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Showing papers by "St Thomas' Hospital published in 1986"


Journal ArticleDOI
TL;DR: Modification in reservoir design has completely avoided the need to catheterize and quality of life after the operation was preferred to an ileostomy by 96 per cent of patients with an intact reservoir.
Abstract: 119 patients (ulcerative colitis 98, polyposis 20, Hirschsprung's disease 1) were treated between 1976 and 1985. There were 1 operative death (0.8 per cent) and 7 failures (5.9 per cent). Three- (68), two- (13) and four-loop (37) reservoirs were constructed. The ileoanal anastomotic complication rate was 25, 15 and 8 per cent respectively. Mean frequency of defaecation was 4.2 +/- 1.3. Continence was normal in 77 per cent; 4 per cent had a significant faecal leakage. Modification in reservoir design has completely avoided the need to catheterize. Quality of life after the operation was preferred to an ileostomy by 96 per cent of patients with an intact reservoir.

266 citations


Journal ArticleDOI
01 Jan 1986-Pain
TL;DR: This paper reviews studies which have evaluated the use of acupuncture for the relief of pain and examines the criteria by which the adequacy of research reports in this field should be assessed.
Abstract: This paper reviews studies which have evaluated the use of acupuncture for the relief of pain. In the preceding paper the concepts and methods of acupuncture are outlined along with a discussion of the special problems of outcome research in this area. Since in our view the overall quality of published accounts of acupuncture research is poor, we have thought it important to examine the criteria by which the adequacy of research reports in this field should be assessed. The principal issues concerning outcome measures, follow-up assessment, trial design, etc., are therefore discussed in the preceding article. The review which follows describes both controlled and uncontrolled therapeutic trials where the major aim of treatment has been the relief of pain. It does not consider laboratory studies of experimentally induced pain. All studies known to the authors which include at least a no-treatment control group have been included unless they are pilot studies with excessively low patient numbers or are inadequately reported. The details of these controlled studies are summarised in Table I. Where uncontrolled trials are concerned, no attempt has been made to provide an exhaustive review. The studies which have been included generally involve either large patient numbers or other features of design or measurement which render them noteworthy.

252 citations


Journal ArticleDOI
Peter Burney1
TL;DR: The trend in asthma mortality has been estimated from published statistics for the years 1974-84, with account being taken of changes due to the revision of the International Classification of Diseases in 1979.

225 citations


Journal ArticleDOI
TL;DR: The character of the VIIc response to fat intake suggested an association with post-prandial lipaemia, and a high fat intake may lead not only to coronary atheroma but also to fibrin deposition and thrombus formation through direct activation of the coagulation system.

222 citations


Journal ArticleDOI
01 Jan 1986-Pain
TL;DR: This paper introduces some basic concepts concerning acupuncture and considers the standards by which clinical studies of acupuncture should be evaluated, and considers certain key methodological issues with special attention to the difficulties of defining suitable control groups.
Abstract: This paper and the one that follows are concerned with the evaluation of acupuncture as a treatment. The following paper will review the studies to date. In this one we introduce some basic concepts concerning acupuncture and consider the standards by which clinical studies of acupuncture should be evaluated. In the first 3 sections we discuss the application of scientific method to a system of medicine that is not scientifically based; the heterogeneity of techniques subsumed under the single term acupuncture, and the unfamiliar approaches to diagnosis sometimes employed. In later sections we consider certain key methodological issues with special attention to the difficulties of defining suitable control groups. Finally we summarise the conclusions of the previous sections and offer certain suggestions for the conduct of future acupuncture trials.

