2 range and their microtubular densities were similar. We conclude that the microtubular content of developing axons correlates with caliber, an architectural feature, and is largely independent of growth and of its myelinated condition. We propose that the cytoskeletal rather than the transport function commands the organization of axonal microtubules.
The all or nothing behaviour of Ca2+-dependent K+ channels has been analyzed in one-step inside-out vesicles. There is a threshold for Ca2+ below which the K+ channels remain silent, and which ranges between the 10(-6) and 10(-8) M for different vesicles under the experimental conditions tested, in the absence of Mg2+. The increase of Ca2+ concentration within this range recruits a larger fraction of the vesicles to the active (permeable to 86Rb+) state. The apparent rate of 86Rb+ transport through each individual channel was found to increase, however, with Ca2+ concentration. This finding is not an artefact due to size heterogeneity of the vesicle population, and it is consistent with the variations of the mean open time of the channels with Ca2+ concentration reported previously in patch-clamp experiments. The electron donor system ascorbate + phenazine-methosulphate increases the rate of 86Rb+ transport through the channels whereas oxidized cytochrome c has the opposite effect.
Proportion, caliber, and microtubular content of the L7 ventral root nonmedullated fibers were studied in the cat. Nonmedullated fibers constituted 28% of the axonal population at the far end of the root. The number of myelinated profiles at the far end of the root and in the vicinity of the ventral surface of the cord (1-2 mm distance) was the same whereas the number of nonmedullated fibers decreased toward the proximal site of the root by 42%. Caliber and microtubular content of nonmedullated fibers were assessed only at the far end of the ventral root. Nearly 90% of the axons were smaller than 0.3 micron2. The average cross-sectional area was 0.15 micron2, a value 35% below that of the L7 dorsal root fibers. The microtubular density was highest in the finest fibers (116 microtubules/micron2 in fibers smaller than 0.1 micron2) and decreased with the increase in cross-sectional area (25 microtubules/micron2 for 0.7-0.8 micron2 axons). The number of microtubules per axon in axons of both roots was similar in fibers smaller than 0.3 micron2; in larger axons, composing about 10% of the population, ventral root fibers had more microtubules than dorsal root fibers. The ventral and dorsal nonmedullated fibers differ slightly but significantly in caliber and microtubule content. However, they are similar in contrast to peripheral nonmedullated fibers, which are three to four times as big and contain two to three times as many microtubules as radicular fibers. Our results confirm the presence of a large admixture of nonmedullated profiles in the L7 ventral root of the cat, support the notion that a number of these fibers make a U turn in the ventral root, and suggest that these arise from the central process of the primary sensory axon.
Pb2+ modified the apparent threshold sensitivity to Ca2+ of individual K+ channels with a biphasic time-course. At first, the sensitivity to Ca2+ was lowered with the result of a decrease of the fraction of activated vesicles at a given Ca2+ concentration. Later, Pb2+ increased the sensitivity to Ca2+ and the fraction of activated vesicles. The increase of Pb2+ concentration increased the extent of the initial inhibition but decreased its duration. The inhibitory effect was not observed when the addition of Ca2+ preceded the addition of Pb2+. The presence of Mg2+ in the incubation medium was also required. In the absence of Mg2+, Pb2+ decreased the rate of uptake of 86Rb, but no decrease in the fraction of activated vesicles could be demonstrated.
The effects of variations of the NAD+/NADH quotient on the uptake of 86Rb by human red cells loaded by non-disruptive means with the chelator Benz2 and different amounts of 45Ca has been examined. The NAD+/NADH quotient was modified by the addition of pyruvate and/or lactate or xylitol. It was found that the uptake of 86Rb at a given intracellular Ca2+ concentrations was faster in the reduced state (lactate or xylitol added). Metabolic changes were associated with variations of the redox state. However, glycolitic intermediates did not significantly modify the apparent affinity for Ca2+ of the Ca2+-dependent K+ channel in one-step inside-out vesicles prepared from the erythrocyte membrane. Taken together, these results suggest that modifications of the cytoplasmic redox potential could modulate the sensitivity to Ca2+ of the Ca2+-dependent K+ channel in the human red cells under physiological conditions. This conclusion is consistent with previous findings in inside-out vesicles of human erythrocytes using artificial electron donors.
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The caliber and microtubular content of the fibers emerging from the superior cervical ganglion of the cat were studied up to 60 days following preganglionic nerve transection. No significant difference was observed between normal and treated animals. This suggests that the caliber and microtubular content of the sympathetic axon are not subject to trophic control by the preganglionic nerve and that the normal firing rate of the pathway seems insufficient to affect the microtubular content of the fiber.