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Biomedical subjects

S J Van Deventer

Publications and source records attributed to S J Van Deventer.

At least 19 recordsLinked to original sources
PubMed2006

Maintenance infliximab does not result in increased abscess development in fistulizing Crohn's disease: results from the ACCENT II study.

BACKGROUND: Rapid fistula healing may predispose Crohn's disease patients to abscess development. AIM: Data from ACCENT II were analysed to determine whether fistula-related abscess development is affected by infliximab exposure. METHODS: Following infliximab 5 mg/kg infusions at weeks 0, 2 and 6, patients were evaluated for fistula response for two consecutive visits at least 4 weeks apart. Patients (N = 282) were randomized at week 14 to either placebo or infliximab 5 mg/kg every 8 weeks through week 46. If response was lost at or after week 22, patients could crossover to a 5 mg/kg higher infliximab dose. Fistula-related abscesses were diagnosed by physical examination or by imaging procedures according to usual practice. RESULTS: Infliximab exposure was approximately twofold higher for the infliximab maintenance group. Twenty-one (15%) patients in the infliximab maintenance group had at least one newly developed fistula-related abscess compared with 27 (19%) in the placebo maintenance group (P = 0.526). The proportion of patients with a new fistula-related abscess was similar regardless of whether or not patients crossed over to a 5 mg/kg higher infliximab dose. The number of fistula-related abscesses diagnosed over time did not differ between groups. CONCLUSION: Abscess development in patients with fistulizing Crohn's disease is not dependent on cumulative infliximab exposure.

Abscess↗
PubMed2001

TNF-alpha compensates for the impaired host defense of IL-1 type I receptor-deficient mice during pneumococcal pneumonia.

To determine the role of IL-1 in the host defense against pneumonia, IL-1R type I-deficient (IL-1R(-/-)) and wild-type (Wt) mice were intranasally inoculated with Streptococcus pneumoniae. Pneumonia resulted in elevated IL-1alpha and IL-1beta mRNA and protein levels in the lungs. Survival rates did not differ between IL-1R(-/-) and Wt mice after inoculation with 5 x 10(4) or 2 x 10(5) CFU. At early time points (24 and 48 h) IL-1R(-/-) mice had 2-log more S. pneumoniae CFU in lungs than Wt mice; at 72 h bacterial outgrowth in lungs was similar in both groups. Upon histopathologic examination IL-1R(-/-) mice displayed a reduced capacity to form inflammatory infiltrates at 24 h after the induction of pneumonia. IL-1R(-/-) mice also had significantly less granulocyte influx in bronchoalveolar lavage fluid at 24 h after inoculation. Since TNF is known to enhance host defense during pneumonia, we determined the role of endogenous TNF in the early impairment and subsequent recovery of defense mechanisms in IL-1R(-/-) mice. All IL-1R(-/-) mice treated with anti-TNF rapidly died (no survivors (of 14 mice) after 4 days), while 10-day survival in IL-1R(-/-) mice (control Ab), Wt mice (anti-TNF), and Wt mice (control Ab) was 7 of 13, 3 of 14, and 12 of 13, respectively. These data suggest that TNF is more important for host defense against pneumococcal pneumonia than IL-1, and that the impaired early host defense in IL-1R(-/-) mice is compensated for by TNF at a later phase.

Animals↗
PubMed2001

Leptin is a growth factor for colonic epithelial cells.

BACKGROUND AND AIMS: Obesity increases the risk of colon cancer, whereas physical activity reduces the risk. Plasma levels of leptin increase in proportion to the level of obesity and are reduced by physical activity. Leptin acts as a growth factor for several cell types and thus may provide a biological explanation for the observed epidemiological risk factors. The aim of this study was to investigate whether leptin is a growth factor for colonic epithelial cells. METHODS: The presence of the leptin receptor in human colon cancer cell lines was assessed using reverse-transcription polymerase chain reaction and immunoblotting, and its presence in human colonic tissue was assessed by immunohistochemistry. The effects of leptin in vitro on HT29 cells were assessed by assessing p42/44 mitogen-activated protein kinase phosphorylation, thymidine incorporation, and cell numbers and in vivo in C57BL/6 mice by colonic bromodeoxyuridine incorporation. RESULTS: The leptin receptor is expressed in human colon cancer cell lines and human colonic tissue. Stimulation with leptin leads to phosphorylation of p42/44 mitogen-activated protein kinase and increases proliferation in vitro and in vivo. CONCLUSIONS: Leptin is a growth factor in colonic epithelial cells and one that may provide a biological explanation for the observed associations between obesity, physical activity, and colon cancer.

