MRC GW4 BioMed DTP PhD Studentship: Serum nitrate as a biomarker of infection in gastroenteritis patients

The MRC has awarded the GW4 BioMed DTP additional studentships for an October 2017 start. This project is in competition with 40 that are now being advertised across the DTP.

Patients with infective gastroenteritis show extreme increases in serum nitrate levels due to high nitric oxide synthesis. Do blood serum nitrate levels reveal the cause of acute diarrhoea in patients admitted as emergency cases to hospital, and can a novel electrochemical sensor facilitate rapid bedside measurements of serum nitrate?

Immune system activation by bacterial pathogens causes inducible nitric oxide synthase expression, thereby increasing nitric oxide (NO) synthesis. NO, nitrate (NO3-) and nitrite (NO2-) are inflammatory markers. Infective gastroenteritis patients display far greater increases in plasma NO3- concentration than in non-infective gastroenteritis (Dykhuizen et al, 1996). The student will test the hypothesis that serum NO3- is useful in determining the cause of acute diarrhoea in patients admitted as emergency cases to hospital. Whilst diarrhoea can be caused by infective gastroenteritis (bacterial/viral), diarrhoea can also be caused by non-infective processes, e.g. inflammatory bowel disease. Distinguishing the causes is critical in hospitals, as treatments differ. Infectious diarrhoea patients must be isolated quickly, to prevent infections spreading. Identifying infectious diarrhoea is difficult. Stool samples can be tested by microbiological culture, but this takes 2-3 days and has poor sensitivity. Polymerase chain reaction (PCR) can be used, for a faster/accurate diagnosis, but is expensive and not widely available in hospitals. A cheap/simple test is needed to distinguish rapidly between non-infective and infective gastroenteritis, and this may be provided by a novel electrochemical NO3- sensor developed in Bath, which will be tested by the student.

The student will investigate serum NO3- level as a differential biomarker of pathogenic infection in patients with acute diarrhoea. Serum NO3- will be compared with a “gold standard” PCR assay, as an unequivocal identifier of bacterial infections including Campylobacter, C. difficile, Salmonella, and viral infections e.g. norovirus. At Torbay Hospital, there are about 50 severe diarrhoea stools samples analysed monthly by the microbiology department. We propose that Torbay microbiology department will test 300 by PCR, of which about 100 will be positive. The student will measure corresponding serum NO3-, allowing a good estimate of sensitivity/specificity.

This study does not need local ethics approval because patients have stool samples and blood taken routinely, and blood will be taken surplus to requirements for normal clinical care. To test the feasibility of serum NO3- as a bedside diagnostic, the student will compare our established spectrophotometric NO3- assay with the novel electrochemical sensor developed in Bath (Gross et al, 2014, below). Later in the project (with ethics approval), the student will compare serum NO3- with salivary/urinary NO3-, alongside chemiluminescence determination of nitrite and electrochemiluminescence measurement of 3-nitrotyrosine in isolated blood cells – all established methods in Exeter. This will provide: (1) insight into metabolism of the large amounts of NO3- generated during infective gastroenteritis, and (2) contingencies for areas to explore in the event that serum NO3- has unexpectedly poor diagnostic potential.

Start date: October 2017

Academic Supervisors:
Professor Paul Winyard, University of Exeter Medical School (UEMS)
http://medicine.exeter.ac.uk/people/profile/index.php?web_id=Paul_Winyard

Professor Frank Marken, University of Bath
http://www.bath.ac.uk/chemistry/contacts/academics/frank_marken/

Dr Miranda Smallwood, UEMS
http://medicine.exeter.ac.uk/people/profile/index.php?web_id=Miranda_Smallwood

Professor Nigel Benjamin, UEMS

Academic criteria:
The DTP welcomes students from non-medical backgrounds, especially in areas of computing, mathematics and the physical sciences, and can fund additional training, including Masters to assist discipline conversion. Applicants for a studentship must have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of medical sciences. Applicants with a Lower Second Class degree will be considered if they also have a Master’s degree or have significant relevant non-academic experience.

English requirements:
If English is not your first language you will need to have achieved at least 6.5 in IELTS (and no less than 6.5 in any section) by the start of the programme.