Complex gastroschisis: a new indication for fetal surgery?

Gastroschisis (GS) is a congenital abdominal wall defect, in which the bowel eviscerates from the abdominal cavity. It is a non-lethal isolated anomaly and its pathogenesis is hypothesized to occur as a result of two hits: primary rupture of the 'physiological' umbilical hernia (congenital anomaly) followed by progressive damage of the eviscerated bowel (secondary injury). The second hit is thought to be caused by a combination of mesenteric ischemia from constriction in the abdominal wall defect and prolonged amniotic fluid exposure with resultant inflammatory damage, which eventually leads to bowel dysfunction and complications. GS can be classified as either simple or complex, with the latter being complicated by a combination of intestinal atresia, stenosis, perforation, volvulus and/or necrosis. Complex GS requires multiple neonatal surgeries and is associated with significantly greater postnatal morbidity and mortality than is simple GS. The intrauterine reduction of the eviscerated bowel before irreversible damage occurs and subsequent defect closure may diminish or potentially prevent the bowel damage and other fetal and neonatal complications associated with this condition. Serial prenatal amnioexchange has been studied in cases with GS as a potential intervention but never adopted because of its unproven benefit in terms of survival and bowel and lung function. We believe that recent advances in prenatal diagnosis and fetoscopic surgery justify reconsideration of the antenatal management of complex GS under the rubric of the criteria for fetal surgery established by the International Fetal Medicine and Surgery Society (IFMSS). Herein, we discuss how conditions for fetoscopic repair of complex GS might be favorable according to the IFMSS criteria, including an established natural history, an accurate prenatal diagnosis, absence of fully effective perinatal treatment due to prolonged need for neonatal intensive care, experimental evidence for fetoscopic repair and maternal and fetal safety of fetoscopy in expert fetal centers. Finally, we propose a research agenda that will help overcome barriers to progress and provide a pathway toward clinical implementation. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Safety and efficacy of smart tracheal occlusion device in diaphragmatic hernia lamb model.

OBJECTIVE: To investigate the efficacy and safety of the 'smart' tracheal occlusion (Smart-TO) device in fetal lambs with diaphragmatic hernia (DH). METHODS: DH was created in fetal lambs on gestational day 70 (term, 145 days). Fetuses were allocated to either pregnancy continuation until term (DH group) or fetoscopic endoluminal tracheal occlusion (TO), performed using the Smart-TO balloon on gestational day 97 (DH + TO group). On gestational day 116, the presence of the balloon was confirmed on ultrasound, then the ewe was walked around a 3.0-Tesla magnetic resonance scanner for balloon deflation, which was confirmed by ultrasound immediately afterwards. At term, euthanasia was performed and the fetus retrieved. Efficacy of occlusion was assessed by the lung-to-body-weight ratio (LBWR) and lung morphometry. Safety parameters included tracheal side effects assessed by morphometry and balloon location after deflation. The unoccluded DH lambs served as a comparator. RESULTS: Six fetuses were included in the DH group and seven in the DH + TO group. All balloons deflated successfully and were expelled spontaneously from the airways. In the DH + TO group, in comparison to controls, the LBWR at birth was significantly higher (1.90 (interquartile range (IQR), 1.43-2.55) vs 1.07 (IQR, 0.93-1.46); P = 0.005), while on lung morphometry, the alveolar size was significantly increased (mean linear intercept, 47.5 (IQR, 45.6-48.1) vs 41.9 (IQR, 38.8-46.1) µm; P = 0.03); whereas airway complexity was lower (mean terminal bronchiolar density, 1.56 (IQR, 1.0-1.81) vs 2.23 (IQR, 2.14-2.40) br/mm2 ; P = 0.005). Tracheal changes on histology were minimal in both groups, but more noticeable in fetal lambs that underwent TO than in unoccluded lambs (tracheal score, 2 (IQR, 1-3) vs 0 (0-1); P = 0.03). CONCLUSIONS: In fetal lambs with DH, TO using the Smart-TO balloon is effective and safe. Occlusion can be reversed non-invasively and the deflated intact balloon expelled spontaneously from the fetal upper airways. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

New device permitting non-invasive reversal of fetal endoscopic tracheal occlusion: ex-vivo and in-vivo study.

