Abscess in Crohn's disease--the knife may not be necessary (an American view).
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Abdominal Abscess↗
Biomedical subjects
S K Nath
Publications and source records attributed to S K Nath.
The PTPN22 C1858T functional polymorphism and autoimmune diseases--a meta-analysis.
OBJECTIVE: To assess whether combined evidence shows the association between the protein tyrosine phosphatase non-receptor 22 (PTPN22) C1858T polymorphism and autoimmune diseases, and to summarize the effect size of the polymorphism associated with susceptibility of autoimmune diseases. METHODS: We surveyed studies on the PTPN22 C1858T polymorphism and autoimmune diseases using comprehensive Medline search and review of the references. Meta-analysis was performed for genotypes T/T (recessive effect), T/T + C/T (dominant effect) and T-allele in random effects models. RESULTS: Twenty-nine studies with 43 comparisons including 13 rheumatoid arthritis (RA), six systemic lupus erythematosus (SLE), six type-1 DM (T1D), three Grave's disease (GD), four inflammatory bowel diseases (IBD), three juvenile idiopathic arthritis (JIA), two psoriasis, two multiple sclerosis, two Addison's disease and two Celiac disease were available for the meta-analysis. The overall odds ratios (ORS) for T-allele, T/T and T/T + C/T genotypes were significantly increased in RA, SLE, GD and T1D (OR for T-allele = 1.58, 1.49, 1.85, 1.61, respectively, P < 0.00001). This meta-analysis showed the association between the T-allele and the T/T genotype and JIA (OR = 1.34, P = 0.03; OR = 1.97, P = 0.02) but did not reveal the association between the PTPN22 C1858T polymorphism and IBD, psoriasis, multiple sclerosis, Addison's disease and Celiac disease. CONCLUSION: This meta-analysis demonstrates that the PTPN22 1858T allele confers susceptibility to RA, SLE, GD, T1D and JIA, supporting evidence of association of the PTPN22 gene with subgroup of autoimmune diseases.
Autoimmune Diseases↗
Linkage analysis of SLE susceptibility: confirmation of SLER1 at 5p15.3.
We detected a novel susceptibility gene, SLER1, for systemic lupus erythematosus (SLE) at 5p15.3.(1) This finding was based on a selected subgroup of SLE families, where two or more family members have had alleged rheumatoid arthritis (SLE-RA). The main objective of this study was to replicate the linkage at 5p15.3 based on an independent data set of 88 SLE-RA families. Heterogeneity in the genetic model led us to use a nonparametric allele-sharing method. Since our a priori hypothesis of linkage at 5p15.3 was fixed, we genotyped six markers at the linked region. Our new results replicate the initial linkage at 5p15.3 (Zlr=2.58, P<0.005, LOD=1.45). Moreover, evidence of linkage was sustained when analysis was restricted to the subset of SLE families who had 3 or more individuals with alleged RA (Zlr=3.32, P=0.008, LOD=2.40) The results of our previous findings, together with these new results, confirm the SLER1 linkage at 5p15.3. Our results also demonstrate the utility of clinically defined subgroup analysis for detecting susceptibility loci for complex genetic diseases, such as SLE.
Arthritis, Rheumatoid↗
Genetic linkage of systemic lupus erythematosus with chromosome 11q14 (SLEH1) in African-American families stratified by a nucleolar antinuclear antibody pattern.
Systemic lupus erythematosus (SLE) is an autoimmune disease with complex genetics. We evaluated pedigrees multiplex for SLE that had an affected with antinucleolar antibodies to increase the homogeneity for genetic linkage analysis. We found a significant linkage effect on chromosome 11q14 at marker D11S2002 in African-American Pedigrees. This effect produced a maximum LOD score of 5.62 using a dominant inheritance model with 95% penetrance in males and 99% penetrance in females. The results were supported by multipoint linkage analysis. Fine mapping of the region with two additional markers within 6 cM of D11S2002 further provided evidence of linkage in this region. Linkage at D11S2002, named SLEH1, was previously found in some of these same African-American pedigrees multiplex for SLE, but who were stratified by hemolytic anemia (Kelly et al, submitted). In conclusion, an important SLE susceptibility gene, SLEH1 at 11q14, is identified in African-Americans when stratifying pedigrees by antinucleolar autoantibodies.
