PubMed Health⌕ Search

Biomedical subjects

A G Cummins

Publications and source records attributed to A G Cummins.

At least 19 recordsLinked to original sources
PubMed2006

Deficiency of invariant natural killer T cells in coeliac disease.

BACKGROUND: Immunoregulatory invariant natural killer (iNK) T cells rapidly produce interleukin (IL)-4 and other cytokines that suppress a Th1 response and are deficient in some autoimmune diseases. AIM: The aim of this study was to investigate any deficiency of iNK T cells in coeliac disease. METHODS: Blood was collected from 86 subjects with coeliac disease and from 152 healthy control subjects for investigation of Valpha24+ T cells by flow cytometry. iNK T cells were assessed by Valpha24 and alpha-galactosylceramide/CD1d tetramer markers in 23 normal controls and 13 subjects with coeliac disease. Intracellular IL-4 was measured after anti-CD3 antibody stimulation. Duodenal biopsies were obtained in a subgroup of subjects with coeliac disease and control subjects for Valpha24 mRNA expression using relative PCR and for Valpha24+ T cells by immunofluorescence. RESULTS: The mean numbers of circulating Valpha24+ T cells and iNK T cells in coeliac disease were 27% (p<0.001) and 16% (p<0.001), respectively, of levels in control subjects. After in vitro anti-CD3 stimulation, numbers of IL-4+ producing iNK T cells from subjects with coeliac disease were unchanged but increased by 21% in control subjects. In subjects with coeliac disease, Valpha24 mRNA intestinal expression was reduced to 17% (p<0.001) by relative PCR and numbers of intestinal Valpha24+ T cells were 16% (p<0.01) of levels in control subjects. CONCLUSIONS: We conclude that Valpha24+ T cells and iNK T cells are deficient in coeliac disease. We speculate that this deficiency could contribute to the failure of immunological oral tolerance that seems to underlie this disease.

Adult↗
PubMed2005

Relationship between dose of methotrexate, apoptosis, p53/p21 expression and intestinal crypt proliferation in the rat.

Previous studies have shown that apoptosis is induced by cytotoxic chemotherapy and precedes hypoproliferation of intestinal crypt cells. However, the relationship between the degree of intestinal apoptosis and crypt cell hypoproliferation may not be directly related. The purpose of this study was to investigate the relationship between apoptosis and hypoproliferation with increasing doses of chemotherapy. Eleven groups of breast cancer-bearing DA rats were treated with two doses of methotrexate (MTX) i. m. at varying concentrations (0.5, 1.5, 2.5 and 5.0 mg/kg) or saline (control). Animals were killed at 6 or 24 h following treatment. The small and large intestines were examined for apoptosis, villous area (small intestine), crypt length and mitotic count per crypt. Immunohistochemical expression of p53 and p21(waf1/cip1) (p21) were examined quantitatively. Data were analysed using Peritz' F-test. Low dose MTX (0.5 mg/kg) did not change p53 expression at 6 h but induced a 15-fold increase in apoptosis in the crypts of the small intestine. This was associated with only a minor reduction in crypt cell proliferation. Higher doses of MTX increased p53 expression and caused a lower (7-fold) but more prolonged peak of apoptosis that was accompanied by reduced villous area, shortened crypts and a more profound reduction in crypt cell proliferation. Unlike the small intestine, apoptosis in the colon was 10-fold lower, proportional to the dose of MTX and did not induce overt damage. Expression of p21 did not change with any dose at either timepoint. We conclude that apoptosis is not always associated with crypt cell hypoproliferation and that the small intestine can recover after low dose MTX despite a heightened peak of apoptosis of crypt cells.

Animals↗
PubMed2002

Effect of breast milk and weaning on epithelial growth of the small intestine in humans.

Breast feeding and weaning are important physiologically significant luminal events that influence the growth of the small intestine in humans. A variety of factors including genetic preprogramming, systemic and local hormones, and permissive factors contribute and modulate intestinal growth. Here, we offer a view that integrates some of these factors, especially those relating to breast feeding and weaning.

Animals↗
PubMed2001

The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis.

