Prion protein N1 cleavage peptides stimulate microglial interaction with surrounding cells.

Microglia act as the protective immune cell of the brain. By surveying the tissue to identify and rectify problems, they function to maintain the health of brain cells. The prion protein N-terminal cleavage fragment, N1, has demonstrated neuroprotective activities in vitro and in vivo. This study aimed to elucidate whether N1 could modulate microglial function and, if so, determine the consequences for the surrounding tissue. Using a mixed neuronal lineage and microglia co-culture system, we showed that N1 stimulation changed overall morphology and metabolism, suggesting enhanced cellular viability. Furthermore, N1 induced an increase in Cxcl10 secretion in the co-cultures. Recombinant Cxcl10, administered exogenously, mediated the changes in the mixed neuronal lineage culture morphology and metabolism in the absence of microglia, but no effect of Cxcl10 was observed on microglia cultured on their own. Direct cell-to-cell contact was required for N1 to influence microglia in the co-cultures, and this was linked with restructuring of microglial membrane composition to include a higher GM1 content at interaction sites with surrounding cells. Our findings show that N1 can play a regulatory role in microglial function in the context of an inter-connected network of cells by changing both cellular interaction sites and cytokine secretion.

Fitting the message to the location: engaging adults with antimicrobial resistance in a World War 2 air raid shelter.

AIMS: There are many different initiatives, global and local, designed to raise awareness of antimicrobial resistance (AMR) and change audience behaviour. However, it is not possible to assess the impact of specific, small-scale events on national and international outcomes-although one might acknowledge some contribution to the individual and collective knowledge and experience-focused 'science capital' As with any research, in preparation for a public engagement event, it is important to identify aims, and appropriate methods whose results might help satisfy those aims. Therefore, the aim of this paper was to develop, deliver and evaluate an event designed to engage an adult audience with AMR. METHODS AND RESULTS: The venue was a World War 2 air raid shelter, enabling comparison of the pre- and postantibiotic eras via three different activity stations, focusing on nursing, the search for new antibiotics and investigations into novel antimicrobials. The use of observers released the presenters from evaluation duties, enabling them to focus on their specific activities. Qualitative measures of audience engagement were combined with quantitative data. CONCLUSIONS: The evaluation revealed that adult audiences can easily be absorbed into an activity-particularly if hands-on-after a brief introduction. SIGNIFICANCE AND IMPACT OF THE STUDY: This research demonstrates that hands-on practical engagement with AMR can enable high-level interaction and learning in an informal and enjoyable environment.

MEK1 transduces the prion protein N2 fragment antioxidant effects.

The prion protein (PrP(C)) when mis-folded is causally linked with a group of fatal neurodegenerative diseases called transmissible spongiform encephalopathies or prion diseases. PrP(C) normal function is still incompletely defined with such investigations complicated by PrP(C) post-translational modifications, such as internal cleavage, which feasibly could change, activate, or deactivate the function of this protein. Oxidative stress induces ß-cleavage and the N-terminal product of this cleavage event, N2, demonstrates a cellular protective response against oxidative stress. The mechanisms by which N2 mediates cellular antioxidant protection were investigated within an in vitro cell model. N2 protection was regulated by copper binding to the octarepeat domain, directing the route of internalisation, which stimulated MEK1 signalling. Precise membrane interactions of N2, determined by copper saturation, and involving both the copper-co-ordinating octarepeat region and the structure conferred upon the N-terminal polybasic region by the proline motif, were essential for the correct engagement of this pathway. The phenomenon of PrP(C) post-translational modification, such as cleavage and copper co-ordination, as a molecular "switch" for activation or deactivation of certain functions provides new insight into the apparent multi-functionality of PrP(C).

