Biomedical subjects

Nikhil Thapar

Publications and source records attributed to Nikhil Thapar.

4 recordsLinked to original sources

PubMed2006

Maintenance of mammalian enteric nervous system progenitors by SOX10 and endothelin 3 signalling.

The transcriptional regulator SOX10 and the signalling molecule endothelin 3 have important roles in the development of the mammalian enteric nervous system (ENS). Using a clonal cell culture system, we show that SOX10 inhibits overt neuronal and glial differentiation of multilineage ENS progenitor cells (EPCs), without interfering with their neurogenic commitment. We also demonstrate that endothelin 3 inhibits reversibly the commitment and differentiation of EPCs along the neurogenic and gliogenic lineages, suggesting a role for this factor in the maintenance of multilineage ENS progenitors. Consistent with such a role, the proportion of Sox10-expressing progenitors in the total population of enteric neural crest cells is reduced in the gut of endothelin 3-deficient embryos. This reduction may be related to the requirement of endothelin signalling for the proliferation of ENS progenitors. The dependence of ENS progenitors on endothelin 3 is more pronounced at the migratory front of enteric neural crest cells, which is associated with relatively high levels of endothelin 3 mRNA. Our findings indicate that SOX10 and endothelin 3 have a crucial role in the maintenance of multilineage enteric nervous system progenitors.

Animals↗

PubMed2005

Long-term outcome of intractable ulcerating enterocolitis of infancy.

BACKGROUND: Chronic enterocolitis is rare in infancy and accounts for less than 0.5% of all newly diagnosed inflammatory bowel disease (IBD) in the UK. Presentation at this young age is usually indicative of underlying immunodeficiency/immunodysregulation. A group of such infants suffer intractable ulcerating enterocolitis of infancy (IE) in which there is a pan-enteritis with marked oro-anal involvement and deep flask like mucosal ulcers throughout the colon. METHODS: Retrospective review of presenting features, treatment and long-term outcome in a series of 8 children with typical IE. RESULTS: The 8 children were aged between 1 and 4 weeks at onset (median 2 weeks, mean 2.3 weeks), of which 7 were followed up for 2-22 years (median 7.5 years, mean 11 years). All 8 children had an intractable disease course requiring a colectomy for control of symptoms. The median age at colectomy was 1.7 years (range 4 months-4 years). Three children developed a generalised lymphadenopathy due to uncontrolled EBV-related lymphoid proliferations (ages 4, 12, 18). These comprised a monomorphous B-lymphoycte lympho-proliferative disorder, a large pleomorphic follicular lymphoma, and a high grade pleomorphic B cell non-Hodgkin's lymphoma. CONCLUSIONS: Infants with IE have a high risk of developing lymphomatous proliferations that appears to be related to the underlying immunodysregulation. Use of aggressive immunosuppression and acquisition of EBV infection appears to accelerate this process; hence we advocate early colectomy in confirmed cases. In children with IE screening for EBV and vigilance for abnormal lymphoid proliferations is paramount.

Adolescent↗

PubMed2004

Diarrhoea in children: an interface between developing and developed countries.

Despite much progress in the understanding of pathogenesis and of management, diarrhoeal illnesses remain one of the most important causes of global childhood mortality and morbidity. Infections account for most illnesses, with pathogens employing ingenious mechanisms to establish disease. In the developed world, an upsurge in immune-mediated gut disorders might have resulted from a disruption of normal bacterial-epithelial cross-talk and impaired maturation of the gut's immune system. Oral rehydration therapies are the mainstay of management of gastroenteritis, and their composition continues to improve. Malnutrition remains the major adverse prognostic indicator for diarrhoea-related mortality, emphasising the importance of nutrition in early management. Drugs are of little use, except for specific indications although new agents that target mechanisms of secretory diarrhoea show promise, as do probiotics. However, preventive strategies on a global scale might ultimately hold the greatest potential to reduce the burden of diarrhoeal disease. These strategies include vaccines and, most importantly, policies to address persisting inequalities between the developed and developing worlds with respect to nutrition, sanitation, and access to safe drinking water.

Child↗

PubMed2003

Neuron and glia generating progenitors of the mammalian enteric nervous system isolated from foetal and postnatal gut cultures.

Cultures of dissociated foetal and postnatal mouse gut gave rise to neurosphere-like bodies, which contained large numbers of mature neurons and glial cells. In addition to differentiated cells, neurosphere-like bodies included proliferating progenitors which, when cultured at clonal densities, gave rise to colonies containing many of the neuronal subtypes and glial cells present in the mammalian enteric nervous system. These progenitors were also capable of colonising wild-type and aganglionic gut in organ culture and had the potential to generate differentiated progeny that localised within the intrinsic ganglionic plexus. Similar progenitors were also derived from the normoganglionic small intestine of mice with colonic aganglionosis. Our findings establish the feasibility of expanding and isolating early progenitors of the enteric nervous system based on their ability to form distinct neurogenic and gliogenic structures in culture. Furthermore, these experiments provide the rationale for the development of novel approaches to the treatment of congenital megacolon (Hirschsprung's disease) based on the colonisation of the aganglionic gut with progenitors derived from normoganglionic bowel segments.

Aging↗