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1.  Epithelial Cell Shedding and Barrier Function 
Veterinary Pathology  2015;52(3):445-455.
The intestinal epithelium is a critical component of the gut barrier. Composed of a single layer of intestinal epithelial cells (IECs) held together by tight junctions, this delicate structure prevents the transfer of harmful microorganisms, antigens, and toxins from the gut lumen into the circulation. The equilibrium between the rate of apoptosis and shedding of senescent epithelial cells at the villus tip, and the generation of new cells in the crypt, is key to maintaining tissue homeostasis. However, in both localized and systemic inflammation, this balance may be disturbed as a result of pathological IEC shedding. Shedding of IECs from the epithelial monolayer may cause transient gaps or microerosions in the epithelial barrier, resulting in increased intestinal permeability. Although pathological IEC shedding has been observed in mouse models of inflammation and human intestinal conditions such as inflammatory bowel disease, understanding of the underlying mechanisms remains limited. This process may also be an important contributor to systemic and intestinal inflammatory diseases and gut barrier dysfunction in domestic animal species. This review aims to summarize current knowledge about intestinal epithelial cell shedding, its significance in gut barrier dysfunction and host-microbial interactions, and where research in this field is directed.
PMCID: PMC4441880  PMID: 25428410
genetically engineered mice; digestive tract; bacterial; immunologic; inflammation; nutritional; immunohistochemistry; imaging
3.  Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel disease 
Gut  2011;61(8):1146-1153.
Loss of intestinal barrier function plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Shedding of intestinal epithelial cells is a potential cause of barrier loss during inflammation. The objectives of the study were (1) to determine whether cell shedding and barrier loss in humans can be detected by confocal endomicroscopy and (2) whether these parameters predict relapse of IBD.
Confocal endomicroscopy was performed in IBD and control patients using intravenous fluorescein to determine the relationship between cell shedding and local barrier dysfunction. A grading system based on appearances at confocal endomicroscopy in humans was devised and used to predict relapse in a prospective pilot study of 47 patients with ulcerative colitis and 11 patients with Crohn's disease.
Confocal endomicroscopy in humans detected shedding epithelial cells and local barrier defects as plumes of fluorescein effluxing through the epithelium. Mouse experiments demonstrated inward flow through some leakage-associated shedding events, which was increased when luminal osmolarity was decreased. In IBD patients in clinical remission, increased cell shedding with fluorescein leakage was associated with subsequent relapse within 12 months after endomicroscopic examination (p<0.001). The sensitivity, specificity and accuracy for the grading system to predict a flare were 62.5% (95% CI 40.8% to 80.4%), 91.2% (95% CI 75.2 to 97.7) and 79% (95% CI 57.7 to 95.5), respectively.
Cell shedding and barrier loss detected by confocal endomicroscopy predicts relapse of IBD and has potential as a diagnostic tool for the management of the disease.
PMCID: PMC3388727  PMID: 22115910
Confocal laser endomicroscopy; mucosal healing; fluorescein; tight junction; barrier function; cell shedding; tumour necrosis factor; Crohn's Disease; ulcerative colitis; inflammatory bowel disease; colonoscopy; endoscopy; Barrett's metaplasia; Barrett's oesophagus; magnifying colonoscopy; apoptosis; colorectal metastases; colorectal cancer; gastrointestinal physiology; gut differentiation; gastrin; IBD basic research; cell death; IBD models
4.  Apoptosis and colorectal cancer 
Gut  2004;53(11):1701-1709.
PMCID: PMC1774275  PMID: 15479695
apoptosis; colorectal cancer
5.  Mycobacterium bovis in England and Wales: past, present and future. 
Epidemiology and Infection  1992;109(1):23-33.
This report reviews the literature concerning tuberculosis resulting from infection with Mycobacterium bovis in man and cattle and summarises data derived from surveillance of M. bovis in England and Wales from 1986 to 1990. Of the 228 isolates of M. bovis examined in this period, 122 (53%) were from patients aged over 60 years and are largely the result of reactivation of infection acquired prior to the institution of control measures. However, eight isolates (3.5%) were from patients aged less than 30 years. The potential sources for these presumed primary infections include the few remaining cattle infected with M. bovis or infectious human cases in the United Kingdom. However, infections acquired abroad, especially in immigrants, may account for some of these cases. Outbreaks of tuberculosis due to M. bovis continue to occur in cattle. Wild animals, particularly badgers, have been implicated as reservoirs of the infection. However, man may also prove to be an important reservoir of M. bovis for cattle as well as humans.