A novel dephosphorylation-activated conductance in a mouse renal collecting duct cell line.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited renal diseases. It is associated with the progressive development of renal tubular cysts, which may subsequently lead to renal failure. Studies into the genetic basis of ADPKD have identified two genes, PKD1 and PKD2, that are mutated in ADPKD patients. The PKD1 and PKD2 genes encode for two different proteins, TRPP1 and TRPP2. Previous studies have demonstrated the presence of both TRPP1 and TRPP2 in the renal collecting duct cell line M8. The aim of the following study was to investigate the functional properties of cation currents in these cells and to examine the effect of overexpression of TRPP1 using a transgenic cell model (M7). In M8 cells, initial whole cell currents were low. However, over time there was activation of a flow-sensitive current, which was inhibited by gadolinium (I(Gd)). The I(Gd) was more selective for cations over anions, but did not discriminate between monovalent cations and was Ca2+ permeable. Activation of I(Gd) was dependent on the presence of Ca2+ and also required dephosphorylation. The protein phosphatase 2A inhibitor okadaic acid prevented activation of I(Gd), suggesting that protein phosphatase 2A plays an important role in channel activation. The properties and magnitude of I(Gd) were unaffected in M7 cells, suggesting that overexpression of TRPP1 was without effect. I(Gd) was selectively inhibited by an antibody raised against the C-terminus of TRPP2. However, its selectivity profile was different to TRPP2, suggesting that it is attributable to a TRPP2-like channel or a TRPP2-containing heteromeric channel. In conclusion, these data describe the functional identification of a novel dephosphorylation- and flow-activated TRPP2-related channel in mouse collecting duct cells.

Involving families who have deaf children using a Family Needs Survey: a multi-agency perspective.

BACKGROUND: Meeting the needs of deaf children and their families is multidisciplinary. Models of multi-agency working are diverse, and there is little evidence on outcome for family and child. Effective collaboration is an essential part of multi-agency working, and how this is achieved is an area that warrants research. METHODS: An approach was developed to identify family needs using a need identification tool called a Family Needs Survey (FNS) in conjunction with a multi-agency meeting. The FNS was introduced in a pilot study to involve parents of deaf children with services and to identify their needs from their perspective. RESULTS AND CONCLUSIONS: A clear pathway was determined for application of the FNS. A model of multi-agency working was developed that involves families directly with different services at one time. Outcomes were measured by uptake of the FNS, parental attendance at multi-agency meetings, and completion of a parent evaluation questionnaire. Discussion of the FNS at a multi-agency meeting facilitates communication between professionals and between professionals and parents. There is some evidence that the FNS may be a useful tool. The majority of parents completed a FNS before multi-agency meetings and have indicated they are happy to share the information with other professionals.

Regulation of prion protein expression: a potential site for therapeutic intervention in the transmissible spongiform encephalopathies.

The Transmissible Spongiform Encephalopathies (TSEs) are a group of rare neurodegenerative diseases, which can be transmitted between members of the same species and possibly across different species. The link between the emergence of Bovine Spongiform Encephalopathy (BSE) and the new variant form of Creutzfedlt Jakob Disease (vCJD) has been the cause of much public concern. vCJD is the most widely known of the human TSEs but by no means the most common; inherited and sporadic forms are much more prevalent. The agent responsible for these diseases is a conformationally altered form of a normal cell surface glycoprotein, called the prion protein (PrP). The normal isoform must be present for the disease to progress, and disease incubation time decreases with increased PrP expression. There is still no cure for any of these diseases but recent advances in the understanding of how prion protein expression is regulated at the genetic level, and of exogenous factors modulating expression levels, may provide new insights into potential therapeutic targets for disease management by down regulation of cellular PrP levels.

A controlled trial of ondansetron in the pruritus of cholestasis.

