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Biomedical subjects

C R Scriver

Publications and source records attributed to C R Scriver.

At least 253 records · Page 14Linked to original sources
PubMed1976

Realized and potential neutralization of mutant genes in man by nutritional selection.

Inborn errors of metabolism are examples of monogenic disease in man that, more often than not, impair adaptation. Appropriate modification of the nutritional environment has been used in several instances to offset the phenotypic effects of the mutant allele, with resultant relaxation of selection. Despite an impressive, if brief, record of its efficacy, nutritional treatment of inborn errors of metabolism remains suboptimal in the absence of relevant and superior food technology and well-established systems for its application to the patient. Some of the more commonly encountered multifactorial diseases are likely to yield in the future to the type of genetic analysis that has been effective for monogenic disease. Delineation of various monogenic subsets in a multifactorial disease profile may permit the application of specific treatment to persons in the universal population at particular risk with the disease. Coronary heart disease is an example of a major disease burden now undergoing such delineation, which may benefit from the assignment of specific nutritional and pharmacological treatment for particular forms of the disease.

Genetic Engineering↗
PubMed1975

Neonatal hypertyrosinemia and evidence for deficiency of ascorbic acid in Arctic and subarctic peoples.

Hypertyrosinemia tyrosine concentration in whole blood greater than 0.42 mmol/l or 7.5 mg/dl is prevalent among lnuit newborn of the Canadian Eastern Arctic. The rate was 14.8 per 100 newborn between January 1970 and December 1972 (first survey period) and 6.2/100 between January 1973 and September 1974 (second survey period); the corresponding rates among Indian newborn of Nouveau Quebec were 2.6 and 2.2%. Among Anglo-Saxons the rate was less than 0.5% and in French Canada it commonly exceeded 0.94%. Serum concentrations of ascorbic acid were low (less than or equal to 0.25 mg/dl) in the pregnant and age-matched adult lnuit when measured by Nutrition Canada during the first survey period. The percentages of inuit children (up to 4 years old) and pregnant women at "high risk" for scurvy (serum concentration of ascorbic acid less than 0.2 mg/dl) were 14.8 and 47.1, respectively; the corresponding national percentages were 3.0 and 2.2, respectively. Deficiency of ascorbic acid in pregnant women is probably the cause of the unusual prevalence of neonatal hypertyrosinemia among the native Arctic and subarctic peoples because ascorbic acid is required to maintain optimal activity of p-hydroxyphenylpyruvic acid hydroxylase and to permit normal oxidation of tyrosine.

Adolescent↗
PubMed1975

Role of epithelial architecture and intracellular metabolism in proline uptake and transtubular reclamation in PRO/re mouse kidney.

The homozygous PRO/Re mouse has less than 1 percent of the very high proline oxidase activity that characterizes normal kidney cortex. In PRO/Re mouse the endogenous proline concentration is eight times normal in plasma and four times normal in kidney cortex cell, but 50 times normal in urine. The integrity of the membrane transport systems for proline uptake at the antiluminal surface of absorbing epithelium is retained in PRO/Re kidney, as determined by the slice method. Clearance studies in vivo under steady-state conditions indicate that the integrity of the luminal uptake system shared by glycine and proline, and serving proline absorption, is also intact. The exaggerated renal clearance of proline in PRO/Re mice (50 times normal) is explained when its raised intracellular concentration, caused by impaired proline oxidation, is considered. Backflux into urine flowing down the nephron will occur under these conditions, thus impairing net reclamation of proline in PRO/Re kidney. The findings reveal that membrane transport and intracellular metabolism of a substrate are, indeed, independent functions, but that metabolism of a substance can influence its transcellular transport.

Animals↗
PubMed1975

Orthophosphate transport in the erythrocyte of normal subjects and of patients with X-linked hypophosphatemia.

We have examined the mechanism of TCA-soluble orthophosphate (Pi) transfer across the membrane of mature human erythrocytes in normal subjects and in patients with X-linked hypophosphatemia (X-LH). The studies were carried out largely at pH 7.4 and 37 degrees C, in partial stimulation of conditions in vivo. (a) At physiological concentrations (1-2 mM) Pi enters the intact normal erythrocyte down its chemical gradient and under no conditions could we identify a steady-state trans-membrane gradient for Pi greater than 0.6. Calculations of the phosphate anion distribution ratio using the Nernst equation yield theoretical values that closely approximate observed values. (b) Glycolytic inhibitors have little effect on total entry of 32Pi inti erythrocytes but they do affect the intracellular distribution of Pi. In the presence of iodoacetamide, label accumulates almost exclusively in the orthophosphate pool and less than 1% enters the organic phosphate pool. (c) Specific activity measurements in unblocked cells indicate that Pi anion equilibrates first with its intracellular Pi pool. These initial findings imply that neither group translocation, nor energy coupling, influence Pi permeation into the human erythrocytes. (d) The relationship between 32P entry and extracellular Pi concentration is parabolic in the presence of chloride, and linear in the presence of sulfate. The kinetics of concentration dependent entrance cannot be examined and saturability of Pi entry cannot be identified under these conditions. (e) The competitive inhibitor arsenate partially inhibits the initial rate and steady-state flux of orthophosphate in erythrocytes treated with iodoacetamide to inhibit glycolysis. However, a significant portion of Pi transport escapes arsenate inhibition. (f) Activation energies for Pi entry, in nonglycolizing erythrocytes are much higher than those required by simple diffusion in an aqueous system. (g) Neither the inward or outward movement of Pi is modulated by trans-phosphate. These latter findings suggest that transport of phosphate across the human erythrocyte is compatible with slow facilitated diffusion with symmetry for influex and efflux. The transmembrane chemical distribution ratio, and the equilibrium flux of Pi were not different from normal in the X-LH erythrocyte. Nor did the extracellular Pi concentration, arsenate, or temperature affect Pi entry differently in the two types of cells. We dedjce that different gene products serve the diffusional type of Pi transport in the erythrocyte membrane and the saturable component of transepithelial absorption in the gut and kidney. Only the latter is affected by the X-LH mutation. The former is apparently present not only in erythrocytes but also in epithelial tissue, where it can serve the absorption of pharmacologic amounts of Pi in the therapeutic repair of the depleted phosphate pools in X-LH.