220 citations


Journal ArticleDOI
D.J. McCance1

163 citations


Journal ArticleDOI
TL;DR: Of an anticoagulant in patients two clotting anticoAGulant of the prothrombin converter complex of the clotting all phospholipid coagulation tests - activated partial thromboplastin (APTT),
Abstract: Attention was first drawn to the presence of an anticoagulant in patients with systemic lupus erythematosus (SLE) by Conley & Hartmann (1952) who described two patients with haemorrhagic disorders and prolonged prothrombin and whole blood clotting times. This anticoagulant appeared to act at the level of the prothrombin converter complex of the clotting cascade and prolonged all phospholipid dependent coagulation tests activated partial thromboplastin time (APTT), the Russell viper venom test (RVVT) and, less often, the prothrombin time. The thrombin time is usually normal. It became evident over the years that this 'lupus anticoagulant' was not particularly associated with bleeding but, paradoxically, with thrombosis (Mueh et al., 1982). A more sensitive and reliable technique of solid phase radioimmunoassay for the detection of antibodies to cardiolipin (a-CL) was devised by Harris et al. (1983a). Subsequent studies have shown a close relationship between these antibodies and the 'lupus anticoagulant', both members of a 'family' of antibodies to phospholipid, an integral part of the clotting cascade. However, phospholipids are also present in cell walls of endothelial cells, platelets and even neuronal cells and the actions of the antibodies against these phospholipids have been thought to be important in the pathogenesis of some of their clinical effects. Approximately 30% of patients with the 'lupus anticoagulant' or antibodies to cardiolipin will have a false positive test for syphilis. The VDRL test is usually of low titre (1:4-1:8) in these patients (Harris et al., 1985a). The mechanism of action of these antibodies remains obscure. Carreras et al. (1982) postulated that they may facilitate coagulation by preventing the release of arachidonic acid from blood vessel endothelium. Prostacyclin production is thereby reduced and platelet aggregation may occur. Inhibition of prekallikrein (Fletcher Factor) and the resulting impairment of fibrin clearance as a mechanism was suggested by Angles-Cano et al. (1979) and this mechanism has been demonstrated in several patients by Sanfellipo & Drayna (1983) and Elias & Eldor (1984). Comp et al. (1983) have described IgG from two patients with tht lupus anticoagulant that inhibited the function of human thrombomodulin, the endothelial co-factor in the activation of protein C by thrombin. Thus the feedback inhibition of coagulation by activated protein C is prevented. This has recently been verified by other workers (Cario et al., 1986). There is also a clear association with thrombocytopenia and Harris et al. (1985a) suggest that anticardiolipin antibodies may play a direct role in mediating platelet destruction. It has been postulated that lupus anticoagulants damage platelets and increase their adhesiveness initiating thrombosis (Editorial, 1984). It has been shown that a-CL antibodies may be of the IgG, IgM or IgA subclass. Harris et al. (1986) have recently demonstrated the importance of the actual levels of a-CL antibodies in predicting thrombosis, recurrent fetal loss or thrombocytopenia and this seems to hold true particularly for the IgG subclass, while a group of patients with drug-induced 'lupus anticoagulant' activity recently analysed were found to have predominantly IgM elevations which appeared to be unassociated with any of the thrombotic clinical complications (Gharavi et al., 1986). Investigations by Dr G.R.V. Hughes and his associates from 1983 onwards at the Hammersmith Hospital and the Rayne Institute of St. Thomas' Hospital, have led the way to further detecting and delineating the character of the antiphospholipid antibodies, their clinical associations and the efficacy ofvarious therapies in the prevention ofthe associated clinical complications. Since then, two International Conferences have been held in London with investigators from many countries participating and it has become clear that not only has the original finding of an association with thrombosis been confirmed but that the clinical associations of antiphospholipid antibodies now extend far beyond the original concept and that there is significant 'spill-over' to non-lupus patients and indeed to the general population.

134 citations


Journal ArticleDOI
C. C. R. Bishop1, S. Powell1, M. Insall1, D. Rutt1, Norman Browse1 
TL;DR: In patients with symptomatic cerebrovascular disease the rise in middle cerebral artery blood-flow velocity in response to hypercapnia, recorded with a pulsed transcranial doppler velocimeter, was significantly less in MCAs above a totally occluded carotid artery than in MC as above a patentCarotid.