OBJECTIVE: One of the drawbacks of fetal endoscopic tracheal occlusion (FETO) for congenital diaphragmatic hernia is the need for a second invasive intervention to re-establish airway patency. The 'Smart-TO' device is a new balloon for FETO that deflates spontaneously when placed in a strong magnetic field, therefore overcoming the need for a second procedure. The safety and efficacy of this device have not yet been demonstrated. The aim of this study was to investigate the reversibility, local side effects and occlusiveness of the Smart-TO balloon, both in a simulated in-utero environment and in the fetal lamb model. METHODS: First, the reversibility of tracheal occlusion by the Smart-TO balloon was tested in a high-fidelity simulator. Following videoscopic tracheoscopic balloon insertion, the fetal mannequin was placed within a 1-L water-filled balloon to mimic the amniotic cavity. This was held by an operator in front of their abdomen, and different fetal and maternal positions were simulated to mimic the most common clinical scenarios. Following exposure to the magnetic field generated by a 1.5-T magnetic resonance (MR) machine, deflation of the Smart-TO balloon was assessed by tracheoscopy. In cases of failed deflation, the mannequin was reinserted into a water-filled balloon for additional MR exposure, up to a maximum of three times. Secondly, reversibility, occlusiveness and local effects of the Smart-TO balloon were tested in vivo in fetal lambs. Tracheal occlusion was performed in fetal lambs on gestational day 95 (term, 145 days), either using the balloon currently used in clinical practice (Goldbal2) (n = 5) or the Smart-TO balloon (n = 5). On gestational day 116, the presence of the balloon was assessed by tracheoscopy. Deflation was performed by puncture (Goldbal2) or MR exposure (Smart-TO). Six unoccluded fetal lambs served as controls. Following euthanasia, the lung-to-body-weight ratio (LBWR), lung morphometry and tracheal circumference were assessed. Local tracheal changes were measured using a hierarchical histologic scoring system. RESULTS: Ex vivo, Smart-TO balloon deflation occurred after a single MR exposure in 100% of cases in a maternal standing position with the mannequin at a height of 95 cm (n = 32), 55 cm (n = 8) or 125 cm (n = 8), as well as when the maternal position was 'lying on a stretcher' (n = 8). Three out of eight (37.5%) balloons failed to deflate at first exposure when the maternal position was 'sitting in a wheelchair'. Of these, two balloons deflated after a second MR exposure, but one balloon remained inflated after a third exposure. In vivo, all Smart-TO balloons deflated successfully. The LBWR in fetal lambs with tracheal occlusion by a Smart-TO balloon was significantly higher than that in unoccluded controls, and was comparable with that in the Goldbal2 group. There were no differences in lung morphometry and tracheal circumference between the two balloon types. Tracheal histology showed minimal changes for both balloons. CONCLUSIONS: In a simulated in-utero environment, the Smart-TO balloon was effectively deflated by exposure of the fetus in different positions to the magnetic field of a 1.5-T MR system. There was only one failure, which occurred when the mother was sitting in a wheelchair. In healthy fetal lambs, the Smart-TO balloon is as occlusive as the clinical standard Goldbal2 system and has only limited local side effects. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Exposición a polvo de harina de trigo en panaderías de la Región Metropolitana / Bakers' exposure to wheat flour dust in Santiago, Chile

Wheat flour is a known sensitizer for humans. Bakers exposed to flour dust may develop occupational rhinitis and asthma. In Chile there is no current permissible limit for occupational exposure to wheat flour. To propose such a limit, 9 bakeries located in 6 districts of Santiago de Chile were evaluated, 6 bakeries were semi-industrial and 3 were small business. Twenty-eight environmental personal samples were obtained by standard sampling methods and they were analyzed at the Institute of Public Health of Chile. No significant differences were found (p = 0,2915, Kruskall-Wallis' test) between air concentrations of flour particles in the working environment of semi-industrial (geometric mean: MG = 0.88 mg/m³,geometric deviation: DEG = 2,68) and small business (MG = 1.39 mg/m³, DEG = 2,31). A permissible limit of wheat flour dust exposure is recommended.

