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K Skorecki

Publications and source records attributed to K Skorecki.

At least 19 recordsLinked to original sources
PubMed2001

Haptoglobin phenotype and diabetic nephropathy.

AIMS/HYPOTHESIS: To determine if the haptoglobin 2 allele is associated with an increased risk for the development of diabetic nephropathy. METHODS: This study included 110 consecutive normotensive subjects with Type I (insulin-dependent) diabetes mellitus and Type II (non-insulin-dependent) diabetes mellitus seen in two outpatient clinics in Israel. Diabetes duration was greater than 10 years for Type I diabetes and more than 5 years for Type II diabetic subjects. Microalbuminuria was defined as urinary protein excretion of 30 to 300 mg/24 h, and macroalbuminuria was defined as urinary protein excretion of greater than 300 mg/24 h. Serum was taken from subjects for haptoglobin typing by gel electrophoresis. RESULTS: Of the participating subjects 54 had Type I and 56 had Type II diabetes. None (0/18) of the subjects homozygous for the haptoglobin 1 allele (1-1) showed any sign of diabetic nephropathy, as compared with 34 % (19/55) of subjects homozygous for the haptoglobin 2 allele (2-2) and 27 % (10/37) of heterozygous subjects (2-1) (p < 0.04). Of the subjects 29 showed macroalbuminuria. The risk of developing macroalbuminuria was found to be greater in subjects with two haptoglobin 2 alleles (22 %) (12/55) as compared with one haptoglobin 2 allele (8 %) (3/37) or no haptoglobin 2 alleles (0%) (0/18) (p < 0.03). CONCLUSION/INTERPRETATION: By showing a graded risk relation to the number of haptoglobin 2 alleles in Type I and Type II diabetic subjects, these studies further support our hypothesis that the haptoglobin phenotype is a major susceptibility gene for the development of diabetic nephropathy.

Albuminuria↗
PubMed2000

Dichotomy of single-nucleotide polymorphism haplotypes in olfactory receptor genes and pseudogenes.

Substantial efforts are focused on identifying single-nucleotide polymorphisms (SNPs) throughout the human genome, particularly in coding regions (cSNPs), for both linkage disequilibrium and association studies. Less attention, however, has been directed to the clarification of evolutionary processes that are responsible for the variability in nucleotide diversity among different regions of the genome. We report here the population sequence diversity of genomic segments within a 450-kb cluster of olfactory receptor (OR) genes on human chromosome 17. We found a dichotomy in the pattern of nucleotide diversity between OR pseudogenes and introns on the one hand and the closely interspersed intact genes on the other. We suggest that weak positive selection is responsible for the observed patterns of genetic variation. This is inferred from a lower ratio of polymorphism to divergence in genes compared with pseudogenes or introns, high non-synonymous substitution rates in OR genes, and a small but significant overall reduction in variability in the entire OR gene cluster compared with other genomic regions. The dichotomy among functionally different segments within a short genomic distance requires high recombination rates within this OR cluster. Our work demonstrates the impact of weak positive selection on human nucleotide diversity, and has implications for the evolution of the olfactory repertoire.

Alleles↗
PubMed2000

Y chromosomes traveling south: the cohen modal haplotype and the origins of the Lemba--the "Black Jews of Southern Africa".

The Lemba are a traditionally endogamous group speaking a variety of Bantu languages who live in a number of locations in southern Africa. They claim descent from Jews who came to Africa from "Sena." "Sena" is variously identified by them as Sanaa in Yemen, Judea, Egypt, or Ethiopia. A previous study using Y-chromosome markers suggested both a Bantu and a Semitic contribution to the Lemba gene pool, a suggestion that is not inconsistent with Lemba oral tradition. To provide a more detailed picture of the Lemba paternal genetic heritage, we analyzed 399 Y chromosomes for six microsatellites and six biallelic markers in six populations (Lemba, Bantu, Yemeni-Hadramaut, Yemeni-Sena, Sephardic Jews, and Ashkenazic Jews). The high resolution afforded by the markers shows that Lemba Y chromosomes are clearly divided into Semitic and Bantu clades. Interestingly, one of the Lemba clans carries, at a very high frequency, a particular Y-chromosome type termed the "Cohen modal haplotype," which is known to be characteristic of the paternally inherited Jewish priesthood and is thought, more generally, to be a potential signature haplotype of Judaic origin. The Bantu Y-chromosome samples are predominantly (>80%) YAP+ and include a modal haplotype at high frequency. Assuming a rapid expansion of the eastern Bantu, we used variation in microsatellite alleles in YAP+ sY81-G Bantu Y chromosomes to calculate a rough date, 3,000-5,000 years before the present, for the start of their expansion.

