Increased variance in second electrode accuracy during deep brain stimulation and its relationship to pneumocephalus, brain shift, and clinical outcomes: A retrospective cohort study.

•Overall electrode accuracy was 0.22+/-0.4 â€‹mm with only 3 (4%) electrodes out with 2 â€‹mm from the intended target.•Accuracy was significantly worse in the GPi versus the STN and on the second side implanted.•Inaccuracy occurred in the X (lateral) plane but was not related to pneumocephalus or brain shift.

Suicide intervention training with law enforcement officers.

Law Enforcement Officers' (LEO) interactions with people facing mental health crises have risen exponentially since the era of deinstitutionalization. On average, about 10% of the individuals law enforcement interacts with daily have mental health challenges. Several factors influence the outcome of these interactions, not least of which is an officer's role as a gatekeeper as well as their training related to people with mental health challenges. We hypothesized that participating in the online QPR Training for Law Enforcement Officers would be associated with improved knowledge about suicide, attitudes to suicide and suicide intervention, and self-efficacy. Additionally, we hypothesized that these outcomes would be associated with greater use of intervention skills when encountering individuals at risk for suicide in the community. Results of our longitudinal analysis find that most of the participating officers reported some prior training and yet demonstrated statistically significant improvements in knowledge and attitudes after controlling for previous training. No significant changes were observed in LEO's use of intervention skills following training. We conclude by suggesting that there is substantial need for increased training; and offering possible conceptual and empirical explanations for the observed results.

Hypertension in the recently weaned Dahl salt-sensitive rat despite a diet deficient in sodium chloride.

The Dahl rat is used as a model of hypertension that is "sensitive" to dietary salt (sodium chloride, NaCl). When dietary salt is supplemented in the Dahl rat, the arterial blood pressure of the "salt-sensitive" strain (S) becomes much greater than that of the "salt-resistant" strain (R). It has been widely reported that arterial blood pressure of the young Dahl S rat is not greater than that of the young Dahl R rat before dietary salt is supplemented. In the present study, however, mean arterial pressure directly measured in unanesthetized, unrestrained S rats was greater than in R rats, both when they had been recently weaned and for at least 10 weeks thereafter, despite their having been fed a diet frankly deficient in salt. In weanling S rats, the ratio of heart weight to body weight was also significantly greater than that in weanling R rats, suggesting that the greater blood pressure in the S rat causes cardiac hypertrophy. Thus, biologic differences demonstrated between the S rat and the R rat after weaning, including the phenomenon of salt-sensitivity, could be a consequence of, or be dependent on, an already extant difference in arterial blood pressure between the two strains.

Dietary chloride as a determinant of "sodium-dependent" hypertension.

The uninephrectomized rat given desoxycorticosterone (DOC) provides a classic model of "sodium-dependent" hypertension. In such rats, the extent to which a given dietary intake of sodium induced an increase in blood pressure depended on whether or not the anionic component of the sodium salt was chloride. With normal and high dietary intakes of sodium, sodium chloride induced increases in blood pressure much greater than that induced by approximately equimolar amounts of sodium bicarbonate, sodium ascorbate, or a combination of sodium bicarbonate and sodium ascorbate. A normal amount of dietary sodium chloride induced hypertension, whereas an equimolar amount of sodium bicarbonate did not increase blood pressure. This difference could not be attributed to differences in sodium or potassium balances, weight gain, or caloric intake. The DOC model of "sodium-dependent" hypertension might better be considered sodium chloride-dependent.

Renal fructose-metabolizing enzymes: significance in hereditary fructose intolerance.

In patients with hereditary fructose intolerance, which is characterized by deficient aldolase activity toward fructose-1-phosphate, fructose induces a renal tubular dysfunction that implicates only the proximal convoluted tubule. Because normal metabolism of fructose by way of fructose-1-phosphate requires fructokinase, aldolase "B," and triokinase, the exclusively cortical location of these enzymes indicates that the medulla is not involved in the metabolic abnormality presumably causal of the renal dysfunction.

Electrical Resistivity and Stoichiometry of CaxC60 and SrxC60 Films.

