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Biomedical subjects

E Delvin

Publications and source records attributed to E Delvin.

At least 37 records · Page 2Linked to original sources
PubMed1997

A novel mechanism for isolated central hypothyroidism: inactivating mutations in the thyrotropin-releasing hormone receptor gene.

Isolated central hypothyroidism, characterized by insufficient TSH secretion resulting in low levels of thyroid hormones, is a rare disorder. We report a boy in whom isolated central hypothyroidism was diagnosed at 9 yr of age. Complete absence of TSH and PRL responses to TRH led us to speculate that he had an inactivating mutation of the TRH receptor gene. The patients' genomic DNA was isolated, and the entire coding region of the TRH receptor was amplified by the PCR and sequenced directly. Confirmation of the mutations and haplotyping of the family was performed using restriction enzymes. The biological activity of the wild-type and mutated TRH receptors was verified by evaluating the binding of labeled TRH and stimulation by TRH of total inositol phosphate accumulation in transfected HEK-293 and COS-1 cells. The patient was found to be a compound heterozygote, having inherited a different mutated allele from each of the parents; both mutations were in the 5'-part of the gene. Mutated receptors were unable to bind TRH and to activate total inositol phosphate accumulation. Our report is the first description of naturally occurring inactivating mutations of a G protein-coupled receptor linked to the phospholipase C second messenger pathway. The prevalence and phenotypic spectrum of TRH receptor mutations in isolated central hypothyroidism remain to be established.

Cell Line↗
PubMed1996

Insulin modulation of newly synthesized apolipoproteins B-100 and B-48 in human fetal intestine: gene expression and mRNA editing are not involved.

We investigated insulin's effect on intestinal lipid, transport and, particularly, the biogenesis of apolipoproteins crucial to lipoprotein secretion. Adding insulin (3 mU) to the serum-free medium of cultured jejunal explants from human fetuses (17-20 weeks) reduced triglyceride and chylomicron production and inhibited apo B-48 and apo B-100 secretion. When apo B mRNA was assayed by RT-PCR and its editing by primer extension, no change was detectable following the addition of insulin. HDL lipid content, apo A-1 synthesis and RNA level were unaffected by insulin. Collectively, these results suggest that the insulin-stimulated decline in intestinal chylomicron output may involve apo B co- or post-translational modifications.

Abortion, Induced↗
PubMed1996

Lipid processing and lipoprotein synthesis by the developing human fetal colon.

Despite significant progress in the elucidation of the ontogeny of gastrointestinal function, little attention has been given to colonic lipid processing during development. The major purpose of this study was to explore the intracellular phase of fat absorption, lipid synthesis, and secretion in the human fetal colon compared with the jejunum originating from the same fetuses. The synthesis of lipids and major apolipoproteins was examined using cultured fetal colonic explants incubated with [14C]oleic acid and [36S]methionine, respectively. Fetal colonic explants demonstrated substantial ability to incorporate [14C]oleic acid (dpm/mg protein) into phospholipids (48,743 +/- 4,783), triglycerides (25,687 +/- 2,469), and cholesteryl esters (6,751 +/- 1,227). The total amount of radiolabeled lipids was much higher within the tissue (87,472 +/- 9,142) than in the medium (51,916 +/- 4,970), indicating a limited capacity of the fetal colon to export newly synthesized lipids. The limited colonic lipid secretory process was even more evident when compared with homologous fetal jejunal de novo synthesized lipids in tissue (133,975 +/- 13,836) and medium (279,858 +/- 1,610), respectively. Similar to the jejunum, the colon was able to elaborate all the phospholipid classes, with phosphatidylcholine accounting for > 70% of tissue phospholipids. However, their individual levels were present in lesser amounts in the colon (P < 0.001). Colonic explants elaborated most of the major lipoprotein classes but were less efficient than jejunal explants in exporting chylomicrons (33-fold), very low density lipoprotein (1.5-fold), and high-density lipoprotein (9-fold) into the medium. Apolipoprotein (apo) B synthesis and apo B mRNA editing were comparable in colonic and jejunal explants; thus they are not responsible for the defective lipoprotein secretion in the fetal large bowel. These results establish for the first time te capability of the human fetal colon to form, but not to efficiently transport, lipids, lipoproteins, and apoproteins.

Apolipoproteins B↗
PubMed1994

Apolipoprotein synthesis in human fetal intestine: regulation by epidermal growth factor.

