Biomedical subjects

Christopher L Bowlus

Publications and source records attributed to Christopher L Bowlus.

At least 19 recordsLinked to original sources

PubMed2006

Differential gene expression between flat adenoma and normal mucosa in the colon in a microarray analysis.

BACKGROUND: Flat adenomas in the colon are associated with a relatively higher potential for malignancy. Distinct genes may be involved in the development of flat adenoma. The aim of this study was to profile gene expression changes in flat adenomas in the colon. METHODS: A genomewide expression analysis was carried out by using flat adenoma and adjacent normal mucosa in the colon to detect differences in gene expression. Because the right and left colon have different embryonic origins, each sample was classified according to its location, and the gene expression levels between flat adenoma and adjacent normal mucosa were also compared among samples derived from the right or left colon. RESULTS: A total of 180 genes were differentially expressed between flat adenoma and normal mucosa in the colon, including matrix metalloproteinase 7 (MMP7), cadherin 3 (CDH3), S100P, and dual oxidase 2 (DUOX2). In addition, a total of 89 and 49 genes were differentially expressed between flat adenoma and normal mucosa among the samples from the right and left colon, respectively. Subsequent quantitative real-time reverse transcriptase-polymerase chain reaction supported the reliability of the expression analysis. Immunohistochemical analysis confirmed differential CDH3 and MMP7 protein expression. CONCLUSIONS: This is the first report characterizing the genes differentially expressed in flat adenomas using a microarray analysis. Considerable differences in the gene expression profiles of flat adenomas also exist between the right and left colon. These data should lead to new insights into the pathogenesis of flat adenomas in the colon as well as to new therapeutic strategies.

Adenoma↗

PubMed2006

Changes in plasma ghrelin levels, gastric ghrelin production, and body weight after Helicobacter pylori cure.

BACKGROUND: Ghrelin is a body weight-regulating peptide produced and secreted primarily by the gastric mucosa. Helicobacter pylori infection impairs gastric ghrelin production, leading to a lower plasma ghrelin concentration. However, the effect of H. pylori eradication on plasma ghrelin levels and its relation to body weight change after H. pylori cure are still uncertain. We examined the association of plasma ghrelin levels with gastric ghrelin production and body weight change before and after H. pylori eradication. METHODS: Plasma ghrelin concentrations, gastric ghrelin expression, and body weight were determined in a total of 134 consecutive individuals before and 12 weeks after successful H. pylori eradication. Gastric ghrelin expression was evaluated by determining mRNA expression levels and the number of ghrelin-producing cells in gastric mucosa biopsy specimens by real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry, respectively. RESULTS: Plasma ghrelin concentration increased in 50 patients and decreased in 84 patients after H. pylori eradication. After H. pylori cure, however, gastric preproghrelin mRNA expression was increased nearly fourfold (P < 0.0001), and the number of ghrelin-positive cells was increased or unchanged. In contrast, plasma ghrelin changes after H. pylori cure were inversely correlated with both body weight change (P < 0.0001) and initial plasma ghrelin levels (P < 0.0001). CONCLUSIONS: Changes in plasma ghrelin concentrations before and after H. pylori cure were inversely correlated with body weight change and initial plasma ghrelin levels but not with gastric ghrelin production in Japanese patients.

Amoxicillin↗

PubMed2006

IL-2 receptor alpha deficiency and features of primary biliary cirrhosis.

Congenital immune deficiency states have often been valuable experimental models of nature that have significantly enhanced our understanding of the immune response. The relationship between CD4+, CD25+ and Treg cells in the induction of autoimmunity has attracted significant attention. We report herein a male child of consanguineous parents who developed at six months recurrent infections, and at age 5 years, liver dysfunction with serological expression of primary biliary cirrhosis (PBC), an autoimmune liver disease that usually affects middle-aged women. Histologically, there was intense mononuclear cell lymphoid infiltration of the intrahepatic portal tracts, CD3+CD4+T cell lymphopenia in blood and serum antibody to PDC-E2. Peripheral blood lymphocytes were completely deficient of the alpha subunit of the IL-2 receptor (IL-2Ralpha, CD 25), a marker for regulatory T cells (Tregs). Allogenic stem cell transplantation led to full recovery. This case illustrates the role of deficiency of CD4+CD25+ Treg cells in causing autoimmunity, and speaks to the potential use of allogenic stem cell transplantation for immunoreconstitution in adult PBC.

