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A Reshef

Publications and source records attributed to A Reshef.

At least 55 records · Page 3Linked to original sources
PubMed1994

Molecular genetics of cerebrotendinous xanthomatosis in Jews of north African origin.

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive sterol storage disease characterized by the accumulation of a bile alcohol, cholestanol, in diverse tissues. The disorder is manifested by extensive nervous system involvement, juvenile cataracts, tendon xanthomas, and premature atherosclerosis and is caused by sterol 27-hydroxylase (EC 1.14.13.15) mutations. Recently, two mutations were shown to cause CTX in four Jewish families of Moroccan origin. An additional mutant allele, found in a Jewish family of Algerian origin is characterized here. Sequence analysis revealed a C to T transition at cDNA position 1037 which predicted a threonine to methionine substitution at residue 306 (designated T306M). It is highly suggestive, but not definitive, that this transition is the mutation causing CTX in this family. A search for additional cases from Jewish families of North African extraction identified five new families including 10 cases. The three sterol 27-hydroxylase gene mutations account for all 10 CTX families and their presence may suggest the existence of positive selective forces that lead to an increased prevalence of this relatively rare disease in Jews from North Africa.

Africa, Northern↗
PubMed1993

A missense mutation in the low density lipoprotein receptor gene causes familial hypercholesterolemia in Sephardic Jews.

Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the low density lipoprotein (LDL) receptor gene. Here, we characterize an LDL receptor mutation that is associated with a distinct haplotype and that causes FH in the Jewish Sephardic population originating from Safed, a town in northern Israel. The mutation was found in eight FH families originating from this community comprising 10% of heterozygote FH index cases screened in Israel. The mutation was not found in four additional FH heterozygotes whose hypercholesterolemia co-segregated with an identical LDL receptor gene haplotype. A guanine to cytosine substitution results in a missense mutation (asp147 to his) in the fourth repeat of the binding domain encoded by exon 4 of the LDL receptor gene. The mutant receptor protein was synthesized in cultured cells as a 120 kDa precursor form that failed to undergo normal processing to a mature cell surface form. Most of the receptor precursors were degraded in the endoplasmic reticulum. The small number of mutant receptors on the cell surface were unable to bind LDL or beta very low density lipoprotein. The abnormal behavior of the mutant receptor was reproduced by site-directed mutagenesis and expression of the mutant protein in CHO cells. The mutation can be diagnosed by allele-specific oligonucleotide hybridization of polymerase chain reaction amplified DNA from FH patients.

Animals↗
PubMed1993

Frameshift and splice-junction mutations in the sterol 27-hydroxylase gene cause cerebrotendinous xanthomatosis in Jews or Moroccan origin.

The sterol 27-hydroxylase (EC 1.14.13.15) catalyzes steps in the oxidation of sterol intermediates that form bile acids. Mutations in this gene give rise to the autosomal recessive disease cerebrotendinous xanthomatosis (CTX). CTX is characterized by tendon xanthomas, cataracts, a multitude of neurological manifestations, and premature atherosclerosis. A relatively high prevalence of the disease has been noted in Jews originating from Morocco. The major objectives of the present investigation were to determine the gene structure and characterize the common mutant alleles that cause CTX in Moroccan Jews. The gene contains nine exons and eight introns and encompasses at least 18.6 kb of DNA. The putative promoter region is rich in guanidine and cytosine residues and contains potential binding sites for the transcription factor Sp1 and the liver transcription factor, LF-B1. Blotting analysis revealed that the mutant alleles do not produce any detectable sterol 27-hydroxylase mRNA. No major gene rearrangements were found and single-strand conformational polymorphism followed by sequence analysis identified two underlying mutations: deletion of thymidine in exon 4 and a guanosine to adenosine substitution at the 3' splice acceptor site of intron 4 of the gene. The molecular characterization of CTX in Jews of Moroccan origin provides a definitive diagnosis of this treatable disease.

Adult↗
PubMed1992

Regulation of lipoprotein lipase by dibutyryl cAMP, cholera toxin, Hepes and heparin in F1 heart-cell cultures.