Adenocarcinoma↗
PubMed2001

Sonic hedgehog regulates gastric gland morphogenesis in man and mouse.

BACKGROUND & AIMS: Gastric epithelial renewal is an asymmetric process. A stem cell located halfway up the tubular unit gives rise to both a basal gland region and a luminal pit compartment, but the mechanisms responsible for the maintenance of this asymmetry are obscure. We investigated whether Sonic hedgehog (Shh), an established polarizing signal protein during development, is expressed and functional in the adult human and murine stomach. METHODS: Expression of Shh and putative transcriptional targets was investigated using immunoblot and immunohistochemistry. Mice were treated with the Shh inhibitor cyclopamine and examined for expression levels of Shh targets and proliferation of gastric epithelial cells. RESULTS: Shh was expressed in the stomach. In cyclopamine-treated mice, we observed decreased expression of HNF3beta, Islet (Isl)-1 and BMP4, 3 putative Shh target genes. Inhibition of Shh markedly enhanced gastric epithelial proliferation and affected the cell cycle of gastric epithelial gland cells, whereas pit cells remained unaffected. CONCLUSIONS: Shh controls the expression of at least 3 factors important for epithelial differentiation and is a negative regulator of gastric gland cell proliferation. Shh is a candidate polarizing signal in the maintenance of gastric pit-gland asymmetry.

Age Factors↗
PubMed2001

The abnormal lipid spectrum in malignant obstructive jaundice in relation to endotoxin sensitivity and the result of preoperative biliary drainage.

BACKGROUND: Biliary obstruction changes the spectrum of lipoproteins, which are now known to bind and neutralize endotoxin. Postoperative septic complications related to an increased susceptibility to endotoxin occur frequently in patients with obstructive jaundice. The effect of preoperative biliary drainage on changes in the lipoprotein spectrum and its relation to endotoxin sensitivity was studied. METHODS: Abnormalities in the lipoprotein spectrum were assessed in 15 patients with malignant obstructive jaundice before and 3 weeks after endoscopic biliary drainage. Changes in endotoxin responsiveness were assessed by using endotoxin-neutralizing reagents (anti-CD14 monoclonal antibody, polymyxin B, and recombinant bactericidal permeability increasing protein) to block cytokine production in whole blood cell cultures that were stimulated by cholestatic plasma taken before and after drainage. RESULTS: Drainage normalized very-low-density, low-density, and high-density lipoprotein cholesterol fractions from, respectively, 43% to 19%, 50% to 65%, and 6% to 16% (P <.01). Ex vivo stimulation of whole blood with predrainage cholestatic plasma was 20-fold higher (P <.001) than with postdrainage plasma. Blocking the endotoxin response during the stimulation with predrainage cholestatic plasma with anti-CD14 monoclonal antibody, polymyxin B or recombinant bactericidal permeability increasing protein resulted in attenuation of the inflammatory response, reducing tumor necrosis factor-alpha levels at least 5-fold. CONCLUSIONS: Preoperative biliary drainage normalizes the changed lipid profile and the endotoxin-stimulating capacity of cholestatic plasma, and this signifies a change in sensitivity to endotoxin.

Bile Ducts↗
PubMed2000

Immunotherapy of Crohn's disease.

CD4+ T-lymphocytes have a central role in the pathogenesis of Crohn's disease. The activation and proliferation of T-lymphocytes following stimulation by antigen-presenting cells is controlled by regulatory cytokines (i.e. IL-10) and by induction of programmed cell death. Tissue damage as a result of T-lymphocyte-mediated inflammation is mediated by pro-inflammatory cytokines, including TNF-alpha. Novel immunodulatory strategies in Crohn's disease are based on these principles, and it has been demonstrated that neutralization of TNF-alpha by administration monoclonal antibodies as well as administration of recombinant human IL-10 have therapeutic activity in Crohn's disease. The current status of these new therapies as well as future developments are discussed.