Amides↗
PubMed1975

Dominantly inherited osteogenesis imperfecta in man: an examination of collagen biosynthesis.

We have examined control subjects and patients in an effor to discover a metabolic basis for dominantly inherited osterogenesis imperfecta (OI). Studies were carried out in vitro with cultured skin fibroblasts obtained from OI patients, and in vivo on peptide-bound hydroxyproline excretion in urine. Urinary hydroxyproline excretion (milligrams/24 hr) adjusted for age is essentially normal in OI patients, although the mean excretion rate is below average. The latter finding is presumably a reflection of the smaller body mass of OI patients. The OI skin fibroblasts, matched for age of donor, site of biopsy, phase of growth, and generation number in culture, incorporated L-proline into hot trichloroacetic acid (TCA)-soluble protein (collagen) at normal rates. The rate of conversion of proline to hydroxyproline in the nascent polypeptides is also normal in OI. Incorporation of L-lysine was also normal in OI. These findings indicate that peptide synthesis of collagen is not impaired in OI. Rates of galactose incorporation into collagen and the extractability of collagen into normal saline or 0.2 M citric acid were all normal both in OI cells and in the culture medium recovered from the monolayer. These findings, in combination with the urinary data on hydroxyproline excretion in vivo reveal that cross-linking and export of collagen in OI is essentially normal. The elution profile after ion exchange chromatography of fibroblast collagen on carboxymethyl (CM)--Sephadex was also examined. The normal 2/1 ratio of peak 1 (largely alpha 1(1) chains) to peak 2 ) largely alpha 2 chains) was found in OI fibroblast extracts, which implies that synthesis and initial aggregation of the two types of polypeptide to yield (alpha1(1))-2 alpha 2 collagen composition is not abnormal in OI. Despite the negative biochemical findings, a consistent defect in the morphology of OI cells was identified in the log phase and the confluent phase of monolayer cultures. The finding is characterized by irregular packing of the aggregated cells and by an irregular tessellated appearance of the individual OI fibroblast. This observation reassures us that the inherited defect is expressed in vitro.

Adolescent↗
PubMed1975

Ontogeny of L-glutamic acid decarboxylase and gamma-aminobutyric acid concentration in human kidney.

GAD activity and GABA, the product of GAD action on L-glutamate, are both prominent in mature human renal cortex. GAD activity is low in fetal kidney but rises several fold preterm to establish the characteristic post-term specific activity. The ontogeny of the initial step in the GABA pathway parallels the need for kidney to accommodate acid-base regulation after birth. PLP coenzyme is required for GAD holoenzyme integrity. Fetal renal GAD was frequently undersaturated with PLP in our series of observations, raising the suggestion that maternal vitamin B6 nutrition is not always adequate.

Age Factors↗
PubMed1975

Response to crystalline 1alpha-hydroxyvitamin D3 in vitamin D dependency.

The therapeutic response to chemically synthesized 1alpha-hydroxycholecalciferol (1alpha-OH-D3) was studied in three patients with autosomal recessive vitamin D dependency (ARVDD). The daily maintenance dose for vitamin D2, to prevent signs of vitamin D deficiency in these patients, was 40-54.4 mug/kg, or about 100 times normal (Table 1). Withdrawal of maintenance therapy with vitamin D2 resulted in the ultimate reappearance of the vitamin D depletion syndrome in patients 1 and 2 (Figs. 1 and 2). The third patient presented with the deficiency syndrome despite adequate vitamin D nutrition and was recognized to have ARVDD. Treatment with 1alpha-OH-D3 by mouth in all three patients at dose levels of 1-3 mug/24 hr (80-100 ng/kg) corrected hypocalcemia and suppressed parathyroid hormone-dependent renal loss of amino acids (Figs. 1, 2, and 4). Rickets healed in 7-9 weeks on 1alpha-OH-D3 alone (Fig. 3). The therapeutic response was rapid. It was usually seen first in the rise of serum calcium (Figs. 5 and 6). Withdrawal of 1alpha-OH-D3 was followed first by a fall of serum phosphorus, then by a fall in serum calcium; the latter occurred within about 2 weeks of withdrawal. Because the synthesis of 1alpha-OH-D3 is simpler than for 1alpha,25-dihydroxycholecalciferol and because the former is an effective therapeutic analog of vitamin D hormone, we believe these studies in ARVDD reveal 1alpha-OH-D3 to be the agent of choice for treatment of this and analogous diseases.

Alkaline Phosphatase↗