Changes to peptide structure, not concentration, contribute to expansion of the lowest avidity cytotoxic T lymphocytes

The efficient in vitro expansion of antigen-specific CD8(+) cytotoxic T lymphocytes (CTL) for use in adoptive immunotherapy represents an important clinical goal. Furthermore, the avidity of expanded CTL populations often correlates closely with clinical outcome. In our study, high-avidity CTL lines could be expanded ex vivo from an antigen-primed animal using low peptide concentration, and intermediate peptide concentrations favored the generation of lower avidity CTL. Further increases in peptide concentration during culture inhibited the expansion of all peptide-specific CD8(+) cells. In contrast, a single amino acid variant peptide efficiently generated functional CTL populations at high or low peptide concentration, which responded to wild-type epitope with the lowest average avidity seen in this study. We propose that for some peptides, the efficient generation of low-avidity CTL responses will be favored by stimulation with altered peptide rather than high concentrations of wild-type epitope. In addition, some variant peptides designed to have improved binding to major histocompatibility complex class I may reduce rather than enhance the functional avidity for the wild-type peptide of ex vivo-expanded CTL. These observations are relevant to in vitro expansion of CTL for immunotherapy and strategies to elicit regulatory or therapeutic immunity to neo-self-antigen when central tolerance has eliminated high-avidity, cognate T cells.

A prospective multicentre study of pharmacist initiated changes to drug therapy and patient management in acute care government funded hospitals

Aims To determine the cost savings of pharmacist initiated changes to hospitalized patients' drug therapy or management in eight major acute care government funded teaching hospitals in Australia. Methods This was a prospective study performed in eight hospitals examining resource implications of pharmacists' interventions assessed by an independent clinical panel. Pharmacists providing clinical services to inpatients recorded details of interventions, defined as any action that directly resulted in a change to patient management or therapy. An independent clinical review panel, convened at each participating centre, confirmed or rejected the clinical pharmacist's assessment of the impact on length of stay (LOS), readmission probability, medical procedures and laboratory monitoring and quantified the resultant changes, which were then costed. Results A total of 1399 interventions were documented. Eight hundred and thirty-five interventions impacted on drug costs alone. Five hundred and eleven interventions were evaluated by the independent panels with three quarters of these confirmed as having an impact on one or more of: length of stay, readmission probability, medical procedures or laboratory monitoring. There were 96 interventions deemed by the independent panels to have reduced LOS and 156 reduced the potential for readmission. The calculated savings was $263 221 for the eight hospitals during the period of the study. This included $150 307 for length of stay reduction, $111 848 for readmission reduction. Conclusions The annualized cost savings relating to length of stay, readmission, drugs, medical procedures and laboratory monitoring as a result of clinical pharmacist initiated changes to hospitalized patient management or therapy was $4 444 794 for eight major acute care government funded teaching hospitals in Australia.

Cyclosporine A-induced changes to erythrocyte redox balance is time course-dependent

Cyclosporine A-treated transplant recipients develop pronounced cardiovascular disease and have increased oxidative stress and altered antioxidant capacity in erythrocytes and plasma. These experiments investigated the time-course of cyclosporine A-induced changes to redox balance in plasma and erythrocytes. Rats were randomly assigned to either a control or cyclosporine A-treated group. Treatment animals received 25 mg/kg of cyclosporine A via intraperitoneal injection for either 7 days or a single dose. Control rats were injected with the same volume of the vehicle. Three hours after the final injections, plasma was analysed for total antioxidant status, a-tocopherol, malondialdehyde, and creatinine. Erythrocytes were analysed for reduced glutathione (GSH), alpha-tocopherol, methaemoglobin, malondialdehyde, and the activities of superoxide dismutase, catalase, GSH peroxidase, and glucose-6-phosphate dehydrogenase (G6PD). Cyclosporine A administration for 7 days resulted in a significant increase (P < 0.05) in plasma malondialdehyde, methaemoglobin, and superoxide dismutase and catalase activities. There was a significant decrease (P < 0.05) in erythrocyte GSH concentration and G6PD activity in cyclosporine A animals. There were no significant differences (P > 0.05) between groups following a single dose of cyclosporine A in any of the measures. In summary, cyclosporine A alters erythrocyte redox balance after 7 days administration, but not after a single dose.

The impact of changes to heroin supply on blood-borne virus notifications and injecting related harms in New South Wales, Australia

Background: In early 2001 Australia experienced a sudden and unexpected disruption to heroin availability, know as the 'heroin shortage'. This 'shortage has been linked to a decrease in needle and syringe output and therefore possibly a reduction in injecting drug use. We aimed to examine changes, if any, in blood-borne viral infections and presentations for injecting related problems related to injecting drug use following the reduction heroin availability in Australia, in the context of widespread harm reduction measures. Methods: Time series analysis of State level databases on HIV, hepatitis B, hepatitis C notifications and hospital and emergency department data. Examination of changes in HIV, hepatitis B, hepatitis C notifications and hospital and emergency department admissions for injection-related problems following the onset of the heroin shortage; non-parametric curve-fitting of number of hepatitis C notifications among those aged 15 - 19 years. Results: There were no changes observed in hospital visits for injection-related problems. There was no change related to the onset heroin shortage in the number of hepatitis C notifications among persons aged 15 - 19 years, but HCV notifications have subsequently decreased in this group. No change occurred in HIV and hepatitis B notifications. Conclusion: A marked reduction in heroin supply resulted in no increase in injection-related harm at the community level. However, a delayed decrease in HCV notifications among young people may be related. These changes occurred in a setting with widespread, publicly funded harm reduction initiatives.