The temperature- and concentration-dependent resistivities of annealed CaxC(60) and SrxC(60) films were measured near room temperature. Resistivity minima were observed at x = 2 and 5. The resistivities of these films were rho(min) approximately 1 ohm-centimeter for x = 2 and rho(min) approximately 10(-2) ohm-centimeter for x = 5. This latter value is comparable to the resistivities found in similar experiments on K(3)C(60) films. There is a maximum in the resistivity between x = 2 and 3, and another at x approximately 7. The conductivity is activated over the whole range of compositions, and the activation energy scales with the logarithm of the resistivity. The results suggest that the conductivity and superconductivity observed in Ca(5)C(60) are associated with the population of bands derived from the t(1g) level of C(6O).

An experimental renal acidification defect in patients with hereditary fructose intolerance. II. Its distinction from classic renal tubular acidosis; its resemblance to the renal acidification defect associated with the Fanconi syndrome of children with cystinosis.

In adult patients with hereditary fructose intolerance (HFI) fructose induces a renal acidification defect characterized by (a) a 20-30% reduction in tubular reabsorption of bicarbonate (T HCO(3) (-)) at plasma bicarbonate concentrations ranging from 21-31 mEq/liter, (b) a maximal tubular reabsorption of bicarbonate (Tm HCO(3) (-)) of approximately 1.9 mEq/100 ml of glomerular filtrate, (c) disappearance of bicarbonaturia at plasma bicarbonate concentrations less than 15 mEq/liter, and (d) during moderately severe degrees of acidosis, a sustained capacity to maintain urinary pH at normal minima and to excrete acid at normal rates. In physiologic distinction from this defect, the renal acidification defect of patients with classic renal tubular acidosis is characterized by (a) just less than complete tubular reabsorption of bicarbonate at plasma bicarbonate concentrations of 26 mEq/liter or less, (b) a normal Tm HCO(3) (-) of approximately 2.8 mEq/100 ml of glomerular filtrate, and (c) during acidosis of an even severe degree, a quantitatively trivial bicarbonaturia, as well as (d) a urinary pH of greater than 6. That the fructose-induced renal acidification defect involves a reduced H(+) secretory capacity of the proximal nephron is supported by the magnitude of the reduction in T HCO(3) (-) (20-30%) and the simultaneous occurrence and the persistence throughout administration of fructose of impaired tubular reabsorption of phosphate, alpha amino nitrogen and uric acid.A reduced H(+) secretory capacity of the proximal nephron also appears operative in two unrelated children with hyperchloremic acidosis, Fanconi's syndrome, and cystinosis. In both, T HCO(3) (-) was reduced 20-30% at plasma bicarbonate concentrations ranging from 20-30 mEq/liter. The bicarbonaturia disappeared at plasma bicarbonate concentrations ranging from 15-18 mEq/liter, and during moderate degrees of acidosis, urinary pH decreased to less than 6, and the excretion rate of acid was normal.

An experimental renal acidification defect in patients with hereditary fructose intolerance. I. Its resemblance to renal tubular acidosis.

In three unrelated patients with hereditary fructose intolerance (HFI), but in none of five normal subjects, the experimental administration of fructose invariably induced a reversible dysfunction of the renal tubule with biochemical and physiological characteristics of renal tubular acidosis. During a state of ammonium chloride-induced acidosis, (a) urinary pH was greater than six and the rate of excretion of net acid (titratable acid plus ammonium minus bicarbonate) was inappropriately low, (b) the glomerular filtration rate remained unchanged or decreased modestly, and (c) urinary excretion of titratable acid increased briskly with diuresis of infused phosphate, although urinary pH changed little. The tubular dysfunction, which also includes impaired tubular reabsorption of alpha amino nitrogen and phosphate, persisted throughout administration of fructose and disappeared afterward. The tubular dysfunction was not causally dependent on hypoglucosemia, ammonium chloride-induced acidosis or osmotic diuresis. Rather, it appeared causally related to the fructose-induced metabolic abnormality of patients with HFI. The causal enzymatic defect, the virtual absence of fructose-1-phosphate aldolase, occurs in the kidney as well as in the liver of patients with HFI.

