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Biomedical subjects

C R Scriver

Publications and source records attributed to C R Scriver.

At least 163 records · Page 9Linked to original sources
PubMed1985

Genetics and mammalian transport systems.

Membranes are organelles of homeostasis that control flux and distribution of molecules in cells. Carriers that mediate flux are gene products; mutations that modify carriers are probes that identify their function. Mutations can provide categorical taxonomies of membrane carriers; in higher organisms they can also identify location and characteristics of carriers. Mendelian human phenotypes reveal at least three different systems for the cationic amino acids (lys, orn, arg) segregated in brush-border (BBM) and basolateral (BLM) membranes of intestinal and renal epithelia; carrier(s) in parenchymal cells (e.g. fibroblasts) are not homologous. At least two gene products for phosphate reabsorption in nephron are revealed by X-linked and autosomal phenotypes; BBM and BLM also contain different forms of the carrier. Mutation reveals two forms of renal glucose reabsorption; the carriers are segregated in different proximal nephron segments. Mutations are potential probes for characterizing both the cellular pathways for synthesis, differentiation, insertion, segregation, turnover, and immobilization of membrane carrier proteins, and the mechanisms by which their function is altered.

Absorption↗
PubMed1985

Ornithine loading did not prevent induced hyperammonemia in a patient with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.

Impairment of urea cycle function in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome is presumably caused, in some patients, by deficient transport of ornithine from cytoplasm into mitochondria. We studied the effect of L-ornithine on L-alanine-induced hyperammonemia in a French-Canadian proband with the syndrome by giving: a 90-min intravenous alanine load (6.6 mmol/kg) together with ornithine (1.1 mmol/kg); an intravenous ornithine bolus (0.3 mmol/kg) followed by ornithine infusion (1.1 mmol/kg) 90 min prior to loading with alanine and ornithine; ornithine supplementation per os (1 g, four times daily X 2 wk) prior to loading with alanine and ornithine. Blood ammonia increased from high normal values to 975, 990, and 750 mumol/liter (normal less than 70) and urinary orotic acid from trace to 539, 494, and 1296 mumol/mmol creatinine (normal 5-11) after the respective loads. Plasma alanine peaked at 1.56-4.24 mmol/liter and ornithine at 1.29-1.95 mmol/liter, but other amino acids were stable. Therefore, ornithine loading did not protect this hyperornithinemia-hyperammonemia-homocitrullinuria patient from hyperammonemia induced by amino-nitrogen loading. Renal fraction excretion of citrulline, lysine, ornithine, glycine, alanine, and tyrosine increased more than 3-fold during ornithine priming, whereas all amino acids were excreted in excess after alanine + ornithine loads; homocitrulline excretion remained unchanged; some urine collections indicated "negative reabsorption" (i.e. apparent secretion) of lysine, histidine, and citrulline. Dietary supplementation with ornithine could deplete lysine pools by impairing lysine reabsorption.

Alanine↗
PubMed1985

Cost-benefit analysis of a thalassemia disease prevention program.

We offer an economic perspective on prevention of beta-thalassemia disease by means of genetic screening and prenatal diagnosis in an established program in Quebec province. The program screens 80 per cent of at-risk persons in the high-risk communities, provides diagnosis to 75 per cent of at-risk couples, and prevented two-thirds of new cases in the period of study. We measured the additional costs, in 1981 Canadian dollars, of medical and public health resources, both incurred and avoided, resulting from use of these prevention services. The total direct cost per case prevented in the program is less than the cost for a single year of treatment for an individual with the disease. Sensitivity analysis accommodating demographic assumptions, participation rates, and discounting rates indicates that, even at rates of marriage, endogamy, and participation lower than observed in the current program, treatment costs will still exceed prevention costs when discounting is set at conventional rates of 4 per cent and 8 per cent. Cost effectiveness of the program is confirmed.

Cost-Benefit Analysis↗
PubMed1984

Sulfate transport by mouse renal cortical slices does not represent uptake by brush-border membrane.

We measured uptake of isotopically 35S-labelled sulfate anion by slices and by brush border membrane vesicles prepared from mouse renal cortex to identify: (i) whether metabolic incorporation of anion influences net transport; (ii) which membrane is primarily exposed in the renal cortex slice. Slices accumulated sulfate without significant incorporation into metabolic pools. Net uptake of sulfate at 0.1 mM by the slice occurred against an electrochemical gradient as determined by measurement of free intracellular sulfate concentration, the isotopic distribution ratio at steady-state, and the distribution of lipophilic ions (TPP+ and SCN-). Carrier mediation of sulfate transport in the slice was confirmed by observing concentration-dependent saturation of net uptake and counter-transport stimulation of efflux. Anion uptake was Na+-independent, K+- and H+-stimulated, and inhibited by disulfonated stilbenes. Brush-border membrane vesicles accumulated sulfate by a saturable mechanism dependent on a Na+ gradient (outside greater than inside); others have shown that uptake of sulfate by brush-border membrane vesicles is insensitive to inhibition by disulfonated stilbenes. These findings indicate that different mechanisms serve sulfate transport in renal cortex slice and brush-border membrane vesicle preparations. They also imply that the slice exposes an epithelial surface different from the brush-border, presumably the basolateral membrane, or its equivalent, since sulfate transport by slices resembles that observed with isolated basolateral membrane vesicles.