Regulation of lipoprotein lipase was studied in mesenchymal rat heart-cell cultures. Treatment of the cultures with dibutyryl cyclic AMP or with cholera toxin resulted in an increase in LPL activity and a comparable increase in LPL mRNA. When the cells were exposed to 100 mM Hepes for 24 h, total enzyme activity rose 2-fold and LPL mRNA increased 2.4-fold. After 72 h, there was a 3-fold increase in LPL mRNA and a 4-fold rise in cellular LPL activity, while medium activity increased 20-fold. Exposure of the cultures to heparin for 24 h resulted in a 3.2-fold increase in total activity and a 36-fold increase in medium activity. This increase was not accompanied by any rise in LPL mRNA. Addition of actinomycin D to control dishes for 24 h resulted in a 33% reduction in LPL mRNA and a 43% reduction in enzyme activity. These values were 71% and 56%, respectively, in Hepes-treated cells, indicating that no stabilization of LPL mRNA occurred under these conditions. It can be concluded that in mesenchymal rat heart-cells in culture cAMP and cholera toxin upregulate lipoprotein lipase at the level of transcription. The increase in LPL activity after 24 h exposure to Hepes could be compatible with transcriptional regulation, while exposure to heparin is not accompanied by a change in LPL mRNA.

Animals↗
PubMed1992

Haplotype analysis at the low density lipoprotein receptor locus: application to the study of familial hypercholesterolemia in Israel.

Familial hypercholesterolemia (FH) results from mutations in the low density lipoprotein (LDL) receptor gene. It has been shown that restriction fragment length polymorphisms (RFLPs) associated with this gene may be used for family and population studies. The present investigation is a population-based study of 19 Jewish families with hypercholesterolemia representing 9 different countries of origin. Ten RFLP sites were used to construct 24 different haplotypes from 112 chromosomes. These haplotypes vary in frequency from 0.9% to 28.6%. Five previously undescribed haplotypes, which comprise 8.1% of the sample, are reported here. The six most common haplotypes account for 70% of the sample. Segregation analysis reveals that, in Israel, distinct LDL receptor haplotypes are associated with hypercholesterolemia in 12 (63%) out of the 19 Jewish families. Five LDL receptor haplotypes co-segregate with hypercholesterolemia. Two of these haplotypes seem to be unique to specific population groups in Israel and may therefore represent founder mutations.

Apolipoproteins B↗
PubMed1992

Prenatal diagnosis of familial hypercholesterolemia caused by the "Lebanese" mutation at the low density lipoprotein receptor locus.

Here, we report the prenatal diagnosis of familial hypercholesterolemia in a Christian-Arab family that carries the "Lebanese" mutation, a single base substitution that creates a HinfI restriction site, at the low density lipoprotein (LDL) receptor locus. Polymerase chain reaction amplification and restriction analysis were performed on genomic DNA extracted from a chorionic villus sample. In conjunction with karyotype analysis, the fetus was identified as a heterozygous female. Analysis of LDL receptor restriction fragment length polymorphisms confirmed the presence of a male parent marker and revealed that the fetus inherited the mutant gene from its mother. This technique offers a simple and rapid diagnostic tool that can be carried out at an early stage of gestation. It is recommended for families and population groups with molecularly defined LDL receptor mutations.

Base Sequence↗
PubMed1992

A nonsense mutation in the LDL receptor gene leads to familial hypercholesterolemia in the Druze sect.

Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the LDL receptor gene. Here we characterize an LDL receptor mutation that is associated with a distinct haplotype and causes FH in the Druze, a small Middle Eastern Islamic sect with a high degree of inbreeding. The mutation was found in FH families from two distinct Druze villages from the Golan Heights (northern Israel). It was not found neither in another Druze FH family residing in a different geographical area nor in eight Arab and four Jewish FH heterozygote index cases whose hypercholesterolemia cosegregates with an identical LDL receptor gene haplotype. The mutation, a single-base substitution, results in a termination codon in exon 4 of the LDL receptor gene that encodes for the fourth repeat of the binding domain of the mature receptor. It can be diagnosed by allele-specific oligonucleotide hybridization of PCR-amplified DNA from FH patients.

Base Sequence↗
PubMed1991

Aberrant regulation of interleukin-2 but not of interferon-gamma gene expression in Down syndrome (trisomy 21).