BACKGROUND: Small intestinal bacterial overgrowth may contribute to the development of non-alcoholic steatohepatitis, perhaps by increasing intestinal permeability and promoting the absorption of endotoxin or other enteric bacterial products. AIMS: To investigate the prevalence of small intestinal bacterial overgrowth, increased intestinal permeability, elevated endotoxin, and tumour necrosis factor alpha (TNF-alpha) levels in patients with non-alcoholic steatohepatitis and in control subjects. PATIENTS AND METHODS: Twenty two patients with non-alcoholic steatohepatitis and 23 control subjects were studied. Small intestinal bacterial overgrowth was assessed by a combined (14)C-D-xylose and lactulose breath test. Intestinal permeability was assessed by a dual lactulose-rhamnose sugar test. Serum endotoxin levels were determined using the limulus amoebocyte lysate assay and TNF-alpha levels using an ELISA. RESULTS: Small intestinal bacterial overgrowth was present in 50% of patients with non-alcoholic steatosis and 22% of control subjects (p=0.048). Mean TNF-alpha levels in non-alcoholic steatohepatitis patients and control subjects were 14.2 and 7.5 pg/ml, respectively (p=0.001). Intestinal permeability and serum endotoxin levels were similar in the two groups. CONCLUSIONS: Patients with non-alcoholic steatohepatitis have a higher prevalence of small intestinal bacterial overgrowth, as assessed by the (14)C-D-xylose-lactulose breath test, and higher TNF-alpha levels in comparison with control subjects. This is not accompanied by increased intestinal permeability or elevated endotoxin levels.

Adult↗
PubMed2001

Improvement in intestinal permeability precedes morphometric recovery of the small intestine in coeliac disease.

It is often difficult to assess small bowel recovery in adults with coeliac disease on a gluten-free diet (GFD). This prospective study compares changes in intestinal permeability with changes in intestinal biopsy at various intervals after commencing a GFD. Intestinal permeability was measured by lactulose/rhamnose absorption from 1 week to 24 months after commencing a GFD. Intestinal morphometry was measured by villus area, crypt length and mitotic count per crypt at diagnosis and after commencing a GFD. Median intestinal permeability values decreased from 0.47 (n = 35) at diagnosis to 0.25 (n = 17) after 1 week and to 0.16 (n = 18) after 2 months of a GFD. Rhamnose absorption improved significantly at an early stage, from 6.6% (untreated) to 15.4% at 3 months of a GFD, whereas the decrease in lactulose permeation took longer: from 3.4% (untreated) to 0.8% after 12 months of a GFD. Mean villus area (n = 29) was reduced to 16% of control values at diagnosis, and improved to a maximum of 48% after 6 months on a GFD, but did not change thereafter. Mean crypt length and mitotic count per crypt were increased by 222% and 356% respectively at diagnosis, and these parameters remained elevated at 172% and 216% above control values after 6 months of a GFD. We conclude that intestinal permeability improves within 2 months after starting a GFD, but that measurable intestinal biopsy improvement requires ingestion of a GFD for at least 3-6 months, and even then remains incomplete.

Adolescent↗
PubMed2000

Chemotherapy for cancer causes apoptosis that precedes hypoplasia in crypts of the small intestine in humans.

BACKGROUND AND AIMS: The mechanism of gastrointestinal damage (mucositis) induced by cancer chemotherapy remains uncertain. The aims of this study were to define the time course and mechanism of small intestinal damage following chemotherapy in humans. METHODS: Patients receiving chemotherapy underwent upper gastrointestinal endoscopy (a maximum of two per patient) with duodenal biopsy prior to chemotherapy and again at 1, 3, 5, and 16 days after chemotherapy. Tissue was taken for morphometry, disaccharidase assays, electron microscopy, and for assessment of apoptosis using the Tdt mediated dUTP-biotin nick end labelling (TUNEL) method. Villus area, crypt length, and mitotic index were measured by a microdissection technique. RESULTS: Apoptosis increased sevenfold in intestinal crypts at one day, and villus area, crypt length, mitotic count per crypt, and enterocyte height decreased at three days after chemotherapy. Disaccharidase activities remained unchanged. Electron microscopy showed increased open tight junctions of enterocytes at day 3, consistent with more immature cells. All indices improved by 16 days. CONCLUSION: Small intestinal mucositis is associated with apoptosis in crypts that precedes hypoplastic villous atrophy and loss of enterocyte height.

Adolescent↗
PubMed1999

Activation of the gut-associated lymphoid tissue with expression of interleukin-2 receptors that peaks during weaning in the rat.

BACKGROUND: Weaning exposes the intestinal mucosa to food and bacterial antigens at an age when the immune system is believed to be immature and functionally defective. The purpose of this study was to investigate changes in activation and phenotype of immune cells of the gut-associated lymphoid tissue during weaning. METHODS: Litters of infant rats were studied from pre- to postweaned life. The activation status, assessed by interleukin-2 receptor (IL-2R) expression, and phenotype of cells in the gut-associated lymphoid tissue were examined by immunostaining. RESULTS: Interleukin-2 receptor expression peaked two to four-fold at midweaning (day 21) in mesenteric lymph nodes, jejunal lamina propria, Peyer's patches, and intraepithelial lymphocytes, compared with adult animals (day 70). CD45+ cells expanded in the lamina propria, epithelium, and lymphocyte-filled villi. With CD45 as the denominator, 10% to 50% of lymphocytes in the lamina propria and epithelium were alphabetaT-cell receptor (TCR)+, but the remaining cells had a null phenotype, because there were low numbers of gammadeltaTCR+ T cells, B cells, and macrophages. Natural killer cells peaked at midweaning in the lamina propria (9%) and epithelium (20%) but were less than 5% of CD45+ cells after weaning. CONCLUSIONS: Rather than being immature or functionally inactive, the gut-associated lymphoid tissue reacts appropriately during weaning with expression of IL-2R and expansion of alphabetaTCR+ T-cells.