Se conoce que la harina de trigo es un sensibilizador en seres humanos. Los panaderos expuestos a polvo de harina pueden desarrollar rinitis y asma ocupacional. En Chile actualmente no existe un límite permisible para la exposición ocupacional a polvo de harina. Con el objetivo de proponer un límite, fueron evaluadas 9 panaderías de 6 comunas de Santiago de Chile, de las cuales 6 fueron semi-industriales y 3 pequeñas. Un total de veintiocho muestras personales de aire fueron obtenidas según método estándar de muestreo y analizadas en el Instituto de Salud Pública de Chile. No se encontraron diferencias significativas (p = 0,2915, prueba de Kruskall-Wallis) en la concentración de partículas de harina en el ambiente de trabajo semi-industrial (media geométrica: MG = 0,88 mg/m³, desviación geométrica: DEG = 2,68) y en el de panaderías pequeñas (MG = 1,39 mg/m³, DEG = 2,31). En base a las observaciones realizadas se recomienda establecer un límite permisible de exposición para polvo de harina de trigo.

Serum antibodies from patients with Crohn's disease and from their household members react with murine lymphomas induced by Crohn's disease tissue filtrates.

Injection into athymic nude mice (nu/nu) of filtrates of Crohn's disease tissue produces lymphoid hyperplasia and lymphomas, which react with serum antibody from other patients with Crohn's disease. We examined for such antibodies in sera of 14 patients with Crohn's disease and 25 of their household members and compared results with sera from 36 healthy unselected controls and from 14 patients with ulcerative colitis and 19 of their household members. Sera from all patients with Crohn's disease and ulcerative colitis and household members were collected in Michigan, coded, and examined by an indirect immunofluorescence assay against two primary nu/nu lymphomas and one transmitted lymphoma produced by three Crohn's disease tissue filtrates. Seven patients with Crohn's disease had antibodies against antigen(s) in the Crohn's disease lymphomas. Seven household members of patients with Crohn's disease and no household members of patients with ulcerative colitis (P less than 0.05) reacted with Crohn's disease lymphomas. However, none of the patients with ulcerative colitis (P less than 0.01) and no control healthy subjects (P less than 0.005) demonstrated immunoreactivity against nu/nu lymphomas. None of the sera reacted with a control nu/nu lymphoma. Five household members who had positive assay results were first-degree blood relatives, and the other two were spouses of patients with Crohn's disease. These results suggest that a common environmental factor may be associated with Crohn's disease, that there is a familial association in Crohn's disease, and that nu/nu mice are an important model to study the pathogenesis of Crohn's disease.

Persistence of an antigen recognized by Crohn's disease sera during in vivo passage of a Crohn's disease-induced lymphoma in athymic nude mice.

Previous studies from this laboratory have shown that lymphoma and lymph node hyperplasia develop in athymic nude mice injected with Crohn's disease tissue filtrates. In addition, use of an indirect immunofluorescence assay has demonstrated that an antigen(s) in these lymphoid tissues is recognized by sera from patients with Crohn's disease. In our study, one such lymphoma was passed through 10 generations of athymic nude mice and used for immunofluorescence studies. Suspended cells (1 to 5 X 10(8)/mouse) from the primary lymphoma and from the lymphomas that developed in mice of each subsequent generation were injected subcutaneously into groups of three to eight mice. As a control, lymphoma induced in a nude mouse by the injection of sarcoid lymph node filtrate was passed through successive generations in the same manner as the Crohn's disease-induced lymphoma. Lymphoma developed locally in 81% of recipient mice 3 to 6 weeks after injection of suspended cells. In 47 mice, representing 10 generations, Crohn's disease-related lymphoma developed at the sites of injection and at axillary or inguinal lymph nodes. These tumors were examined by immunofluorescence assay using a panel of 20 sera coded for Crohn's disease or control. Immunofluorescence assay yielded positive results in 61% of the lymphomas and 59% of the lymph node with sera from patients with Crohn's disease, but not with control sera. Control lymphomas did not stain with any serum. Our studies demonstrate the transmissibility or inducibility of an antigen(s) in lymphoid tissue of athymic nude mice that is recognized by sera from patients with Crohn's disease, but not by control sera.

Studies of the etiology of Crohn's disease using athymic nude mice.