Antibodies, Monoclonal↗
PubMed1999

Study of calcium signaling in non-excitable cells.

The fundamental importance of calcium signaling in the control of cellular physiology is widely recognized. A dramatic illustration of this is the fact that a Medline search for review articles containing the word "calcium" in the title reveals 4,629 hits, whereas the whole body of calcium signaling literature (approximately 2 x 10(6) pages) is more than enough to fill a decent-sized library. Most of this literature deals with calcium signaling in excitable cells types (mainly neurons and muscle cells), but non-excitable cell types are capable of calcium signaling as well. Although calcium fluxes in the latter cell types have attracted much less interest, the literature involved is still vast. Nevertheless, in this review article we hope to contribute some valuable insights to the field. First we shall discuss the experimental techniques available to the researcher interested in calcium signaling in non-excitable cell types with special attention to patch clamp electrophysiology. Subsequently, we shall review some of the results obtained with these techniques by focussing on the calcium-regulating mechanisms in non-excitable cells and discussing the importance of these mechanisms for physiology.

Animals↗
PubMed1999

Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease.

BACKGROUND & AIMS: Infliximab, an anti-tumor necrosis factor monoclonal antibody, rapidly reduces signs and symptoms of active Crohn's disease. The aim of this study was to determine whether repeated infusions of infliximab would effectively and safely maintain the remitting benefit. METHODS: The efficacy, safety, pharmacokinetics, and immunogenicity of 4 repeated treatments with 10 mg/kg infliximab given every 8 weeks were compared with the effects of placebo in a randomized, double-blind, placebo-controlled, parallel group trial. Seventy-three patients with active Crohn's disease who had not adequately responded to conventional therapies and then had demonstrated a clinical response (>/=70-point decrease in the Crohn's Disease Activity Index) to an initial infusion of infliximab (or placebo) were studied. RESULTS: Retreatment with infliximab maintained the clinical benefit through the retreatment period and 8 weeks after the last infusion in nearly all patients retreated with infliximab. Median values for Crohn's Disease Activity Index, inflammatory bowel disease questionnaire (a quality of life measurement), and serum C-reactive protein concentration were maintained at remission levels with infliximab retreatment, but not with placebo retreatment. Retreatment with infliximab every 8 weeks maintained serum infliximab concentration and was well tolerated with a low incidence of immunogenicity. One case of lymphoma and 1 case of suspected lupus were reported; the complete long-term safety profile of infliximab requires additional clinical investigation. CONCLUSIONS: Long-term treatment with infliximab showed efficacy and tolerability in managing symptoms of patients with active Crohn's disease not responding to conventional treatments.

Adolescent↗
PubMed1999

Sequential measurements of chemokines in urosepsis and experimental endotoxemia.

Chemokines are a superfamily of small chemotactic proteins. While increased levels of interleukin-8 have been measured in serum and urine during urinary tract infection, little is known about other chemokines in this condition. Monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and interferon-gamma inducible protein (IP)-10 were measured in 30 patients with culture-proven urosepsis during a 3-day follow-up and in 11 healthy humans after intravenous injection of endotoxin (4 ng/kg). Urine and serum levels of MCP-1, MIP-1beta, and IP-10, but not of MIP-1alpha were elevated in patients on admission, and decreased after initiation of antibiotic treatment. Endotoxin administration to healthy subjects induced increases in plasma and urine concentrations of all four chemokines. These data indicate that clinical and experimental gram-negative infection in humans is associated with enhanced production of chemokines that act mainly on mononuclear cells and that these chemokines are at least in part locally produced.

Adult↗
PubMed1999

Serum concentrations of cytokines in patients with active tuberculosis (TB) and after treatment.

During TB cytokines play a role in host defence. To determine the cytokine pattern during various disease stages of TB, serum levels of IL-12, interferon-gamma (IFN-gamma), IL-4, IL-6 and IL-10 were measured in 81 patients with active TB, 15 patients during therapy and 26 patients after anti-tuberculous therapy as well as in 16 persons who had been in close contact with smear-positive TB and in 17 healthy controls. IFN-gamma was elevated during active TB when compared with healthy controls, declining during and after treatment. IL-12 (p40 and p70) serum levels were not significantly higher in patients with active TB compared with any of the other groups. IL-4 levels were low in all groups. IL-6 and IL-10 serum levels were elevated in patients with active TB and during treatment. In patients with active TB serum levels of IFN-gamma and IL-6 were higher in patients with fever, anorexia and malaise. IL-12 levels were higher in patients with a positive smear. Cytokine levels did not correlate with localization of TB (pulmonary versus extrapulmonary), or skin test positivity. Cytokines directing a Th1 response (IL-12) or a Th2 response (IL-4) were not elevated in sera of this large group of patients with pulmonary and extrapulmonary TB. In patients with active TB, cytokines that were elevated in serum were IFN-gamma, IL-6 and IL-10.