Autoimmunity↗

PubMed2006

The potentiating and protective effects of ascorbate on oxidative stress depend upon the concentration of dietary iron fed C3H mice.

Ascorbic acid (AA) is an antioxidant that, in the presence of iron and hydrogen peroxide, increases the production of hydroxyl radicals in vitro. Whether AA has similar pro-oxidant properties in vivo may depend upon the relative balance of iron and AA concentrations. In this study, C3H mice were fed diets supplemented with 100 or 300 mg/kg iron, with or without AA (15 g/kg), for 12 months. Liver AA concentrations were greater in mice fed AA-supplemented diets with either low or high iron (P=.0001), while the high-iron diet was associated with a significantly lower liver AA concentration regardless of AA supplementation (P=.0001). Only mice fed the high-iron diet with AA had a significantly greater liver iron concentration (P=.05). In the high-iron group, AA reduced oxidative stress, as measured by greater activities of glutathione peroxidase, superoxide dismutase (SOD) and catalase and by significantly lower concentrations of 4-hydroxylalkenal (HAE) and malondialdehyde (MDA). In mice fed the low-iron diet, AA was associated with greater concentrations of HAE and MDA and with lower activities of SOD. However, AA did not increase the concentrations of modified DNA bases with the low-iron diet but was associated with significantly lower concentrations of modified DNA bases in mice fed the high-iron diet. In conclusion, dietary AA appears to have mild pro-oxidant properties at low-iron concentrations but has a strong antioxidant effect against oxidative stress and DNA damage induced by dietary iron in mouse liver.

Aldehydes↗

PubMed2006

Analysis of MAdCAM-1 and ICAM-1 polymorphisms in 365 Scandinavian patients with primary sclerosing cholangitis.

BACKGROUND/AIMS: Mucosal addressin cellular adhesion molecule-1 (MAdCAM-1) has been implicated in the aberrant homing of intestinal lymphocytes to the liver in primary sclerosing cholangitis (PSC). Intercellular adhesion molecule-1 (ICAM-1) has also been implicated in the pathogenesis of PSC and the E/E genotype of the K469E polymorphism has been reported to be associated with PSC susceptibility. The aims of this study were to determine if MAdCAM-1 polymorphisms or the K469E polymorphism of ICAM-1 are associated with PSC in Scandinavia. METHODS: Seven single nucleotide polymorphisms (SNPs) in MAdCAM-1 and the G421R and K469E ICAM-1 SNPs were genotyped in 365 PSC patients from Norway and Sweden. 327 Norwegian ulcerative colitis (UC) patients and 368 Norwegian bone marrow donors served as controls. RESULTS: No significant association with PSC was found for any of the MAdCAM-1 or ICAM-1 SNPs. Allele frequencies for these polymorphisms were not significantly different between PSC patients with UC, UC patients and healthy controls. CONCLUSIONS: Polymorphisms in MAdCAM-1 are not likely to significantly affect PSC susceptibility. In addition, the E/E genotype of the K469E in ICAM-1 does not influence PSC susceptibility in Scandinavia.

Case-Control Studies↗

PubMed2006

Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis.