BACKGROUND: In patients with pruritus of cholestasis, response to conventional drug treatment may be unsatisfactory. Activation of 5-hydroxytryptamine receptors on dermal sensory nerve-endings plays a role in the perception of pruritus. The 5-hydroxytryptamine(3) receptor antagonist, ondansetron, has been used in the treatment of pruritus of cholestasis, but there are few controlled data. AIM: To determine whether ondansetron is effective in treating the pruritus of cholestasis. METHODS: A total of 19 patients with resistant pruritus were randomized, double blind, to receive either ondansetron 8 mg or placebo as a single intravenous bolus, followed by oral ondansetron 8 mg or placebo twice daily for 5 days. Patients' perception of pruritus was recorded hourly using a visual analogue scale, and scratching activity measured by means of a piezo-electric crystal attached to the fingernail. RESULTS: Mean pruritus score using visual analogue scale and scratching activity were reduced on the first treatment day compared with baseline in both the ondansetron and placebo groups (P < 0.05), but there were no significant differences in mean pruritus perception or scratching activity between the two groups. CONCLUSION: Ondansetron was of no benefit in this group of pruritic patients during short-term treatment.

Volume regulation is defective in renal proximal tubule cells isolated from KCNE1 knockout mice.

The membrane protein KCNE1 has been implicated in cell volume regulation. Using a knockout mouse model, this study examined the role of KCNE1 in regulatory volume decrease (RVD) in freshly isolated renal proximal tubule cells. Cell diameter was measured using an optical technique in response to hypotonic shock and stimulation of Na(+)-alanine cotransport in cells isolated from wild-type and KCNE1 knockout mice. In HEPES buffered solutions 64% of wild-type and 56% of knockout cells demonstrated RVD. In HCO3- buffered solutions 100% of the wild-type cells showed RVD, while in the knockout cells the proportion of cells displaying RVD remained unchanged. RVD in the knockout cells was rescued by valinomycin, a K+ ionophore. In wild-type HCO3- dependent cells the K+ channel inhibitors barium and clofilium inhibited RVD. These data suggest that mouse renal proximal tubule is comprised of two cell populations. One cell population is capable of RVD in the absence of HCO3-, whereas RVD in the other cell population has an absolute requirement for HCO3-. The HCO3- dependent RVD requires the normal expression of KCNE1.

Post-operative nausea and vomiting in patients undergoing day-case surgery: an international, observational study.

Post-operative nausea and vomiting (PONV) are complications of surgical procedures, and are of particular relevance in the day-case setting. The aim of this study was to examine the incidence and impact of PONV before and after discharge from day surgery units. Patients recorded the incidence, severity and impact of PONV for 5 days following surgery. The incidence of PONV in the 561 eligible patients was 17% upon waking, 14% travelling home and 3% by the 5th day post-surgery. PONV was most common in gastrointestinal, obstetric and gynaecological surgery. Although freedom from pain and PONV are requirements for discharge after ambulatory surgery, PONV is still a problem post-discharge.

The management of ischaemic and periampuation pain.

This article describes the development and pilot application of a management tool designed to support healthcare practitioners in the management of ischaemic and periamputation pain. The ischaemic management periamputation care (IMPAC) guidelines have been piloted in the authors' clinical area and early results suggest that there are positive benefits accruing to patients and ward staff.

Contribution of multidisciplinary team to pain management.

A fundamental part of satisfactory acute pain management is the regular and objective assessment of the patient's pain. The responsibility for this ongoing assessment is generally incorporated into the nursing role. Given the multidisciplinary nature of modern health care it is contended that this assessment is not the sole obligation of nursing or medical staff and that any healthcare professional who is offering treatment of therapy to patients should incorporate pain assessment into their treatment plan. This article outlines a small research study that assesses the contribution that the multidisciplinary team (MDT) makes towards pain management and pain assessment in particular. It highlights the importance of pain assessment and the fact that management is a multidisciplinary issue.

A comparison of oral ondansetron syrup or intravenous ondansetron loading dose regimens given in combination with dexamethasone for the prevention of nausea and emesis in pediatric and adolescent patients receiving moderately/highly emetogenic chemotherapy.