In this investigation, human fetal intestine (17-20 wk) was used to study the synthesis of apolipoproteins (apo) A-I and B and its modulation by epidermal growth factor. Cultured jejunal explants were incubated with [3%S]-methionine, homogenized, immunoprecipitated and subjected to gel analysis. Radioactivity was detected mostly in apo A-I and, to a lesser extent, in both apo B-48 and apo B-100. However, apo B-48 was always the predominant form. The addition of EGF (100 ng/ml) resulted in a simultaneous decrease in apo B-100 synthesis and increase in apo B-48 production without a marked effect on apo A-I. Moreover, the incubation of jejunal explants with [14C] oleic acid documented the ability of fetal intestine to produce chylomicrons, VLDL, LDL and HDL. Therefore, the human fetal intestine has an efficient lipoprotein-lipid transport system and EGF is able to modulate levels of both apo B species as well as lipoprotein fractions.

Abortion, Legal↗
PubMed1992

Isolation and characterization of a cDNA for osteopontin-k: a kidney cell adhesion molecule with high homology to osteopontins.

Screening of a bovine renal cDNA library with MAbs resulted in the isolation of a 1447 bp cDNA. This cDNA (pBk2.1) was sequenced and shown to contain an open reading frame with a putative protein of 261 amino acids, with a molecular weight of 29,573 (minute leader sequence) and a hydrophobic leader sequence of 16 amino acids. pBk2.1 was shown to share a high level of nucleic acid sequence homology over portions of its sequence to human, porcine, mouse, and rat osteopontins (40-60%). The peptide (osteopontin-k) had a potential glycosylation site (Asn-X-Ser/Thr), a GRGDS receptor binding region, a high level of asparagine residues, and a high abundance of acid amino acids characteristic of osteopontin-like cell adhesion molecules. The N-terminal amino acid region of pBk2.1 (the first 82 amino acids) and 42 amino acids at the C terminus had the highest level of homology with the osteopontins at 86%. The middle portion of the peptide had greatly reduced homology, ranging from 50% (amino acids 83-174) to 12% (amino acids 175-219). There were also deletions and additions of sequence in osteopontin-k that were not found in the other osteopontins. The homologies suggest that these proteins are highly related and may be derived from a common gene by alternative splicing. A 678 bp cRNA probe constructed from pBk2.1, containing a region with low homology to the osteopontins (amino acids 183-219 with less than 20% homology, plus amino acids 220-261 and untranslated sequence), was used in northern blots and RNAse protection assays.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Human neonatal hypocalcemia.

Hypocalcemia is commonly observed in the neonatal period and is usually transient from a few days to a few weeks. On only rare occasions is neonatal hypocalcemia permanent and secondary to congenital hypoparathyroidism caused by either isolated absence of parathyroid glands or in association with other malformations. Most cases of neonatal hypocalcemia fall into one of two clinical categories. Namely early neonatal hypocalcemia occurs in 24-48 h of life and it is usually observed in premature infants or infants of diabetic mothers. Late neonatal hypocalcemia is observed at the end of the first week of life. In addition of these two major categories, neonatal hypocalcemia may occur in association with hypomagnesemia.

Female↗
PubMed1989

[Late neonatal hypocalcemia. Apropos of 33 cases treated with 1 alpha-hydroxycholecalciferol].

Thirty-three observations of late-onset neonatal hypocalcemia were reviewed retrospectively. Their etiological, clinical and biological features were consistent with a transient congenital hypoparathyroidism, associated with a materno-foetal vitamin D deficiency. 1 alpha-hydroxycholecalciferol was used for rapid correction of calcemia and proved to be satisfactorily metabolized after its oral administration.

Calcium↗
PubMed1982

Early oral administration of vitamin D and its metabolites in premature neonates. Effect on mineral homeostasis.

For five days, three groups of six premature infants each were fed human milk and given a daily dosage of one of the following: vitamin D3 (30 micrograms), 25-OH D3 (10 micrograms) and 1,25-OH D3 (0.5 micrograms). The infants in the groups were matched for gestational age and birthweight. Administration of 25-OH De or 1,25-(OH)2 D3 did not significantly modify the course of early neonatal hypocalcemia as compared with infants receiving vitamin C3. Mean plasma Ca +/- S. D. (mg/100 ml) decreased to nadir values at 48 hr (D3: 5.7 +/-1.2; 25 OH D3: 6.8 +/- 0.9; 1.25-(OH)2 D3: 6.7 +/-1.1). A progressive increase toward normal values was seen at 120 and 168 hr in the three groups. Mean plasma immunoreactive parathyroid hormone +/- S.D. (microliters Eq/ml) followed an opposite pattern with peak values at 48 hr (D3: 231 +/- 137; 25-OH D3: 281 +/- 138; 1,25-(OH)2 D3:211 +/- 149). Mean plasma +/- S.D. 25-OH values (ng/ml) were low at 1.2 hr (8.7 +/- 4.8) n: 16) and increased significantly after 7 days of D3 (18.2 +/- 4.2 P less than 0.001) and 25-OH D3 administration (46 +/- 10.3 P less than 0.001)/Mean plasma iCT +/- S.D. (pg/ml) reached peak values at 24 hr (D3: 457 +/- 186; 25-OH D3: 415 +/- 121; 1.25-(OH)2 D3: 443 +/- 183). These data suggest that the various forms of vitamin D are well absorbed in preterm infants and that administration of vitamin D metabolites during the first days of life is not warranted for they prophylaxis of early neonatal hypocalcemia.