118 citations


Journal ArticleDOI
TL;DR: The results suggest that increased leucine concentration in insulin deficiency is due to elevatedLeucine production rate caused by increased proteolysis, and that leucines concentration is restored to normal by insulin treatment.
Abstract: Leucine production rate, metabolic clearance rate and oxidation rate were measured in 10 Type 1 (insulin-dependent) diabetic patients after (1) 24 h insulin withdrawal, (2) conventional insulin therapy and (3) an overnight insulin infusion to maintain normoglycaemia, and in 10 control subjects. In the insulin-withdrawn patients, leucine concentration (259 ± 17 μmol/1), production rate (2.65 ± 0.29 p mol·min−1 kg−1) and oxidation rate (0.69 ± 0.10 μmol · min−1 · kg−1) were significantly greater (p < 0.001;p < 0.05;p < 0.005 respectively) than corresponding values in control subjects (127±6; 1.81 ± 0.12; 0.19 ± 0.02). Following conventional insulin therapy, leucine concentration (162 ± 12 μmol/1) and oxidation rate (0.43 ± 0.05 μmol · min−1 · kg−1) were lower than after insulin withdrawal but were still significantly greater than in control subjects (p<0.05;p<0.005). Although leucine concentration, production rate and metabolic clearance rate were normal after an overnight insulin infusion, leucine oxidation rate was still greater than normal (0.34 ± 0.06 μmol · min−1 kg−1;p<0.05). These results suggest that increased leucine concentration in insulin deficiency is due to elevated leucine production rate caused by increased proteolysis, and that leucine concentration is restored to normal by insulin treatment.

92 citations


Journal ArticleDOI
TL;DR: Very large differences in height were detected between ethnic groups, indicating that the use of British standards of height based on Caucasian children to assess growth of a child of another ethnic group in England should be interpreted with caution.
Abstract: A new surveillance system was initiated on selected growth and nutritional characteristics of children living in inner-city areas and children from ethnic minorities. The heights of Caucasian, Afro-Caribbean and Indo-Pakistani children in this study were compared with those of children in an existing surveillance study, who were chosen to be representative of the English population. Data for this representative sample were collected in 1982 and for the ethnic groups in inner city areas in 1983. The analysis included 13,107 boys and girls aged 5-11 years. Very large differences in height were detected between ethnic groups. The Afro-Caribbean children were the tallest, on average around 3.5 cm taller than the 1982 sample, while the Gujarati children were the shortest, on average about 3 cm below the 1982 sample. Adjustment for a large set of biological and social variables did not eliminate differences in height between ethnic groups. This would indicate that the use of British standards of height based on Caucasian children to assess growth of a child of another ethnic group in England should be interpreted with caution. Multiple regression analyses by ethnic group revealed differences in the pattern of associations between height and social and biological factors among groups. Generalizations from findings in one ethnic group to another in England are not appropriate.

85 citations


Journal ArticleDOI
TL;DR: It was established that breast-milk pumps on the post-natal wards were being disinfected inadequately, resulting in contamination of milk and cross-infection within the SCBU.

Journal ArticleDOI
TL;DR: A clear relationship between both total and free serum testosterone levels were found with nocturnal penile tumescence, and FSH, LH, SHBG, and prolactin showed no relationship.
Abstract: Ten patients with chronic epilepsy were selected; five had high and five had low total serum testosterone levels. Each patient slept for two nights in the sleep laboratory. EEG monitoring and measurements of nocturnal penile tumescence were carried out during sleep. A clear relationship between both total and free serum testosterone levels were found with nocturnal penile tumescence. FSH, LH, SHBG, and prolactin showed no relationship. The five patients with low serum testosterone levels all showed reduced sexual activity.

Journal ArticleDOI
TL;DR: There was a trend for tumours exhibiting an infilrating mode of growth and poor tubule formation to have a diploid DNA content and low S phase fraction.
Abstract: DNA flow cytometry was performed on fixed embedded histological material from 56 radical gastrectomies for human gastric cancer. The ploidy and proportion of cells in the DNA synthetic phase of the cell cycle (S phase fraction) were estimated and the results correlated with histological features. DNA aneuploidy was encountered in 73 per cent of cases. Aneuploid and diploid tumours both had significantly higher fractions of cells in S phase than normal mucosa. S phase fractions for aneuploid tumours were higher than diploid tumours. There was a trend for tumours exhibiting an infiltrating mode of growth and poor tubule formation to have a diploid DNA content and low S phase fraction. No difference was observed between the results obtained from tumours with or without lymph node metastases. Early uniform fixation greatly improved the quality of the flow cytometry results measurable by a reduction in the mean coefficient of variation.