Black People↗
Genome scan stratified by the presence of anti-double-stranded DNA (dsDNA) autoantibody in pedigrees multiplex for systemic lupus erythematosus (SLE) establishes linkages at 19p13.2 (SLED1) and 18q21.1 (SLED2).
Anti-double-stranded DNA (anti-dsDNA) is arguably one of the most specific autoantibodies in systemic lupus erythematosus (SLE). This antibody is associated with more severe SLE and with glomerulonephritis. From 196 pedigrees multiplex for SLE, we selected those that had any SLE affected positive for anti-dsDNA by the Crithidia luciliae kinetoplast imunofluorescence assay. This stratification strategy tested the hypothesis that anti-dsDNA would identify a more genetically homogeneous group of pedigrees, in which previously undetected linkage effects could be established. A genome screen data for linkage to SLE was available at 307 microsatellite markers for this selected group of 71 pedigrees: 37 European-American, 29 African-American, and five others. The most significant results were obtained at 19p13.2 (LOD(max) = 4.93), named SLED1, in the 37 European-American pedigrees using a dominant model with mixed penetrances (92% for females and 49% for males) at 100% homogeneity (theta = 0). A second linkage effect, SLED2, was established in the 29 African-American pedigrees at 18q21.1 (LOD(max) = 3.40) using a recessive model with 100% penetrance (theta = 0.1). Parametric and non-parametric multipoint analyses were performed, which provided further evidence and support of susceptibility genes residing in these regions. In conclusion, two powerful linkages have been detected with SLE based on the presence of anti-dsDNA. These findings show SLE to be a richly complicated disease phenotype that is now ripe for important new discovery through a genetic approach.
Animals↗
Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo-related systemic lupus erythematosus.
Both systemic lupus erythematosus (SLE) and vitiligo are autoimmune disorders that have strong evidence of complex genetic contributions to their etiology, but, to date, efforts using genetic linkage to find the susceptibility genes for either phenotype have met with limited success. Since autoimmune diseases are thought to share at least some of their genetic origins, and since only a small minority (16 of 92) of the European-American pedigrees multiplex for SLE in our collection have one or more affected members with vitiligo, we hypothesized that these pedigrees might be more genetically homogeneous at loci important to both SLE and vitiligo and, hence, have increased power for detection of linkage. We therefore evaluated genomewide microsatellite-marker-scan data for markers at an average marker density of approximately 11 cM in these 16 European-American pedigrees and identified a significant linkage at 17p13, where the maximum multipoint parametric LOD score was 3.64 (P<4.3x10(-5)) and the nonparametric linkage score was 4.02 (P<2.8x10(-5)), respectively. The segregation behavior of this linkage suggests a recessive mode of inheritance with a virtually homogeneous genetic effect in these 16 pedigrees. These results support the hypotheses that SLE and vitiligo may share important genetic effects and that sampling on the basis of clinical covariates dramatically improves power to identify genetic effects.
Chromosome Mapping↗
Two-trait-locus linkage analyses of asthma susceptibility.
A genome-wide search was conducted to identify chromosomal regions likely to harbor genes for asthma susceptibility. One hundred and twelve Caucasian families ascertained through a proband with a diagnosis of asthma by the Collaborative Study on the Genetics of Asthma (CSGA) were used for this search. Genotype data on 323 polymorphic markers were analyzed via parametric and nonparametric linkage analysis in an initial genome scan to identify potential asthma susceptibility region(s). The regions where hold or nonparametric linkage scores were greater than 2.0 were selected for further investigation using two-trait-locus linkage analysis models.
Adult↗
Comparison of three methods for obtaining principal components from family data in genetic analysis of complex disease.
Three multivariate techniques used to derive principal components (PCs) from family data were compared for their ability to model family data and power to detect linkage. Using the simulated data from Genetic Analysis Workshop 12, the five quantitative traits were first adjusted for age, sex, and environmental factors 1 and 2. Then, standard PCs, PCs obtained from between-family covariance, and PCs obtained from within-family genetic covariance were derived and subjected to multivariate sib pair linkage analysis. The standard PCs obtained from the overall correlation matrix allowed identification of key features of the true genetic model more readily than did the other methods. For detection of linkage, standard PCs and PCs obtained from the between-family genetic covariance performed similarly in terms of both power and type 1 error, and both methods performed better than the PCs obtained from within-family genetic covariance.