PMCID: PMC2272235  PMID: 1499671
6.  Regional localisation of p53-independent apoptosis determines toxicity to 5-fluorouracil and pyrrolidinedithiocarbamate in the murine gut 
British Journal of Cancer  2006;95(1):35-41.
Pyrrolidinedithiocarbamate (PDTC) enhanced the activity of 5-fluorouracil (5-FU) in a colorectal cancer xenograft model. Pyrrolidinedithiocarbamate also reduced gastrointestinal toxicity associated with 5-FU therapy in large but not small bowel. We sought to clarify the basis of this differential enteric toxicity. Apoptosis and mitosis were assessed on a cell positional basis in small and large intestinal crypts of p53 wild-type (+/+) and p53 null (−/−) mice 6, 12, 24, 36, 48 and 72 h after the administration of high (200 mg kg−1) or low (40 mg kg−1) dose 5-FU±250 mg kg−1 PDTC. Regimens were chosen to model a single human dose and a weekly schedule. The effects of another antioxidant N-acetylcysteine (NAC) were also investigated. Large intestinal crypts affect apoptosis purely by p53-dependent mechanisms, whereas small intestinal crypts are able to initiate both p53-dependent and -independent pathways following treatment with 5-FU. Pyrrolidinedithiocarbamate and NAC antagonised p53-dependent but potentiated p53-independent apoptotic activity. Consequently, the proportion of surviving clonogens increased in the large but not in the small intestine. Regional availability of p53-dependent and -independent apoptotic pathways in small and large intestine together with separate modulation of these pathways by antioxidants explains the different regional enterotoxicity following 5-FU therapy.
PMCID: PMC2360501  PMID: 16804527
colorectal cancer; 5-fluorouracil; pyrrolidinedithiocarbamate; N-acetylcysteine; p53; apoptosis
7.  Are proximal colorectal cancers always associated with distal adenomas? 
Gut  2003;52(3):317-318.
PMCID: PMC1773551  PMID: 12584206
screening; sigmoidoscopy; colonic neoplasms; index adenoma
8.  Tuberculosis and HIV: estimates of the overlap in England and Wales. 
Thorax  1993;48(3):199-203.
BACKGROUND: A study was designed to determine the extent of the interaction between tuberculosis and human immunodeficiency virus infection in England and Wales. METHODS: Data were obtained from the United Kingdom national AIDS surveillance and the Medical Research Council tuberculosis notification surveys in England and Wales (1983 and 1988). The proportion of patients reported with AIDS known to have had tuberculosis and the proportion of patients notified with tuberculosis known to have HIV infection were estimated. RESULTS: Of the 4360 patients with AIDS reported by 30 June 1991, 200 (4.6%) were in patients reported to have had tuberculosis. Only one of the 3002 patients (0.03%) reported in the 1983 survey of tuberculosis notifications in England and Wales was known to be infected with HIV compared with nine of 2163 patients (0.42%) in the 1988 survey. CONCLUSION: Although the reported number of cases of HIV infection with tuberculosis in this country is increasing it remains small. Complete reporting of cases of AIDS and notification of cases of tuberculosis are essential to enable the two infections to be monitored as the HIV epidemic develops. Special studies, such as those reported here, will need to be undertaken regularly to assess the future extent of the interaction.