Africa, Southern↗
PubMed2000

Hypoxic induction of vascular endothelial growth factor is markedly decreased in diabetic individuals who do not develop retinopathy.

OBJECTIVE: A small percentage of patients do not develop any evidence of diabetic retinopathy (DR) even after many years of diabetes. Vascular endothelial growth factor (VEGF) has been implicated in the development of DR. Therefore, we sought to determine if the regulation of VEGF differs in those patients who develop DR after many years of diabetes compared with those who do not develop DR. RESEARCH DESIGN AND METHODS: We performed standard 7-field stereoscopic fundus photography on 95 consecutive patients with type 1 and type 2 diabetes. Patients were categorized into 3 groups according to the presence or absence of DR and the duration of diabetes: group 1 was defined by presence of DR, group 2 was defined by absence of DR after >10 years duration of diabetes, and group 3 was defined by absence of DR with long-standing diabetes (> or =20 years for type 1 diabetes and > or =15 years for type 2 diabetes). Monocytes from 40 ml peripheral blood were isolated from all patients, and the hypoxic induction of VEGF was determined in vitro. RESULTS: We found no significant difference in the basal level of VEGF in patients with and without DR. However, we did find a markedly significant difference in the hypoxic induction of VEGF between patients from group 1 and group 3 (4.35+/-0.55 vs. 1.87+/-0.3, P<0.00013). CONCLUSIONS: This study suggests that 1 mechanism for the absence of DR in patients with long-standing diabetes is a decreased hypoxic induction of VEGF.

Cell Hypoxia↗
PubMed1999

Interindividual heterogeneity in the hypoxic regulation of VEGF: significance for the development of the coronary artery collateral circulation.

BACKGROUND: The coronary artery collateral circulation may be beneficial in protecting against myocardial ischemia and necrosis. However, there is a tremendous interindividual variability in the degree of new collateral formation in patients with coronary artery disease. The basis for this interindividual heterogeneity is not understood. In this study we test the hypothesis that failure to generate collateral vessels is associated with a failure to appropriately induce with hypoxia or ischemia the angiogenic factor, vascular endothelial growth factor (VEGF). METHODS AND RESULTS: We correlated the VEGF response to hypoxia in the monocytes harvested from patients with coronary artery disease with the presence of collaterals visualized during routine angiography. We found that there was a highly significant difference in the hypoxic induction of VEGF in patients with no collaterals compared with patients with some collaterals (mean fold induction 1.9+/-0.2 versus 3.2+/-0.3, P<0.0001). After subjecting the data to ANCOVA, using as covariates a number of factors that might influence the amount of collateral formation (ie, age, sex, diabetes, smoking, hypercholesterolemia), patients with no collaterals still have a significantly lower hypoxic induction of VEGF than patients with collaterals. CONCLUSIONS: This study provides evidence in support of the hypothesis that the ability to respond to progressive coronary artery stenosis is strongly associated with the ability to induce VEGF in response to hypoxia. The observed interindividual heterogeneity in this response may be due to environmental, epigenetic, or genetic causes. This interindividual heterogeneity may also help to explain the variable angiogenic responses seen in other conditions such as diabetic retinopathy and solid tumors.

Cell Hypoxia↗
PubMed1998

Acid-base disorders.

Explore the source record for details and available documents.

Acid-Base Equilibrium↗
PubMed1998

The epithelial sodium-hydrogen antiporter Na+/H+ exchanger 3 accumulates and is functional in recycling endosomes.

