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Biomedical subjects

A Gutman

Publications and source records attributed to A Gutman.

At least 19 recordsLinked to original sources
PubMed1996

Fragile X syndrome in two siblings with major congenital malformations.

We report on 2 brothers with both fragile X and VACTERL-H syndrome. The first sibling, age 5, had bilateral cleft lip and palate, ventricular septal defect, and a hypoplastic thumb. The second sibling, age 2 1/2, had a trachesophageal fistula, esophageal atresia, and vertebral abnormality. High-resolution chromosome analysis showed a 46, XY chromosome constitution in both siblings. By PCR and Southern blot analysis, the siblings were found to have large triplet repeat expansions in the fragile X gene (FMR 1) and both had methylation mosaicism. Enzyme kinetic studies of iduronate sulfatase demonstrated a two-fold increase in activity in the first sib as compared to the second. Possible mechanisms through which the fragile X mutation can cause down-regulation of adjacent loci are discussed.

Abnormalities, Multiple↗
PubMed1994

Multiple positive and negative regulatory elements in the promoter of the mouse homeobox gene Hoxb-4.

Mouse Hoxb-4 (Hox-2.6) is a homeobox gene that belongs to a family which also includes Hoxa-4, Hoxc-4, and Hoxd-4 and that is related to the Deformed gene in Drosophila melanogaster. We have determined the sequence of 1.2 kb of 5' flanking DNA of mouse Hoxb-4 and by nuclease S1 and primer extension experiments identified two transcription start sites, P1 and P2, 285 and 207 nucleotides upstream of the ATG initiator codon, respectively. We have shown that this region harbors two independent promoters which drive CAT expression in several different cell lines with various efficiencies, suggesting that they are subject to cell-type-specific regulation. Through detailed mutational analysis, we have identified several cis-regulatory elements, located upstream and downstream of the transcription start sites. They include two cell-type-specific negative regulatory elements, which are more active in F9 embryonal carcinoma cells than in neuroblastoma cells (regions a and d at -226 to -186 and +169 to +205, respectively). An additional negative regulatory element has been delimited (region b between +22 and +113). Positive regulation is achieved by binding of HoxTF, a previously unknown factor, to the sequence GCCATTGG (+148 to +155) that is essential for efficient Hoxb-4 expression. We have also defined the minimal promoter sequences and found that they include two 12-bp initiator elements centered around each transcription start site. The complex architecture of the Hoxb-4 promoter provides the framework for fine-tuned transcriptional regulation during embryonic development.

Animals↗
PubMed1994

Gelfand-Tsetlin principle of minimal afferentation and bistability of dendrites.

Neurons with bistable dendrites may fire persistently without persistent synaptic excitation while transient afferentation shifts the frequency of the persistent firing. These neurons change the firing frequency until they minimize their afferential input in a properly designed network. The afferentation minimum in this network is a stable state. The concept of the stable afferentation minimum generalizes Feldman's spring model of muscle control. An oversimplified network imitating the gamma-loop demonstrates the above statements.

Dendrites↗
PubMed1993

Bi-stable dendrite in constant electric field: a model analysis.

Some neurons possess dendritic persistent inward current, which is activated during depolarization. Dendrites can be stably depolarized, i.e. they are bi-stable if the net current is inward. A proper method to show the existence of dendritic bi-stability is putting the neuron into the electric field to induce transmembrane potential changes along the dendrites. Here we present analytical and computer simulation of the bi-stable dendrite in the d.c. field. A prominent jump to a depolarization plateau can be seen in the soma upon initial hyperpolarization of its membrane. If a considerable portion of dendrites are parallel to the field it is impossible to switch off the depolarization plateau by changing the direction and the strength of the electric field. There is nothing similar in neurons with ohmic dendrites. The results of the simulation conform to the experimental observations in turtle motoneurons [Hounsgaard J. and Kiehn O. (1993) J. Physiol., Lond. (in press)]; comparison of the theoretical and the experimental results makes semi-quantitative estimation of some electrical parameters of dendrites possible. We propose modifications of the experiment which enable one to measure dendritic length constants and other parameters of stained neurons.

Dendrites↗
PubMed1993

Recurrent metabolic decompensation in profound carnitine palmitoyltransferase II deficiency.

A 3-year-old boy had recurrent episodes of lethargy, encephalopathy, and hepatomegaly accompanied by hypoglycemia, elevated liver aminotransferase and creatine kinase values, and nonketotic dicarboxylic aciduria; the serum carnitine level was moderately reduced. Carnitine palmitoyltransferase II activity was decreased in lymphocytes and fibroblasts. Therapy with L-carnitine and a diet low in long-chain triglycerides did not prevent recurrent episodes.