Animals↗
PubMed1998

Comparison of culture, histopathology and urease testing for the diagnosis of Helicobacter pylori gastritis and susceptibility to amoxycillin, clarithromycin, metronidazole and tetracycline.

Gastric biopsy specimens were taken from 737 patients undergoing upper gastrointestinal endoscopy and assessed for Helicobacter pylori infection. The diagnostic utilities of H. pylori culture (733 patients), detection of urease production (724 patients) and histopathological examination (469 patients) were compared. Since each of these techniques may fail to diagnose patients infected with H. pylori, an attempt was made to estimate the true rate of infection using a mathematical approach that combined the results of culture, histopathology and urease testing; 34% of the 733 patients were thought to be infected. Using this figure as a benchmark, the sensitivity, specificity, positive predictive value and negative predictive value of H. pylori culture were 73.2%, 100%, 100% and 86.3%, respectively, compared with 58.7%, 100%, 100% and 89.6%, respectively for urease production and 77.0%, 100%, 100% and 82.4%, respectively for histopathology. Thus, histopathological examination was the single most reliable test. A combination of histopathological examination and H. pylori culture diagnosed 99.5% of patients that were estimated to be truly infected. The minimum inhibitory concentrations of a number of antibiotics were measured for 135 isolates of H. pylori. All isolates were susceptible to amoxycillin and tetracycline whereas 5.2% were resistant to clarithromycin and 60% were resistant to metronidazole.

Amoxicillin↗
PubMed1998

Epithelial growth of the small intestine in human infants.

BACKGROUND: Findings in studies in rodents have suggested that epithelial growth of the small intestine is dependent on activation of the immune system. The purpose of this study was to compare changes of postnatal epithelial growth with immunologic activity in humans. METHODS: Duodenal biopsies were obtained by endoscopy from 74 infants. Villus area, crypt length, and mitotic count were measured, using a microdissection technique. Enterocyte height, intraepithelial lymphocytes and mucosal mast cells were recorded in histologic sections, and soluble interleukin-2 receptor levels were measured in sera. These data were compared with those from 77 adult control subjects. RESULTS: Mean +/- SD villus area was similar in infants compared with that in adults (0.364 +/- 0.108 mm2 vs. 0.339 +/- 0.1 mm2); but mean crypt length was 31% longer (270 +/- 56 microm vs. 206 +/- 29 microm; p < 0.0001), and mitotic count was 68% higher (4.2 +/- 2.8 vs. 2.5 +/- 1 per crypt; p < 0.0001) in infants. Enterocyte height was lower during infancy (27.0 +/- 3.4 microm vs. 30.9 +/- 4.6 microm; p < 0.0001). There was no evidence of a trophic effect on the small intestine of breast feeding compared with the effect of bottle feeding. Counts of intraepithelial lymphocytes but not mucosal mast cells were significantly less in infants. Mean soluble interleukin-2 receptor levels peaked during early infancy, compared with levels in adults (1,820 +/- 596 U/ml vs. 695 +/- 359 U/ml). CONCLUSION: These results indicate that epithelial proliferation is increased during infancy at an age when immunologic activity is high.

Adult↗
PubMed1998

Transforming growth factor-beta levels in maternal milk and expression in postnatal rat duodenum and ileum.

After birth, the gastrointestinal tract of the neonate is exposed to food and bacterial and environmental antigens. Maternal milk components may play a role in regulation of mucosal immune activity to luminal antigens. In this study we determine the ontogeny of transforming growth factor (TGF)-beta1-producing cells in the rat pup small intestine and assess maternal milk concentrations of TGF-beta. Intestinal tissue samples of duodenum and ileum were collected, processed, and stained for TGF-beta1, and in situ hybridization for TGF-beta1 mRNA was also performed on the duodenum. TGF-beta levels in milk were assayed by ELISA. TGF-beta2 levels in milk were high at d 6, and declined thereafter at d 10 and 19. TGF-beta1 was not detected. In contrast, the cell number and intensity of staining of TGF-beta1 peptide in the small intestine was low in 3- and 10-d-old rats and increased markedly by 19 d of life. In the duodenum mRNA levels mirrored this trend. TGF-beta1 expression in the lamina propria was absent before d 19, and increased progressively over time. Maternal milk TGF-beta2 levels are high in early milk and decrease during the weaning period. In contrast, endogenous TGF-beta production in the small intestine increases during the weaning period.