PMCID: PMC464352  PMID: 8497815
9.  Tuberculosis among the homeless at a temporary shelter in London: report of a chest x ray screening programme. 
STUDY OBJECTIVE--To estimate the prevalence of active pulmonary tuberculosis in a homeless population in London and to assess whether those with suspected disease could be integrated into the existing health care system for further follow up and treatment. DESIGN--Voluntary screening programme based on a questionnaire survey and chest x ray. SETTING AND CASES--Screening programmes were set up over the Christmas period in 1992 and 1993 at a shelter for the homeless in London. An offer of screening was made to all individuals who visited the centre and an interviewer administered questionnaire was completed on those who volunteered for the screening. Chest x rays were carried out, developed, and read on site. Individuals with chest x rays features suggestive of tuberculosis or other medical problems were referred to a hospital of their choice. RESULTS AND OUTCOME--In 1992 nearly 1600 people visited the centre, of whom 372 volunteered for the screening and 342 were x rayed. Nineteen of the 342 (5.6%) had radiological features suggestive of active tuberculosis. In 1993 around 2000 homeless people visited the centre, of whom 270 volunteered for the screening and 253 were x rayed. Eleven (4.3%) had features consistent with active tuberculosis on the basis of the chest x rays and clinical examination by a chest physician. Overall, of 595 people x rayed in the two surveys, 30 (5%) had changes suggestive of active tuberculosis. Further investigations confirmed nine (1.5%) with active pulmonary disease and eight with no active tuberculosis. In 13, the diagnosis was not determined as four declined further investigation and nine did not attend their hospital appointment. CONCLUSION--Tuberculosis among the homeless remains a cause for concern. Follow up and treatment present unique difficulties. Services for the homeless need to include mechanisms for timely diagnosis and monitored treatment. Control programmes designed for the needs of the homeless are required.
PMCID: PMC1060180  PMID: 8596100
11.  Screening migrants at risk of tuberculosis. 
BMJ : British Medical Journal  1993;307(6918):1539-1540.
PMCID: PMC1679539  PMID: 8274925
14.  Excess winter mortality  
BMJ : British Medical Journal  2002;324(7349):1337.
PMCID: PMC1123286  PMID: 12039836
15.  Assessment of the obstetric flying squad in an urban area. 
British Medical Journal  1976;1(6007):446-448.
The experience of an obstetric flying squad in an urban area over one year was reviewed. Very few calls were found to be justifiable, and it is concluded that few if any circumstances in modern obstetric practice merit continuing the flying squad in the urban area.
PMCID: PMC1638996  PMID: 943203
16.  Tuberculosis in England and Wales in 1993: results of a national survey. Public Health Laboratory Service/British Thoracic Society/Department of Health Collaborative Group 
Thorax  1997;52(12):1060-1067.
BACKGROUND: A national survey of tuberculosis notifications in England and Wales was carried out in 1993 to determine the notification rate of tuberculosis and the trends in the occurrence of disease by ethnic group in comparison with the findings of similar surveys in 1978/79, 1983, and 1988. The prevalence of HIV infection in adults notified with tuberculosis in the survey period was also estimated. METHODS: Clinical, bacteriological, and sociodemographic information was obtained on all newly notified cases of tuberculosis in England and Wales during the six months from 2 January to 2 July 1993. The prevalence of HIV infection in 16-54 year old patients with tuberculosis notified throughout 1993 was assessed using "unlinked anonymous" testing supplemented by matching of the register of patients with tuberculosis with that of patients with AIDS reported to the PHLS AIDS centre. Annual notification rates were calculated using population estimates from the 1993 Labour Force Survey. RESULTS: A total of 2706 newly notified patients was eligible for inclusion in the survey of whom 2458 were previously untreated the comparable figures for 1988 were 2408 and 2163. The number of patients of white ethnic origin decreased from 1142 (53%) in 1988 to 1088 (44%) in 1993 whereas those of patients of Indian, Pakistani, or Bangladeshi (Indian subcontinent (ISC)) ethnic origin increased from 843 (39%) in 1988 to 1014 (41%) and those of "other" (non-white, non-ISC) ethnic origins increased from 178 (8%) to 356 (14%). The largest increase was seen in the black African ethnic group from 37 in 1988 to 171 in 1993. Forty nine per cent of patients had been born abroad and the highest rates were seen in those who had recently arrived in this country. The overall annual notification rate for previously untreated tuberculosis in England and Wales increased between 1988 and 1993 from 8.4 to 9.2 per 100,000 population. The rate declined in the white, Indian, and black Caribbean ethnic groups and increased in all other groups. In the white group the rate of decline has slowed since the last survey: in several age groups the rates were higher in 1993 than 1988 but the numbers in these groups were small. Thirty six (4.1%) of the 882 previously untreated respiratory cases were resistant to isoniazid and three (0.3%) to isoniazid and rifampicin. Sixty two (2.3%) adults aged 16-54 years were estimated to be HIV-infected. Evidence of under-reporting of HIV positive tuberculosis patients was found. CONCLUSIONS: The number of cases and annual notification rate for previously untreated tuberculosis increased between 1988 and 1993. Although the decline in rates in the white population has continued, the rate of decline has slowed. The high rates in the ISC ethnic group population have continued to decline since 1988 whereas rates in the black African group have increased. An increased proportion of cases were found among people born abroad, particularly those recently arrived in this country. In previously untreated cases the level of drug resistance remains low and multi-drug resistance is rare. A small proportion of adults with tuberculosis were infected with HIV but there may be selective undernotification of tuberculosis in these patients. 