Na+/H+ exchangers (NHEs) mediate electroneutral exchange of Na+ for H+ and thereby play a central role in pH regulation and Na+ homeostasis. NHE3, the predominant epithelial isoform, is found in apical membranes of renal and intestinal epithelial cells, where it contributes to NaCl (re)absorption. NHE activity has been detected in endomembrane vesicles of epithelial cells, but the precise compartment involved and its functional role have not been defined. Many aspects of the targeting machinery that defines the compartmentation and polarity of epithelia are also functional in nonepithelial cells. We therefore compared the targeting of NHE1, the basolateral isoform, with that of NHE3 in Chinese hamster ovary cells. To circumvent the confounding effects of endogenous exchangers, epitope-tagged constructs of NHE1 and NHE3 were stably expressed in antiport-deficient (AP-1) cells. While NHE1 was found almost exclusively in the surface membrane, NHE3 was also found intracellularly, accumulating in a juxtanuclear compartment. Confocal microscopy showed this compartment to be distinct from the Golgi, trans-Golgi network, and lysosomes. Instead, NHE3 colocalized with transferrin receptors and with cellubrevin, markers of recycling endosomes. The activity of NHE3 in endomembranes was assessed by targeting pH-sensitive probes to the recycling endosomes using a chimeric cellubrevin construct with an accessible extracellular epitope. Fluorescence ratio imaging indicated that cellubrevin resides intracellularly in an acidic compartment. In AP-1 cells, endosomal acidification was unaffected by omission of Na+ but was dissipated entirely by concanamycin, a blocker of H(+)-ATPases. In contrast, the cellubrevin compartment was more acidic in NHE3 transfectants, and the acidification was only partially reduced by concanamycin. Moreover, removal of extracellular Na+ resulted in a significant alkalization of the endocytic compartment. These results indicate that NHE3 is present and active in recycling endosomes. By recruiting NHE3 to the plasma membrane, modulation of vesicular traffic could contribute to the regulation of Na+ reabsorption across epithelia.

Animals↗
PubMed1997

Induction of cytosolic phospholipase A2 by oncogenic Ras in human non-small cell lung cancer.

Mutations in Ras family members that confer oncogenic potential are frequently observed in specific human cancers. We report that human non-small cell lung cancer (NSCLC) lines that harbor oncogenic mutations in Ki-Ras (H460, A549, H2122) synthesized high levels of prostaglandin E2 (PGE2) compared with NSCLC lacking Ras mutations or non-transformed lung epithelial cells (BEAS-2B). This increased PGE2 production was mediated by constitutively high expression of 85-kDa cytosolic phospholipase A2 (cPLA2) and cyclooxygenase 2 (COX-2). The increased expression of cPLA2 protein was mediated through elevated mRNA levels and activation of the cPLA2 promoter. Induction of cPLA2 promoter activity was blocked by expression of dominant-negative forms of Ras. Inhibition of Ras by the farnesyltransferase inhibitor BZA-5B inhibited prostaglandin synthesis in H2122 cells by decreasing expression of both cPLA2 and COX-2. Finally, inhibitors of eicosanoid synthesis blocked anchorage-independent growth of NSCLC lines exhibiting Ki-Ras mutations. These results identify cPLA2 as a novel Ras-inducible regulator of eicosanoid synthesis that participates in cellular transformation.

Carcinoma, Non-Small-Cell Lung↗
PubMed1996

Genetic variant near cytosolic phospholipase A2 associated with schizophrenia.

Two studies were undertaken to determine a possible genetic basis for alterations in phospholipid metabolism in schizophrenia. Initial results demonstrated an association in 65 schizophrenics compared with a matched normal control population. A follow-up haplotype relative risk study of 44 triads (mother, father, affected offspring), confirmed the results seen in the association study. Results suggest that a genetic variant near the promotor region of the gene for cytosolic phospholipase A2, the rate-limiting enzyme in the synthesis of prostaglandins from arachindonic acid, is associated with schizophrenia.

Female↗
PubMed1995

Cytosolic phospholipase A2 gene in human and rat: chromosomal localization and polymorphic markers.

