• HOME
• ABOUT US
• NEWS & EVENTS
• FUNDING
• TRAINEES
• RESOURCES
• PROJECTS
• CONTACT US

ARS Heath Family Grant

Differential expression of nociceptin receptor (NOP) and pre-pro nociceptin / orphanin FQ (pp-N/OFQ) amongst leucoctyes and their subpopulations

Dr Simon Scott

Background: Sepsis is the leading cause of death amongst patients admitted to Intensive Care Units, with over a third of patients with severe sepsis dying. Sepsis is characterised by increases in heart rate, respiratory rate, temperature and white cells (the cells the body uses to fight infection) in response to infection. As the disease progresses, the organs of the body can start to fail even though the cause of the infection may have been eradicated. Researchers have looked at different chemicals or cytokines produced by the body in response to infection, many of which are implicated as causing the symptoms as well as death from sepsis. One such substance is called nociceptin, a type of opioid (a little like endorphins - another opioid). Its receptor has been shown to be present on white cells, the cells that fight infection, and research has also shown that high levels of nociceptin in patients with sepsis are associated with death. Previous work in our laboratory has shown that granulocytes (a type of white blood cell) are most associated with the nociceptin pathway. However this work was done on non-septic blood from volunteers. We are yet to demonstrate that a specific type of granulocyte cell (the neutrophil) is key to nociceptin production and release in sepsis.
Aims: We want to prove which exact type of white cell is most involved in the nociceptin system by measuring nociceptin release, and genetic code for the production of other important components of the nociceptin pathway.
Methodology: This is a laboratory based project that will look at 50 samples of blood taken from volunteers and healthy patients (patients due for elective surgery being recruited from a pre-assessment clinic). After appropriate ethics approval and consent, we will take 30 ml (about half a tea-cup) of blood from each recruited person. This blood will then be divided into two. White cells will then be extracted from the samples, and one will be stimulated with a substance that makes the cells behave as if fighting infection (i.e. septic) and the other will be used as a control. We will then separate out the various cell types, and measure which cells produce molecules involved in the nociceptin system by analysing their RNA (the way in which cells use the code in DNA to make molecules when required by the body). For this we need specific sensitive and reliable equipment that can assess the purity and amount of RNA.
Expected outcomes: We hope to demonstrate that neutrophils are of primary importance in the nociceptin pathway in response to infection.
Implications: Much of the recent work investigating the role of nociceptin in sepsis has assumed neutrophils have a key role, yet evidence for this predominance is lacking. This study hopes to clarify the role of neutrophils and further demonstrate that the nociceptin pathway is activated in sepsis. If confirmed, this might provide a suitable target for future therapies that may improve survival from sepsis.

Determining the relationships between perioperative risk, socioeconomic characteristics, short term postoperative morbidity, and long term patient reported health gain and survival after joint replacement surgery

Dr Samantha Wilson

Background: >140,000 hip and knee joint replacements are performed annually in England; these are major operations aimed at improving quality of life. The NHS reports deaths within 90 days of joint replacement surgery; while these are relatively rare (around 1%), research shows that complications (a.k.a. morbidity) are much more common (estimates up to 50% depending on several factors) and large studies from the US have shown that the development of complications after major operations is associated with reduced long term survival. Furthermore, some complications may be avoidable through particular treatments or methods of healthcare delivery. Despite this, neither complications nor long term survival after major surgery are routinely reported in the NHS. The DoH now asks patients having hip or knee replacements to complete quality of life questionnaires called 'Patient Reported Outcome Measures' (PROMs) immediately before and six months after surgery. The difference between pre- and post-operative scores ('health gain') is recorded for every patient to measure the 'success' of surgery. There are medical and sociodemographic reasons why some patients may not gain as much benefit from surgery as others. An understanding of whether patient risk factors (e.g. chronic illnesses) predict outcome is important, so that individual patients can understand the potential risks and benefits of surgery to them before consenting to treatment, and limited healthcare resources can be used on patients who will derive the most benefit. Our research centre routinely records sociodemographic data and patient risk factors for patients having joint replacement surgery in two hospitals using a score called 'Orthopaedic POSSUM' (O-POSSUM). We also record complications using the Post Operative Morbidity Survey (POMS). PROMs and patient mortality data are held centrally by the NHS.
Aims: We will evaluate the relationships between patient risk (O-POSSUM scores), socioeconomic characteristics (SEC), complications (POMS scores), patient reported health gain (PROMs) and long term survival after joint replacement surgery.
Methodology: O-POSSUM, SEC and POMS collected for patients undergoing hip or knee joint replacement at two hospitals will be linked to centrally-held PROMs and long term mortality data. We will use statistical tests to calculate the relationships between these factors.

Expected outcomes: We will answer the following questions in joint replacement surgery:

• Does patient risk (O-POSSUM scores) or SEC predict health gain +/- long term survival?
  
• Do O-POSSUM scores or SEC predict whether patients develop complications?
  
• Does the occurrence of complications predict patient reported health gain +/- long term survival?

Implications:

• If O-POSSUM +/- SEC predict complications or health gain, then this information can be used to improve the quality of informed patient consent
  
• If a relationship is found between O-POSSUM +/- SEC, and either complications, health gain +/- long term survival, then future work can be directed at identifying interventions aimed at modifying these relationships to improve patient outcome.
  
• If we find that complications are predictive of health gain or mortality, this will support the measurement of complications in the wider NHS, providing patients and commissioners with more information about the quality of healthcare in different institutions.