Rural Clinical School - Research Publications
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ItemRetrograde continence enema in children with spina bifida: Not as effective as first thought(WILEY, 2017-04)AIM: The aim of the study is to investigate the effectiveness of Peristeen retrograde continence enema (RCE) in the management of faecal incontinence in children with spina bifida. METHODS: We identified a homogenous group of spina bifida patients in whom RCE was initiated (Jan 2006-July 2013). Confidential assessments included (i) Fecal Incontinence Quality Of Life (FIQOL), (ii) St Marks Faecal Incontinence score, (iii) Cleveland Clinic Constipation score and (iv) Neurogenic Bowel Dysfunction score. RESULTS: Of 20 patients, 11 (mean age 14.5 ± 5.3 years) were male. Of 20 patients, nine were still using RCE (mean follow-up 4.1 years). Three patients ceased RCE within 10 days, six after 4-12 months and two after 36-48 months. Reasons for cessation included balloon difficulties (n = 4), procedure deemed too difficult (n = 4) and pain (n = 3). There were no differences between the groups in length of training time for technique, instillate fluid/volume used and time taken to perform RCE. There were no differences between the groups for quality of life, faecal incontinence or constipation scores. CONCLUSIONS: We demonstrated a high rate of cessation with RCE in patients with spina bifida. This could not be explained by associated conditions, or by enema-related parameters. One possible explanation is the lack of ongoing outpatient support for the children and their families.
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ItemDelayed diagnosis of anorectal malformations in neonates(WILEY, 2019-10)BACKGROUND: Anorectal malformations (ARM) are common congenital abnormalities of the terminal hindgut. Ideally, ARM should be diagnosed at, or shortly following, birth by careful physical examination of the perineum. Delayed diagnosis has been implicated as a risk factor for complications, including intestinal perforation. This study aimed to determine the rate of delayed diagnosis and associated intestinal perforation in ARM. METHODS: A retrospective review was performed for all ARM patients managed at The Royal Children's Hospital over a 16-year period (2000-2015). Data collected included ARM type, timing of diagnosis and complications. Delayed diagnosis was defined as being at more than 24 h of age. RESULTS: A total of 243 ARM patients (male 146/243, 60%) were included. The most frequent ARM types were perineal fistula (83/243, 34%) and rectovestibular fistula (40/243, 16%). Diagnosis was delayed beyond 24 h of age in 92 of 243 (38%) patients. The ARM type most commonly delayed in diagnosis was perineal fistula (37/83, 45%). Two patients in whom diagnosis was delayed suffered an intestinal perforation. CONCLUSION: Delayed diagnosis in ARM patients remains a common, and potentially fatal, occurrence. Improved assessment of newborns is required to ensure timely diagnosis of ARM, and avoidance of complications associated with delayed diagnosis.
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ItemScreening for associated anomalies in anorectal malformations: the need for a standardized approach(WILEY, 2019-10)BACKGROUND: Anorectal malformations (ARM) are common congenital abnormalities of the terminal hindgut. The high incidence of associated anomalies necessitates systematic screening, which should include renal and spinal ultrasonography, spinal radiography and an echocardiogram. This study aimed to determine the incidence of associated anomalies in ARM, and whether screening protocols were appropriately applied. METHODS: A retrospective review was performed of all ARM patients managed at The Royal Children's Hospital, Melbourne over a 16-year period (2000-2015). Data collected included ARM type, presence of associated anomalies, as well as utilization of renal and spinal ultrasonography, spinal radiography and echocardiography. RESULTS: A total of 243 patients (male 146/243, 60%) were reviewed. The most frequent ARM types were perineal fistula (83/243, 34%) and rectovestibular fistula (40/243, 16%). Full screening was performed in 153/243 (63%), while 18/243 (7%) received no screening. In fully screened patients, associated anomalies were diagnosed in 143/153 (93%), with cardiovascular, renal and musculoskeletal anomalies being most frequent. CONCLUSIONS: The high incidence of associated anomalies identified in fully screened ARM patients highlights the importance of systematic screening. Clinically significant anomalies may have been overlooked in the more than one-third of ARM patients in whom screening was absent or incomplete. Standardized screening protocols for ARM patients have now been implemented.