Journal ArticleDOI
TL;DR: It is concluded that a large inter-observer variation may occur in the measurement of a number of histomorphometric indices, even when section preparation and methodology are identical, which should be used in basing the diagnosis of metabolic bone disease on strictly defined control data from other observers.
Abstract: Inter-observer variation has been examined for a number of histomorphometric indices in 20 normal human iliac crest biopsies. Quantitation was performed using an eye-piece graticule and eye-piece micrometer. The same sections were examined by two observers and the methodology was identical. Intra-observer variation was also assessed. Significant inter-observer differences were found for the measurement of total trabecular bone volume, osteoid volume and surface, double plus single and double tetracycline labeled surfaces, and the mean osteoid seam width. The percentage variance due to inter-observer variation was highest for osteoid surface and volume, total resorption surface, and mean osteoid seam width. Intra-observer variation in both observers was small. We conclude that a large inter-observer variation may occur in the measurement of a number of histomorphometric indices, even when section preparation and methodology are identical. Caution should be used in basing the diagnosis of metabolic bone disease on strictly defined control data from other observers, particularly when this has been obtained from centers where the effects of inter-observer variation may be magnified by differences in methodology.

Journal ArticleDOI
TL;DR: Even though the proportion of diabetics entering British end-stage renal failure programmes is rising, many patients who may benefit from treatment are probably not receiving it.

Journal ArticleDOI
01 Jan 1986-Bone
TL;DR: It is suggested that osteoporosis is the major type of metabolic bone disease in patients with chronic cholestatic liver disease and biochemical evidence of osteomalacia is absent.

Journal ArticleDOI
TL;DR: There is an urgent need to improve health education and supervision before and during pregnancy in all diabetic women if the prevalence of malformations amongst their offspring is to be reduced.
Abstract: In 1979-80 a national survey of the incidence of congenital malformations in babies born to diabetic mothers in the United Kingdom was carried out by questionnaire. Of the 1034 mothers reported, 773 were known to have diabetes before the index pregnancy. The incidence of congenital malformations ws 7.1% which is significantly higher than the 2.1% in the offspring reported to the Office of Population, Censuses and Surveys (OPCS) for England and Wales in 1979-80. The increase was most pronounced for malformations of the heart, spine, lungs, and brain. In 40% of the diabetic mothers blood glucose was not recorded during the first trimester of pregnancy, and in this group the malformation rate was twice that in babies born of mothers who had had at least one reported blood glucose estimation during this time. We conclude that there is an urgent need to improve health education and supervision before and during pregnancy in all diabetic women if the prevalence of malformations amongst their offspring is to be reduced.

Journal ArticleDOI
TL;DR: A report on an interim analysis of a large placebo-controlled double-blind randomized clinical trial evaluating the role of fibrinolytic enhancement in the management of venous ulceration says there was a trend in favour of improved healing for those ulcers treated with stanozolol.
Abstract: A report on an interim analysis of a large placebo-controlled double-blind randomized clinical trial evaluating the role of fibrinolytic enhancement in the management of venous ulceration is descri...

Journal ArticleDOI
TL;DR: The presence of calcitonin and CEA is of value in the diagnosis of medullary carcinoma, and enable its distinction from anaplastic thyroid carcinoma.
Abstract: Ten cases each of papillary, follicular, anaplastic and medullary carcinoma of the thyroid were stained for thyroglobulin, calcitonin, epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA) and cytokeratin (CAM 5.2). Monoclonal or affinity purified polyclonal antibodies, and an indirect immunoperoxidase technique were used. All the papillary and follicular tumours, 5/10 anaplastic and 3/10 medullary carcinomas contained thyroglobulin. Only the 10 medullary carcinomas stained positively for calcitonin. Three out of 10 papillary, 1/10 follicular, 0/10 anaplastic and 10/10 medullary carcinomas were positive for CEA. Nine out of ten papillary, 7/10 follicular, 2/10 anaplastic and 3/10 medullary carcinomas were positive for EMA. Ten out of 10 papillary, 10/10 follicular, 5/10 anaplastic and 10/10 medullary carcinomas were positive for cytokeratin. The presence of calcitonin and CEA is of value in the diagnosis of medullary carcinoma, and enable its distinction from anaplastic thyroid carcinoma. Thyroglobulin is a useful marker in thyroid carcinomas.

Journal ArticleDOI
TL;DR: The mainstay of treatment is the reduction of edema by regular elevation and massage and external compression with elastic stockings, and Pneumatic leggings are also helpful.