Following injection of Crohn's disease tissue filtrates, lymphomas and hyperplastic lymph nodes developed in 16% of athymic nude (nu/nu) mice; whereas only 4% of control nude mice developed lymphadenopathy (p less than 0.025). One hundred forty coded sera from 111 patients (Crohn's disease = 36, ulcerative colitis = 28, diarrheal and other controls = 47) were assayed by indirect immunofluorescence for immunoreactivity with the lymphomas and hyperplastic lymph nodes. Coded sections were examined by two observers and scored on a 0 to 3 + scale. Fifty-four percent of the sera from patients with Crohn's disease were reactive with the Crohn's disease induced lymphoma by this assay. Eighty percent of sera from patients with symptomatic Crohn's disease were positive, whereas 22% of sera from patients in remission were positive. Sixty-six percent of sera from patients with symptomatic Crohn's disease reacted against hyperplastic lymph nodes induced by Crohn's disease filtrates. In contrast, only one control serum (from a patient with ulcerative colitis) reacted with the lymphomas or hyperplastic lymph nodes. Lymphomas induced by other means or arising spontaneously did not show immunofluorescence with Crohn's disease or control sera. Electron microscopy revealed C-type viral particles in five lymphomas induced by Crohn's disease filtrates and in one control lymphoma, but not in five hyperplastic lymph nodes and five control lymph nodes. Absorption of Crohn's disease sera with control lymphoma or with murine leukemia virus infected fibroblasts did not diminish immunoreactivity, whereas similar absorption with lymphomas induced by Crohn's disease filtrates abolished the immunofluorescence. These studies indicate that Crohn's disease tissue, when injected into athymic nude mice, induces lymphoid hyperplasia and lymphomas that contain an antigen(s) recognized by Crohn's disease sera.

Glomerular immune complex formation and induction of lymphoma in athymic nude mice by tissue filtrates of Crohn's disease patients.

Lymph nodes and intestinal filtrates from Crohn's disease patients produced lymphoma in five and plasma cell hyperplasia in two of 63 athymic (nu/nu) mice. None of 27 mice injected with intestinal filtrates from ulcerative colitis patients but one of 13 mice injected with normal-appearing colon developed lymphoma. With an indirect immunofluorescence technique, sera from all nine patients with symptomatic Crohn's disease and one of 15 patients with asymptomatic Crohn's disease demonstrated cytoplasmic immunofluorescence in a lymphoma produced by Crohn's disease filtrates, but not in a control filtrate-induced lymphoma. None of 46 sera from ulcerative colitis patients or control subjects demonstrated immunofluorescence. In addition, immunofluorescent staining with symptomatic Crohn's disease sera recognized an antigen(s) within glomeruli that were also stained with anti-mouse IgG and IgM. Kidneys from the control mice did not show any staining. These studies suggest that an agent present in lymph nodes and intestine of patients with Crohn's disease can induce lymphoma and glomerular immune complexes in nu/nu mice.

Crohn disease lymph node homogenates produce murine lymphoma in athymic mice.

To study the putative agent(s) related to Crohn disease, we intraperitoneally in injected mesenteric lymph node homogenates from four patients with active Crohn disease into 10-week-old athymic (nu/nu) mice. Control mice (nu/nu) were injected with homogenates of mesenteric lymph nodes from two patients with ulcerative colitis and four patients undergoing elective cholecystectomy, and with a homogenate of a cervical lymph node containing sarcoid granuloma. Thirty-four mice received filtered or unfiltered homogenates from Crohn disease lymph nodes. Thirty-two mice received homogenates or filtrates from lymph nodes of control patients. Four mice from the group injected with Crohn disease homogenates from four different patients developed generalized lymphadenopathy due to lymphoma 10-28 weeks after th injection. Two additional mice developed lymphadenopathy due to plasma cell hyperplasia. None of the control mice developed lymphomas or lymphadenopathy. Two lymphomas were homogenized, filtered, and injected intraperitoneally into a second group of nu/nu mice, which also developed lymphoma within 8 weeks of injection. Two lymphomas were cultured in vitro and B cell sur?ACE MARKERS WERE IDENTIFIED. Indirect immunofluorescence studies in two lymphomas showed cytoplasmic staining of lymphoma cells with sera from 10 patients with active Crohn disease but not with sera from 13 control subjects, including 6 with ulcerative colitis and 7 with other gastrointestinal disorders. These results suggest that a transmissible factor present in Crohn disease lymph nodes produces lymphoma in nu/nu mice. Furthermore, sera of Crohn disease patients contain an antibody that recognizes an "antigen(s)" in the murine lymphoma.