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Biomedical subjects

A J Wakefield

Publications and source records attributed to A J Wakefield.

At least 37 records · Page 2Linked to original sources
PubMed2000

Measles vaccination and inflammatory bowel disease: a national British Cohort Study.

OBJECTIVE: Measles vaccination has been suggested as a risk for inflammatory bowel disease. Atypical age of measles infection has also been associated with Crohn's disease. This study was designed to examine the relationship of measles vaccination and age of measles vaccination with later inflammatory bowel disease. METHODS: A prospective population-based national birth cohort was used, of those born in 1 wk in April 1970 in Great Britain. The data are from 7616 responding members of the 1970 British Cohort Study with complete vaccination data, who were traced at age 26 yr. A diagnosis of Crohn's disease, ulcerative colitis, and diabetes mellitus (a control disease) was obtained by survey at age 26 yr, and confirmed by physicians. Vaccination data were from survey at age 5 yr. Measles and mumps infection data were obtained from the survey at age 10 yr. Adjustment was made for sex, household crowding in childhood, and father's social class at birth. RESULTS: No statistically significant association was found between measles vaccination status at 5 yr and Crohn's disease (adjusted odds ratio [OR] 0.67, 95% confidence interval [CI] 0.27-1.63), ulcerative colitis (adjusted OR 0.57, 95% CI 0.20-1.61), or diabetes (adjusted OR 0.75, 95% CI 0.33-1.74). There was a statistically significant trend (p = 0.040) with increasing age of measles vaccination for risk of Crohn' s disease, although this was based on very few cases vaccinated after age 2 yr. CONCLUSIONS: In this cohort, monovalent measles vaccination status is not associated with inflammatory bowel disease by age 26 yr. Older age at measles vaccination needs to be examined in other studies to confirm whether it is a genuine risk for Crohn's disease.

Adult↗
PubMed1999

Paramyxovirus infections in childhood and subsequent inflammatory bowel disease.

BACKGROUND & AIMS: Measles virus has been implicated in the etiology of both inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis. Subacute sclerosing panencephalitis (SSPE) is caused by atypical measles infection. This study investigated the patterns of infection that are risks for SSPE, early infection and a close temporal relationship between measles and another infection, as potential risks for IBD. METHODS: The data are from 7019 members of a nationally representative 1970 British Cohort Study. The ages of five childhood infections were recorded before onset of IBD symptoms. Diagnoses of IBD and insulin-dependent diabetes mellitus (IDDM), as a control disease, were identified by age 26 years. RESULTS: Mumps infection before age 2 years was a risk for ulcerative colitis (odds ratio, 25.12; 95% confidence interval, 6. 35-99.36). Measles and mumps infections in the same year of life were significantly associated with ulcerative colitis and Crohn's disease, with odds ratios of 7.47 (2.42-23.06) and 4.27 (1.24-14.46), but not with IDDM. These relationships are independent of each other as well as sex, social class at birth, household crowding in childhood, and family history of IBD. CONCLUSIONS: Atypical paramyxovirus infections in childhood may be risk factors for later IBD.

Adult↗
PubMed1999

Anti-neutrophil cytoplasmic autoantibodies (ANCA) to bactericidal/permeability-increasing (BPI) protein recognize the carboxyl terminal domain.

OBJECTIVES: to identify the region of bactericidal/permeability-increasing protein (BPI) recognized by anti-BPI ANCA. METHODS: sera from 140 patients with a variety of clinical diagnoses (20 systemic vasculitis, 12 cystic fibrosis, 22 bronchiectasis/chronic obstructive airways disease, three diabetes mellitus, 13 chronic renal failure, 12 primary sclerosing cholangitis, eight ulcerative colitis, three Crohn's disease, seven cancer, and 40 other or unknown diagnoses) known to be reactive against native (nBPI), were screened by solid phase enzyme linked immunosorbent assay (ELISA) against a panel of recombinant fusion proteins; holo BPI (rBPI), recombinant lipopolysaccharide binding protein (rLBP), an N-terminal fragment of rBPI (rBPI21 ) and 'fusion' proteins containing the C- or N-terminal ends of BPI spliced with N-or C-ends of LBP, respectively. RESULTS: a strong correlation was seen between the degree of reactivity to rBPI and the BPI C-terminal fusion protein, r=0.69, P < 0.001, as well as between nBPI and rBPI protein, r=0.55, P < 0.001, but not between nBPI and the N-terminal region of BPI (rBPI21), or proteins containing only the N-terminal fragment. Binding to proteins containing the BPI C-terminus was confirmed to be specific by fluid phase inhibition ELISA and Western blot analyses. CONCLUSIONS: together these data suggest that circulating autoantibodies to BPI from patients with different diseases recognize the C-terminal region of BPI.