Impaired renal conservation of sodium and chloride during sustained correction of systemic acidosis in patients with type 1, classic renal tubular acidosis.

In 10 patients with classic renal tubular acidosis in whom correction of acidosis was sustained with orally administered potassium bicarbonate, renal conservation of sodium was evaluated when dietary intake of sodium was restricted to 9--13 meq/day. In five patients, renal conservation of sodium was impaired by at least one criterion of impairment. In the remaining patients, renal conservation of sodium appeared to be relatively well-maintained, but an impairment could not be excluded. In each of six patients studied during induced water diuresis, including two in whom renal conservation of sodium was not unequivocally impaired, the minimal urinary concentrations of sodium were inappropriately high and the urinary excretion rates of sodium were flow-dependent. These results provide direct evidence that an abnormality in renal transport of sodium can occur in classic renal tubular acidosis, and compel a reconsideration of the pathophysiology of disordered renal transport of sodium in this disorder. The results indicate that in at least some patients with classic renal tubular acidosis impaired renal conservation of sodium is not exclusively a reversible consequence of the renal acidification defect. These findings raise the question whether renal transport of sodium is unimpaired in any patients with classic renal tubular acidosis. In the presently studied patients, the impairment in renal conservation of sodium appeared to be in part the consequence of an impaired ability of the vasopressin-responsive segments of the distal nephron to generate and maintain appropriately steep transepithelial sodium concentration gradients.

Attainment and maintenance of normal stature with alkali therapy in infants and children with classic renal tubular acidosis.

Growth was evaluated in a group of 10 infants and children with familial or idiopathic classic renal tubular acidosis in whom alkali therapy was initiated at ages ranging from 8 days to 9.5 yr and administered at dosage schedules documented to sustain correction of acidosis in at least four prolonged observation periods on the Pediatric Clinical Research Ward. When alkali therapy was begun, six patients (four infants and two children) were stunted (height <2.5 SD below mean). Of the four who were not, two infants were too young (<2 wk of age) to have become stunted, and two children had been documented earlier to be nonacidotic. At the start of alkali therapy, the heights of the patients correlated inversely with the maximal possible duration of prior acidosis. WITH SUSTAINED ALKALI THERAPY: (a) each patient attained and maintained normal stature; (b) the mean height of the 10 patients increased from the 1.4+/-4 to the 37.0+/-33 percentile (of a normal age- and sex-matched population); (c) the mean height reached the 69th percentile in the eight patients whose heights could be analyzed according to parental prediction (Tanner technique); (d) the rate of growth increased two- to threefold, and normal heights were attained within 6 mo of initiating alkali therapy in the stunted infants and within 3 yr in the stunted children; (e) the height attained correlated inversely with the maximal possible duration of acidosis (before alkali therapy) only in those patients in whom alkali therapy was started after 6 mo of age, and not in those treated earlier. The amount of alkali required to sustain correction of acidosis increased substantially during the course of treatment in each patient. The maximal alkali requirement ranged from 4.8 to 14.1 meq/kg per day, and in each patient its amount was determined principally by the magnitude of renal bicarbonate wasting.

Renal tubular acidosis in infants: the several kinds, including bicarbonate-wasting, classic renal tubular acidosis.