PMCID: PMC1758462  PMID: 9516900
19.  Study of the effectiveness of influenza vaccination in the elderly in the epidemic of 1989-90 using a general practice database. 
Epidemiology and Infection  1995;115(3):581-589.
The effectiveness of influenza vaccination in preventing serious illness and death was determined in an elderly population during the influenza epidemic of was determined in an elderly population during the influenza epidemic of was determined in an elderly population during the influenza epidemic of 1989-90. A retrospective cohort study was carried out using computerized general practitioner records on nearly 10,000 patients aged 55 years and over. After adjustment for potential confounding factors, recent immunization was found to have a protective effect of 75% (95% confidence intervals: 21-92%) against death. Protection did not appear to vary with either age or the presence of underlying chronic disease. As the complications of influenza are most common in those with underlying chronic disease, the study findings are consistent with the recommended policy for the use of influenza vaccine in the UK. Further work is necessary to determine the cost-effectiveness of extending immunization to other groups.
PMCID: PMC2271576  PMID: 8557090
21.  Nosocomial Legionnaires' disease in England and Wales, 1980-92. 
Epidemiology and Infection  1994;112(2):329-345.
Two hundred and eighteen nosocomial cases of Legionnaires' disease with 68 deaths were reported to the National Surveillance Scheme for Legionnaires Disease between 1980 and 1992, representing 15% of the reported infections acquired in England and Wales. Twenty-two nosocomial outbreaks accounted for 135 (62%) of these cases, the remainder occurring as single cases either in hospitals where other single cases or outbreaks had been reported in different years or as 'sporadic' cases in hospitals from which no other cases were reported. A clinical history prior to onset of Legionnaires' disease was available for 124 patients, 61 of whom had undergone recent transplant therapy or were immunosuppressed for other reasons. Sixty cases (27%) were diagnosed by culture of the organism and isolates from 56 patients were typed; 25 (42%) were non L. pneumophila serogroup 1 infections. Methods for prevention and control of nosocomial outbreaks are discussed, in particular the susceptibility to Legionnaires' disease of certain groups of hospital patients.
PMCID: PMC2271466  PMID: 8150007
22.  Re-emergence of tuberculosis. 
BMJ : British Medical Journal  1993;306(6882):932.
PMCID: PMC1677346  PMID: 8490442
23.  Two outbreaks of Legionnaires' disease in Bolton Health District 
Epidemiology and Infection  1990;104(2):159-170.
In 1988, there were two outbreaks of legionellosis in Bolton Health District. Altogether 37 cases of Legionnaires' disease and 23 cases of non-pneumonic legionellosis were identified. Twenty-five patients with Legionnaires' disease were associated with an engineering plant, 4 with Bolton town centre, and 8 with both the plant and town centre. Twenty-two people with non-pneumonic legionellosis were linked with the engineering plant and one with the plant and the town centre. A case-control study carried out among 37 employees with legionellosis and 109 control subjects at the plant showed that infection was associated with one of the 15 cooling towers on the site. Legionella pneumophila indistinguishable by serological and genetic typing methods was isolated from this cooling tower and from sputum samples from two patients. In the town centre, no one tower was linked with infection and L. pneumophila was not cultured from any of the nine towers identified. Control measures were implemented and to date there have been no further cases of legionellosis associated with Bolton Health District.
PMCID: PMC2271757  PMID: 2323354

Results 1-25 (41)