Adolescent↗
PubMed1999

The colonic mesenteric margin is most susceptible to injury in an experimental model of colonic ulceration.

BACKGROUND: Crohn's disease ileal ulcers and indomethacin-induced jejunal ulceration in the rat tend to occur in the mucosa nearest to the mesentery (mesenteric margin), an area of the bowel wall that has a critical blood supply. Mercuric chloride induces caecal and colonic ulceration in the Brown Norway rat. AIM: To examine whether the mesenteric margin is more sensitive to injury by a substance known to be vasculotoxic in the caecum and colon. METHODS: Brown Norway rats received a single subcutaneous dose of either mercuric chloride 1 mg/kg or saline. The gastrointestinal tract was examined macro- and microscopically for lesions 48 h later. The vascular anatomy of the normal rat colon and caecum was also examined using the carbon ink perfusion technique. RESULTS: Mercuric chloride induced caecal and colonic ulceration preferentially along the mesenteric margin of the bowel wall. Histologically, the lesions showed mucosal necrosis and neutrophil infiltration. There was also extensive vascular degeneration/necrosis with microaneurysm formation and extensive submucosal haemorrhage. Cellular infiltration of the vasculature was not a feature. The caecal and colonic mesenteric margins in control rats were supplied by small end arteries. CONCLUSIONS: The colonic and caecal mesenteric margins are susceptible to injury by mercuric chloride, a chemical known to induce haemorrhagic vasculopathy in the rat gastrointestinal tract. The large bowel mesenteric margin may be susceptible to injury by mercuric chloride because of the critical blood supply to that side of the bowel wall.

Animals↗
PubMed1999

Asian ethnic origin and the risk of inflammatory bowel disease.

OBJECTIVE: To assess whether inflammatory bowel disease (IBD) is more prevalent in young Asians than Europeans living in Great Britain. DESIGN: Longitudinal birth cohort study of all those born 5-11 April 1970 in Great Britain--the 1970 British Cohort Study (BCS70). METHODS: The relationship of a diagnosis of ulcerative colitis or Crohn's disease by age 26 years with ethnic origin was investigated among 8,432 cohort members with complete data using multiple logistic regression. We adjusted for potential confounding factors, household crowding and sex, as well as for a family history of IBD. RESULTS: Young Asians born in Britain were significantly more likely than indigenous Europeans to have a diagnosis of IBD by age 26 years, with relative odds of 6.10 (95% CI 2.14-17.33). This group of cohort members had ethnic origins in India, Pakistan or Bangladesh (although none of those from Bangladesh had IBD). This relationship remained statistically significant after adjustment for the potential confounding factors and family history of IBD. CONCLUSION: Young Asians who were born in Britain are at a significantly higher risk of developing IBD than the indigenous European population. This may reflect a greater genetic predisposition to IBD that is uncovered by exposure to environmental factors.

Adult↗
PubMed1999

Crohn's disease: the case for measles virus.

Crohn's disease has the epidemiological and pathological hallmarks of an infection with a long natural history. Its emergence in developed countries in the middle of the 20th Century represents an instant in the continuum of human evolution, indicating either a new infection or, as with poliomyelitis, a changing pattern of exposure to a common childhood pathogen. Both short- and long-term outcomes from viral infection are largely dependent upon age and dose of exposure. We and others have suggested that measles virus may be causally related to Crohn's disease, and that the associated risk is an atypical pattern of exposure. Early, intensive, and concurrent infections have been identified as risks for subacute sclerosing panencephalitis, a delayed sequelae to measles virus infection, possibly through a process of high zone immunological tolerance and persistent infection. The data for Crohn's disease suggest that persistent infection may follow early low dose exposure and low zone immunological tolerance. The changing pattern of measles virus exposure this century would be consistent with a shift towards lower dose of infection. Such an exposure would also be consistent with persistence of the virus at very low copy number within discrete foci of granulomatous inflammation. The ability of measles virus to profoundly disrupt mucosal immune responses may provide the human counterpart of the cytokine-gene knockout.

Adult↗
PubMed1998

Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children.