In four infants with renal tubular acidosis (RTA), including three with apparently classic RTA and one with Fanconi syndrome (FS), the physiologic character of the renal acidification defect was investigated. In two of the infants with apparently classic RTA, the acidification defect was physiologically separable from that described in both adult patients and children with classic RTA (type 1 RTA) in the following ways. (a) The fractional excretion of filtered bicarbonate (C(HCO3)/C(ln)) was not trivial but substantial (6-9%), as well as relatively fixed, over a broad range of plasma bicarbonate concentrations (15-26 mmoles/liter). (b) This value of C(HCO3)/C(ln), combined with a normal or near normal glomerular filtration rate, translated to renal bicarbonate wasting (RBW). (c) RBW at normal plasma bicarbonate concentrations was the major cause of acidosis, and its magnitude was the major determinant of corrective alkali therapy (5-9 mEq/kg per day), just as in the patient with FS, who was found to have type 2 ("proximal") RTA. (d) Persistence of RBW at substantially reduced plasma bicarbonate concentrations, which did not occur in FS, accounted for the spontaneous occurrence of severe acidosis and its rapid recurrence after reduction in alkali therapy. (e) During severe acidosis the urinary pH was >7, a finding reported frequently in infants with apparently classic RTA and "alkali-resistant" acidosis but rarely in adult patients with classic RTA. Continued supplements of potassium were required to maintain normokalemia during sustained correction of acidosis with alkali therapy. Yet, in at least two of the three infants with apparently classic RTA, but in distinction from the patient with FS and other patients with type 2 RTA, fractional excretion of filtered potassium decreased when plasma bicarbonate was experimentally increased to normal values. In one of the two infants with apparently classic RTA and RBW, C(HCO3)/C(ln) and the therapeutic alkali requirement decreased concomitantly and progressively over 2 yr, but RBW continued. Renal tubular acidosis has persisted in all four patients for at least 3 yr, and in three for 4 years.

On the mechanism of renal potassium wasting in renal tubular acidosis associated with the Fanconi syndrome (type 2 RTA).

The mechanism of renal potassium wasting in renal tubular acidosis associated with the Fanconi syndrome (type 2 RTA) was investigated in 10 patients, each of whom had impaired proximal renal tubular reabsorption of bicarbonate as judged from a greater than 15-20% reduction of renal tubular bicarbonate reabsorption (THCO(3) (-)) at normal plasma bicarbonate concentrations. When the plasma bicarbonate concentration ([HCO(3) (-)]p) was experimentally increased to normal levels in three patients with a fractional potassium excretion (C(K)/C(in)) of less than 1.0 during acidosis, C(K)/C(in) and urinary potassium excretion (U(K)V/C(in)) increased strikingly and concurrently with a striking increase in urinary sodium (U(Na)V/C(in)) and bicarbonate (U(HCO3-)V/C(in)) excretion. When [HCO(3) (-)]p was increased to normal levels in two patients with a C(K)/C(in) of greater than 1.0 during acidosis and in whom U(Na)V/C(in) and U(HCO3-)V/C(in) were already markedly increased, C(K)/C(in) did not increase further. When [HCO(3) (-)]p was decreased to subnormal levels in a patient given ammonium chloride, U(K)V/C(in), C(K)/C(in), and U(HCO3-)V/C(in) decreased concurrently. In the six patients in whom [HCO(3) (-)]p was maintained at normal levels (oral alkali therapy) for 2 months or longer, C(K)/C(in) was directly related to the urinary excretion rates of sodium and bicarbonate, hence was directly related to the magnitude of reduction of THCO(3) (-) at normal [HCO(3) (-)]p; C(K)/C(in) was greater than 0.55 in all six patients and greater than 1.0 in four. In eight patients with classic RTA (type 1 RTA), proximal renal tubular reabsorption of bicarbonate was largely intact as judged from a trivial reduction of THCO(3) (-) at normal [HCO(3) (-)]p. When [HCO(3) (-)]p was either increased from subnormal to normal levels, or decreased from normal to subnormal levels, U(HCO3-)V/C(in) remained essentially constant, and U(K)V/C(in) did not change significantly. When correction of acidosis was sustained, U(HCO3-)V/C(in) remained a trivial fraction of that filtered, and C(K)/C(in) was consistently less than 0.55. These results provide evidence that renal potassium wasting in type 2 RTA is physiologically separable from that in type 1 RTA and in part the result of a reduction in the rate at which the proximal tubule reabsorbs bicarbonate and the distal delivery of supernormal amounts of sodium bicarbonate. With an increased stimulus to distal sodium reabsorption, indicated by the finding of hyperaldosteronism, delivery to the distal nephron of supernormal amounts of sodium with the relatively impermeant bicarbonate anion would be expected to increase intraluminal negativity in the distal nephron, and as a consequence, increase potassium secretion and promote renal potassium wasting.

