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Background: Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. \ud \ud \ud \ud Objectives: To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). \ud \ud \ud \ud Methods: Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in μm), crypt depth (CrD, in μm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. \ud \ud \ud \ud Results: The median VH in NCGS was significantly shorter (600, IQR: 400–705) than controls (900, IQR: 667–1112) (p < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390–620) vs. 427 µm (IQR: 348–569, p = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls (p < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, p < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. \ud \ud \ud \ud Conclusion: NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.

The purpose of this review is to provide a definitive account of small intestinal mucosal structure and interpretation. The coeliac lesion has been well known, but not well described to date and this review aims to identify the interpretative difficulties which have arisen over time with the histological assessment of coeliac disease. In early coeliac interpretation, there were significant inaccuracies, particularly surrounding intraepithelial lymphocyte counts and the degree of villous flattening which occurred in the tissue. Many of these interpretive pitfalls are still encountered today, increasing the potential for diagnostic errors. These difficulties are mostly due to the fact that stained 2-dimensional sections can never truly represent the 3-dimensional framework of the intestinal tissue under investigation. Therefore, this review offers a critical account occasioned by these 2-dimensional interpretative errors and which, in our opinion, should in general be jettisoned. As a result, we leave a framework regarding the true 3-dimensional knowledge of mucosal structure accrued over the 70-year period of study, and one which is available for future reference.

Additional to NDE, there are further phenomenological events that, simultaneously, convince subjects in thinking they are out of their bodies. These hallucinatory occurrences are termed out-of-body experiences (OBE), and are typically associated with (i) motion such as flying, ascending, spinning, accelerations upwards, falling downwards, (ii) floating due to weightlessness and without apparent attachment to a physical body (iii) aberrant mis-perceptions of bodily location in para-centric space, and (iv) finally of suddenly being, or bumping, back into the body after an episode of weightlessness as full conscious-awareness is returning to the subject. Such accounts are exemplified, and ratified, by the following excerpts

The word religion derives from the Latin “religare”, to bind, although that idea obviously involves a multiplicity of cognitive, affective and behavioural domains, neither of which might necessarily be expected to exhaust its widest connotations. “That which binds” is referential not only to individual believers and their obligatory bonds towards the particular deity given obeisance, but to the social influences in binding those believers into a worshipping community or congregation (whether of church, mosque, synagogue, meeting house, chapel). Thus religion, seen from those perspectives, can be personal or collective. The collective element additionally embraces induction into a particular system of belief, religious upbringing, and the relevant metaphysical underpinnings. In general, I am concerned more with the three Abrahamic faiths, without necessarily feigning ignorance of all other religions throughout the world, and from time immemorial. Indeed, Swanson lists at least thirty “gods” (1960, 66–70) while in his recent book, Torrey (2017: 240) claims 25 “gods” across time and geography, but that total, overall, is likely to be far larger.

This Section deals formally with near-death (ND) and out-of-body experiences (OBE). In the past, each component (NDE and OBE) was usually merged, simply because they were thought to represent one single process. However, based on neurophysiological investigations, each could now be regarded as having aetiologically a distinct neural cause. For those reasons, although features of each component may be experienced within a single event, NDE and OBE will be dealt with separately in this and the following chapters. The current chapter sets the scene in providing a broad critical overview of NDE. That is followed by two further essays concerned with normal sleep (Addendum II.1) and, in Chap. 5, abnormal forms of sleep which are of great significance regarding our understandings of the neurology of NDE. There then follows an outline of the OBE and its neurological perturbations (Chap. 6). Next, in respect of OBE, I summarise briefly the subject of upwards flight and its multiple significances with in the religious sphere, and how that universal concept and its adoption could have its original derivation from the experiential phenomenology of OBE (Chap. 7). Finally, I deal with the all-important aspect of the post-ND/OBE subject and the psychological changes in personality which follow the event and their impact on ancient societies in respect of sensing the divine (Chap. 8).

Part II began by asking whether it was appropriate for NDE subjects to conclude that ND/OBE are completely unrelated to dreams. Ordinary daytime living consciousness comprises three state-boundaries: wakefulness, and the two modes of natural sleep: rapid-eye movement (REM) and non-REM (NREM) sleep. Essentially, these are mutually controlled by the “cerebral monoaminergic fountain” (Fig. 5.1) between acetyl-choline, serotonin, dopamine, and adrenaline (nor-epinephrine) secretion. Reversion from one state-boundary to another can be almost instantaneous as we all recognise if having overslept, that crisis being immediately followed by the rapid reversion to attention required in meeting immediate responsibilities. Although subjects while sleeping may seem to be “unconscious”, their brains are considerably active, especially during the REM sleep mode. REM sleep-mode is, surprisingly, an example of intense cortical arousal following secretion of nor-adrenaline and serotonin (secreted from midbrain/pontine neurones), during which physical parameters (pulse, temperature and blood pressure, and the EEG) suggest that subjects are actually awake. Sleeping itself comprises several recurring cycles of NREM and REM sleep. Dreaming occurs during both, but more so within successive REM periods, while NREM dreams are generally more abstract in nature. Above, the striking parallels between various forms of normal dreaming and ND/OBE phenomenology were brought to light ( Addendum II.1).