Chromosome Mapping↗
Linkage disequilibrium analysis of biallelic DNA markers, human quantitative trait loci, and threshold-defined case and control subjects.
Linkage disequilibrium (LD) mapping has been applied to many simple, monogenic, overtly Mendelian human traits, with great success. However, extensions and applications of LD mapping approaches to more complex human quantitative traits have not been straightforward. In this article, we consider the analysis of biallelic DNA marker loci and human quantitative trait loci in settings that involve sampling individuals from opposite ends of the trait distribution. The purpose of this sampling strategy is to enrich samples for individuals likely to possess (and not possess) trait-influencing alleles. Simple statistical models for detecting LD between a trait-influencing allele and neighboring marker alleles are derived that make use of this sampling scheme. The power of the proposed method is investigated analytically for some hypothetical gene-effect scenarios. Our studies indicate that LD mapping of loci influencing human quantitative trait variation should be possible in certain settings. Finally, we consider possible extensions of the proposed methods, as well as areas for further consideration and improvement.
Alleles↗
Squalamine, a novel cationic steroid, specifically inhibits the brush-border Na+/H+ exchanger isoform NHE3.
Squalamine, an endogenous molecule found in the liver and other tissues of Squalus acanthias, has antibiotic properties and causes changes in endothelial cell shape. The latter suggested that its potential targets might include transport proteins that control cell volume or cell shape. The effect of purified squalamine was examined on cloned Na+/H+ exchanger isoforms NHE1, NHE2, and NHE3 stably transfected in PS120 fibroblasts. Squalamine (1-h pretreatment) decreased the maximal velocity of rabbit NHE3 in a concentration-dependent manner (13, 47, and 57% inhibition with 3, 5, and 7 micrograms/ml, respectively) and also increased K'[H+]i. Squalamine did not affect rabbit NHE1 or NHE2 function. The inhibitory effect of squalamine was 1) time dependent, with no effect of immediate addition and maximum effect with 1 h of exposure, and 2) fully reversible. Squalamine pretreatment of the ileum for 60 min inhibited brush-border membrane vesicle Na+/H+ activity by 51%. Further investigation into the mechanism of squalamine's effects showed that squalamine required the COOH-terminal 76 amino acids of NHE3. Squalamine had no cytotoxic effect at the concentrations studied, as indicated by monitoring lactate dehydrogenase release. These results indicate that squalamine 1) is a specific inhibitor of the brush-border NHE isoform NHE3 and not NHE1 or NHE2, 2) acts in a nontoxic and fully reversible manner, and 3) has a delayed effect, indicating that it may influence brush-border Na+/H+ exchanger function indirectly, through an intracellular signaling pathway or by acting as an intracellular modulator.
Animals↗
NHE2 contains subdomains in the COOH terminus for growth factor and protein kinase regulation.
The cloned epithelial cell-specific Na+/H+ exchanger (NHE) isoform NHE2 is stimulated by fibroblast growth factor (FGF), phorbol 12-myristate 13-acetate (PMA), okadaic acid (OA), and fetal bovine serum (FBS) through a change in maximal velocity of the transporter. In the present study, we used COOH-terminal truncation mutants to delineate specific domains in the COOH terminus of NHE2 that are responsible for growth factor and/or protein kinase regulation. Five truncation mutants (designated by the amino acid number at the truncation site) were stably expressed in NHE-deficient PS120 fibroblasts. The effects of PMA, FGF, OA, FBS, and W-13 [a Ca2+/calmodulin (CaM) inhibitor] were studied. Truncation mutant E2/660, but not E2/573, was stimulated by PMA. OA stimulated E2/573 but not E2/540. FGF stimulated E2/540 but not E2/499. The most truncated mutant, E2/499, was stimulated by FBS. W-13 stimulated the basal activity of the wild-type NHE2. However, W-13 had no effect on E2/755. By monitoring the emission spectra of dansylated CaM fluorescence, we showed that dansylated CaM bound directly to a purified fusion protein of glutathione S-transferase and the last 87 amino acids of NHE2 in a Ca2+-dependent manner, with a stoichiometry of 1:1 and a dissociation constant of 300 nM. Our results showed that the COOH terminus of NHE2 is organized into separate stimulatory and inhibitory growth factor/protein kinase regulatory subdomains. This organization of growth factor/protein kinase regulatory subdomains is very similar to that of NHE3, suggesting that the tertiary structures of the putative COOH termini of NHE2 and NHE3 are very similar despite the minimal amino acid identity in this part of the two proteins.