Renal potassium wasting in renal tubular acidosis (RTA): its occurrence in types 1 and 2 RTA despite sustained correction of systemic acidosis.

IN TWO PATIENTS WITH CLASSIC RENAL TUBULAR ACIDOSIS (RTA) AND IN TWO PATIENTS WITH RTA ASSOCIATED WITH THE FANCONI SYNDROME, RENAL POTASSIUM WASTING PERSISTED DESPITE SUSTAINED CORRECTION OF ACIDOSIS: (a) during moderate degrees of hypokalemia, daily urinary excretion of potassium exceeded 80 mEq in each patient; (b) during more severe degrees of hypokalemia, daily urinary excretion of potassium exceeded 40 mEq in two patients and 100 mEq in another. These urinary excretion rates of potassium are more than twice those observed in potassium-depleted normal subjects with even minimal degrees of hypokalemia. The persistence of renal potassium wasting may have resulted in part from hyperaldosteronism, since urinary aldosterone was frankly increased in two patients and was probably abnormally high in the others relative to the degree of their potassium depletion. The hyperaldosteronism persisted despite sustained correction of acidosis, a normal sodium intake, and no reduction in measured plasma volume, and was not associated with hypertension; its cause was not defined. In the two patients with classic RTA, neither renal potassium wasting nor hyperaldosteronism could be explained as a consequence of a gradient restriction on renal H(+) - Na(+) exchange because the urinary pH remained greater than, or approximately equal to, the normal arterial pH or considerably greater than the minimal urinary pH attained during acidosis. The findings provide no support for the traditional view that renal potassium wasting in either classic RTA or RTA associated with the Fanconi syndrome is predictably corrected solely by sustained correction of acidosis with alkali therapy.

Physiologic regulation of the serum concentration of 1,25-dihydroxyvitamin D by phosphorus in normal men.

We asked this question: in normal humans, is either a normal dietary intake or normal serum concentration of phosphorus a determinant of the serum concentration of 1,25(OH)2D? In seven normal men whose dietary phosphorus was decreased from 2,300 to 625 mg/d, each intake for 8-9 d, under strictly controlled, normal metabolic conditions, we measured serum concentrations of 1,25(OH)2D daily, and concentrations of phosphorus hourly throughout a 24-h period, before and after restriction. Decreasing dietary phosphorus induced: (a) a 58% increase in serum levels of 1,25(OH)2D; (b) a 35% decrease in serum levels of phosphorus measured in the afternoon; (c) a 12% decrease in the 24-h mean serum level of phosphorus; but, (d) no decrease in morning fasting levels of phosphorus. Serum concentrations of 1,25(OH)2D varied inversely and significantly with 24-h mean concentrations of phosphorus (r = -0.77, P less than 0.001). When these data are combined with those of our prior study in which dietary phosphorus was varied over an extreme range, the relationship between serum levels of 1,25(OH)2D and 24-h mean serum levels of phosphorus is even stronger (r = -0.90, P less than 0.001). In the aggregate, the results demonstrate that in normal men, dietary phosphorus throughout a normal range and beyond, can finely regulate the renal production and serum concentration of 1,25(OH)2D, and provide evidence that this regulation is mediated by fine modulation of the serum concentration of phosphorus.

Endothelin-induced increases in vascular smooth muscle Ca2+ do not depend on dihydropyridine-sensitive Ca2+ channels.