Given the markedly increased interest in both the experiential, phenomenological, neurophysiological and neuropathological aspects of ND/OBE, it is most surprising that far less interest has been devoted to the important outcomes involving post-experiential alterations in personal lifestyles. This seems to be a grave oversight since the changed phenotype of these post-ND/OBE subjects is, in my view, of the greater importance. That importance has twofold implications: first, because we need to know the mechanisms that give rise to those changes in psycho-phenotype and second, how that changed phenotype impacts both the ensuing direction of that person’s life, but also upon those people with whom they are most closely associated. That is, there are psychological, neurophysiological and social outcomes that need to be pursued here. Previously, I have previously suggested that this remarkable change in expressed phenotype is the real outcome of the ND/OBE rather than the experience (NDE) itself. Indeed, the sheer transience of the phenomenon itself, although such a vivid occurrence, could be viewed simply as an epiphenomenal outcome in relation to its precipitating causes (Marsh 2016). Clearly, such changes in personality would have been noticed among early hominins who had undergone these experiences.

In Chap. 2 and the two preceding Addenda, I sketched out a brief evolutionary history of mankind including aspects of the origins of language and the more specialised and supportive functions of pre-frontal cortex in conferring ability to read others’ minds (Theory of Mind) and to provide the neural foundations for a moral attitude essential, in my view, for any serious apprehension of divinity and what that entails in terms of personal behaviour. That provides a working framework on which to evaluate the advent of more recent modern humans, together with their associated cultural growth and achievements.

In the ambience of today’s Western culture, death probably signifies the end of existence with little, if any, prospect of something or anything replacing it. Consistent with that view is the fact that only 14% of British subjects (~1.4 million) attend church. Much of that dwindling congregation increasingly consists of ever-ageing female worshippers. By contrast, the total membership of the non-religious British Humanist Society and British Secular Society claims ~80,000–100,000 members, from a population of about 70 million UK inhabitants. So for the remaining and presumably uncommitted majority, it would appear that in terms of a so-called “eternity”, death has little meaning or relevance, a trend which is likely reflective of most major Western nations.

We should formally begin, perhaps, with our universe originating some 13 billion years ago from what cosmologists call the “Big Bang”. Life, whether from unitary or multiple derivations, arose on this planet considerably more recently: surprisingly, in fact, only ~400 million years ago (mya). Approximately 5–6mya, a split from our last common ancestor (LCA) gave rise to two distinct lineages, chimpanzees and the other destined to generate various evolutionary species of “hominins” (a term used non-specifically throughout in describing pre-human species). The origins of anatomically modern humans (AMH) from these pre-human hominins began ~2mya, at which time the chimpanzees split to produce the highly intelligent miniature, or Bonobo, chimpanzee. Concepts regarding our common heritage and cultural developments derive from the findings of ancient skeletal remains and their associated artefacts from the southern limestone caves of South Africa; the Rift Valley in Eastern Africa (Ethiopia and Tanzania); Asia; together with other sites across North Africa; Asia; and throughout Europe. Here, in this chapter, I attempt to put some of the pieces of the jigsaw together, not so much as a scholarly essay on mankind’s evolution, but more a less formalised tale pointing out the major features of our earliest history, and from which we can more helpfully assess the emerging thematic of sensing the divine.

Introduction Intestinal epithelial cell damages generated by inflammation in coeliac disease (CD) ranges from sub-microscopic to severe architectural distortion. Translation of quantitative morphological changes in intestinal microorgans, like villus/crypt transformation, distribution of inflammatory cells and diagnostic cut offs, is lacking for CD and gluten related micro-enteropathies. Method Investigators from 22 centres, 9 countries of 4 continents, recruited CD patients with Marsh 0-II histology (n=299), NCGS (n=151), and 262 controls. Based on an agreed protocol, epithelial morphology including intraepithelial lymphocyte (IEL) density, villus height and crypt depth were measured in well-oriented duodenal biopsies. Results In total 712 subjects were recruited from Australia (20), Finland (20), India (25), Iran (37), Italy (246), Romania (10), Turkey (30), UK (166) and USA (158). Preliminary analyses showed raw IEL density (IEL/100EC) was poorly correlated with tTG, villus height, crypt depth or their ratios, and even significant findings did not show strong correlation coefficients ( Conclusion The most specific and strongest biomarker for CD with microenteropathy is serology acting as the gold standard in this group. Villus height and crypt depth would serve as complementary tools in diagnosis of mild CD and NCGS patients. NCGS seem to have a milder morphological change compared to CD even when they present with similar Marsh scores. This study also confirms the cut off of IEL for CD with microenteropathy is similar to CD with severe enteropathy at 25 IEL/100EC.