Animals↗
PubMed1984

A private view of heterozygosity: eight-year follow-up study on carriers of the Tay-Sachs gene detected by high school screening in Montreal.

We surveyed 264 persons (132 carriers, 132 matched noncarriers) screened for Tay-Sachs heterozygosity during 1974-76 in a program directed at senior high school students in Montreal. Among 198 who apparently received the questionnaire in 1982, the response rate was 42% (38 carriers, 45 noncarriers; age range 21-26 yr). Respondents and nonrespondents had no apparent demographic differences. Of eight unable to remember their genotype only one was a carrier (these persons were excluded from the study). The subjects were: single (75%), married (20%), engaged (3%), divorced (1%); 32% of carriers were engaged or married vs 16% of noncarriers. (There were no carrier couples in our sample, but one such couple, who married after being screened in the high school program, requested amniocentesis in 1981.) Only three of the 12 spouses or fiancé(s) of carriers have not been tested (vs 3 of 6 noncarrier partners). Only 19% of carriers now attach any "worry" to heterozygosity (vs 46% at the earlier time of test disclosure, P = 0.001); carriers with spouses or fiancé(e)s are less "worried" than unattached carriers. Only 3% of carriers claim they would change marriage plans if their fiancé(e) was also a carrier. Carriers and noncarriers uniformly approve (96%) genetic screening for themselves and for other mutant genotypes; 92% of carriers and 95% of noncarriers approve being screened in high school. These findings indicate that Canadians screened in high school: 1) have largely positive attitudes toward genetic screening long after the experience, and 2) are making appropriate use of the test result.

Adult↗
PubMed1984

Genetic causes of chronic musculoskeletal disease in childhood are common.

We surveyed admissions to a pediatric orthopedics hospital for calender years 1957 (polio era) and 1982 (post-polio era). The relative importance of genetic causes of musculoskeletal disease increased after poliomyelitis immunization became universal. Admissions for musculoskeletal disease with a genetic cause (chromosomal, Mendelian, multifactorial, and familial) accounted for 45% of the total in 1957 and 57% in 1982 (p less than 0.02); non-genetic causes were 44% in 1957 and 28% in 1982 (p less than 0.001). The high probability of recurrent disease in the families of these patients implies that genetics has an important place in the provision of services and in the education of staff in pediatric orthopedic hospitals.

Bone Diseases↗
PubMed1984

Osteogenesis imperfecta: a heterogeneous morphologic phenotype in cultured dermal fibroblasts.

Osteogenesis imperfecta (OI) is a phenotype with clinical and biochemical heterogeneity. We report here that expression of the OI phenotype extends to the level of dermal fibroblast morphology in vitro. Growth characteristics and morphology of control (n = 6) and OI cell strains (n = 10, representing the four major OI categories, Sillence classification) were compared by measuring the following: (i) days required in culture to reach confluence after plating at uniform density; (ii) cell density at confluence; (iii) width and length of cells (measured on phase contrast micrographs at 300 X magnification). Our results show that: (i) OI fibroblasts take longer (11-27 days, mean 20 days) than control cells (10-19 days, mean 16 days) to reach stationary phase; (ii) all OI phenotypes achieve a lower cell density (0.87 X 10(6) cells/P60, range 0.3-1.6 X 10(6] at stationary phase relative to control cells (2.2 X 10(6) cells/P60, range 1.7-2.6 X 10(6); F4,77 = 56.1, p less than 0.01, indicating that OI cells are larger than normal). Cell shape (expressed as the width : length ratio) was also abnormal in OI cells. (F4,730 = 37.6, p less than 0.01), types I and II OI cells have significantly increased ratios (p less than 0.01) relative to control, type III, and type IV cells. Intra-group phenotypic heterogeneity was also apparent in the OI categories and also within the control population. These findings confirm deviant morphologic phenotypes in OI dermal fibroblasts and further demonstrate interindividual heterogeneity in the expression of genes that determine size and shape of dermal fibroblasts in both OI and normal donors.

Cells, Cultured↗
PubMed1984

Beta-thalassemia disease prevention: genetic medicine applied.