Endothelin is a potent mammalian vasoconstrictive peptide with structural homology to cation channel-binding insect toxins. We tested the proposal that this peptide directly activates dihydropyridine-sensitive Ca2+ channels in cultured vascular smooth muscle (VSM) cells. First, we found that cell Ca2+ can be altered in VSM by activation of voltage-operated Ca2+ channels. KCl-induced depolarization and the dihydropyridine Ca2+ channel agonist (-) Bay K 8644 (10 microM) both raised cell Ca2+ more than twofold; the effect of KCl was blocked by the inhibitory enantiomer, (+) Bay K 8644 (40 microM). Similar responses were observed in Chinese hamster ovary (CHO) cells. Synthetic endothelin (4 x 10(-8) M) raised Ca2+ in VSM but not CHO cells from 100 +/- 17 to 561 +/- 34 nM within 12 s. Ca2+ subsequently fell to basal levels after 30 min. Half maximal Ca2+ response was at 4 x 10(-9) M endothelin. Unlike endothelin, thrombin raised Ca2+ in both VSM and CHO cells. The Ca2+ responses to endothelin and thrombin were not affected by nicardipine (1 microM), (+) Bay K 8644, or Ca2+-free solutions. Lastly, both hormones caused release of inositol phosphates in VSM cells. However, the response to thrombin was more than 10-fold larger and was more rapid than the response to endothelin; the thrombin response was sensitive to pertussis toxin, while the response to endothelin was not. Thus endothelin, like thrombin, raises cell Ca2+ in VSM by mobilization of intracellular stores and not by activation of dihydropyridine-sensitive Ca2+ channels. However, their receptors are distinct and they exhibit important differences in signal transduction.

Exaggerated phosphaturic response to circulating parathyroid hormone in patients with familial X-linked hypophosphatemic rickets.

To determine whether the phosphaturic response to circulating parathyroid hormone (PTH) is exaggerated in patients with familial x-linked hypophosphatemic vitamin D-resistant rickets (FHR), we examined the phosphaturic response to parathyroid extract (PTE) (administered intravenously in the posthypercalcemic state) in two unrelated adult hemizygotes with FHR. In these two patients whose plasma concentration of PTH was normal (determined by radioimmunoassay). neither vitamin D nor phosphate therapy had been given during the past 10 yr. Two normal men and a hypophosphatemic man with intestinal malabsorption, hypocalcemia, and osteomalacia served as control subjects. In all subjects, calcium gluconate was adminstered intravenously from 6 p.m. to 12 midnight at a rate that maintained the concentration of serum calcium at 13-15 mg/100 ml during the administration of calcium. When normocalcemia had recurred the next morning, and the plasma PTH concentration and urinary excretion of cyclic 3', 5'-AMP were reduced. PTE was administered intravenously at successively increasing rates of 0.1, 0.4, and 0.8 U/kg per h, each rate lasting 90 min. Minutes after the initiation of PTE in the affected hemizygotes, fractional excretion of filtered phosphate increased from negligible values to values strikingly greater than those of similarly studied control subjects and plateaued at strikingly greater values throughout further administration of PTE. This phenomenon of exaggerated phosphaturia could not be attributed to volume expansion, decreases in serum concentration of calcium during the study, differences in percent of administered calcium retained, or hemodynamic changes. Only the phosphaturic response to PTE appeared to be exaggerated. At any cumulative dose of PTE, urinary excretion of cyclic 3', 5'-AMP in the hemizogytes was indistinguishable from that of control subjects. The findings in this study suggest that in patients with FHR, circulating PTH is required for the genetically transmitted abnormality to be physiologically expressed as a reduction in net renal reabsorption of phosphate, and that this physiological expression of the genetic abnormality is expressed fully at normal or nearly normal circulating levels of PTH.

Vitamin D status regulates 25-hydroxyvitamin D3-1 alpha-hydroxylase and its responsiveness to parathyroid hormone in the chick.