The diagnosis of celiac disease (CD) no longer rests on a malabsorptive state or severe mucosal lesions. For the present, diagnosis will always require the gold-standard of a biopsy, interpreted through its progressive phases (Marsh classification). Marsh classification articulated the immunopathological spectrum of gluten-induced mucosal changes in association with the recognition of innate (Marsh I infiltration) and T cell-based adaptive (Marsh II, and the surface re-organisation typifying Marsh III lesions) responses. Through the Marsh classification the diagnostic goalposts were considerably widened thus, over its time-course, permitting countless patients to begin a gluten-free diet but who, on previous criteria, would have been denied such vital treatment. The revisions of this classification failed to provide additional insight in the interpretation of mucosal pathology. Morever, the subclassification of Marsh 3 imposed an enormous amount of extra work on pathologists with no aid in diagnosis, treatment, or prognosis. Therefore, it should now be apparent that if gastroenterologists ignore these sub-classifications in clinical decision-making, then on that basis alone, there is no need whatsoever for pathologists to persist in reporting them. Since new treatments are under critical assessment, we might have to consider use of some other higher level histological techniques sensitive enough to detect the changes sought. A promising alternative would be to hear more voices from imaginative histopathologists or morphologists together with some more insightful approaches, involving molecular-based techniques and stem cell research may be to evaluate mucosal pathology in CD.

Our experiences, through day and night, are not as clear-cut as might seem on first thought. Considerable aspects of life comprise illusory phenomena, some of which are realised, while others are not. Moreover, the boundaries between illusion and hallucination can be very blurred. This essay considers specific situations exemplary of these aberrations – the phantom limb phenomenon, the effects of migraine and temporal lobe epilepsy, sleep disturbances, out-of-body and near-death experiences, conjuring, and the technique of pick-pocketing. Life is never as certain or as sure as we think.

The acceptability of assisted suicide, irrespective of subjects' competency, evokes differential Christian responses. Existing ethical systems seem unlikely to resolve the impasse. Soon, enacted legal provision(s) may permit assisted suicide. Those provisions, based on Lord Falconer's actions, surprisingly refer to the Abortion Act (1967) and its two certifying doctors. This paper asserts that Falconer's calls for law reform, his reliance on that Act, and the manipulation and ‘bending’ of the Act during its 45-year lifespan, are arguably unsafe, if, indeed, necessary. Supervisory measures offering mandatory oversights before any death is completed or resultant ‘slippery slopes’ incurred, are detailed here.

Introduction The current prevalence of Coeliac Disease (CD) in UK is said to be around 1 per 100 (1%) individuals[1,2]. For the last 10 years there has been a regional drive from our CCG to discharge confirmed coeliac patients back to their GPs for community based care. It often seems that we see these patients later on in their disease course, with complications that were potentially avoidable. Iron deficiency anaemia (IDA) is a common problem in CD, and is said to occur with a prevalence as high as 46% [1], whilst up to 8.7% of all unexplained IDA appears to be associated with CD [2]. Objective To assess the prevalence of IDA in our CD cohort, and the recurrence of IDA in these patients over a 7 year period. In those failing to correct (eg. with oral iron), we aimed to review the proportion that received intravenous (IV) iron. Method The Luton and Dunstable University Hospital serves a catchment of 3 30 000 and has a CD database of 1430 patients (0.43%), which is slightly lower than the 1% National prevalence rate. Over the last 7 years we have compiled a database documenting each occasion a patient has presented for blood tests and has had evidence of confirmed IDA. For the purposes of this study we defined iron deficiency anaemia as a haemoglobin level of Results Coeliac disease was found to be associated with 1.7% (967/54977) of all the IDA picked up over the 7 year review period. Conversely, 420 (or 29%) of our 1430 local CD patients were found to have IDA. 388 CD patients presented 967 times with IDA (an average of 2.5 times each, range 1–35 times). Of these 420 CD patients with IDA, just 4% (17/420) received an IV iron infusion. Conclusion Over a 7 year review period 29% of our CD cohort were found to have IDA. Despite tiredness and lethargy being the most common symptom CD patients complain of impacting on their daily lives, just 4% of these received IV iron supplementation. Many of these patients had presented on multiple occasions with IDA (average 2.5 times). Due to the previous CCG drive to discharge these patients back to their GPs for community based follow up, it is possible that these results show a failure in the community monitoring and management system. References . Bottaro G, Cataldo F, Rotolo N, Spina M, Corazza GR. The clinical pattern of subclinical/silent celiac disease: an analysis on 1026 consecutive cases. Am J Gastroenterol 1999; 94:691–696. . Hematologic manifestations of celiac disease. Thorvardur R. Halfdanarson, Mark R. Litzow and Joseph A. Murray. Blood 2007 109:412–421. Disclosure of Interest None Declared