Aging↗
PubMed1997

Postnatal changes in mucosal immune response: a physiological perspective of breast feeding and weaning.

There are profound changes of immune activity during infancy from suppression during breast feeding, activation with weaning, and later intrinsic down-regulation after weaning. Breast feeding, as well as protecting against infections, seems to have a fundamental role in modifying the immune system against certain disease states. Transforming growth factor (TGF)beta in breast milk may mediate this immunosuppressive effect. Although the infant immune system is not in an adult state, the notion that the infant immune system is immature is difficult to reconcile with evidence that most infants respond appropriately to immunization and to infections. The systemic immune system of neonates may be subject to Th2 immune deviation, while the mucosal immune system, particularly of the gastrointestinal tract and probably the respiratory tract, is up-regulated with physiological inflammation during infancy. Weaning is associated with a peak of intestinal immune activation which includes mucosal mast cells and T cells. The physiological effects of this activation are promotion of epithelial growth of the small intestine and initial activation of mechanisms leading to subsequent down-regulation of the physiological heightened immune activity. This coincides with the development of mucosal (oral) tolerance to food and bacterial antigens.

Breast Feeding↗
PubMed1997

Effect of high-dose chemotherapy on intestinal permeability in humans.

1. Mucositis is a common side-effect of chemotherapy which is difficult to assess except by invasive means such as upper gastrointestinal endoscopy. Differential absorption of mono- and di-saccharides, such as rhamnose and lactulose, is a non-invasive measure of intestinal damage. 2. The purpose of the study was to assess the duration and severity of intestinal damage in patients undergoing high-dose chemotherapy and autologous blood stem-cell transplantation for malignant disease. 3. Thirty-five patients were studied before treatment and at 7, 28, 60 and 90 days after treatment. 4. The median lactulose/rhamnose ratios before treatment and at 7 and 90 days post-treatment were 0.09, 0.62 and 0.06 respectively. Altered permeability was due to both increased lactulose permeation and decreased rhamnose absorption. These abnormalities suggest a defect in tight-junction integrity as well as a decrease in surface area of small bowel. 5. We conclude that chemotherapy given for malignant disease is associated with a transient abnormality in intestinal sugar permeability, which peaks at 7 days after treatment and is composed of both mono- and di-saccharide absorption abnormalities.

Adolescent↗
PubMed1996

Dependence of epithelial growth of the small intestine on T-cell activation during weaning in the rat.

BACKGROUND & AIMS: Intestinal crypt hyperplasia is associated with local T-cell activation in both clinical and experimental examples of immunologically mediated enteropathy. This suggests that T cell-derived factors may be trophic for epithelial proliferation in the intestine postnatally. The purpose of this study was to investigate T-cell activity during weaning in the rat and to investigate immune dependence of intestinal growth on T-cell activation. METHODS: The expression of interleukin-2 receptor (IL-2R) by mesenteric lymph node T cells was investigated from days 14 to 160 of life. Rats were treated with monoclonal antibodies against the IL-2R that were nonblocking (control) or blocking (experimental) from day 7, and intestinal growth was assessed at days 19, 25, and 29 of life. RESULTS: The mean +/- SEM of T cells expressing the IL-2R during weaning (days 15-28) was 6.1% +/- 0.3% compared with 3.3% +/- 0.3% at other ages (P < 0.001). The small intestine in rats treated with blocking antibody had reduced crypt length and mitotic count compared with control animals. CONCLUSIONS: Weaning is associated with activation of T cells and blockade of the IL-2R reduces intestinal growth.

Animals↗
PubMed1994

Immune activation during infancy in healthy humans.

Immune activity during infancy was investigated using blood samples from 30 neonates and 52 healthy infants between 2 and 15 months of age attending for immunization. The purpose of this study was to assess the total immune activity of T cells using soluble interleukin-2 receptor (IL-2R) and interferon-gamma concentrations. These were compared with the proportion of CD4 CD45RO-, IL-2R (CD25)-, and transferrin receptor (CD71)-positive peripheral blood lymphocytes. The median duration of breast-feeding and of introduction of solid feeds was 4.2 and 4.0 months, respectively. Compared to neonates, the mean +/- SE soluble IL-2R concentration peaked at 4 months of age (1670 +/- 94 vs 3060 +/- 252 U/ml; P < 0.0001), as did pooled interferon-gamma levels. The percentage of CD4 CD45RO T cells remained low and the proportion of activated peripheral blood lymphocytes decreased during infancy. We conclude that noncirculatory immune activity is increased during infancy and this is associated with weaning.

Antigens, CD↗