We asked this question: Under normal or near-normal metabolic conditions, does the prevailing normal or near-normal vitamin D status dampen the activity of 25-hydroxyvitamin-D3-1 alpha-hydroxylase (1 alpha-hydroxylase) such that it determines not only its "basal" activity but also its responsiveness to stimulation by increased circulating concentrations of parathyroid hormone (PTH)? To answer this question, we measured the activity of 1 alpha-hydroxylase in chicks, with and without administration of PTH, immediately before and during deprivation of vitamin D. Before deprivation of vitamin D, 1 alpha-hydroxylase activity increased only slightly with administration of PTH. With deprivation of vitamin D for 5 and 10 d, while the plasma concentrations of calcium and phosphorus persisted normal and unchanged, 1 alpha-hydroxylase activity not only increased progressively but also became sharply and increasingly responsive to stimulation by administration of PTH. But after 15 d of vitamin D deprivation, and the supervention of hypocalcemia, 1 alpha-hydroxylase activity was not further increased by the administration of PTH. With deprivation of vitamin D, the progressive increase in 1 alpha-hydroxylase correlated inversely with circulating levels of 1,25-dihydroxyvitamin D (1,25-[OH]2D), and the decreasing calcemic response to PTH correlated inversely with the responsiveness of 1 alpha-hydroxylase to PTH (in chicks deprived of vitamin D for 1-10 d). These results demonstrate that: under normal metabolic conditions, the normal vitamin D status regulates the activity of 1 alpha-hydroxylase so as to dampen both its "basal" activity and its responsiveness to stimulation by PTH; and vitamin D deprivation insufficient to cause hypocalcemia enhances both the "basal" activity of 1 alpha-hydroxylase and its responsiveness to stimulation by PTH. The results suggest that the normal dampening of 1 alpha-hydroxylase and both of the demonstrated enhancements of its activity are mediated by normal and reduced levels of circulating 1,25-(OH)2D, respectively. The finding that PTH fails to further stimulate 1 alpha-hydroxylase when vitamin D deprivation is sufficient in duration to cause hypocalcemia confirms the findings of other investigators and again demonstrates that observations made during abnormal metabolic circumstances may bear little on the physiologic regulation of 1 alpha-hydroxylase under normal or near-normal metabolic circumstances.

Dietary intake of phosphorus modulates the circadian rhythm in serum concentration of phosphorus. Implications for the renal production of 1,25-dihydroxyvitamin D.

We recently reported that in healthy men, changes in the production rate (PR) of 1,25-dihydroxyvitamin D [1,25-(OH)2D] accounted for the 80% increase and the 30% decrease in its serum concentration that was induced by restriction and supplementation, respectively, of dietary phosphorus. These changes in PR and serum concentration of 1,25-(OH)2D could be mediated by changes in serum concentrations of phosphorus that occur after the morning fasting period. To examine this hypothesis, we measured serum concentrations of phosphorus in blood drawn at hourly intervals for 24 h in six healthy men in whom dietary phosphorus was initially maintained at 1,500 mg/70 kg body weight per day for 9 d, then restricted to 500 mg/d (coupled with orally administered aluminum hydroxide) for 10 d, and then supplemented to 3,000 mg/d for 10 d. When dietary phosphorus was normal, the serum concentration of phosphorus exhibited the normal circadian rhythm: a rapid decrease in early morning to a nadir at 1100, followed by an increase to plateau at 1600 h and a further increase to an acrophase (peak) at 0030 h. The variation in serum levels of phosphorus can be described as the sum of sinusoidal functions with periodicities of 24 and 12 h. Phosphorus restriction for 10 d induced a 40% reduction in the 24-h mean serum level of phosphorus, abolished the early afternoon rise in its serum level (i.e., the 12-h periodic component of the time series), and delayed the acrophase by 3 h to 0330 h. Phosphorus supplementation for 10 d induced a 14% increase in the 24-h mean serum level of phosphorus but no significant change in its morning fasting level, exaggerated the early afternoon rise in serum phosphorus, and advanced the acrophase by 9 h to 1530 h. The changes in the PR of 1,25-(OH)2D induced by restriction and supplementation of dietary phosphorus varied inversely and significantly with those induced in the 24-h mean serum level of phosphorus (R = -0.88, P less than 0.001). These data demonstrate that in healthy men, dietary phosphorus is an important determinant of the serum concentration of phosphorus throughout most of the day. The data suggest that diet-induced changes in serum levels of phosphorus mediate the changes in PR and serum concentration of 1,25(OH)2D.

Parathyroidectomy reduces 25-hydroxyvitamin D3-1 alpha-hydroxylase activity in the hypocalcemic vitamin D-deficient chick.