CD4+CD25high regulatory T cells (Tregs) play a critical role in self-tolerance, as seen in murine autoimmunity. Studies on Tregs in human autoimmunity have focused primarily on peripheral blood samples. A study targeting diseased tissue should identify direct relationships between Tregs and autoimmunity. Peripheral blood samples were collected from 91 patients with primary biliary cirrhosis (PBC), 28 immediate relatives, and 41 healthy controls, and Treg frequencies were determined as a percentage of CD4+CD25high T cells in CD4+TCR-alphabeta+ T cells. A tissue-targeted determination of frequency and distribution of FoxP3+ Tregs was also performed on 90 different liver tissue specimens exhibiting PBC (n = 52), chronic hepatitis C (CHC) (n = 30), and autoimmune hepatitis (AIH) (n = 8). Treg suppression studies were performed on 50 PBC patients and 27 controls. Patients with PBC demonstrated a relative reduction of Tregs compared with controls (P < .0002). Interestingly, a deficiency in CD4+CD25+ Tregs was also found in the daughters and sisters of PBC patients compared with controls (P < .0007). However, functional studies did not reveal a global PBC Treg defect. The level of FoxP3-expressing Tregs was markedly lower in affected PBC portal tracts compared with CHC and AIH (P < .001). In addition, the CD8+T cell/FoxP3+ Treg ratio was significantly higher in livers of late-stage PBC compared with those of CHC (P < .001) and early-stage AIH (P < .001). In conclusion, these data provide support for a genetic modulation of Treg frequency and illustrate the role Tregs play in the loss of tolerance in PBC.

Autoimmunity↗

PubMed2006

Revisiting hereditary hemochromatosis: current concepts and progress.

Originally regarded as a rare affliction notable for its distinctive evolution to "bronze diabetes," hereditary hemochromatosis is now recognized as the most common genetic disorder in populations of European ancestry. Recent advances in our understanding of iron metabolism, the identification of the gene responsible for hemochromatosis, and large epidemiologic studies have changed the diagnostic approach toward patients with hereditary hemochromatosis and other forms of iron overload. This article reviews the pathophysiology, epidemiology, clinical features, diagnostic testing, and management of hemochromatosis for the primary care provider.

Diagnosis, Differential↗

PubMed2005

T cell immunity and graft-versus-host disease (GVHD).

Graft-versus-host disease (GVHD), induced by the reaction of donor T cells to recipient histoincompatible antigens, is a serious complication of allogeneic bone marrow transplantation (BMT), resulting in considerable morbidity and mortality. In MHC-disparate BMT, donor T cells directly react with major histocompatibility complex (MHC) antigens, while in MHC-matched BMT, T cells react with minor histocompatibility antigens (miHA) presented by shared MHC molecules. Clinically, acute and chronic GVHD can be distinguished on the basis of the time of onset, clinical manifestations and distinct pathobiological mechanisms. Acute GVHD usually occurs within 2 to 6 weeks following allogeneic BMT and primarily affects the skin, liver and the gastrointestinal tract with T cell infiltration of the epithelia of the skin, mucous membranes, bile ducts and gut. In addition, hair follicle cells, airways, bone marrow, and a variety of other tissue systems can be involved. Acute GVHD occurs in up to 50% of allogeneic HLA-matched and 70% of HLA-disparate BMT recipients despite prophylactic immunosuppressive drugs. Chronic GVHD involves a wider range of organs and clinical manifestations include scleroderma, liver failure, immune complex disease, glomerulonephritis, and autoantibody formation.

Animals↗

PubMed2005

T cell immunity in autoimmune hepatitis.

T cells play a central role in the immunopathogenesis of AIH. Until recently CD4+ T cells were thought to be critical for disease development, increasing evidence has shown that CD8+ T and gammadelta T cells also play a significant role. The predisposition of certain HLA genotypes to AIH as well as the clonal expansion of a limited number of T cell receptors suggests that the presentation of a self-antigen or a molecular mimic may be responsible for the initiation of the immune response. Given the association of AIH with viral hepatitis, it is thought that the loss of tolerance begins with an infection of hepatocytes and subsequent cytolysis by CD8+ T cells. The presentation of self-antigens or molecular mimics leads to activation and clonal expansion of T cells; this process may be increased by impaired regulatory T cells and a defect in apoptosis. Ultimately T cells initiate B cell production of autoantibodies, proinflammatory cytokines and finally hepatocyte cytotoxicity.