Introduction Counting intraepithelial lymphocytes (IEL) has been a prominent diagnostic histological approach for distinguishing normal disease-control (DC) mucosae from celiac disease (CD) patients for over five decades. Most surprisingly, during that period, no definitive definition of a ”normal” count has ever appeared: indeed, the existing literature on this point is extremely fragile. In this new, multi-centre study, ROC-curve analysis was used to determine the optimal cut-off between normal and CD (Marsh III lesion) mucosae, based on IEL counts on over 400 mucosal biopsy specimens. Method The study was designed during the International Meeting on Digestive Pathology, Bucharest 2015 in which investigators from 19 centres from eight countries and involving three continents recruited patients to measure numbers of IEL per 100 enterocytes in well-oriented duodenal biopsies. All centres worked to an agreed protocol to ensure uniformity of approach. Demographic and serological data were also collected, wherever feasible, to compare cases and controls. Results The mean age of DC and CD groups were 38.3 and 45.5 years respectively, of which 59% and 71% were female. The mean IEL count was 54±18/100 enterocytes for CD compared with 13±8 for DC (p=0.0001). ROC-curve analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with a sensitivity and specificity of 99% and 92%: the area under the curve was 0.0995. Using this technique we showed that other proposals in the literature, between 20–40 IEL, were far less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the sub-classification of the Marsh III lesion. Conclusion The IEL count is not normally-distributed in CD. The numerical overlapping confirmed that IEL do not represent a bi-modally distributed population[s], thus being indicative of a continuously graded dose-response by IEL to environmental (gluten) antigenic influence. In the largest study of this type, we showed using ROC-curve analysis that for Marsh III lesions, a cut-off value of 25 IEL/100 enterocytes is the optimal dividing line between DC and CD biopsies. Finally, we were unable to demonstrate any difference in IEL counts between Marsh Stage III a,b,c, subdivisions, with histology or immunocytochemisty. These results are consistent with a growing literature that finds this sub-classification of little value. Disclosure of Interest None Declared

Introduction Lower gastrointestinal (GI) endoscopy is frequently requested in patients with coeliac disease (CD) who present with a change in their bowel habit (CIBH), towards diarrhoea or “looser stools” (regardless of age, and often in the absence of other red-flag features such as weight-loss). This is primarily driven by the need to exclude microscopic colitis (MSC). There is, however, little evidence in the current literature to determine direct causation between CD and MSC, whilst the strength of the association is still not fully known. We set out to review the number of CD patients referred locally for lower gastrointestinal (GI) procedures, the primary referral reason and the outcomes. Method The Luton and Dunstable University Hospital has a database of 1317 patients with coeliac disease [Male n=467, Female n=850; Age range: 1–102 years old; mean age 58]. Using the database for reference, the hospital coding system was used to analyse the total number of lower GI endoscopy procedures performed for these patients during 2005–2016. Indications for the procedures were identified, along with their further histopathological analysis. Results Over the 12 year period, the 1317 patients underwent a total of 527 lower GI procedures; 413 colonoscopies, 108 flexible sigmoidoscopies and 6 pouchoscopies. These were performed for the following primary indications: 252 for CIBH (reflecting diarrhoea/loose stools); 53 for rectal bleeding; 52 for the Bowel Cancer Screening Programme; 54 for concomitant inflammatory bowel disease (IBD) assessment; 48 for anaemia; 21 for abnormal radiology; 15 post-cancer resection reviews; 9 for abdominal pain and 23 others. MSC was found in just 4 patients presenting with CIBH (4/252, 1.6%). Other findings included 20 new lower GI malignancies (1 with CIBH), 26 new cases of IBD (16 with CIBH), and 101 with melanosis coli (97 for CIBH, 3 for rectal bleeding and 1 for anaemia). Conclusion 48% of the lower GI procedures performed in CD patients were due to CIBH, and MSC was only found in 4 of these patients, suggesting a weak association. Melanosis coli was histologically identified in 38.5% of procedures performed for CIBH. We know constipation is a common symptom in CD and melanosis coli is often attributed to use of laxatives, however a direct pathological link between CD and melanosis coli cannot be excluded. Consultations relating to CIBH in CD patients should focus on constipation and use of laxatives, however, the role of calprotectin +/- endoscopy remains crucial, given the number of new cases of colorectal cancer (20, 4%) and IBD (26, 5%) identified in our CD cohort. Disclosure of Interest None Declared