To test the hypothesis that in the vitamin D-deficient state the activity of 25-hydroxyvitamin D3-1 alpha-hydroxylase (25-OHD3-1 alpha-hydroxylase) is modulated by parathyroid hormone and the plasma concentration of phosphate only in the presence of small amounts of 1,25-dihydroxyvitamin D3 (or some other metabolite of vitamin D), we measured the activity of this enzyme 24 h after parathyroidectomy (PTX) in frankly hypocalcemic, vitamin D-deficient chicks that were not supplemented with vitamin D or one of its metabolites. The otherwise predictable complications of PTX in this metabolic setting (hypocalcemia of increasing severity, tetany, moribundity, and death) were prevented by continuous intravenous administration of calcium (as a solution of calcium chloride/calcium gluconate 1:1) through a catheter in the external jugular vein placed at the time of PTX. The findings were as follows: (a) The activity of 25-OHD3-1 alpha-hydroxylase was significantly less in the parathyroidectomized group than in the sham-operated control chicks (P less than 0.001). (b) The reductive effect of PTX on the activity of this enzyme was significantly attenuated when hypophosphatemia was increased in severity by administration of glucose. (c) In the post-PTX state the activity of 25-OHD3-1 alpha-hydroxylase and plasma concentration of phosphate were significantly, inversely related (P less than 0.001). (d) In the sham-operated control group the activity of this enzyme and the plasma concentration of phosphate were not significantly correlated. These findings indicate that in the vitamin D-deficient state, both circulating parathyroid hormone and the plasma concentration of phosphate can significantly modulate the activity of 25-OHD3-1 alpha-hydroxylase in the absence of vitamin D or its metabolites. The findings also suggest that in the vitamin D-deficient state the plasma concentration of phosphate modulates the activity of this enzyme only when the concentration of circulating parathyroid hormone is not increased.

Evidence that the severity of depletion of inorganic phosphate determines the severity of the disturbance of adenine nucleotide metabolism in the liver and renal cortex of the fructose-loaded rat.

To test the hypothesis that in both the liver and renal cortex of the fructose-loaded rat, severity of depletion of inorganic phosphate (P(i)), and not the magnitude of accumulation of fructose-1-phosphate (F-1-P), determines the severity of the dose-dependent reduction of ATP, we intraperitoneally injected fed rats with fructose, 20 and 40 mumol/g, alone, and at the higher load, in combination with (a) sodium phosphate, 20 mumol/g, administered shortly beforehand or subsequently or, (b) adenosine, 2 mumol/g, administered beforehand. The following observations were made: (a) With fructose loading alone, at the higher load, both P(i) and total adenine nucleotides (TAN) were reduced by one third in the renal cortex and (as previously observed) by two thirds in the liver; and at either load, the reduction of ATP (and TAN) and the accumulation of F-1-P were less severe in the renal cortex than in the liver. (b) Prior phosphate loading largely prevented the reductions of ATP and TAN in the renal cortex and significantly attenuated them in the liver, yet doubled the renal cortical accumulation of F-1-P. (c) Adenosine loading substantially attenuated the reductions of ATP, TAN, and P(i) only in the renal cortex. (d) ATP varied directly with P(i) (P < 0.001, r = 0.98) in the domain of control and reduced values of P(i) taken from both liver and renal cortex. (e) As judged from tissue and plasma concentrations of fructose and glucose, and tissue concentrations of fructose-6-phosphate and glucose-6-phosphate, the rate at which the renal cortex and liver converted fructose to glucose was much lower at the higher fructose load. (f) Prior phosphate loading prevented this decrease in rate in the renal cortex and attenuated it in the liver; adenosine loading attenuated it only in the renal cortex. We conclude that in both the renal cortex of the fructose-loaded rat: (a) Depletion of P(i) is critical to the causation of the reductions in both ATP and TAN and, at the higher fructose load, of a decrease in the rate at which ATP is regenerated. (b) The severity of depletion of P(i) determines the severity of these disturbances. (c) By differentially mitigating the depletion of P(i), prior phosphate loading largely prevents these disturbances in the renal cortex, and attenuates them in the liver; and adenosine loading attenuates them only in the renal cortex. The findings provide some basis for the observation that in patients with hereditary fructose intolerance experimentally exposed to fructose, prior loading with sodium phosphate substantially attenuates the renal but not hepatic dysfunction.