Animals↗
Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21.
Schizophrenia is a common disorder characterized by psychotic symptoms; diagnostic criteria have been established. Family, twin and adoption studies suggest that both genetic and environmental factors influence susceptibility (heritability is approximately 71%; ref. 2), however, little is known about the aetiology of schizophrenia. Clinical and family studies suggest aetiological heterogeneity. Previously, we reported that regions on chromosomes 22, 3 and 8 may be associated with susceptibility to schizophrenia, and collaborations provided some support for regions on chromosomes 8 and 22 (refs 9-13). We present here a genome-wide scan for schizophrenia susceptibility loci (SSL) using 452 microsatellite markers on 54 multiplex pedigrees. Non-parametric linkage (NPL) analysis provided significant evidence for an SSL on chromosome 13q32 (NPL score=4.18; P=0.00002), and suggestive evidence for another SSL on chromosome 8p21-22 (NPL=3.64; P=0.0001). Parametric linkage analysis provided additional support for these SSL. Linkage evidence at chromosome 8 is weaker than that at chromosome 13, so it is more probable that chromosome 8 may be a false positive linkage. Additional putative SSL were noted on chromosomes 14q13 (NPL=2.57; P=0.005), 7q11 (NPL=2.50, P=0.007) and 22q11 (NPL=2.42, P=0.009). Verification of suggestive SSL on chromosomes 13q and 8p was attempted in a follow-up sample of 51 multiplex pedigrees. This analysis confirmed the SSL in 13q14-q33 (NPL=2.36, P=0.007) and supported the SSL in 8p22-p21 (NPL=1.95, P=0.023).
Adult↗
Brush border phosphatidylinositol 3-kinase mediates epidermal growth factor stimulation of intestinal NaCl absorption and Na+/H+ exchange.
In terminally differentiated ileal villus Na+-absorptive cells, epidermal growth factor (EGF) stimulates NaCl absorption and its component brush border Na+/H+ exchanger, acting via basolateral membrane receptors, and as we confirm here, a brush border tyrosine kinase. In the present study we show that brush border phosphatidylinositol 3-kinase (PI 3-kinase) is involved in EGF stimulation of NaCl absorption and brush border Na+/H+ exchange. In rabbit ileum studied with the Ussing chamber-voltage clamp technique, EGF stimulation of active NaCl absorption is inhibited by the selective PI 3-kinase inhibitor wortmannin. PI 3-kinase, a largely cytosolic enzyme, translocates specifically to the brush border of ileal absorptive cells following EGF treatment. This translocation occurs as early as 1 min after EGF treatment and remains increased at the brush border for at least 15 min. EGF also causes a rapid (1 min) and large (4-5-fold) increase in brush border PI 3-kinase activity. Involvement of PI 3-kinase activity in intestinal Na+ absorption is established further by studies done in the human colon cancer cell line, Caco-2, stably transfected with the intestinal brush border isoform of the Na+/H+ exchanger, NHE3 (Caco-2/NHE3 cells). Brush border Na+/H+ exchange activity was measured using the pH-sensitive fluorescent dye 2'7'-bis(carboxyethyl)5-(6)-carboxyfluorescein. EGF added to the basolateral surface but not apical surface of Caco-2/NHE3 cells increased brush border Na+/H+ exchange activity. The EGF-induced increase in brush border Na+/H+ exchange activity was completely abolished in cells pretreated with wortmannin. EGF treatment caused increased tyrosine phosphorylation of PI 3-kinase in both ileal brush border membranes and Caco-2/NHE3 cells, suggesting that a tyrosine kinase upstream of the PI 3-kinase is involved in the EGF effects on Na+ absorption. In conclusion, the present study provides evidence in two separate intestinal models, the ileum and a human colon cancer cell line, that PI 3-kinase is an intermediate in EGF stimulation of intestinal Na+ absorption.
