Comparison of subconjunctival TRIamcinolone acetonide injection and intravitreal dexamethasone (OZurdex) injection for uveitic and postoperative macular oedema: the TRIOZ study.

AIMS: To compare effectiveness of subconjunctival triamcinolone acetonide injections and intravitreal injections of dexamethasone 700 µg implants in reducing central macular thickness (CMT) in uveitic and postoperative macular oedema (ME). METHODS: We conducted an open-label, French multicentre randomised comparative trial with a logarithmic CMT non-inferiority margin set at 0.06. Patients were adults with non-infectious inflammatory ME, without any contraindication to the treatments. They were randomised 1:1 to receive either triamcinolone or dexamethasone. The primary endpoint was the difference in CMT among treated eyes between baseline and 2 months, measured with spectral-domain optical coherence tomography. Secondary outcomes included visual acuity, laser flare, vitreous haze, duration of action, tolerance to injections and adverse events. RESULTS: Between January 2016 and January 2020, 106 patients were enrolled (54 in the triamcinolone group and 52 in the dexamethasone group). Subconjunctival triamcinolone injections seemed to be non-inferior to intravitreal dexamethasone injections, especially at month 3 (and nearly at month 1). Nevertheless, we could not demonstrate it, with a treatment effect at month 2 of 0.05 (0.01 ; 0.09) (p value=0.001). This was corroborated by post hoc analyses in the postoperative subgroup, for whom the non-inferiority was nearly demonstrated at month 2 with a treatment effect of 0.02 (-0.03 ; 0.08) (p=0.37). There was no significant difference in the occurrence of adverse effects. CONCLUSION: We could not demonstrate the non-inferiority of triamcinolone injections at month 2. Nevertheless, they showed some efficacity, particularly in treating postoperative ME, being as safe as dexamethasone injections, without any loss of chance if a therapeutic switch is necessary.

Ocular Manifestations in Patients with Inflammatory Bowel Disease in the Biologics Era.

Background: Extra-intestinal manifestations are frequent in inflammatory bowel disease (IBD). Ocular disorders are generally under diagnosed as they are challenging diagnosis. Aims: We assessed the prevalence of ophthalmological manifestations in patients with IBD, and investigated characteristics associated with ocular manifestations. Methods: We performed a retrospective study including patients followed for IBD and had an ophthalmologic visit from January 2013 to July 2020, among 1432 patients followed during this period. Two groups were considered: the first group included patients whose an ocular diagnosis was considered as "related to IBD", and the second group including patients whose an ocular diagnosis was considered "not related to IBD". Results: Among 1432 patients with IBD, eighty-seven (6.1%) patients had an ophthalmologic visit. Fifty-three patients (3.7%) were considered to have an ocular extra-intestinal manifestation or an iatrogenic effect of IBD treatment, and 34 diagnoses (2.4%) were considered not related to IBD. Inflammatory surface pathologies were the most frequent (33.2%), including 15 patients with dry eye (17.2%), 9 with blepharitis (10.3%), and 5 with chalazions (meibomian cyst) (5.7%). Uveitis was diagnosed in 13 patients (14.9%), episcleritis in 5 patients (5.7%), and scleritis in 2 patients (2.3%). Characteristics of patients with an ophthalmological diagnosis "related to IBD" versus "not related to IBD" were not statistically different. Conclusion: In our cohort, less than 5% of patients had ophthalmological extra-intestinal manifestation. The most frequent ocular diagnosis were dry eye and uveitis. No disease characteristics of IBD were found to be associated with ocular manifestations.

Assessment of extraintestinal manifestations in inflammatory bowel diseases: A systematic review and a proposed guide for clinical trials.