Animals↗

PubMed2005

The immunobiology of primary sclerosing cholangitis.

An understanding of the immunobiology of primary sclerosing cholangitis (PSC) is essential to improving both diagnosis and treatment. There have been significant gains in the discovery of genetic polymorphisms that generate susceptibility to disease, but only limited data on etiologic events that may initiate the inflammatory response. Colonic inflammation produces memory T cells that have the ability to bind both biliary and colonic endothelial cells. One possible mechanism for the development of PSC is the homing of these memory T cells to the biliary tree. In addition, TNF(alpha) may contribute to the oxidative damage of the biliary system. Finally, although speculative, mononuclear cell responses against biliary epithelial cells may create a persistent inflammatory response, eventually leading to fibrosis.

Autoantibodies↗

PubMed2005

Transforming growth factor beta (TGF-beta) and autoimmunity.

TGF-beta1 deficient mice develop multifocal inflammatory autoimmune disease and serve as a valuable animal model of autoimmunity. Transgenic expression of a dominant negative form of TGF-beta receptor type II in T cells have enabled the study of cell lineage specific effects of TGF-beta providing clues to the potential etiology of autoimmunity. These studies suggest that TGF-beta deficiency may induce autoimmune disease by influencing a number of immunological phenomena including lymphocyte activation and differentiation, cell adhesion molecule expression, regulatory T cell function, the expression of MHC molecules and cytokines, and cell apoptosis. The spectrum of effects appears to be significant in mucosal immunity and may contribute to the pathogenesis of inflammatory bowel disease.

Animals↗

PubMed2005

Factors associated with advanced liver disease in adults with alpha1-antitrypsin deficiency.

BACKGROUND & AIMS: Alpha 1 -antitrypsin deficiency (AAT) is an autosomal recessive disease that affects 1 in 2500 persons and might lead to cirrhosis. Our study aim was to characterize the liver disease in AAT and identify factors associated with advanced liver disease. METHODS: A cohort of the Alpha-1 Foundation Registry who reported liver disease was surveyed with a liver disease questionnaire to obtain information related to liver disease, liver transplantation, and AAT phenotype. RESULTS: One hundred sixty-five of the 2175 participants in the registry reported a history of jaundice or liver disease, and 139 (84.2%) completed the questionnaire. Of these, 71.3% were PiZZ, 18.0% were PiMZ, and 5.7% did not know their phenotype. Analysis of 104 participants with a known age of diagnosis included 30 participants diagnosed with liver disease before 18 years, of whom 15 had advanced liver disease defined as liver transplantation or listed for liver transplantation. No differences in age, age at diagnosis, gender, race, phenotype, or infant jaundice were identified. Seventy-four participants were diagnosed after age 18 years, of whom 25 had advanced liver disease. In this group, advanced liver disease was associated with male gender ( P = .006) and a greater mean body mass index ( P = .01), but not with race, Pi phenotype, infant jaundice, diabetes, or hypercholesterolemia. Viral hepatitis was more frequently reported in the nontransplant group (34.7% vs 8.0%, P = .01), and the mean daily alcohol use was significantly greater in this group ( P = .04). CONCLUSIONS: Our results suggest that male gender and obesity but not alcohol or viral hepatitis predispose to advanced liver disease in adults with AAT.

Adult↗

PubMed2005

Prss16 is not required for T-cell development.

PRSS16 is a serine protease expressed exclusively in cortical thymic epithelial cells (cTEC) of the thymus, suggesting that it plays a role in the processing of peptide antigens during the positive selection of T cells. Moreover, the human PRSS16 gene is encoded in a region near the class I major histocompatibility complex (MHC) that has been linked to type 1 diabetes mellitus susceptibility. The mouse orthologue Prss16 is conserved in genetic structure, sequence, and pattern of expression. To study the role of Prss16 in thymic development, we generated a deletion mutant of Prss16 and characterized T-lymphocyte populations and MHC class II expression on cortical thymic epithelial cells. Prss16-deficient mice develop normally, are fertile, and show normal thymic morphology, cellularity, and anatomy. The total numbers and frequencies of thymocytes and splenic T-cell populations did not differ from those of wild-type controls. Surface expression of MHC class II on cTEC was also similar in homozygous mutant and wild-type animals, and invariant chain degradation was not impaired by deletion of Prss16. These findings suggest that Prss16 is not required for quantitatively normal T-cell development.