We report the chromosomal localization and a simple sequence repeat (SSR) in the cytosolic phospholipase A2 (cPLA2) gene in both human and rat. A (CA)18 repeat in the promoter of the rat gene was determined to exhibit length polymorphism when analyzed using the polymerase chain reaction (PCR) in 19 different inbred rat strains. Genotyping for this marker in 234 F2 progeny of a SHR x BN intercross mapped the gene to rat chromosome 13. Using a PCR strategy, a fragment of the promoter for the human gene was isolated, and a (CA)18 repeat was identified. Since this marker displayed a low heterozygosity index, we also identified a mononucleotide repeat in the promoter for cPLA2 that displayed a polymorphism information content value of 0.76. The human gene was mapped using fluorescence in situ hybridization (FISH) to chromosome 1q25. Of interest, the gene encoding the enzyme prostaglandin-endoperoxide synthase 2 (cyclooxygenase-2), which acts on the arachidonic acid product of cPLA2, was previously localized to this same chromosomal region, raising the possibility of coordinate regulation. Identification of intragenic markers may facilitate studies of polymorphic variants of these genes as candidates for disorders in which perturbations of the eicosanoid cascade may play a role.

Animals↗
PubMed1994

Cytosolic phospholipase A2 gene expression in rat mesangial cells is regulated post-transcriptionally.

Cytosolic phospholipase A2 (cPLA2) is thought to be the rate-limiting enzyme in the arachidonic acid/eicosanoid cascade. The ability of various agonists to increase steady-state cPLA2 mRNA levels has previously been reported. The current study delineates the contributions of transcriptional and post-transcriptional processes to the regulation of cPLA2 gene expression in response to a variety of agonists in cultured rat glomerular mesangial cells. Epidermal growth factor, platelet-derived growth factor, serum and phorbol myristate acetate all increase the half-life of cPLA2 mRNA transcripts, indicating a role for post-transcriptional modulation of gene expression. The presence of three ATTTA motifs in the 3' untranslated region (3'UTR) of the rat cPLA2 cDNA is ascertained. Heterologous expression of chimeric constructs with different 3'UTRs ligated into the 3' end of the luciferase coding region reveals that the presence of the cPLA2 3'UTR results in reduced luciferase activity compared with constructs without the cPLA2 3'UTR. Furthermore, the luciferase activity in the constructs with the cPLA2 3'UTR is increased in response to the same agonists which stabilize endogenous cPLA2 mRNA. A negligible effect of these agonists on transcriptional control of cPLA2 is evident using promoter-reporter constructs expressed in transient and stable transfectants. Taken together, these results indicate predominant post-transcriptional regulation of cPLA2 mRNA levels.

Animals↗
PubMed1994

Isolation of promoter for cytosolic phospholipase A2 (cPLA2).

Cytosolic phospholipase A2 (cPLA2) releases arachidonic acid from membrane phospholipids and is believed to be the rate-limiting enzyme in the arachidonic acid pathway. We report herein the isolation of a 3 kb fragment of rodent genomic DNA containing part of the first intron, the first exon and 5'-flanking sequence. The start site of transcription was mapped by 5'-rapid amplification of cDNA ends and corroborated by ribonuclease protection assay. The gene has a TATAless promoter with no classical Sp1 binding sites or initiator element. A microsatellite series of CA repeats was noted in the 5'-flanking region of both the rodent and human promoters. Deletion constructs have been analysed for luciferase activity and confirmed promoter activity.

Amino Acid Sequence↗
PubMed1994

Reduced phospholipase A2 activity is not accompanied by reduced arachidonic acid release.

Arachidonic acid release in cells highly over expressing cytosolic phospholipase A2 has been attributed to mitogen-activated protein kinase phosphorylation of cytosolic phospholipase A2 on serine-505. To investigate the role of cytosolic phospholipase A2 in cellular physiology, we attempted to inhibit cytosolic phospholipase A2 in the intact cell employing an antisense RNA strategy. Swiss 3T3 cells were stably transfected with an antisense cytosolic phospholipase A2 expression vector. A clone of cells with reduced immunodetectable cytosolic phospholipase A2, compared to a vector transfected cell line, was identified by Western blotting and a corresponding decrease in phospholipase A2 activity was confirmed by enzymatic assay in cell free extracts. However, arachidonic acid release from intact cells in response to agonists was not different between antisense and control cell lines. Thus, arachidonic acid release in intact cells with decreased cytosolic phospholipase A2 activity is likely to be modulated by rate limiting factors that are extrinsic to cytosolic phospholipase A2.

3T3 Cells↗