Carnitine O-Palmitoyltransferase↗
PubMed1992

Insulin resistance in spontaneously hypertensive rats but not in deoxycorticosterone-salt or renal vascular hypertension.

OBJECTIVE: To investigate whether the reported association between insulin resistance and hypertension in spontaneously hypertensive rats (SHR) is a primary defect or a secondary phenomenon in hypertension. DESIGN: Comparisons of glucose metabolism between three groups of hypertensive rats: deoxycorticosterone (DOCA)-salt hypertensive rats; two-kidney, one clip renovascular hypertensive (RVH) rats; SHR; and their respective control groups. There was also an additional group of weight-matched SHR and respective Wistar-Kyoto (WKY) controls. METHODS: A trace amount of 3H-deoxyglucose (3H-DOG) was administered in vivo to evaluate its plasma half-life and tissue uptake. In vitro adipose tissue segments were incubated with 14C-glucose and increasing doses of insulin. RESULTS: Compared with age-matched WKY rats, SHR had significantly higher insulin levels, longer plasma half-life and lower 3H-DOG uptake by heart and striated muscle. Plasma glucose levels and incorporation of 14C-glucose into CO2, triglycerides and glycogen by adipose tissue in response to increasing insulin concentrations was similar for both groups of SHR and WKY rats. No differences were found between hypertensive rats and controls in either the DOCA or RVH groups. CONCLUSION: Evidence of insulin resistance in spontaneous, but not secondary, rat hypertension indicates that the resistance is a primary rather than a secondary event in hypertension.

Animals↗
PubMed1991

Autosomal recessive lethal infantile cytochrome C oxidase deficiency.

Three bedouin children with mitochondrial myopathy due to cytochrome c oxidase deficiency presented with progressive muscle weakness, failure to thrive, proximal renal tubular acidosis, and lactic acidemia leading to death. Two died by age 5 months and one by age 16 months. Cytochrome c oxidase was markedly reduced in skeletal muscle extracts of all three. Three other children of the same family with most probably the same metabolic aberration are also described. We suggest an autosomal recessive inheritance for this lethal mitochondrial myopathy.

Acidosis, Renal Tubular↗
PubMed1991

The c-Ets oncoprotein activates the stromelysin promoter through the same elements as several non-nuclear oncoproteins.

The c-ets protooncogenes have recently been shown to code for transcription factors that activate the oncogene responsive unit of the polyoma virus enhancer. We show that transcription of the stromelysin gene, which is highly expressed in transformed cells and tumours, is efficiently activated by c-Ets-1 and -2 through two DNA elements. The distal element is a highly conserved palindrome composed of two strong binding sites for c-Ets-1. The proximal element does not bind c-Ets-1, but may be activated indirectly by increased synthesis of c-Jun and c-Fos. Both ets responsive elements mediate activation by the oncoproteins Ha-Ras, v-Src and v-Mos. These results suggest that c-Ets participates in the mechanisms by which stromelysin gene expression is deregulated in transformed cells and tumours.

Animals↗
PubMed1991

Generation of full-length cDNA recombinant vectors for the transient expression of human fibronectin in mammalian cell lines.

In order to study the roles of the different alternatively spliced variants of human fibronectin (FN) as well as of its binding sites and structural domains in the processes of extracellular matrix assembly, cell adhesion, and cell migration, we constructed expression vectors coding for different human full-length FN polypeptides and deleted versions of these constructs. We expressed them transiently in mammalian cells by calcium phosphate transfection and microinjection techniques. While the deleted recombinants were expressed by both transfection and microinjection, the full-length recombinants could be only expressed by microinjection. Calcium phosphate transfection leads to the accumulation of recombinant FN in cytoplasmic vesicles of both matrix-forming and nonforming cells. On the contrary, microinjection leads to the accumulation of recombinant FN in cytoplasmic vesicles in cells that do not form a matrix, but to the rapid incorporation into the extracellular matrix of matrix-forming cells in addition to a cytoplasmic localization. Identical results were obtained when the FN signal and propeptides were replaced by those of E-cadherin.

Animals↗
PubMed1991

Nuclear targets for transcription regulation by oncogenes.

Recent discoveries have highlighted the importance of transcription in cellular transformation. Transcription factors have a crucial role as nuclear targets that convert mitogenic signals from oncogenes into changes in gene expression.

Amino Acid Sequence↗
PubMed1991

Cell-specific regulation of oncogene-responsive sequences of the c-fos promoter.

We have identified oncogene-responsive sequences in the human c-fos promoter that mediate induction of transcription by several nonnuclear oncoproteins and the tumor promoter TPA. These sequences are regulated in a cell-specific manner. (i) In NIH 3T3 cells, the CArG box of the c-fos promoter is sufficient to mediate activation by oncogenes. (ii) In contrast, in HeLa cells, additional flanking sequences are also required, including the outer arm of the serum response element and the FAP site. We also show that the serum response factor, which binds to the CArG box, activates transcription in vivo in NIH 3T3 cells but not in HeLa cells. Finally, we present evidence that the intracellular level of the c-Fos protein could be a major determinant of cell-specific regulation of these oncogene-responsive elements of the c-fos promoter.