Adolescent↗
PubMed1998

Altered expression of interferon-gamma and interleukin-4 in inflammatory bowel disease.

Experimental data indicate that mucosal CD4+ T cells play an important role in the pathogenesis of inflammatory bowel disease (IBD). Based on the pattern of cytokine production, CD4+ T cells may be distinguished into two different phenotypes. Th1 responses are characterized by secretion of interleukin (IL)-2, tumor necrosis factor (TNF)-alpha, lymphotoxin, and interferon (IFN)-gamma and are associated with delayed-type hypersensitivity reactions, whereas Th2 responses, which are characterized by secretion of IL-4, IL-5, and IL-10, have been associated with humoral immune responses and allergy. To assess the number of IFN-alpha and IL-4 positive cells in IBD and normal intestinal specimens, frozen sections from intestinal specimens from 10 Crohn's disease (CD), 8 ulcerative colitis (UC), and 8 healthy controls were examined by immunohistochemistry. Monoclonal antibodies for CD3, CD8, IFN-gamma, and IL-4 were used. T-lymphocyte infiltration and cytokine expression by epithelial, lamina propria, and submucosal cells were scored on a four-point scale by two independent observers who were blinded for the clinical data. One-way analysis of variance (ANOVA) testing was used for statistical analysis. In intestinal specimens from IBD patients, the number of CD3+ cells was found increased in the lamina propria and, within the submucosa, this increase was significant (p < 0.001). In CD the number of lamina propria IFN-gamma positive cells was significantly increased as compared with controls (p < 0.002). In UC the number of both IFN-gamma and IL-4 producing cells in the lamina propria was not significantly increased as compared with controls. The present results confirm the existence of a Th1-biased pattern production in CD but not in UC.

Adolescent↗
PubMed1998

Genetic analysis of inflammatory bowel disease in a large European cohort supports linkage to chromosomes 12 and 16.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is a complex disorder of unknown etiology. Epidemiological investigations suggest a genetic basis for IBD. Recent genetic studies have identified several IBD linkages. The significance of these linkages will be determined by studies in large patient collections. The aim of this study was to replicate IBD linkages on chromosomes 12 and 16 in a large European cohort. METHODS: Three hundred fifty-nine affected sibling pairs from 274 kindreds were genotyped using microsatellite markers spanning chromosomes 12 and 16. Affection status of the sibling pairs was defined as Crohn's disease (CD) or ulcerative colitis (UC). RESULTS: Nonparametric statistical analyses showed linkage for both chromosomes. Two-point results for chromosome 12 peaked at D12S303 (logarithm of odds [LOD], 2.15; P = 0.003) for CD and at D12S75 (LOD, 0.92; P = 0.03) for UC. Multipoint analyses produced a peak LOD of 1.8 for CD. Chromosome 16 showed linkage for CD at marker D16S415 (LOD, 1.52; P = 0.007). Multipoint support peaked above markers D16S409 and D16S411 (LOD, 1.7). CONCLUSIONS: These data are consistent with linkage of IBD to chromosomes 12 and 16. The replication of genetic risk loci in a large independent family collection indicates important and common susceptibility genes in these regions and will facilitate identification of genes involved in IBD.

Chromosomes, Human, Pair 12↗
PubMed1997

Normalization of plasma vitamin B12 concentration by intranasal hydroxocobalamin in vitamin B12-deficient patients.