Journal ArticleDOI
TL;DR: A significant depletion of the neuropeptides was found in the region of the wound within two days, and this persisted for two weeks, and a smaller and delayed depletion also occurred in intact skin of the same dermatome, but not in an adjacent dermatome.

Book ChapterDOI
TL;DR: This chapter discusses the neuronal mechanisms that operate in the normal filling and emptying phases of the bladder function, and it is clear that even apparently simple reflexes do not represent simple central circuity.
Abstract: Publisher Summary This chapter discusses the neuronal mechanisms that operate in the normal filling and emptying phases of the bladder function. The experimental evidence derives mostly from animal studies, but there are no reasons to believe that human bladder reflexes have a fundamentally different organization. The study of an autonomic or vegetative event, such as micturition, has shown that it is inappropriate to consider these functions as “simple” reflexes. In the periphery, a high level of co-ordinated activity between the different structures is necessary for the successful operation of this system. It is clear that even apparently simple reflexes, such as the pelvic nerve efferent firing that is seen on the pelvic afferent stimulation, do not represent simple central circuity.

Journal ArticleDOI
TL;DR: A 21-year-old woman with systemic lupus erythematosus and high titers of antiphospholpid antibodies who developed chorea soon after she began oral contraceptive (OC) use is described.
Abstract: The authors describe a case of a 21-year-old woman with systemic lupus erythematosus and high titers of antiphospholpid antibodies who developed chorea soon after she began oral contraceptive (OC) use. Chorea is an infrequently documented central nervous system complication of OC use. Systemic lupus erythematosus had been diagnosed in 1980 and the patient was treated with high doses of prednisone. In 1984 the patient complained of fidgeting of her left hand; she related this to the commencement of OC use (Binovum) 3 months previously. The chorea markedly improved following discontinuation of OC use. The occurrence of chorea in OC users has been reported with increasing frequency since 1966 when the first such case was described. Chorea commonly occurs in patients who have had previous episodes of chorea either in association with streptococcal infection or pregnancy and tends to emerge 1-4 months after the start of OC use. Both high and low-dose OCs have produced chorea; however it has been suggested that estrogens alone are the causative agent. Although antithrombin III levels are lowered in most OC users this has not been the pattern among lupus patients. The patient in this case had high levels of anticardiolipin antibodies for several years before taking OCs. Such high levels in patients with systemic lupus erythematosus may represent an additional risk factor for the development of thrombotic complications in OC users.

Journal ArticleDOI
TL;DR: The postoperative care of 143 cardiac surgical patients has been successfully conducted in a general surgical recovery ward and the intra‐operative anaesthetic management was considered to have played an important part in this technique.
Abstract: Summary The postoperative care of 143 cardiac surgical patients has been successfully conducted in a general surgical recovery ward. Admission was limited to overnight stay only and all but two patients were returned to the general ward the following day. There were no deaths. The intra-operative anaesthetic management was considered to have played an important part in the success of this technique.

Journal ArticleDOI
TL;DR: It is suggested that morbidity and socioeconomic factors are not the only determinants of mortality variation among areas for these particular diseases, although regional diagnostic and reporting differences and variation in disease severity among areas must also be considered.
Abstract: This study is concerned with variations in mortality from diseases amenable to medical intervention in England and Wales. The focus is on the extent to which these variations can be used to evaluate the quality of medical care provided by the National Health Service. The data concern 98 Area Health Authorities and are for the period 1974-1978. The results suggest that differences in morbidity and socioeconomic factors are not the only determinants of mortality and that variations in the quality of health care may also be relevant factors. (ANNOTATION)

Journal ArticleDOI
06 Sep 1986-BMJ
TL;DR: Clinicians should consider the possibility of nocturnal hypoxia in patients with unexplained polycythaemia, and establish whether they had an intermittent hypoxic stimulus to erythropoiesis that was undetected by conventional investigations for hypoxic secondary polycytaemia.
Abstract: The aetiology of polycythaemia is unclear in up to 30% of patients. Twenty patients with unexplained polycythaemia were investigated to see whether they had an intermittent hypoxic stimulus to erythropoiesis that was undetected by conventional investigations for hypoxic secondary polycythaemia. Overnight polygraphic sleep studies showed that five patients had prolonged nocturnal hypoxaemia. Their arterial oxygen saturation was below 92%, the level at which appreciable hypoxic stimulation of erythropoiesis occurs, for 26-68% of the time for which they were studied. Considerable evidence is accumulating that intermittent hypoxia is a potent stimulus to erythropoiesis, and clinicians should consider the possibility of nocturnal hypoxia in patients with unexplained polycythaemia. Appropriate investigation will lead to the correct diagnosis of polycythaemia secondary to hypoxia in some cases previously regarded as idiopathic, and treatment may then be planned accordingly.