BACKGROUND AND AIMS: Extraintestinal manifestations are common in inflammatory bowel disease patients, although there are few data available on their diagnosis, management and follow-up. We systematically reviewed the literature evidence to evaluate tools and investigations used for the diagnosis and for the assessment of the treatment response in inflammatory bowel disease patients with extraintestinal manifestations. METHODS: We searched in PubMed, Embase and Web of Science from January 1999-December 2019 for all interventional and non-interventional studies published in English assessing diagnostic tools and investigations used in inflammatory bowel disease patients with extraintestinal manifestations. RESULTS: Forty-five studies (16 interventional and 29 non-interventional) were included in our systematic review, enrolling 7994 inflammatory bowel disease patients. The diagnostic assessment of extraintestinal manifestations was performed by dedicated specialists in a percentage of cases ranging from 60-100% depending on the specific condition. The clinical examination was the most frequent diagnostic strategy, accounting for 35 studies (77.8%). In patients with primary sclerosing cholangitis or rheumatological symptoms, biochemical and imaging tests were also performed. Anti-TNF agents were the most used biological drugs for the treatment of extraintestinal manifestations (20 studies, 44.4%), and the treatment response varied from 59.1% in axial spondyloarthritis to 88.9% in ocular manifestations. No benefit was detected in primary sclerosing cholangitis patients after treatment with biologics. CONCLUSIONS: In the clinical management of inflammatory bowel disease patients with extraintestinal manifestations the collaboration of dedicated specialists for diagnostic investigations and follow-up is key to ensure the best of care approach. However, international guidelines are needed to homogenise and standardise the assessment of extraintestinal manifestations.

Prevalence and risk factors for outer retinal layer damage after macula-off retinal detachment.

PURPOSE: To report the prevalence of outer retinal layer (ORL) damage after macula-off rhegmatogenous retinal detachment (RRD) surgery and to determine its associated preoperative risk factors. METHODS: 253 eyes successfully operated for macula-off RRD were included in the study. The integrity of the external limiting membrane (ELM), ellipsoid zone (EZ) and cone interdigitation zone (CIZ) of the photoreceptors was assessed at 1 month and 6 months using spectral-domain optical coherence tomography. Risk factors were analysed using univariate and multivariate logistic regression. The correlation between ORL integrity and visual outcomes was also evaluated. RESULTS: CIZ, EZ and ELM defects were found in, respectively, 198 (93.4%) eyes, 100 (47.2%) eyes, 64 (30.2%) eyes at 1 month and in 160 (63.2%) eyes, 44 (17.4%) eyes and 18 (7.1%) eyes at 6 months. In multivariate analysis, duration of macular detachment was the only factor associated with ORL damage at 6 months (p=0.007). Best-corrected visual acuity significantly improved from 0.5±0.3 at 1 month to 0.3±0.3 logarithm of minimal angle of resolution at 6 months (p<0.001) and was strongly correlated with the number of affected bands (p<0.001). CONCLUSION: Prevalence of outer retinal band defects substantially decreased through the study period, confirming the ability of photoreceptors to recover over time. However, shorter interval to surgery and better visual outcomes were significantly associated with fewer defects within the ORL at 6 months. These findings suggest that earlier surgery may limit RRD-associated photoreceptor degeneration and improve the patient's visual prognosis.

EYESI surgical simulator: validity evidence of the vitreoretinal modules.

PURPOSE: To investigate the validity of six vitreoretinal modules on the Eyesi Surgical Simulator. METHODS: Fifteen residents with no vitreoretinal experience and six trained vitreoretinal surgeons (>100 procedures per year) were included in the study. Four modules were selected in agreement with an experienced surgeon: the navigation (Nav), forceps (For), vitrector (Vit) and epiretinal membrane (ERM) peeling modules. The first level of the basic training modules (Nav1 and For1) and the first two levels of the more procedural modules (Vit1, Vit2, ERM1 and ERM2) were completed twice by both groups in the above order. The performance parameters for each task were calculated by the simulator software. The results from both iterations were recorded for analysis. RESULTS: Experienced vitreoretinal surgeons outperformed residents with regard to the overall score on the Nav1 (p = 0.01), For1 (p < 0.01), ERM1 (p = 0.02) and ERM2 (p = 0.04) modules. No differences in overall score were found between the two groups on the Vit1 (p = 0.17) and Vit2 modules (p = 0.26). CONCLUSION: Validity for the simulator metrics was found on four vitreoretinal modules not previously investigated, with regard to construct validity, content and the response process. These exercises could be included in a future competency-based training programme that could potentially be applied in the standard ophthalmological curriculum.

Keratoconus in Inflammatory Bowel Disease Patients: A Cross-sectional Study.