The regulated expression of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) genes was analyzed in peripheral blood mononuclear cells derived from 29 noninstitutionalized Down syndrome individuals and compared to that of 32 normal donors. Culture conditions were chosen that measure the transient, phytohemagglutinin-induced expression of IL-2 and IFN-gamma mRNA, as well as the intactness of post-transcriptional and suppressor T cell-dependent mechanisms that control this expression. The latter was achieved by analyzing, respectively, the superinduction of IL-2 and IFN-gamma mRNA occurring upon culture with cycloheximide or after low-dose gamma-irradiation. A convenient, sensitive, and quantitative assay for specific mRNA was devised, suitable for measuring mRNA levels expressed in cells from 1 ml of peripheral blood. Analysis of individuals with Down syndrome revealed a pronounced decrease in inducibility of the IL-2 gene. By contrast, induction of IFN-gamma mRNA was as vigorous as that observed for normal donors. In cells from trisomic subjects, superinduction of IFN-gamma mRNA by cycloheximide was at least as extensive as for normal donors, while in the case of IL-2 mRNA, it was weaker. These abnormal patterns of IL-2 gene expression were seen irrespective of age. Our findings demonstrate a selective impairment of IL-2 gene expression in Down syndrome, rather than a general deficiency in helper T cells.

Adult↗
PubMed1991

The effect of carbamazepine and ethosuximide on hyperoxic seizures.

The main manifestations of CNS oxygen toxicity are generalized tonic-clonic seizures. We tested the protective effect of 2 antiepileptic drugs, carbamazepine and ethosuximide, which are commonly used for the treatment of generalized seizures, on hyperbaric oxygen-induced convulsions. Rats implanted with chronic cortical electrodes for continuous EEG monitoring were injected i.p. with either carbamazepine (5 doses in the range of 1.5-50 mg/kg), ethosuximide (400 mg/kg), or their vehicles (40% propylene glycol and saline, respectively). The rats were exposed to 5 ATA (0.5 MPa) oxygen. The duration of the latency until the appearance of electrical discharges in the EEG was used as an index of toxicity. Ethosuximide did not protect against hyperoxic seizures. In contrast, rats pretreated (30 min) with carbamazepine exhibited a dose-related protective effect against hyperoxically induced seizures. The results of our study suggest that carbamazepine should be considered for prevention of oxygen-induced seizures during hyperbaric oxygen therapy.

Animals↗
PubMed1991

Regulation of interleukin-2 and interferon-gamma gene expression in renal failure.

Regulated expression of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) genes, induced in cultured peripheral blood mononuclear cells from patients with end-stage renal disease on hemodialysis (HD; N = 13) or peritoneal dialysis (PD; N = 13), was compared to that of 32 normal donors. Culture conditions were chosen that measure the transient, phytohemagglutinin-induced expression of IL-2 and IFN-gamma messenger RNA (mRNA), as well the intactness of post-transcriptional and suppressor T cell-dependent mechanisms that control this expression. The latter was achieved by analyzing the superinduction of IL-2 and IFN-gamma mRNA occurring upon culture with cycloheximide or after low-dose gamma-irradiation, respectively. HD subjects showed a complete loss of inducibility of the IL-2 gene, concomitant with decreased inducibility of IFN-gamma mRNA. In PD subjects, by contrast, expression of IL-2 mRNA was as vigorous as in normal donors, while IFN-gamma mRNA was even more strongly inducible. This difference in gene inducibility is caused by a lack of T cell function in HD subjects. The defect in IL-2 gene expression in HD subjects, occurring most likely at transcription, may underly their impaired immune function.

Adult↗
PubMed1991

Vitamins and trace metals status in non insulin dependent diabetes mellitus.

The status of various vitamins and trace metals in plasma of 100 Non Insulin Dependent Diabetes Mellitus subjects was compared to those of 112 age and sex matched healthy subjects. The plasma concentration of riboflavin, pyridoxine and folic acid were found to be decreased in the diabetic patients while retinol and ascorbic acid were relatively increased, in comparison to the healthy subjects. However in the Non Insulin Dependent Diabetes Mellitus subjects the mean plasma concentration of all the metals and vitamins except for riboflavin were within the range of normal values. In spite of these findings, the percent of diabetic patients with various vitamin or metal deficiencies, e.g. riboflavin, carotene, thiamin, retinol, zinc and iron were significantly higher than those in the healthy population. We conclude that vitamin and metal deficiency is common in Non Insulin Dependent Diabetes Mellitus subjects.

Adult↗
PubMed1991

A common Lithuanian mutation causing familial hypercholesterolemia in Ashkenazi Jews.

Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the low-density-lipoprotein (LDL) receptor. Here we characterize an LDL-receptor founder mutation that is associated with a distinct LDL-receptor haplotype and is responsible for FH in 35% of 71 Jewish-Ashkenazi FH families in Israel. Sixty four percent (16/25) of the Ashkenazi patients who carry this mutant allele were of Lithuanian origin. The mutation was not found in 47 non-Ashkenazi FH families. This mutation was prevalent (8/10 FH cases) in the Jewish community in South Africa, which originated mainly from Lithuania. The mutation, a 3-bp in-frame deletion that would result in the elimination of Gly197, has been previously designated FH-Piscataway. PCR amplification of a DNA fragment that includes the mutation in heterozygous individuals results in the formation of a heteroduplex that can be demonstrated by PAGE and used for molecular diagnosis.

Alleles↗
PubMed1990

Expression of the human IL-2 receptor on lymphocytes involves rapid turnover of its p55 alpha-subunit (Tac).

Upon mitogenic stimulation, both mRNA encoding the p55 alpha-subunit (Tac) of the human IL-2R alpha and IL-2R alpha protein are induced and expressed in tonsil lymphocyte populations over several days. Using a quantitative dot-blot immunoassay for the IL-2R alpha subunit, a rapid disappearance of this polypeptide from cells is demonstrated in the presence of the translation inhibitor, cycloheximide. The half-life of IL-2R alpha subunit protein is 2 to 3 h. This decline in cell-associated IL-2R alpha subunit is matched by a rapid decline in IL-2R alpha on the cell surface and is not accompanied by any increase in soluble IL-2R alpha protein. Long term expression of the IL-2R on the cell surface is thus the result of continual synthesis and rapid breakdown of IL-2R alpha chains in the cell. Steady state expression of the IL-2R after an immune stimulus hence depends upon continuous expression of the IL-2R alpha subunit gene. Rapid turnover of the unstable alpha-subunit on the cell surface provides a novel mechanism for sensitive control of functional IL-2R expression.

Blotting, Northern↗
PubMed1990

Primary prevention of cardiovascular diseases in childhood: changes in serum total cholesterol, high density lipoprotein, and body mass index after 2 years of intervention in Jerusalem schoolchildren age 7-9 years.

A school health education and promotion program, the Israeli version of the American Health Foundation's "Know Your Body" program, was developed by the Department of Public Health of the Municipality of Jerusalem in 1983. Eight experimental and eight control schools participated in this cohort study of Arab and Jewish first-grade children. After the first 2 years of intervention, comparison of experimental and control groups showed a significant increase in serum high density lipoproteins among Jewish children and a decrease in serum total cholesterol and body mass index among both Jewish and Arab children. These results indicate that changes in cardiovascular disease risk factors such as blood total cholesterol, high density lipoproteins, and body mass index are possible after a health education program is introduced to first-grade students for a relatively short period of time.

Body Mass Index↗
PubMed1990

The potential to express or suppress human interleukin-2 and interferon-gamma genes is not restricted to distinct cell subsets.

Cell surface markers CD4, CD8, Leu8 and Leu15 (CD11) were used to separate human lymphoid cell subsets with monoclonal antibody-coated immunomagnetic beads. We show that each of these subsets is able to suppress the induction of IL-2 and IFN-gamma genes effectively. This is manifested by a pronounced superinduction of IL-2 and IFN-gamma mRNA, as well as IFN-gamma protein, in cell populations depleted of one of these subsets. Co-culture of cell subsets with total cell populations or depleted ones, on the other hand, leads to severe inhibition of expression of these genes. In these experiments, cells in suppressor subsets exhibit little, if any, expression of IL-2 and IFN-gamma genes. By contrast, depending on donor and lymphoid tissue examined (tonsils or peripheral blood mononuclear cells), CD4, CD8, Leu8, and Leu15 cell subsets are also able to express IL-2 or IFN-gamma genes to high levels. Moreover, in Leu8+ cells that do not express the IFN-gamma gene, extensive expression of both mRNA and protein can be elicited by inhibiting the activation of suppressor cells with gamma-irradiation before induction. These results support the concept that the potential to express or suppress human IL-2 and IFN-gamma genes is not restricted to distinct cell subsets. Suppression or expression can be elicited in cells carrying a given surface marker, depending on the state of the immune system in a lymphoid tissue.

Antigens, CD↗