Journal ArticleDOI
TL;DR: Observations indicate that development of antisperm antibodies can be stimulated in some individuals by NGU, indicating probable immunization against sperm antigens at the time of infection.

Journal ArticleDOI
TL;DR: The anatomical basis of resistance and compliance changes of the pulmonary arterial bed was studied in rats exposed to chronic hypoxia and the findings were compared with those of normoxic rats, finding evidence that arterial length was increased in chronically hypoxic rats and no evidence of arteriolar loss.
Abstract: The anatomical basis of resistance and compliance changes of the pulmonary arterial bed was studied in rats exposed to chronic hypoxia (10% O2, 3 weeks) and the findings were compared with those of normoxic rats. The lungs were perfused with a Ba-gelatine mixture at different pressures and studied by radiology and histology. The diameter of the pulmonary arteries (greater than 0.5 mm), measured from X-rays, was less in chronically hypoxic than normoxic rats when filled at the same perfusion pressure. Diameters increased in both groups with increasing perfusion pressure but at a given pressure those of chronically hypoxic rats were always smaller than those of normoxic rats. We found evidence that arterial length was increased in chronically hypoxic rats. Arterioles of 50 micron or less in diameter adjacent to gas exchange units were of similar external diameter in normoxic and chronically hypoxic rats, but most of the latter had developed a muscular coat and a second elastic lamina internal to the single elastic lamina of control arterioles. These changes reduced the lumen by an estimated 10-14% and would increase pulmonary arteriolar resistance in chronically hypoxic rats, resulting in a changed pressure profile. We found no evidence of arteriolar loss in chronically hypoxic rats although at a given pressure, the Ba-gelatine mixture penetrated less far for reasons which are discussed.

Journal ArticleDOI
TL;DR: Coeliac disease patients tended to have raised IgG antibody levels (especially IgG1) to all three antigens but these overlapped considerably with that seen in egg allergic and atopic dermatitis patients, suggesting that some of the symptoms of food allergy may be caused by IgG antibodies to food proteins.
Abstract: Previous studies have suggested that, apart from IgE-mediated reactions, some of the symptoms of food allergy may be caused by IgG antibodies to food proteins. This study was carried out to see if there were any distinctive features of the IgG sub-class antibody response to dietary antigens which occurs in food allergic patients. IgG sub-class antibodies were measured using a quantitative enzyme-linked immuno-sorbent assay (ELISA) to wheat gliadin, ovalbumin and bovine casein in twenty patients who had coeliac disease and in twenty-eight egg allergic patients. These were compared with twenty-one atopic dermatitis patients who did not have food allergy and twenty-six healthy control subjects. Coeliac disease patients tended to have raised IgG antibody levels (especially IgG1) to all three antigens but these overlapped considerably with that seen in egg allergic and atopic dermatitis patients. Coeliacs who avoided gluten had anti-gliadin antibody levels which did not differ from those seen in healthy subjects but nevertheless had raised anti-ovalbumin and casein-specific antibodies. The IgG antibody was largely restricted to IgG1 and IgG4 sub-class although the relative amount of each varied with the antigen. Although gliadin-specific antibodies were mainly IgG1, ovalbumin-specific antibodies were mainly IgG4. The increased antibody levels to all three antigens in coeliacs were caused by a raised IgG1 response, IgG4 antibodies were usually normal. Egg allergic patients also had raised IgG1 but not IgG4 antibodies to ovalbumin. These data show that the response to different dietary antigens can vary with the antigen. The fact that IgG1 and not IgG4 antibodies were raised to all three antigens in patients with coeliac disease suggests that they are a secondary consequence of the disease, perhaps reflecting increased transport of antigens across a damaged gut mucosa rather than a specific immunopathological reaction. However, the observation that antibodies to gliadin, and not ovalbumin or casein, fell following gluten avoidance shows that the response to gliadin, at least, is dependent upon continued exposure to antigen.