We report here an evaluation of a program for thalassemia-disease prevention, comprising education, population screening for heterozygotes, and reproductive counseling; the evaluation includes cost analysis. A preprogram survey in 1978 of 3,247 citizens in the high-risk communities (85% were high-school students) showed that 88% favored a program but that only 31% considered fetal diagnosis as an acceptable option. Screening in high school or before marriage was preferred by 56%. In a 25-month period (December 1979-December 1982), we screened 6,748 persons, including 5,117 senior high-school students, using MCV/HbA2 indices. The participation rate was 80% in the high-school group. The frequency for beta-thalassemia heterozygosity was 4.7% with 10-fold variation among ethnic groups at risk; the overall frequency for all variants found was 5.4%. We surveyed 60 carriers and 120 noncarriers after screening high-school students (response rate 77%): most carriers told parents (95%) and friends (67%) the test result; and 38% of the carriers' parents (vs. 18% of the noncarriers' parents) were also screened. Carriers would ascertain their spouses' genotype (91%) and approved uniformly (95%) the high-school screening experience and its goal. We performed 11 fetal diagnoses in a 25-month interval (greater than 75% participation in target population) either by fetoscopy and globin-chain analysis or by amniocentesis and genomic DNA analysis; two of three affected fetuses were aborted at parental request, there was one spontaneous abortion (after fetoscopy), and seven live births. The at-risk couples claimed pregnancy would not be contemplated without the fetal-diagnosis option. We analyzed economic costs of the program: cost per case prevented is approximately equal to $ 6,700, slightly less than cost-per-patient-treatment-year or about 4% of undiscounted treatment cost incurred in the first 25 years of life for an affected individual. These findings indicate: collective acceptance of the program, appropriate attitudes among carriers, general acceptance and efficacy of fetal diagnosis, and global cost-effectiveness.

Adolescent↗
PubMed1984

The effects of Mendelian mutation on renal sulfate and phosphate transport in man and mouse.

We examined renal handling of sulfate and phosphate anions in normal subjects, in patients with two Mendelian disorders of phosphate homeostasis [X-linked hypophosphatemia (XLH) and hypophosphatemic bone disease (HBD)], and in normal male mice (+/Y) and male littermates with murine X-linked hypophosphatemia (Hyp/Y). Serum sulfate was 0.30 +/- 0.04 mmol/l (mean and SD, n = 15) in control human subjects. The corresponding fractional excretion was 0.43 +/- 0.12, and absolute sulfate reabsorption, 15.1 +/- 5.0 mumol/100 ml GF. Patients with impaired phosphate homeostasis had normal renal handling of sulfate. Parathyroid hormone infusion inhibited phosphate reabsorption in normal subjects but did not change tubular reabsorption of sulfate. Serum sulfate was 1.24 +/- 0.20 mmol/l (mean and SD, n = 11) in +/Y mice; the corresponding fractional excretion was 0.38 +/- 0.13. Values in Hyp/Y littermates were not significantly different (1.21 +/- 0.16 mmol/l and 0.32 +/- 0.10, respectively). Brush-border membrane vesicles isolated from Hyp/Y renal cortex demonstrated impaired Na+-dependent phosphate uptake (45% of +/Y control) whereas Na+-dependent sulfate uptake was the same as control. These findings constitute further evidence that sulfate and phosphate anions are conserved from renal filtrate by independent processes in the brush-border membrane of mammalian kidney.

Animals↗
PubMed1983

Apparent gastrointestinal origin of cis-4-hydroxycyclohexanecarboxylic acid.

We identified by gas chromatography-mass spectrometry the unusual substance cis-4-hydroxycyclohexanecarboxylic acid (4-HCH) in the urine of a child. Urinary excretion of 4-HCH and intestinal bacteria were both suppressed by neomycin treatment. We propose that 4-HCH is a by-product of bacterial metabolism.

Bacteria↗
PubMed1983

Metabolism of ethylmalonate to mesaconate in the rat. Evidence for trans-dehydrogenation of methylsuccinate.

Rats excrete increased ethylmalonate and methylsuccinate when given ethylmalonate in the diet; when given methylsuccinate they excrete methylsuccinate and mesaconate. Tenfold more labelled mesaconate was produced from threo-methyl[2,3-2H2] succinate precursor than from the erythro isomer. Our findings suggest trans-dehydrogenation of methylsuccinate and are the first direct evidence linking the metabolism of ethylmalonate, methylsuccinate and mesaconate.

Animals↗
PubMed1983

Panostotic fibrous dysplasia: a congenital disorder of bone with unusual facial appearance, bone fragility, hyperphosphatasemia, and hypophosphatemia.

We report a boy with unusual facial appearance, melanotic patches ("coast-of-Maine" type), myelofibrosis, recurrent femoral fractures, and widespread fibrous dysplasia of bone. Biochemical findings included raised serum alkaline phosphatase (bone isozyme) and 1,25-(OH)2 vitamin D, and low serum phosphorus levels. Elevated urinary excretion rates of total hydroxyproline, glycylproline, and gamma-carboxyglutamic acid indicated increased turnover of bone matrix. Transiliac bone biopsy showed a dearth of marrow elements, greatly increased bone turnover, and absence of normal trabecular organization. Serial radiographs showed progressive cortical thinning and loss of bony trabeculae. Calcitonin and etidronate treatments had no lasting effect on the progressive bone disease. The term "panostotic fibrous dysplasia" is suggested for this condition.

Alkaline Phosphatase↗