Introduction Due to financial pressures within the NHS, many CCG’s have recently decommissioned gluten-free prescriptions for coeliac disease (CD) patients. Unfortunately, the true financial impact of coeliac disease on the NHS, has never been fully understood. In order to protect the care of CD patients in our local catchment, we sort to understand the existing burden of care of these patients, particularly on the hospital admission system, through daycase procedures and direct inpatient stay. Method The Luton and Dunstable University Hospital has a database of 1317 patients with coeliac disease [Male n=467, Female n=850; Age range: 1–102 years old; mean age 58; current paediatric patients (age ≤16) n=61]. Using this database for reference, the hospital coding system was used to analyse the total number of inpatient (stay) and day-case admissions between 2005–2016, and identify the admitting specialties. Results For the 1317 coeliac patients, there were 1267 inpatient admissions. The number of inpatient admissions per patient (all ages) ranged from 0–51. The length of inpatient stay ranged from 1–64 days, with a total 5018 days spent within hospital, at an average 3.96 days per inpatient stay. Patients were admitted under a range of different specialities; general medicine n=556; paediatrics n=384; general surgery n=181; trauma and orthopaedics n=76; Obstetrics and Gynaecology (O and G) n=35; ear, nose and throat n=13; maxillofacial surgery n=13; urology n=9. There were 698 daycases involving the CD patients: the top 3 ranking specialties included dermatology n=124; O and G n=91, and ophthalmology n=88. Conclusion A total 1965 hospital admissions were attained by CD patients over 12 years (163.75 admissions/year), accounting for a total 5716 days spent within the hospital setting. On average, each patient had a mean of 1.49 hospital admissions. In total, 30% of all the CD inpatient admissions were seen in paediatric patients, highlighting its importance in the health of these younger patients. A surprisingly high number of cataract operations (74) were performed in these CD patients (independent of age) raising the possibility of a link. 24 miscarriages and 2 ectopic pregnancies were also documented, suggesting that CD may have a more important role in fertility and fecundity than previously thought. The role of coeliac disease within fertility may be underestimated. Not all the hospital admissions were directly related to underlying coeliac disease, but there clearly appears to be an increased demand placed on the local hospital admission services from these patients. Disclosure of Interest None Declared

Introduction Coeliac disease remains a huge burden on the NHS with an incidence of 1 in 100 people. For the last 10 years there has been a drive from our CCG to discharge patients with confirmed coeliac disease back to their GP’s for community based management. In this study, we set about establishing the total cost and demand made on the Luton and Dunstable District General Hospital in managing these coeliac patients, despite this policy. Main objective: To assess the demand and the cost of outpatient services provided to patients with coeliac disease, and to understand what outpatient services were being utilised. Method Luton and Dunstable Hospital has a database of 1317 patients with a diagnosis of coeliac disease. Using the hospital’s coding system we were able to analyse the total number of outpatient appointments (OPAs) made over 11 years between 2005 and 2016. Total costs were calculated using a range of different prices for different specialties, and depending on whether the OPAs were new (£210-£265) or follow up (£83-£136) clinic appointments. In addition, the burden on certain specialties was analysed in more detail. Results Over the 11 year period, 33 150 outpatient appointments were made by the 1317 coeliac patients (25.17 per person; 2.29 per person per year) costing the local trust a total of £5,167,396. The total number of appointments per patient ranged from 1 to 167. Including paediatrics, there were 3,235 Gastroenterology appointments made (836 new and 2399 follow-up) costing a total of £4 62 858. There were also 1468 appointments made with the dietitians (473 new and 995 follow-up) costing a total of £2 22 024 and 949 OPAs made with the Dermatology team (356 new and 592 follow-up) costing a total of £1 49 848. Interestingly, there were also 1451 OPAs made with the Ophthalmology team and 906 appointments made with the Audiology team. Conclusion Over 11 years, the 1317 patients made 33,150 OPAs, 10.25% of which were with the Gastroenterology team. The total cost of OPAs with specialties other than Gastroenterology was £4,704,538, however a large proportion of this cost, including Dietetic and Dermatology appointments, were likely to be related to the coeliac burden. In addition, with the established link between coeliac disease and ophthalmological manifestations secondary to associated autoimmune disease and nutritional deficiency, the burden of Ophthalmology OPAs was high in this group. Finally, there was also an unexpectedly high number of Audiology OPAs raising the suspicion that extra-intestinal manifestations of coeliac disease may be contributory. There is little in the literature regarding the auditory sequelae of coeliac disease, so further work in this area is needed. Disclosure of Interest None Declared