BACKGROUND AND AIMS: Increasing evidence suggests that keratoconus may have an inflammatory component. The possible association of keratoconus with inflammatory bowel disease (IBD) has yet to be determined. The aim of this study was to determine the prevalence of keratoconus and suspect keratoconus in patients with IBD. METHODS: All consecutive adult IBD patients seen in the Department of Gastroenterology, Nancy, University Hospital, France, between March 2014 and June 2014 were included. Pregnant women, rigid lens wearers, patients with a family history of keratoconus and patients with a history of refractive surgery were excluded. A control group of healthy subjects was included. All included patients underwent a corneal topography (OPD-Scan III, Nidek) to detect keratoconus or suspect keratoconus. Rabinowitz videokeratographic indices were the basis of corneal topography interpretation. RESULTS: Two hundred and one IBD patients were included, 150 with Crohn's disease and 51 with ulcerative colitis. Mean age was 38.7 years and 121 were women. Mean disease duration was 10.8 years. Two IBD patients were diagnosed with keratoconus (1%) and 38 with suspect keratoconus (18.9%). Overall prevalence of keratoconus and suspect keratoconus was 19.9% (95% confidence interval [CI] 17.5-22.0). None of the 100 healthy subjects had keratoconus, while three were diagnosed with suspect keratoconus (p = 0.0002 versus IBD patients). Only smoking was identified as a risk factor (p = 0.029), especially in Crohn's disease. CONCLUSION: Inflammatory bowel disease patients may carry an increased risk of keratoconus and suspect keratoconus, smoking further increasing this risk. This supports the hypothesis of an inflammatory origin of keratoconus.

Ocular Manifestations of X-linked Chronic Granulomatous Disease: About Two Atypical Case Reports.

PURPOSE: Two atypical cases of ocular localizations of chronic granulomatous disease are reported. METHODS: The first case is about a 22-year-old woman carrier of the disease who developed active intraocular inflammation and choroidal granulomas successfully treated by steroids. The second is about a 2-year-old boy consulting for unilateral anterior uveitis and subsequent anterior chamber granuloma development as first signs of the disease. RESULTS: X-linked chronic granulomatous disease is a rare inherited primary immunodeficiency syndrome characterized by disorders of phagocytic cells resulting in recurrent infections and development of granulomas. Ophthalmological manifestations are not rare and are mainly represented by surface and intraocular inflammation with possible choroidal granulomas. The two cases reported here are atypical, one of active inflammation in a carrier and the other revealing the disease. CONCLUSION: Ophthalmologists must be aware of chronic granulomatous disease and the possible ocular involvement of this disorder.

A case of nicorandil-induced unilateral corneal ulceration.

Nicorandil, a second-generation nitro derivative, has been reported to induce single or multiple ulcerations in many locations, including oral, anal, perianal, vulvovaginal, perivulval, penile, gastrointestinal, colic, peristomal and skin locations. Ocular locations are now highly suspected. Herein, we report the case of a 78-year-old woman who experienced corneal ulceration at second cataract surgery (right eye) while being treated with nicorandil for 3 years. Four years before, she had had an uneventful first cataract surgery (left eye). The ulcers healed within 6 weeks after simple withdrawal of nicorandil, an expected delay for this type of chemical ulcer. The substitution of nicorandil with classic nitric oxide donors has already been done without complication. Surgical intervention is unnecessary and inappropriate. Case reports of ocular side effects induced by nicorandil are rare and probably underestimated.

Ocular symptoms are not predictive of ophthalmologic inflammation in inflammatory bowel disease.

BACKGROUND: Ocular manifestations are frequent in patients with inflammatory bowel disease. AIM: To evaluate for the first time the value of ocular symptoms in predicting ophthalmologic inflammation in inflammatory bowel disease. METHODS: All consecutive inflammatory bowel disease patients seen in the Department of Gastroenterology (Nancy, University Hospital, France) between April 2009 and July 2011 were interviewed for this cross-sectional study using a pre-established questionnaire. If the patient had at least one ocular symptom, he systematically underwent an ophthalmologic examination (visual acuity, Break-Up Time test, Schirmer Test, slit-lamp exam with fundus examination). RESULTS: This cross-sectional survey was completed by 305 patients: 169 were women (55.2%), 228 had Crohn's disease (74.5%). Ninety-eight patients (32%) reported at least one ocular symptom: ocular irritation (56.8%), red eye (40.5%), blurred vision (37.8%), progressive visual loss (34.4%), ocular pain (31.1%), myodesopsia (23.3%), eyelid secretion (12.2%), dry eye (9.5%), watering (6.8%), diplopia (5.4%), metamorphopsia (4%), and sudden visual loss (4%). Following ophthalmologic examination (n=74), 41.9% patients had evidence of dry eye (n=31), 14.9% blepharitis (n=11) and 1.4% scleritis (n=1). No uveitis was reported. CONCLUSION: Ocular symptoms are frequent in inflammatory bowel disease, but are non-specific and rarely associated with ocular inflammation. Systematic ocular symptoms assessment is of poor value for diagnosing ocular inflammation in inflammatory bowel disease.