Administration, Oral↗
PubMed1977

The in vivo use of dithiothreitol in cystinosis.

Two male patients with late stage (uremic) infantile nephropathic cystinosis (INC) (Table 1) were treated by mouth with the reducing agent dithiothreitol (DTT), at doses not exceeding 25 mg-kg-1 body weight three times per day. Three sequential periods of observation were obtained in both patients: on thiol (8.5 months); off thiol (8-9 months); on thiol again (7 months or longer). Other than nausea and vomiting at the maximum dose range, no apparent toxicity was observed. One subject died in uremia in the 24th month of the study. The half-cystine concentration in peripheral blood leukocytes decreased during both treatment periods in each patient from initial pretreatment levels in excess of 8 nmol-mg-1 protein (normal less than 0.1 nmol-mg-1) to 10-20% of initial values (Table 2 and Fig. 1, A and B). Reduction in total number of blood leukocytes or in the neutrophil fraction, where cystine storage occurs selectively in cystinosis, did not occur (Table 3) as a possible explanation for these findings; nor did storage of samples, a possible artifact, influence the cystine content of cystinotic cells (Fig. 2). Multiple site rectal mucosa biopsy clearly revealed cystine storage but serial biopsies did not reflect a positive DTT response when compared with the leukocyte assay (Table 4). High intersample variation in cystine content, even between samples taken at one time, prevented measurement of a treatment response. DTT had no apparent detrimental effect on the concentration of representative proteins, including hemoglobin (Table 3), serum insulin, and serum immunoglobulin during the treatment trials. Renal function (glomerular and tubular) was severely depressed and did not improve during the period of observation in either patient (Table 2; Fig. 3, A and B). Postmortem tissues from one patient revealed 10-40-fold excess cystine accumulation in kidney cortex and liver (Table 5). However, these levels of accumulation are at the lower range of or even below published values for cystine in cystinotic kidney and liver. Whereas chemical methods are not reliable for detecting and measuring DTT in biologic fluids, preliminary evidence indicates that a silylated derivative of oxidized DTT can be detected in the urine of patients receiving DTT by mouth (Fig. 4). This finding suggests that the thiol is absorbed and excreted.

Autopsy↗
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↗
PubMed1971

Transport and metabolism of sarcosine in hypersarcosinemic and normal phenotypes.

An adolescent male proband with hypersarcosinemia was discovered incidentally in a French-Canadian family; no specific disease was associated with the trait. The hypersarcosinemia is not diminished by dietary folic acid even in pharmacologic doses (30 mg/day). The normal absence of sarcosine dehydrogenase in cultured human skin fibroblasts and in leukocytes was confirmed, thus eliminating these tissues as useful sources for further investigation of mutant sarcosinemic phenotypes and genotypes. The response in plasma of sarcosine and glycine, after sarcosine loading, distinguished the normal subject from the subjects who were presumably homozygous and heterozygous for the hypersarcosinemia allele. Sarcosine clearance from plasma was delayed greatly (t(1/2), 6.1 hr) in the presumed homozygote and slightly (t(1/2), 2.2 hr) in the presumed heterozygote, while plasma glycine remained constant in the former and rose in the latter. Normal subjects clear sarcosine from plasma rapidly (t(1/2), 1.6 hr) while their plasma glycine trend is downward. The phenotypic responses suggest that hypersarcosinemia is an autosomal recessive trait in this pedigree. Renal tubular transport of sarcosine was normal in the proband even though he presumably lacked the sarcosine oxidation which should normally occur in kidney. Sarcosine catabolism is thus not important for its own renal uptake. Sarcosine interacts with proline and glycine during its absorption in vivo. Studies in vitro in rat kidney showed that sarcosine transport is mediated, saturable, and energy dependent. Sarcosine has no apparent transport system of its own; it uses the low K(m) transport systems for L-proline and glycine to a minor extent and a high K(m) system shared by these substances for the major uptake at concentrations encountered in hypersarcosinemia. Intracellular sarcosine at high concentration will exchange with glycine on one of these systems, which may explain a paradoxical improvement in renal transport of glycine after sarcosine loading in the hypersarcosinemic proband.

Absorption↗