Animals↗

PubMed2005

Liver hepcidin mRNA correlates with iron stores, but not inflammation, in patients with chronic hepatitis C.

PURPOSE: Liver iron is frequently elevated in chronic hepatitis C and may contribute to liver injury. The pathophysiology behind this phenomenon may involve hepcidin, a gene that is up-regulated in the liver by inflammation and iron. Inappropriately low hepcidin is important to the pathophysiology of hereditary hemochromatosis. However, the role of hepcidin in the iron loading of patients with hepatitis C is unknown. SUBJECTS AND METHODS: To determine whether liver hepcidin mRNA correlates with markers of hepatic inflammation and iron status in patients with hepatitis C, we extracted total RNA from liver biopsy specimens of patients with chronic hepatitis C and quantified hepcidin mRNA. Liver hepcidin mRNA levels were then correlated with aspartate aminotransferase, alanine aminotransferase, ferritin, viral load, fibrosis, hepatic iron concentration, and Hepatic Activity Index (HAI). RESULTS: Among patients with hepatitis C, there was a significant correlation of hepcidin mRNA expression in the liver with hepatic iron concentration and serum ferritin (r = 0.72, P = 0.006, and r = 0.60, P = 0.01, respectively). Hepcidin mRNA expression in the liver did not correlate with aspartate aminotransferase, alanine aminotransferase, HAI, or viral load. No differences in hepcidin mRNA were found based on viral genotype or the presence of fibrosis. CONCLUSION: In contrast to other inflammatory states, hepcidin mRNA expression in the liver was independent of markers of inflammation in hepatitis C. Instead, our results suggest that iron stores in patients with hepatitis C regulate hepcidin expression and that iron loading in chronic hepatitis C is not due to inappropriate hepcidin expression.

Adult↗

PubMed2004

Transcription profile of Helicobacter pylori in the human stomach reflects its physiology in vivo.

BACKGROUND: Little is known about levels of expression of Helicobacter pylori genes in the human host. We therefore developed a quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR) assay to measure transcript profiles of H. pylori in the human stomach. METHODS: In vivo expression of 16 genes on the cag pathogenicity island and of 18 putative virulence genes was quantitated by isolation of total RNA directly from infected human gastric mucosa. The results were compared with in vitro expression determined from H. pylori cells grown in culture. RESULTS: The highest levels of expression were found for cag1 and cag25 and for genes, such as urease and catalase, that may be important for bacterial homeostasis in the relatively hostile environment of the gastric mucosa. Transcript abundance, relative to 16S rRNA, was lower in vivo than in vitro, which suggests that H. pylori cells are in stationary phase in the gastric environment. This was particularly apparent for cagA. Since CagA is arguably of unique importance, in terms of interaction with the host, tight control of its in vivo expression might be particularly important. CONCLUSIONS: qRT-PCR is a powerful tool to measure gene expression in human or animal tissue that contains minute amounts of microbial mRNA, and the results reflect on the physiology of the pathogen in its natural host.

Adult↗

PubMed2004

Obesity in BSB mice is correlated with expression of genes for iron homeostasis and leptin.