Sentinel lymph node biopsy in patients with conjunctival and eyelid cancers: experience in 17 patients.

PURPOSE: To assess lymph node invasion through the use of sentinel lymph node biopsy (SLNB) in conjunctival and eyelid tumor patients and ascertain the impact of this technique in therapeutic management recommended by the multidisciplinary consensus committee. METHODS: A single center prospective nonrandomized clinical study was conducted between January 2008 and January 2010. Seventeen patients were included: 4 (2 conjunctiva and 2 eyelid) melanomas, 4 eyelid Merkel cell tumors, 8 (2 conjunctiva, 2 eyelid, 2 eyelid and conjunctiva, 2 cornea and conjunctiva) squamous cell tumors, and 1 eyelid meibomian carcinoma. Preoperative lymphoscintigraphy was done the day before surgery to label lymph node(s). The surgical biopsy was then performed along with an extemporaneous pathological examination followed by secondary complete lymph node dissection only in instances of positive histology. RESULTS: In all cases, one or more sentinel lymph nodes were identified (3-13). Two biopsies (1 Merkel cell carcinoma and 1 squamous cell carcinoma) revealed neoplastic invasion and led to complete cervical node dissection. Adjunct regional treatment was indicated for 1 melanoma, for 4 Merkel cell tumors, and for 2 squamous cell carcinomas. One false negative result was noted in the group of squamous cell carcinomas after 6 months, and it was treated. No relapse or death was observed for the other 16 patients. The mean overall follow-up was 18.2 months. CONCLUSION: As in previous studies, we found that SLNB for eyelid and conjunctival tumors is safe and effective in identifying microscopically positive SLNs. This procedure may also revive interest in the study of cervicofacial lymphatic drainage. Our current investigation is to be expanded and extended to other medical teams.

Dacryoadenitis associated with subcutaneous Sweet's syndrome in a patient with acute myeloid leukemia.

A 26-year-old woman presented with a painful skin eruption which led to the diagnosis of acute myeloid leukemia. During chemotherapy, she developed an unusual orbital inflammation. Careful observation of the clinical course, computed tomography, and orbital biopsy were necessary to establish the diagnosis of dacryoadenitis associated with subcutaneous Sweet's syndrome. The skin eruption and the dacryoadenitis resolved rapidly with corticosteroid therapy. This is the first report of dacryoadenitis in the course of subcutaneous Sweet's syndrome.

Mass community screening for diabetic retinopathy using a nonmydriatic camera with telemedicine.

BACKGROUND: Diabetic retinopathy is a leading cause of blindness. Studies have shown the value of screening and early, timely treatment. Our aim was to measure the effectiveness and degree of acceptance of community screening for diabetic retinopathy using telemedicine. METHODS: In this prospective, population-based cross-sectional study, diabetics recruited through a regional multimedia campaign were surveyed and screened for retinopathy using a nonmydriatic camera and evaluated through telemedical imaging. RESULTS: Of the 291 diabetics recruited over a 3-week period (37% by the regional diabetes association and 30% by the media), 49.4% reported having their most recent eye examination within 1 year, 30.7% between 1 to 2 years, 9.7% over 2 years, and 10.1% had never had an exam. 98.6% found our screening method acceptable, with 95.1% wanting to return for their next screening and 91.2% stating it would increase their compliance to annual screening. INTERPRETATION: Telemedicine provided a reliable and highly acceptable method for diabetic retinopathy screening. It can attract a significant number of people with diabetes and potentially recruit patients who would otherwise be missed by the current methods of vision screening.

Ocular tissue interactions during the development of human fetal neuroretina grafted into nude mice.