Androstadienes↗
Hyperosmolarity inhibits the Na+/H+ exchanger isoforms NHE2 and NHE3: an effect opposite to that on NHE1.
The effect of hyperosmolarity on cloned Na+/H+ exchanger (NHE) isoforms NHE2 and NHE3 was studied in stably transfected PS120 fibroblasts. Na+/H+ exchanger activity was determined spectrofluorometrically in acidified cells that were exposed to isosmolar (300 mosmol/kg) or hyperosmolar (450 mosmol/kg) media, in which the only difference is the presence or absence of 150 mM mannitol. Hyperosmolar solution reversibly inhibited NHE2 and NHE3 with a delay of approximately 15 s. Hyperosmolarity significantly reduced their maximal reaction velocity compared with isosmolar medium but did not alter their Michaelis-Menten constant for intracellular H+. The Michaelis-Menten constant of the exchangers for extracellular Na+ in hyperosmolar medium was not different from that in isosmolar medium. Pretreatment of PS120/NHE3 cells with the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, the tyrosine kinase inhibitor genistein, and the serine/threonine protein phosphatase inhibitor okadaic acid did not affect the hyperosmolar inhibition of NHE3. Hyperosmolar inhibition of Na+/H+ exchanger activity was also observed in PS120 cells transfected with truncated NHE3 cDNAs (E3/585, E3/543, E3509, and E3/475) and NHE2 cDNA (E2/499). We conclude that 1) hyperosmolarity inhibits NHE2 and NHE3, in contrast to the stimulatory effect on the housekeeping isoform NHE1, 2) this inhibition is reversible, and 3) the COOH termini of NHE2 and NHE3 are not necessary for hyperosmolar inhibition of NHE2 and NHE3.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
The effect of L-glutamine on salt and water absorption: a jejunal perfusion study in cholera in humans.
OBJECTIVES: To assess the efficacy of an L-glutamine solution on jejunal salt and water absorption in cholera patients. DESIGN: A randomized double-blind jejunal perfusion study. SETTING: International Centre for Diarrhoeal Disease Research, Bangladesh. PATIENTS: Nineteen adults with acute cholera. INTERVENTIONS: Perfusion of balanced salt solutions alternated with defined glucose salt solution and glutamine glucose salt or alanine glucose salt solutions. MAIN OUTCOME MEASURES: Net jejunal water and sodium secretion. RESULTS: Perfusion of glutamine in the presence of glucose significantly reduced net water secretion (JnetH2O = -2.6 +/- 1.3 ml/h/cm) and also reduced net sodium secretion (JnetNa = -213 +/- 153 mumol/h/cm). Similar results were observed during the perfusion of solutions that contained alanine in addition to glucose (JnetH2O = -4.2 +/- 1.1 ml/h/cm and JnetNa = -444 U +/- 142 mumol/h/cm, respectively) or glucose alone (JnetH2O = -4.3 +/- 1.7 ml/h/cm and JnetNa = -452 +/- 212 mumol/h/cm, respectively). In addition, a higher basal secretion was associated with a greater stimulation of water absorption (F = 17, P < 0.001). CONCLUSION: Glutamine in the presence of glucose significantly reduces net water secretion and also reduces sodium secretion; higher basal secretion is associated with greater water absorption. As glutamine is able to stimulate water absorption to the same degree as glucose and alanine, and because it has the theoretical advantage of providing fuel for the mucosa, the inclusion of glutamine as the sole substrate in oral rehydration solution warrants further study.
Adult↗
Separate C-terminal domains of the epithelial specific brush border Na+/H+ exchanger isoform NHE3 are involved in stimulation and inhibition by protein kinases/growth factors.