BACKGROUND & AIMS: Patients with previous stomach and terminal ileum resections are often treated with intramuscular vitamin B12 injections. Disadvantages are, on a worldwide scale, the frequent need for medical personnel to administer injections and the sometimes painful way of application. This study was designed to investigate the feasibility of intranasal hydroxocobalamin suppletion in cobalamin-deficient patients and to assess whether intranasal hydroxocobalamin application could be an alternative for intramuscular injection. METHODS: Six patients with plasma cobalamin concentrations of < 200 ng/L were recruited. A dose of 1500 micrograms hydroxocobalamin was applied intranasally at days 0, 14, and 21. Plasma cobalamin concentrations were determined 1 hour after hydroxocobalamin application and on days 0, 7, 21, 28, and 35. RESULTS: All patients showed substantial increase of cobalamin concentrations 1 hour after intranasal application. In these 6 patients, there was an eightfold increase of mean baseline cobalamin concentrations. All patients showed a sustained increase of baseline cobalamin concentrations 1 week after prior intranasal application of hydroxocobalamin. No side effects were noted. CONCLUSIONS: Intranasal application of hydroxocobalamin in cobalamin-deficient patients results in fast nasal absorption and leads to sustained increase of baseline cobalamin concentrations.

Administration, Intranasal↗
PubMed1996

Efficacy of recombinant granulocyte colony-stimulating factor (rhG-CSF) in experimental colitis.

Inflammatory bowel disease is associated with mucosal neutrophil recruitment and activatation, mediated in part by arachidonic acid metabolites. G-CSF attenuates the immune response to sepsis and ameliorates glycogen storage disease Ib-related colitis. These actions may be effected through the shedding of neutrophil adhesion molecules, or inhibition of proinflammatory mediator synthesis. Immune complex colitis was used to evaluate the effect of rhG-CSF on colonic mucosal inflammation, neutrophil recruitment and the generation of eicosanoids. Immune complex colitis was induced in White New Zealand rabbits. Animals were pretreated with rhG-CSF either 24 h before induction, or at induction, with dosages of 50 and 200 micrograms/kg. rhG-CSF caused a time- and dose-dependent neutrophilia in all animals. Pretreatment with rhG-CSF resulted in increased tissue myeloperoxidase levels, despite a histologically similar mucosal polymorphonuclear cell infiltrate between treated and control colitis groups. Leukotriene B4 (LTB4) and thromboxane B2 (TXB2) dialysis fluid levels were lower in treated animals, in particular in the groups receiving two doses (LTB4: both P < 0.01; TXB2: both P < 0.01. Prostaglandin E2 (PGE2) levels in dialysis fluid of the rhG-CSF-treated animals showed no difference from controls. In this model of experimental colitis, high-dose therapy with G-CSF resulted in a marked decrease of proinflammatory mediators, but mucosal generation of the protective PGE2 was preserved. These results suggest that prolonged high-dose therapy with G-CSF may have anti-inflammatory effects in colitis.

Animals↗
PubMed1996

Inflammatory bowel disease is associated with increased mucosal levels of bactericidal/permeability-increasing protein.

BACKGROUND & AIMS: Clinical sepsis seldom accompanies inflammatory bowel disease. The aim of this study was to measure colonic mucosal levels of the neutrophil product bactericidal/permeability-increasing protein (BPI), which kills gram-negative bacteria in addition to inactivating endotoxin. METHODS: Enzyme-linked immunosorbent assay and immunohistochemistry for BPI were performed on homogenates and tissue secretions of biopsy specimens from patients with ulcerative colitis (n=11) and Crohn's disease (n=5) and from normal controls (n=5). RESULTS: Mucosal neutrophil content (144 +/- 23 vs. 35 +/- 9 neutrophils/mg protein; P<0.007) and BPI content (2.07 +/- 0.75 vs. 0.12 +/- 0.02 ng/mg protein; P<0.002) were greater in the colitis groups and correlated closely (r=0.68; P<0.001). This relationship held for both ulcerative colitis (P<0.002) and Crohn's disease (P<0.01) with a trend towards greater levels in Crohn's disease. There was a trend towards higher BPI levels with an increasing endoscopic inflammation score (grade I, 1.32 +/- 0.6 ng/mg protein; grade II, 2.82 +/- 1.4 ng/mg protein). Immunohistochemistry and the biopsy culture showed BPI to be both intracellular and extracellular, to be present in the crypt lumen, and to be released into incubating medium. CONCLUSIONS: Mucosal levels of BPI are increased in colitis. Such localization may ameliorate mucosal responses to gram-negative bacteria and their products.

Adolescent↗