ObjectivesCounting intraepithelial lymphocytes (IEL) is central to the histological diagnosis of coeliac disease (CD), but no definitive ‘normal’ IEL range has ever been published. In this multicentre study, receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off between normal and CD (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens.DesignThe study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centres, eight countries of three continents, recruited 198 patients with Marsh III histology and 203 controls and used one agreed protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. Demographic and serological data were also collected.ResultsThe mean ages of CD and control groups were 45.5 (neonate to 82) and 38.3 (2–88) years. Mean IEL count was 54±18/100 enterocytes in CD and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the subclassification of the Marsh III lesion.ConclusionOur ROC curve analyses demonstrate that for Marsh III lesions, a cut-off of 25 IEL/100 enterocytes optimises discrimination between normal control and CD biopsies. No differences in IEL counts were found between Marsh III a, b and c lesions. There was an indication of a continuously graded dose–response by IEL to environmental (gluten) antigenic influence.

Disablement pervades life more than is realised, involving matters beyond actual physical or mental handicap. Age-related degenerations are intrinsic to everyone, while any inhumane behaviour causes extreme hurt - within caring institutions, through war - and by psychopaths who reflect lack of empathy and compassion. The able-disabled, alternatively, have fought through various means to establish a dignified presence, thereby forcing themselves to be accorded esteem by society. Disability can be envisaged as divine calling, and, as indicator of divine holiness. Much longer-lasting damage and vulnerability, reflecting evil throughout Creation, requires responses met only by incarnational theology through Christ's humiliating suffering. Great hope, then, is needed by those awaiting full restoration of well-being in resurrection.

The diagnosis of coeliac disease depends on the finding of characteristic, though not specific changes, of intraepithelial lymphocytosis, crypt hyperplasia and various degrees of villous height reduction identified in duodenal biopsies of individuals ingesting a gluten containing diet, together with symptomatic and histologic improvement on gluten withdrawal. Serologic testing has become the main mode of determining who will undergo biopsy. The IgA endomysial antibody and IgA tissue transglutaminase antibody have approximately 90% sensitivity and specificity, though there are reports of lower sensitivity and specificity in the clinical practice setting. This is due to lower titers of these antibodies in the presence of lesser degrees of mucosal damage. The widespread availability of serologic tests for coeliac disease allows the diagnosis to be considered by any physician. Gastroenterologists will be required to interpret the results of serologic tests and perform duodenal biopsies when indicated. Pathologists likewise need to be better acquainted with the more subtle changes of cell mediated immunity within the mucosa that are suggestive of underlying gluten sensitivity.

Coeliac disease is caused by T cell sensitisation of the intestine to cereal prolamins, which results in a range of mucosal abnormalities that may lead to malabsorption.1 The population prevalence in western countries is ∼1 in 200.2–4 Evidence for an inherited predisposition to coeliac disease comes from studies of first degree relatives of patients and studies of twins.5,6 A strong association is seen between coeliac disease and the HLA-DQ (α1*05, β1*02) heterodimer (DQ2) which is present in approximately 95% of patients,7–9 compared with 20-30% of healthy subjects.10,11 The difference in concordance rates between monozygotic twins and HLA identical sibs (80-100% v 25%) implicates non-HLA genes in the genetic predisposition to coeliac disease.11 The overall relative risk in sibs is at least 20 and is therefore four-fold higher than that attributable to HLA alone under model of inheritance.7 Genome linkage searches carried out on Irish,12 Italian,13, and UK14 coeliac disease families have identified a number of potential sites for the location of non-HLA linked genes. The putative candidate loci detected in the three studies are, however, largely inconsistent and the findings have not been replicated in other populations.15–19 Here we report the results of a genome screen of 24 multiplex families with coeliac disease and discuss the findings of this study in relation to previously published analyses. Twenty-four families with two or more members affected with coeliac disease were recruited for this study (fig 1). Nine of these families (Nos 1, 3, 4, 6, 30, 32, 39, 43, and 44) have been used in a previous study of candidate regions.16 All the families were of northern European ancestry. Twelve of the families were recruited from the UK, nine from Sweden, two from Switzerland, …