NHE3, a cloned intestinal and renal brush border Na+/H+ exchanger, has previously been shown to be both stimulated and inhibited by different protein kinases/growth factors. For instance, NHE3 is stimulated by serum and fibroblast growth factor (FGF) and inhibited by protein kinase C. In the present study, we used a series of NHE3 C terminus truncation mutants to identify separate regions of the C-terminal cytoplasmic tail responsible for stimulation and inhibition by protein kinases/growth factors. Five NHE3 C terminus truncation mutant stable cell lines were generated by stably transfecting NHE3 deletion cDNAs into PS120 fibroblasts, which lack any endogenous Na+/H+ exchanger. Using fluorometric techniques, the effects of the calcium/calmodulin (CaM) inhibitor W13, calcium/CaM kinase inhibitor KN-62, phorbol myristate acetate, okadaic acid, FGF, and fetal bovine serum on Na+/H+ exchange were studied in these transfected cells. Inhibition of basal activity of full-length NHE3 is mediated by CaM at a site C-terminal to amino acid 756; this CaM effect occurs through both kinase dependent and independent mechanisms. There is another independent inhibitory domain for protein kinase C between amino acids 585 and 689. In addition, there are at least three stimulatory regions in the C-terminal domain of NHE3, corresponding to amino acids 509-543 for okadaic acid, 475-509 for FGF, and a region N-terminal to amino acid 475 for fetal bovine serum. We conclude that separate regions of the C terminus of NHE3 are involved with stimulation or inhibition of Na+/H+ exchange activity, with both stimulatory and inhibitory domains having several discrete subdomains. A conservative model to explain the way these multiple domains in the C terminus of NHE3 regulate Na+/H+ exchange is via an effect on associated regulatory proteins.
Base Sequence↗
Ribotyping of nosocomial methicillin-resistant Staphylococcus aureus isolates from a Canadian hospital.
OBJECTIVE: To evaluate the clonality of methicillin-resistant Staphylococcus aureus (MRSA) strains among hospitalized patients. SETTING: University-affiliated, 465-bed tertiary-care teaching hospital with adjacent cancer clinic in Hamilton, Ontario, Canada. DESIGN: Thirty-five colonized and 30 infected patients from January 2, 1992, through August 31, 1993, were investigated retrospectively. Analysis by restriction fragment-length polymorphisms of ribosomal RNA genes (ie, ribotyping) of 103 nosocomial isolates of MRSA from these 65 patients and of 25 selected unrelated strains was completed. Ribotyping results were compared with the phage typing data obtained prospectively during the course of prospective MRSA surveillance. RESULTS: HindIII ribotyping was more discriminating than phage typing when epidemiologically unrelated strains were differentiated by these methods (19 different ribotypes versus 14 page types; P < .005). Two early index cases were identified. Isolates from the index cases were two different strains, identified by ribotyping analysis as ribotype A (clonal group 1) and ribotype B (clonal group 2), respectively. These two ribotypes were not found when typing the unrelated control strains. Thirty-six colonized and infected patients (55%) had clonal group 1 isolates, and 20 (31%) had clonal group 2 isolates. These two clones emerged in the hospital in January and February 1992 and dominated the entire investigated period. There also were six patients with an additional clonal group (group 4) that emerged and disappeared in the second quarter of 1993. CONCLUSIONS: This study highlights the utility of ribotyping in investigating nosocomial MRSA. Three MRSA clones caused nosocomial colonization or infection in patients at this hospital. Two of these MRSA clones, once introduced, were maintained among our patients throughout the study period.
Bacteriophage Typing↗
Mammalian Na+/H+ exchanger gene family: structure and function studies.
Na+/H+ exchangers are integral plasma membrane proteins that exchange extracellular Na+ for intracellular H+ with a stoichiometry of one for one. They are inhibitable by the diuretic amiloride and have multiple cellular functions, including intracellular pH homeostasis, cell volume control, and electroneutral NaCl absorption in epithelia. The presence of multiple forms of the exchangers was demonstrated by the recent cloning of four mammalian Na+/H+ exchangers, NHE1, NHE2, NHE3, and NHE4. All of these cloned Na+/H+ exchangers have 10-12 putative transmembrane helixes and a long cytoplasmic carboxyl domain. Despite the structural similarity, these Na+/H+ exchanger isoforms differ in their tissue distribution, kinetic characteristics, and response to external stimuli. The present review deals with the recent developments in the molecular identification of the Na+/H+ exchanger gene family, the functional characteristics, and the short-term regulation of Na+/H+ exchange at molecular and cellular levels.
Amino Acid Sequence↗