To determine the roles of different ocular tissues in the development of the human fetal neuroretina, a study ethically and technically impossible in human subjects, human embryonic and fetal retinas were heterotopically implanted into nude mice. Ninety-five eyeballs were obtained from legally aborted 6- to 7-week-old embryos or 8- to 10-week-old fetuses. Ten isolated neuroretinas with vitreous but without pigment epithelium, 20 half-eyeballs and 70 intact eyeballs, of which 12 had a thick layer of periocular tissue, were microsurgically grafted. Five intact eyeballs were used for reference. Over a period of 1-245 days, all of the grafts were removed for light and electron microscopy observations. All of the isolated neuroretinas had disappeared by the second day after transplantation. Grafts of the posterior section of the eyeball contained only some clusters of pigment epithelium, occasionally covered with undifferentiated neuroretinal cells. Grafts of the retrolental section of the eyeball contained small areas of dysplasic neuroretina with folds and rosettes. Grafts of the 70 intact eyeballs were successful, but only 26 showed normal histological organization of the choriocapillaris, the retinal pigment epithelium and the neuroretina in the posterior part of the posterior chamber. Photoreceptor differentiation was evident in these retinas after approximately 80 days of transplantation and was complete after 166 days. Their anterior part was always dysplasic, with occasional ciliary differentiation. Twenty-three grafted eyeballs had a dysplasic neuroretina with folds, rosettes and necrotized areas. Twenty-one were atrophic, 12 of which were the eyeballs grafted with periocular tissue. These results demonstrate the role of the fetal mesenchyme and pigment epithelium in the rapid revascularization, and subsequent survival and tissue organization, of the neuroretina. The stratified development of the neuroretina required a thin mesenchymal environment for revascularization of the graft by human vasculogenesis or neoangiogenesis and a normal retinal pigment epithelium for normal neuroretinal differentiation. When these conditions were not satisfied, the neuroretina disappeared or was dysplasic, partly necrotized or atrophic. This model might prove useful for a number of therapeutic or clinical studies.

Effectiveness and safety of screening for diabetic retinopathy with two nonmydriatic digital images compared with the seven standard stereoscopic photographic fields.

BACKGROUND: The use of nonmydriatic cameras, which offer ease of screening and 45 degrees immediate imaging of the fundus, is gaining increasing acceptance for screening programs tailored to diverse conditions. We performed a study to evaluate the effectiveness and safety of screening for diabetic retinopathy with two nonmydriatic camera images compared with the seven standard stereoscopic 30 degrees fields (7SF). We also wished to determine whether safe screening guidelines could be established to identify patients needing referral to an ophthalmologist. METHODS: In this prospective masked cross-sectional study, we evaluated agreement in the assessment of the severity of diabetic retinopathy by means of two 45 degrees images centred on the optic disc and on the macula obtained with the Topcon CRW6 nonmydriatic camera and by means of 7SF photography and ophthalmologic slit-lamp biomicroscopy, both performed with pupil dilation. Between November 2000 and June 2001, 98 adult patients known to have type 1 or 2 diabetes mellitus who presented for the first time to the diabetic retinopathy clinic of a tertiary care centre in Montreal were enrolled consecutively. Thus, patient recruitment was weighted toward more severe retinopathy to ensure sufficient representation of less frequent but more severe levels. Each patient underwent nonmydriatic fundus photography of both eyes, followed by a complete ophthalmologic examination with pupil dilation by a single retina specialist and 7SF photography of both eyes with pupil dilation. The level of retinopathy was graded independently in each eye from the 7SF photographs according to the Early Treatment Diabetic Retinopathy Study (ETDRS) scale by two graders; an independent retina specialist adjudicated the rare instances of interreader disagreement in a masked fashion. Two months later, two graders independently graded the nonmydriatic images in a blinded fashion according to the ETDRS scale; a third observer adjudicated the rare instances of interreader disagreement. We measured concordance between grading results with the various screening techniques using the weighted and unweighted kappa statistic. We used sensitivity and specificity indices to determine safe screening guidelines to identify patients needing referral to an ophthalmologist. RESULTS: There was substantial agreement in the grading of retinopathy with nonmydriatic camera imaging and with 7SF photography, both for all eyes (kappa = 0.626 [standard deviation (SD) 0.045]) and for the eye with more severe disease (kappa = 0.654 [SD 0.063]). With nonmydriatic camera imaging, screening thresholds for patient referral to an ophthalmologist of very mild retinopathy (ETDRS grade 20), mild retinopathy (ETDRS grade 35) and moderate retinopathy (EDTRS grade 43) had sensitivity values of 97.9%, 97.1% and 53.3% respectively and specificity values of 81.3%, 95.5% and 96.9% respectively. Screening thresholds of very mild or mild retinopathy both correctly identified 100% of eyes with severe nonproliferative or proliferative retinopathy. With a screening threshold of mild retinopathy, screening with the nonmydriatic camera would lead to referral to an ophthalmologist of 37.8% of patients because of detected disease and of an additional 17.3% because of insufficient image quality in at least one eye, for a total of 55.1%. The overall sensitivity and specificity of a two-field nonmydriatic screening strategy with a threshold of mild retinopathy for referral of patients with insufficient image quality in at least one eye are 97.7% and 84.0% respectively. INTERPRETATION: Our results suggest that two-field nonmydriatic camera imaging is a safe screening strategy that may identify the patients with diabetes most in need of ophthalmologic care.