BACKGROUND: We investigated a consecutive series of children with chronic enterocolitis and regressive developmental disorder. METHODS: 12 children (mean age 6 years [range 3-10], 11 boys) were referred to a paediatric gastroenterology unit with a history of normal development followed by loss of acquired skills, including language, together with diarrhoea and abdominal pain. Children underwent gastroenterological, neurological, and developmental assessment and review of developmental records. Ileocolonoscopy and biopsy sampling, magnetic-resonance imaging (MRI), electroencephalography (EEG), and lumbar puncture were done under sedation. Barium follow-through radiography was done where possible. Biochemical, haematological, and immunological profiles were examined. FINDINGS: Onset of behavioural symptoms was associated, by the parents, with measles, mumps, and rubella vaccination in eight of the 12 children, with measles infection in one child, and otitis media in another. All 12 children had intestinal abnormalities, ranging from lymphoid nodular hyperplasia to aphthoid ulceration. Histology showed patchy chronic inflammation in the colon in 11 children and reactive ileal lymphoid hyperplasia in seven, but no granulomas. Behavioural disorders included autism (nine), disintegrative psychosis (one), and possible postviral or vaccinal encephalitis (two). There were no focal neurological abnormalities and MRI and EEG tests were normal. Abnormal laboratory results were significantly raised urinary methylmalonic acid compared with age-matched controls (p=0.003), low haemoglobin in four children, and a low serum IgA in four children. INTERPRETATION: We identified associated gastrointestinal disease and developmental regression in a group of previously normal children, which was generally associated in time with possible environmental triggers.

Child↗
PubMed1998

Localization of the beta(beta)3-adrenoceptor in the human gastrointestinal tract: an immunohistochemical study.

BACKGROUND: Activation of human and non-human colonic beta(beta)3-adrenoceptors causes smooth muscle relaxation. beta3-Adrenoceptor agonists protect against experimental indomethacin-induced jejunal ulceration. The mechanism of protection may involve spasmolytic/vasodilatory agonist activity. The precise localization of beta3-adrenoceptors in the human gut is not known. AIM: To localize the beta3-adrenoceptor within the human gastrointestinal tract using the immunohistochemical technique. METHODS: Human beta3-adrenoceptors were immuno-localized in paraffin sections of human oesophagus (OS), stomach (ST), duodenum (DU), ileum (IL), sigmoid colon (SC), rectum (R) and gall-bladder (GB) using the rabbit polyclonal antibody anti-P12. Staining was graded , ++, + and 0. Immunostaining of SC was also done with pre-incubation of anti-P12 with P12 peptide. Western blotting of anti-P12 on human and murine IL and SC isolated membrane proteins was performed. RESULTS: All epithelia, vascular endothelial cells and ganglia scored 0. Smooth muscle of the vasculature, muscularis propria, muscularis mucosae and mucosa was graded, respectively, as follows; OS ( , , ,-), ST (++, , ++, ++), DU (++, , , +), IL (++, ++, ++, +), SC ( , ++, ++, ++), R (++, ++, +, +), GB ( , , -, 0). Pre-incubation of anti-P12 with P12 peptide almost abolished SC smooth muscle positivity. Western blot analysis using anti-P12 on human, but not murine, IL and SC membrane proteins revealed a single 5 5 kDa band, a size consistent with the predicted size of a partially glycosylated form of the human beta3-adrenoceptor. CONCLUSIONS: This immunohistochemical study has localized the beta3-adrenoceptor to vascular and nonvascular smooth muscle in the human gastrointestinal tract. These findings support a role for the beta3-adrenoceptor in the control of blood flow and motility in the human gastrointestinal tract.

Amino Acid Sequence↗
PubMed1998

Reversal and protection against indomethacin-induced blood stasis and mucosal damage in the rat jejunum by a beta3-adrenoceptor agonist.

BACKGROUND: In the rat, indomethacin causes jejunal villous shortening, microvascular distortion, and blood stasis prior to ulceration. The beta3-adrenoceptor agonist CL316,243 (CL) prevents both the early histological changes and ulceration. AIM: To test the hypothesis that the beta3-adrenoceptor agonist CL316,243 exerts its protective effect by prevention and/or reversal of blood flow changes in the rat jejunum exposed to indomethacin. METHODS: In anaesthetized rats, jejunal villous blood flow was measured in surface capillaries using fluorescence microscopy. Stasis of superficial capillary blood flow was induced by combined topical and i.v. indomethacin (100 microg/mL, 2.8 x 10(-4) M). To examine the effect of CL on blood stasis, CL was applied either i.v. (1 mg/kg) or luminally (100 microg/mL, 2.5 x 10(-5)M) at the onset of stasis. Prophylactic protection was assessed by giving i.v. CL simultaneously with indomethacin. Results were compared with controls which received luminal saline applied at blood stasis. The effect of i.v. CL (1 mg/kg) alone, or luminal CL (100 microg/mL) alone on basal villous blood flow was also examined. The small intestines were perfusion-fixed with 10% formol saline, and removed for histology, n = 5 for all groups. RESULTS: Luminal CL given at stasis reversed indomethacin-induced stasis within 10 min, whereas i.v. CL did not. Pretreatment with i.v. CL prevented the onset of stasis. Basal blood flow was raised slightly only by luminal CL. CONCLUSION: The beta-adrenoceptor agonist CL316,243 can protect against indomethacin-induced blood stasis in rat jejunal villi.

Adrenergic beta-Agonists↗
PubMed1998

Characterization of the humoral immune response to Klebsiella species in inflammatory bowel disease and ankylosing spondylitis.