Clinically, celiac disease has always been regarded as a wasting, malabsorptive disorder due to disease of the small intestinal mucosa. It has been difficult for clinicians to recognize that this condition is primarily due to sensitization of mesenteric T lymphocytes to wheat protein (gluten) in genetically predisposed (DQ2+) individuals. On contact with dietary-derived gluten in the upper intestine, these sensitized T lymphocytes are activated leading to inflammation of and morphologically altered mucosal architecture: the latter reverts to normal with a gluten-free diet. The circulation of sensitized T lymphocytes to other parts of the intestinal mucosa explains why identical immunopathological inflammation can be induced in ileal and rectal mucosa. It appears, then, that in predisposed DQ2+ subjects, mesenteric T lymphocytes recognize gluten as foreign (non-self) antigen, thereby inducing mucosal pathology secondary to the initiating lymphocyte-protein interaction, analogously to the mucosal lesions that typify graft-vs-host reactions, or nematode or Giaraia infestations. Today, as this article describes, we recognize that celiac disease often exists in a subclinical, or "compensated-latent," form, or with symptoms that do not immediately suggest an origin in the gastrointestinal tract.

The purpose of this study was to evaluate the use of rectal gluten challenge in the diagnosis of coeliac disease. A total of 103 patients with features suggestive of this diagnosis were prospectively enrolled into the study; a diagnosis of coeliac disease was based on strictly defined criteria used in judging the proximal jejunal biopsy. On that basis, 45 out of the 103 patients were deemed to have coeliac disease. A slurry of gluten powder in physiological saline was introduced into the rectum, and biopsies taken before and at 2 h or 4 h after the challenge were examined immunohistochemically by computerized image analysis. Cell counts were analysed by logistic regression, and the best equations were obtained for each challenge group. The 2 h challenge yielded diagnostic sensitivity and specificity of 69.6% and 78.6% respectively. The 4 h challenge provided sensitivity and specificity of 100% and 100% respectively. These results were compared with other clinical diagnostic predictors, including anti-endomysial antibodies, which yielded diagnostic sensitivity and specificity of 70% and 98% respectively. It is concluded that a 4 h rectal challenge is a highly sensitive means of identifying gluten-sensitized individuals, and would be of particular value in cases showing negative antibody screening or equivocal biopsy appearances.

A strong HLA association is seen in coeliac disease [specifically to the DQ(alpha1*0501,beta1*0201 heterodimer], but this cannot entirely account for the increased risk seen in relatives of affected cases. One or more genes at HLA-unlinked loci also predispose to coeliac disease and are probably stronger determinants of disease susceptibility than HLA. A recent study has proposed a number of candidate regions on chromosomes 6p23 (distinct from HLA), 6p12, 3q27, 5q33.3, 7q31.3, 11p11, 15q26, 19p13.3, 19q13.1, 19q13.4 and 22cen for the location of a non-HLA linked susceptibility gene. We have examined these regions in 28 coeliac disease families by linkage analysis. There was excess sharing of chromosome 6p markers, but no support for a predisposition locus telomeric to HLA. No significant evidence in favour of linkage to coeliac disease was obtained for chromosomes 3q27, 5q33.3, 7q31.3, 11p11, 19p13.3, 19q13.1, 19q13.4 or 22cen. There was, however, excess sharing close to D15S642. The maximum non-parametric linkage score was 1.99 (P = 0.03). Although the evidence for linkage of coeliac disease to chromosome 15q26 is not strong, the well established association between coeliac disease and insulin dependent diabetes mellitus, together with the mapping of an IDDM susceptibility locus (IDDM3) to chromosome 15q26, provide indirect support for this as a candidate locus conferring susceptibility to coeliac disease in some families.