Comparison of two, three and four 45 degrees image fields obtained with the Topcon CRW6 nonmydriatic camera for screening for diabetic retinopathy.

BACKGROUND: The use of the nonmydriatic camera is gaining increasing acceptance for the detection of diabetic retinopathy when integrated into a community-tailored program. We performed a study to evaluate the optimal number and positioning of photographic fields necessary to screen for diabetic retinopathy with the Topcon CRW6 nonmydriatic camera. METHODS: In this prospective masked cross-sectional comparative study, we compared the assessment of diabetic retinopathy using two, three or four 45 degrees fundus images (centred respectively on the disc and the macula; on the disc, on the macula and temporal to the macula; and on the disc, on the macula, temporal to the macula and superotemporal to the macula, including the superior temporal vein) acquired with the Topcon CRW6 nonmydriatic camera, with the grading of the seven standard stereoscopic 30 degrees field photographs (7SF). The study population consisted of 98 consecutive adult patients known to have type 1 or 2 diabetes mellitus who presented for the first time to the diabetic retinopathy clinic of a tertiary care centre in Montreal. All patients underwent four nonmydriatic fundus photography sessions of both eyes, 7SF photography with pupil dilation and a complete ophthalmologic examination with pupil dilation by a retina specialist. RESULTS: Compared to the 7SF, the sensitivity and specificity of screening for any retinopathy (Early Treatment Diabetic Retinopathy Study [ETDRS] grade greater than 10) using the two central fields were 95.7% and 78.1% respectively. The corresponding values with three image fields were 97.6% and 71.9%, and with four image fields, 97.6% and 65.6%. The sensitivity and specificity of screening for mild or worse disease (ETDRS grade 35 or greater) using the two central fields were 87.5% and 92.3%. The corresponding values with three image fields were 88.9% and 94.6%, and with four image fields, 88.9% and 91.9%. Poor image quality occurring with the addition of extra fields resulted in an increase of 6.2% in the rate of referral to an ophthalmologist. The use of two image fields missed no cases of retinopathy. INTERPRETATION: The use of image fields in addition to the two 45 degrees images centred on the disc and the macula on imaging with the Topcon CRW6 nonmydriatic camera did not significantly increase the sensitivity or specificity of screening for diabetic retinopathy. Contrary to the desired effect, the addition of fields resulted in diminished utility and cost-effectiveness of this screening approach.

Xenografted human whole embryonic and fetal entoblastic organs develop and become functional adult-like micro-organs.

BACKGROUND AND AIMS: The aim of this study was to study the morphological and functional development in vivo of whole human embryonic and fetal stomachs, intestines, tracheas, and lungs, which would otherwise be ethically and technically impossible to perform in utero, by microsurgically grafting these organs into nude mice. MATERIALS AND METHODS: Five hundred fifty-seven human organs obtained from legally aborted embryos and fetuses of 6-10 weeks were microsurgically grafted into nude mice for 1 to 273 days. Following different grafting times, biopsies were taken for optical and electron microscopy, in situ hybridization, and cellular kinetics studies. A catheter was introduced into the human organs in order to collect and analyze secretions. RESULTS: All of the grafts took successfully. Macroscopic growth was fast during the first 6 to 10 weeks, following which organ size was stable. In situ hybridization studies detected only a minute level of mouse mesenchymal chimerism in the grafts. The different epithelial cells differentiated, became of adult type, and remained normal during the remainder of the grafting periods. The pH of gastric juice from stomachs grafted for 10 to over 90 days dropped from 8.0 +/- 0.1 to 1.58 +/- 0.29 over this time period (P < 0.001), intrinsic factor levels were stable, and pepsin ranged from 6.8 +/- 7.8 to 134 +/- 51 units (P < 0.001). CONCLUSIONS: These results demonstrate that the development of entoblastic organs from human embryos and fetuses microsurgically grafted into nude mice is similar to that occurring in utero. As such, this method provides a model for the analysis of whole human organs in development and later normal adult-like micro-organs for physiological, therapeutic, and pathological studies.