This double-blind, parallel-group, multicenter study compared the efficacy and safety of intravenous (i.v.) ondansetron with oral syrup ondansetron plus oral dexamethasone in the prevention of nausea and emesis in pediatric patients receiving moderately/highly emetogenic chemotherapy. On each day of chemotherapy, patients were administered ondansetron 5 mg/m2 i.v. and placebo syrup orally (n = 215) or ondansetron 8 mg syrup orally and placebo i.v. (n = 223) plus dexamethasone 2-4 mg p.o. Ondansetron 4 mg syrup p.o. was administered twice daily for 2 days following the cessation of chemotherapy. Complete or major control of emesis was obtained in 89% patients in the i.v. group and 88% patients in the oral syrup group during the worst day of chemotherapy treatment (90% CI: -6, 4) and in 85% and 82% patients, respectively, during the worst day of the study period (90% CI: -8, 3). Intravenous or oral syrup ondansetron plus dexamethasone was well tolerated and effective in preventing chemotherapy-induced emesis in pediatric patients.

A comparison of anaesthesia using remifentanil combined with either isoflurane, enflurane or propofol in patients undergoing gynaecological laparoscopy, varicose vein or arthroscopic surgery.

BACKGROUND: Anaesthesia comprising remifentanil plus isoflurane, enflurane or propofol was randomly evaluated in 285, 285 and 284 patients, respectively, undergoing short-procedure surgery. METHODS: Anaesthesia was induced with propofol (0.5 mg x kg(-1) and 10 mg x 10 s(-1)), and a remifentanil bolus (1 microg x kg(-1)) and infusion at 0.5 microg x g(-1) x min(-1). Five minutes after intubation, remifentanil infusion was halved and 0.5 MAC of isoflurane or enflurane, or propofol at 100 microg x kg(-1) x min(-1) were started and titrated for maintenance. RESULTS: Patient demography and anaesthesia duration were similar between the groups. Surgery was performed as daycases (52%) or inpatients (48%). The median times (5-7 min) to extubation and postoperative recovery were similar between the groups. Responses to tracheal intubation (15% vs 8%) and skin incision (13% vs 7%) were significantly greater in the total intravenous anaesthesia (TIVA) group (P<0.05). Fewer patients given remifentanil and isoflurane (21%) or enflurane (19%) experienced > or =1 intraoperative stress response compared to the TIVA group (28%) (P<0.05). Median times to qualification for and actual recovery room discharge were 0.5-0.6 h and 1.1-1.2 h, respectively. The most common remifentanil-related symptoms were muscle rigidity (6-7%) at induction, hypotension (3-5%) and bradycardia (1-4%) intraoperatively and, shivering (6-7%), nausea and vomiting postoperatively. Nausea (7%) and vomiting (3%) were significantly lower with TIVA compared with inhaled anaesthetic groups (14-15% and 6-8%, respectively; P<0.05). CONCLUSION: Anaesthesia combining remifentanil with volatile hypnotics or TIVA with propofol was effective and well tolerated. Times of extubation, postanaesthesia recovery and recovery room discharge were rapid, consistent and similar for all three regimens.

Drug development in anaesthesia: the remifentanil.

Drug development in anaesthesia poses specific challenges. Describing the development of remifentanil highlights some of these. A new drug in anaesthesia must achieve its clinical goals in all patients and significant levels of toxicity are unacceptable. Rather than asking, "What new drugs does the anaesthetist need?" it may be more relevant to pose the question, "How can we design drugs to do things better?". Recent trends in anaesthesia have led to the development of short acting agents--one of these agents, remifentanil, has been designed to provide a mu-opioid receptor agonist with a rapid and predictable offset of action. The insertion of an alkyl ester group into this 4-anilidopiperidine molecule has resulted in a compound which, whilst retaining the desired mu-opioid receptor pharmacology, is susceptible to metabolism by non-specific esterases in the blood and tissues. The rapid onset and offset of action means that the anaesthetist can deliver high doses of opioid resulting in stable anaesthesia and the lack of accumulation ensures that even after prolonged infusion remifentanil does not compromise recovery. This ability to control the anaesthetic process has relevance in both short and long procedures and the unique characteristics of remifentanil may also in the future prove to have utility in the intensive care setting.