This study was carried out to characterize the antibody class response by ELISA to seven Klebsiella pneumoniae serotypes (K2, K3, K17, K21, K26, K36, K50) in five different groups, 40 HLA-B27-positive ankylosing spondylitis (AS) patients, 46 patients with Crohn's disease (CD), 38 patients with ulcerative colitis (UC), 50 patients with active anti-endomysial antibody-positive coeliac disease and 40 healthy controls, using whole bacteria and capsular polysaccharide. IgG antibody levels were significantly elevated in AS patients to K17, K36, K50; IgA to K2, K3, K21, K26, K36 and K50; and IgM to serotype K21 when compared to normal controls. Furthermore, IgG antibody levels were significantly elevated in CD patients to K2, K17, K21, K26, K36 and K50; IgA to K2, K3, K21, K26, K36 and K50; and IgM to K2, K3, K17, K21 and K50. Increased IgG antibody levels in the UC group were limited only to K17, K36 and K50. No antibody class was increased to any of the K. pneumoniae serotypes in the coeliac disease group. The immune responses in AS patients also involve Klebsiella bacteria having capsular serotypes other than K26, K36 and K50. The similarity in the immune responses between CD and AS groups suggests that many AS patients may have occult bowel inflammation.

Adolescent↗
PubMed1998

Patients consulting with Crohn's disease in primary care in England and Wales.

OBJECTIVE: To determine annual incidence and prevalence for patients consulting their GP because of Crohn's disease in England and Wales and compare demographic details with matched controls. DESIGN: We used the fourth Morbidity Statistics in General Practice study (MSGP-4) which covered 468 042 person-years during a 12-month period in 1991-92. METHODS: All GPs reporting a patient with Crohn's disease in MSGP-4 were sent a questionnaire to confirm the diagnosis and obtain supportive details (surgical, pathological, radiological and/or endoscopic). Data concerning ethnicity, social class, smoking status, living in an urban or rural environment and employment had been collected previously. Conditional logistic regression models were used to analyse the data for cases and matched controls. RESULTS: Three hundred and fifteen patients were reported to have Crohn's disease. Replies were obtained to 251 (80%) questionnaires. The diagnosis of Crohn's disease was confirmed in 184 cases (89%) and refuted in 23 cases (11%) -- details were unavailable for 44 patients. The mean age of patients was 44 years, the female:male ratio was 1.46:1, and 108 (59%) patients had required surgery. Thirty-three of 178 (18.5%) patients were diagnosed within the study period. Hence, this study detected a prevalence for consulting Crohn's disease of 54.6-59.8/100,000 and an annual incidence of 10.1-11.1/100,000 in 1991-92. No significant differences were found between cases (n = 291) and controls (n = 1682) with regard to ethnicity, social class, smoking or living in an urban/rural environment. Patients with Crohn's disease had similar employment levels as controls, but were significantly more likely to be registered as permanently sick, odds ratio 4.01 (CI 2.21-7.29). CONCLUSIONS: This national survey, including 1% of the population, suggests there are approximately 30,600 patients consulting their GP because of Crohn's disease in England and Wales, with 5700 new cases diagnosed per year.

Adolescent↗
PubMed1998

Focal reduction of villous blood flow in early indomethacin enteropathy: a dynamic vascular study in the rat.

BACKGROUND: Oral indomethacin causes villous shortening, microvascular damage, and distortion, which might induce mucosal ischaemia and necrosis. AIMS: In order to determine the early events in indomethacin induced jejunal injury we examined the temporal relations between morphological damage and changes in villous blood flow following indomethacin. METHODS: In anaesthetised rats, mid jejunal villi were exteriorised in a chamber and observed by fluorescence microscopy. Blood flow in surface capillaries was calculated from velocities and diameters. Indomethacin was applied by both luminal and intravenous routes for 90 minutes, after which the animal was perfusion fixed and the villi were processed for histological examination. Control animals received intravenous or luminal bicarbonate (1.25%). RESULTS: Blood flow slowed in individual villi at 20 minutes, and progressed to complete stasis (in another group) by 45 minutes. Histological examination at 20 minutes revealed microvascular distortion, but no villous shortening; crypt depth:villous height ratios were 0.356 (0.02) in test and 0.386 (0.01) in surrounding villi (p > 0.05). At stasis, the villi under study showed epithelial clumping and were shortened: crypt depth:villous height ratios were 0.92 (0.2) in test and 0.42 (0.06) in surrounding villi (p < 0.02). Vehicle alone had no effect on either blood flow or histology. CONCLUSIONS: Focal slowing of villous blood flow and microvascular distortion precede villus shortening and epithelial disruption, and indicate that damage to surface microvasculature is an early event in indomethacin induced mucosal injury in this model.

Animals↗