The evolving history of the small intestinal biopsy and its interpretation—and misinterpretations—are described in this paper. Certain interpretative errors in the technical approaches to histological assessment are highlighted—even though we may never be rid of them. For example, mucosal “flattening” does not reduce individual villi to their cores, as still seems to be widely believed. Neither is the mucosa undergoing an atrophic process—since it can recover structurally. Rather, the intestinal mucosa manifests a vast hypertrophic response resulting in the formation of large plateaus formed from partially reduced villi and their amalgamation with the now increased height and width of the inter‐villous ridges: this is associated with considerable increases in crypt volumes. Sections through mosaic plateaus gives an erroneous impression of the presence of stunted, flat‐topped villi which continues to encourage both the continued use of irrelevant “atrophy” terminologies and a marked failure to perceive what random sections through mosaic plateaus actually look like. While reviewing the extensive 40+ year literature on mucosal analysis, we extracted data on intraepithelial lymphocytes (IEL) counts from 607 biopsies, and applied receiver‐operating characteristic (ROC)‐curve analysis. From that perspective, it appears that counting IEL/100 enterocyte nuclei in routine haematoxylin and eosin (H&E) sections provides the most useful discriminator of celiac mucosae at histological level, with an effective cut‐off of 27 IEL, and offering a very high sensitivity with few false negatives. ROC‐curve analysis also revealed the somewhat lesser accuracies of either CD3+ or γδ+ IEL counts. Current official guidelines seem to be somewhat inadequate in clearly defining the spectrum of gluten‐induced mucosal pathologies and how they could be optimally interpreted, as well as in promoting the ideal manner for physicians and pathologists to interact in interpreting intestinal mucosae submitted for analysis. Future trends should incorporate 3‐D printing and computerised modelling in order to exemplify the subtle micro‐anatomical features associated with the crypt‐villus interzone. The latter needs precise delineation with use of mRNA in‐section assays for brush border enzymes such as alkaline phosphate and esterase. Other additional approaches are needed to facilitate recognition and interpretation of the features of this important inter‐zone, such as wells, basins and hypertrophic alterations in the size of inter‐villous ridges. The 3‐D computerised models could considerably expand our understandings of the microvasculature and its changes—in relation both to crypt hypertrophy, in addition to the partial attrition and subsequent regrowth of villi from the inter‐villous ridges during the flattening and recovery processes, respectively.

Gluten sensitivity is associated with a spectrum of mucosal lesions, arbitrarily termed pre-infiltrative, infiltrative-hyperplastic, flat-destructive and atrophic-hypoplastic. Histologically and immunohistologically these lesions are all compatible with T-cell-driven events operative at a local mucosal level. They are classifiable either in terms of antibody titres (pre-infiltrative) (see Chapter 10) or by the characteristic disposition of IELs throughout the surface and crypt epithelium. From in-vivo challenges, it has been demonstrated: (i) that all these lesions comprise a dynamically interrelated series of events, culminating in the severe flat-destructive lesion; and (ii) that gluten evokes a dose-responsive infiltration of IELs (CD3+ CD8+ and TCR alpha beta + or gamma delta +) into the epithelium. Apart from that, little is known of the functions of IELs; it is possible they may have little to do with the evolving mucosal pathology of gluten sensitivity. Increasing work seems to support a view, proposed from this laboratory over 10 years ago, that the immune-mediated responses in jejunal tissue in gluten sensitivity arise in the lamina propria, in association with DR+ macrophages and an abundance of CD4(+)-activated lymphocytes. Many other inflammatory consequences flow from these interactions, involving activation of mast cells, eosinophils and neutrophils, elaboration of cytokines and other products of inflammation, and increased hyperpermeability of the microvasculature with upregulation of adhesion molecules. The result is a doubling of lamina propria volumes in the severe flat lesion. Evidence is also given to show that measurable changes in lamina propria inflammation occur with the infiltrative-hyperplastic lesion. Symptomatology is not related to the degree of proximal mucosal pathology, but to the extent of the mucosal lesion. Data, although scanty, suggests that lesional pathology involves only 30-50% of the entire small bowel mucosa. Thus, most patients, irrespective of proximal mucosal damage, have latent (or asymptomatic) gluten sensitivity. Symptom development requires additional environmental triggers, of which infection is a major contributor. It should also be noted that, while these various environmental triggers may precipitate symptomatology, they do not advance the severity of the mucosal lesion.

To study changes in rectal mucosa that might be attributable to the effects of gluten, rectal biopsy specimens from untreated and treated gluten sensitised subjects were analysed morphometrically and by immunohistochemical techniques and were compared with a series of disease control mucosae. Although morphometry showed increased populations of plasma cells, lymphocytes, and mast cells in the mucosae of untreated patients, which were reduced (except for mast cells) by dietary gluten restriction, immunohistochemical techniques were far more sensitive in defining these changes. There were highly significant increases in CD3+ and gamma delta+ lymphocytes within both the lamina propria and the epithelium while neutrophils (CD15+ cells) were not at all prominent. Activated (CD25+) lymphocytes expressing interleukin (IL)-2 receptors were increased in lamina propria, usually subjacent to basal lamina, although a few IL-2R+ intraepithelial lymphocytes were found: other IL-2R+ cells were deemed to be macrophages (CD68+). These results clearly indicate that in untreated, gluten sensitised subjects the rectal mucosa shows a lymphoplasmacytoid reaction that is responsive to gluten restriction. The absence of neutrophilia suggests that this lesion is not a conventional inflammatory type proctitis, but rather one presumed to be induced by gluten antigen(s) present in the faecal stream--that is, a cell mediated form of response.