Postoperative pain control following remifentanil-based anaesthesia for major abdominal surgery.

Eighty patients undergoing major abdominal surgery using remifentanil-based anaesthesia were randomly allocated in a double-blind manner to receive an intravenous bolus of fentanyl, buprenorphine, morphine or piritramide 20 min before the end of surgery. A reduced dose was administered postoperatively when patients reported moderate pain. Subsequent analgesia was provided by patient-controlled analgesia (PCA). The mean time from the end of anaesthesia to spontaneous respiration was 9 +/- 5 min. At first pain assessment, 63% of patients reported no or mild pain; 80% of patients required the second opioid bolus, those receiving piritramide needed the bolus significantly later than patients receiving buprenorphine or fentanyl. First PCA requirement also occurred significantly later in the piritramide group. This technique provided effective postoperative pain relief and transition to routine PCA and did not compromise recovery.

Postoperative pain management and recovery after remifentanil-based anaesthesia with isoflurane or propofol for major abdominal surgery. Remifentanil Study Group.

We have assessed if recovery times after morphine or fentanyl, given before terminating remifentanil anaesthesia with isoflurane or propofol, are compromised. We studied patients undergoing elective, major abdominal surgery, allocated randomly to receive remifentanil and isoflurane (n = 277) or remifentanil and propofol (n = 274) anaesthesia. Twenty-five minutes before the end of surgery, patients received fentanyl 0.15 mg or morphine 15 mg in a randomized, double-blind manner followed by a second dose (fentanyl 0.05 mg, morphine 7 mg) for moderate or severe pain in recovery. Recovery was rapid and at an Aldrete score > or = 9 (median 12-15 min), 42-51% of patients reported none or mild pain. However, 26-35% of patients reported severe pain and > 90% required a second dose of opioid within 21-27 min after anaesthesia.

Efficacy of an ondansetron orally disintegrating tablet: a novel oral formulation of this 5-HT(3) receptor antagonist in the treatment of fractionated radiotherapy-induced nausea and emesis. Emesis Study Group for the Ondansetron Orally Disintegrating Tablet in Radiotherapy Treatment.

A significant number of patients who are receiving radiotherapy experience the distressing side effects of emesis and nausea. Although prophylactic antiemetics are often given to patients who are receiving single-fraction, high-dose radiotherapy to the abdomen, a survey has revealed that antiemetic prophylaxis is not routinely offered to those receiving fractionated radiotherapy. Hence there is a need for an effective treatment of emesis for use in this group of patients. Ondansetron is an effective and well-tolerated antiemetic, which is used for the prevention of both chemotherapy and radiotherapy-induced emesis and nausea. This agent has been developed as a novel freeze-dried oral formulation. Ondansetron orally disintegrating tablets (ondODT) disperse rapidly when placed on the tongue. As the tablet does not need to be swallowed with water, it is a particularly useful formulation for patients who have difficulty with swallowing or who do not feel able to drink. This study was undertaken to investigate the efficacy of ondODT in the treatment of established emesis and nausea induced by radiotherapy. Two doses of ondODT, 8 mg and 16 mg, were compared with placebo in patients who developed emesis and/or moderate/severe nausea after receiving fractionated radiotherapy to sites located between the thorax and the pelvis. The study showed that ondODT was clinically superior to placebo in treating emesis and nausea successfully over a 12-hour period after taking the medication. There were no statistically significant differences between the two doses of ondODT. In the 2 hours after taking the study medication, patients who received ondODT (8 mg and 16 mg) had significantly fewer emetic episodes compared with those who received placebo. They also experienced significantly less nausea. In conclusion, ondODT 8 mg is effective in the treatment of radiotherapy-induced emesis and nausea and provides an effective alternative to the conventional ondansetron tablet.