OBJECTIVE: We searched for genes whose alleles cause obesity and novel pathways correlated with obesity. RESEARCH METHODS AND PROCEDURES: BSB mice are a model of complex obesity due to interactions among genes from C57BL/6J (B) and Mus spretus (SPRET) in (B x SPRET) x B backcross mice. Stringent criteria identified 50 genes differentially expressed in epididymal adipose tissue from 7 pairs of lean vs. obese BSB mice. Quantitative reverse transcription-polymerase chain reaction of adipose tissue RNA from 48 BSB mice with a range of obesity was assayed. Leptin was evaluated in inbred (SPRET/Ei) and outbred (SPRET/Pt) BSB mice. RESULTS: Leptin (Lep) and adipsin expressions had the greatest fold differences between obese and lean mice. Four genes involved in iron homeostasis were included in the 50 differentially expressed genes [hemochromatosis (Hfe), diaphorase 1, transferrin receptor (Trfr) 2, and protoporphyrinogen oxidase] and two additional iron-related genes did not quite meet the stringent criteria for differential expression (Trfr and lactotransferrin). Hfe and Trfr mRNA levels and liver iron were negatively correlated with fat mass. Variation in obesity phenotypes explained 49%, 40%, and 37%, respectively, of the variance in Hfe, Lep, and Trfr mRNA levels. Leptin differed by haplotype at the Lep locus in outbred BSB. The quantitative trait locus identified in the outbred cross did not occur in inbred BSB. DISCUSSION: Our results suggest that iron homeostasis in BSB mice is coordinately regulated in vivo in adipose depots in response to obesity. Lep alleles derived from outbred, but not inbred, SPRET are a positional candidate for the chromosome 6 quantitative trait locus in BSB mice.

Alleles↗

PubMed2004

Ascorbic acid does not increase the oxidative stress induced by dietary iron in C3H mice.

Iron is a potent prooxidant that can induce lipid peroxidation. Ascorbic acid, a potent antioxidant, has prooxidant effects in the presence of iron in vitro. We investigated whether ascorbic acid and iron co-supplementation in ascorbic acid-sufficient mice increases hepatic oxidative stress. C3H/He mice were fed diets supplemented with iron to 100 mg/kg diet or 300 mg/kg diet with or without ascorbic acid (15 g/kg diet) for 3 wk. Liver iron concentration, malondialdehyde (MDA), glutathione (GSH), glutathione S-transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) were measured. High dietary iron increased liver iron concentrations slightly (P < 0.05), whereas it dramatically increased hepatic MDA (P < 0.0001). Ascorbic acid increased MDA but only in mice fed the low-iron diet (P < 0.05). The high-iron diet reduced GPx (P < 0.0001), CAT (P < 0.0005), SOD (P < 0.05), and GST (P < 0.005) activities regardless of ascorbic acid supplementation. In contrast, ascorbic acid reduced GPx (P < 0.0001) and CAT (P < 0.05) activities only in mice fed the low-iron diet. In conclusion, ascorbic acid supplementation can have prooxidant effects in the liver. However, ascorbic acid does not further increase the oxidative stress induced by increased dietary iron.

Animals↗

PubMed2003

Ascorbic acid reduces the frequency of iron induced micronuclei in bone marrow cells of mice.

Iron is a potent oxidant that can lead to the formation of genotoxic lipid peroxides. Ascorbic acid, which enhances dietary iron absorption, has been suggested to enhance the oxidant effects of iron and to directly lead to the formation of lipid peroxides. The combined effects of dietary iron and ascorbic acid on genotoxicity were investigated by measuring the frequency of micronuclei in the bone marrow cells of C3H/He mice. In addition, liver iron concentration was measured in all treated groups. Three weeks old mice were fed diets for 3 weeks containing iron at 100 or 300 mg/kg diet in the form of FeSO(4) that were supplemented either with or without ascorbic acid (15 g/kg diet). The results of the bone marrow micronucleus test revealed that the high iron diet resulted in an increased frequency of micronucleated polychromatic erythrocytes (MnPCEs) as compared to low iron. Ascorbic acid supplementation in the low iron diet did not show any effect on incidence of MnPCEs and protected against the increased frequency of MnPCEs induced by the high iron diet. However, liver iron concentration was significantly increased only in the high iron treated and ascorbic acid supplemented group as compared to all other groups. These results demonstrate that ascorbic acid protects against the clastogenic effects of iron.

Administration, Oral↗