Base Sequence↗
PubMed1991

Fructose-1,6-diphosphatase deficiency in Israel.

The clinical and biochemical data on nine patients belonging to six families with fructose-1,6-diphosphatase deficiency are reported. Two of the six families were Jewish, three were Moslem Arabs and one was of Druze origin. All patients had had neonatal hypoglycemia, lactic acidosis and an abnormal fructose or glycerol loading test. At a later age, instances of hypoglycemia occurred in patients both with and without preceding illness. Hypoglycemic attacks were associated with severe hyperuricemia and metabolic acidosis. Therapeutic measures included a restriction in fructose intake and avoidance of prolonged fasting, particularly during febrile episodes.

Consanguinity↗
PubMed1990

Medium-chain versus long-chain triacylglycerol emulsion hydrolysis by lipoprotein lipase and hepatic lipase: implications for the mechanisms of lipase action.

To explore how enzyme affinities and enzyme activities regulate hydrolysis of water-insoluble substrates, we compared hydrolysis of phospholipid-stabilized emulsions of medium-chain (MCT) versus long-chain triacylglycerols (LCT). Because substrate solubility at the emulsion surface might modulate rates of hydrolysis, the ability of egg yolk phosphatidylcholine to solubilize MCT was examined by NMR spectroscopy. Chemical shift measurements showed that 11 mol % of [13C]carbonyl enriched trioctanoin was incorporated into phospholipid vesicles as a surface component. Similar methods with [13C]triolein showed a maximum solubility in phospholipid bilayers of 3 mol % (Hamilton & Small, 1981). Line widths of trioctanoin surface peaks were half that of LCT, and relaxation times, T1, were also shorter for trioctanoin, showing greater mobility for MCT in phospholipid. In assessing the effects of these differences in solubility on lipolysis, we found that both purified bovine milk lipoprotein lipase and human hepatic lipase hydrolyzed MCT at rates at least 2-fold higher than for LCT. With increasing concentrations of MCT, saturation was not reached, indicating low affinities of lipase for MCT emulsions, but with LCT emulsion incubated with lipoprotein lipase, saturation was reached at relatively low concentration, demonstrating higher affinity of lipase for LCT emulsions. Differences in affinity were also demonstrated in mixed incubations where increasing amounts of LCT emulsion resulted in decreased hydrolysis of MCT emulsions. Increasing MCT emulsion amounts had little or no effect on LCT emulsion hydrolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

The collagenase gene promoter contains a TPA and oncogene-responsive unit encompassing the PEA3 and AP-1 binding sites.

PEA3 is a transcription factor which binds to the polyoma virus enhancer and whose activity is regulated by the expression of a number of oncogenes. We show here that PEA3 also binds specifically to the collagenase and fos cellular promoters. On the collagenase promoter, PEA3 acts synergistically with AP-1 to achieve maximum levels of transcription activation by 12-O-tetradecanoylphorbol-13-acetate (TPA), and non-nuclear oncoproteins, thereby defining a TPA- and oncogene-responsive unit (TORU). From a comparative study of the collagenase TORU and the analogous polyoma virus TORU, we conclude that both the binding affinity of the PEA3 motif and the spacing between PEA3 and AP-1 modulate transcription activation induced by oncogene expression.

Base Sequence↗
PubMed1990

Experimental model of acute appendicitis in the rabbit with determination of leucine amino peptidase (LAP) and acid phosphatase (acid-P) activities in portal blood samples.

The activities of leucine amino peptidase (LAP) and acid phosphatase (Acid-P), conceivable markers of acute appendicitis, were determined in the portal blood of rabbits with acute appendicitis. An experimental model of acute appendicitis was established using No.-O silk ties to block the base of the appendix. The clinical and histopathological picture of acute appendicitis was seen after 12 hr in all the rabbits in the model group (9/9) and in none of the control group. Catheterization of the superior mesenteric vein was performed in rabbits with acute appendicitis, and portal blood samples were taken at 0, 6, and 12 hr for assay of LAP and Acid-P activities. No statistically significant difference between the experimental group and the control group, in the activities of LAP and Acid-P, was found at any time interval. The experimental model of acute appendicitis in the rabbit which is described here is simple and carries a high rate of success. This is probably the first report of using continuous catheterization and repeated sampling of portal blood, for the measurement of enzyme activities, in an experimental model of acute appendicitis. It was concluded that serum LAP and Acid-P activities cannot be used as markers for acute appendicitis.

Acid Phosphatase↗