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ItemEnteric Neural Cells From Hirschsprung Disase Patients Form Ganglia in Autologous Aneuronal Colon(ELSEVIER INC, 2016-01)BACKGROUND & AIMS: Hirschsprung disease (HSCR) is caused by failure of cells derived from the neural crest (NC) to colonize the distal bowel in early embryogenesis, resulting in absence of the enteric nervous system (ENS) and failure of intestinal transit postnatally. Treatment is by distal bowel resection, but neural cell replacement may be an alternative. We tested whether aneuronal (aganglionic) colon tissue from patients may be colonized by autologous ENS-derived cells. METHODS: Cells were obtained and cryopreserved from 31 HSCR patients from the proximal resection margin of colon, and ENS cells were isolated using flow cytometry for the NC marker p75 (nine patients). Aneuronal colon tissue was obtained from the distal resection margin (23 patients). ENS cells were assessed for NC markers immunohistologically and by quantitative reverse-transcription polymerase chain reaction, and mitosis was detected by ethynyl-2'-deoxyuridine labeling. The ability of human HSCR postnatal ENS-derived cells to colonize the embryonic intestine was demonstrated by organ coculture with avian embryo gut, and the ability of human postnatal HSCR aneuronal colon muscle to support ENS formation was tested by organ coculture with embryonic mouse ENS cells. Finally, the ability of HSCR patient ENS cells to colonize autologous aneuronal colon muscle tissue was assessed. RESULTS: ENS-derived p75-sorted cells from patients expressed multiple NC progenitor and differentiation markers and proliferated in culture under conditions simulating Wnt signaling. In organ culture, patient ENS cells migrated appropriately in aneural quail embryo gut, and mouse embryo ENS cells rapidly spread, differentiated, and extended axons in patient aneuronal colon muscle tissue. Postnatal ENS cells derived from HSCR patients colonized autologous aneuronal colon tissue in cocultures, proliferating and differentiating as neurons and glia. CONCLUSIONS: NC-lineage cells can be obtained from HSCR patient colon and can form ENS-like structures in aneuronal colonic muscle from the same patient.
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ItemFGF10 and the Mystery of Duodenal Atresia in Humans(FRONTIERS MEDIA SA, 2018-11-09)Background: Duodenal atresia (DA) is a congenital obstruction of the duodenum, which affects 1 in 7000 pregnancies and requires major surgery in the 1st days of life. Three morphological DA types are described. In humans, the association between DA and Down syndrome suggests an underlying, albeit elusive, genetic etiology. In mice, interruption of fibroblast growth factor 10 (Fgf10) gene signaling results in DA in 30-50% of embryos, supporting a genetic etiology. This study aims to validate the spectrum of DA in two novel strains of Fgf10 knock-out mice, in preparation for future and translational research. Methods: Two novel CRISPR Fgf10 knock-out mouse strains were derived and embryos generated by heterozygous plug-mating. E15.5-E19.5 embryos were genotyped with respect to Fgf10 and micro-dissected to determine the presence and type of DA. Results: One twenty seven embryos (32 wild-type, 34 heterozygous, 61 null) were analyzed. No wild-type or heterozygous embryos had DA. However, 74% of Fgf10 null embryos had DA (49% type 1, 18% type 2, and 33% type 3). Conclusion: Our CRISPR-derived strains showed higher penetrance of DA due to single-gene deletion of Fgf10 in mice than previously reported. Further, the DA type distribution in these mice more closely reiterated that observed in humans. Future experiments will document RNA and protein expression of FGF10 and its key downstream signaling targets in normal and atretic duodenum. This includes exploitation of modern, high-fidelity developmental tools, e.g., Fgf10 flox/+-tomatoflox/flox mice.