Cyclosporine A induced changes to plasma and erythrocyte antioxidant defences

Organ transplant recipients develop pronounced cardiovascular disease, and decreased antioxidant capacity in plasma and erythrocytes is associated with the pathogenesis of this disease. These experiments tested the hypothesis that the immunosuppressant cyclosporine A (CsA) alters erythrocyte redox balance and reduces plasma antioxidant capacity. Female Sprague-Dawley rats were randomly assigned to a control or CsA treated group. Treatment animals received 25 mg/kg/day of CsA via intraperitoneal injection for 18 days. Control rats were injected with the same volume of the vehicle. Three hours after the final CsA injection, rats were exsanguinated and plasma analysed for total antioxidant status (TAS), alpha-tocopherol, malondialdehyde (MDA), and creatinine. Erythrocytes were analysed for superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and glucose-6-phosphate dehydrogenase (G6PD) activities, alpha-tocopherol, and MDA. CsA administration resulted in a significant (P < 0.05) decrease in plasma TAS and significant increases (P < 0.05) in plasma creatinine and MDA. Erythrocyte CAT was significantly (P < 0.05) increased in CsA treated rats compared to controls. There were no significant differences (P > 0.05) in erythrocyte SOD, GPX, G6PD, alpha-tocopherol or MDA between groups. In summary, CsA alters erythrocyte antioxidant defence and decreases plasma total antioxidant capacity.

Changes to porcine blastocyst vitrification methods and improved litter size after transfer

The objective was to improve the protocol that was used to obtain the first reported piglets from transferred vitrified and warmed zona-intact blastocysts. Blastocysts were collected from superovulated sows and gilts, centrifuged to polarize lipid, vitrified, warmed and cultured for 24 h or transferred immediately. Removing the zona pellucida after warming increased the number of cells in the surviving blastocysts (zona-free 60.8 +/- 4.3, zona-intact 39.1 +/- 2.8; P < 0.05). Thinning the zona pellucida produced similar results to zona removal. Changing the basal medium of the vitrification and warming solutions from modified PBS to phosphate buffered NCSU-23 increased the number of cells (44.7 +/- 2.2 versus 56.0 +/- 3.9, respectively; P < 0.05). Reducing the plunge temperature of the liquid nitrogen from - 196 degrees C to less than -204 degrees C improved the embryo survival rate (61.9% versus 82.9%, respectively; P < 0.05). These modifications were incorporated into the vitrification protocol that was used to vitrify and warm 105 blastocysts (that were subsequently transferred into four recipients). Three recipients became pregnant, farrowing three litters (average litter size, 5.3; 18.8% embryo survival in farrowing sows). Changing the warming protocol to using sucrose rather than ethylene glycol resulted in a trend towards improved embryo survival (73.5% versus 91.2%) but this was not statistically significant. Incorporating this modification, 203 blastocysts were vitrified, warmed and transferred into seven recipients. Five became pregnant and 36 fetuses were recovered (average litter size 7.2; 24.8% embryo survival in pregnant sows) at Day 40 of pregnancy. In conclusion, changes made to the vitrification protocol improved pregnancy rate and in vivo embryo survival compared to an earlier study using the original protocol. (c) 2005 Elsevier Inc. All rights reserved.

Doing educational development ambivalently: Applying post-colonial metaphors to educational development?

Post‐colonial theories about liminality, hybridity, unhomeliness, and identity form a novel lens through which to re‐theorise educational development work. Applying these conceptual frameworks allows practitioners and the academics they work with the opportunity to problematise some of educational development’s colonial underpinnings and assumptions. They also enable an exploration of the states of betweenness that form educational developers’ identities and impact implicitly and explicitly upon the nature of their changing practices. This paper seeks to read educational development and research supervisor development in particular “against the grain”. It also seeks to illustrate these concepts through some vignettes of my academic development practice.

Purchasing behaviour for non-prescription medicines

Background: The non-prescription medicine, market is constantly challenges. With changes to scheduling and market dynamics, a need for current Australian data on medicines purchasing behaviour was identified. Objectives: This survey aimed to report on the purchasing behaviour of non-prescription medicine customers, the medicines bought and influences on medicine sales. Methods: Researchers were stationed in 15 community pharmacies in southeast Queensland during mid-August 2004. Interview and observational data were collected for all eligible medicine purchases -over approximately 35 hours per pharmacy. Results: Data were collected for 3017 medicines purchased by 2583 customers. Most purchases were made by females (65%) and customers aged 26-35 years (25.8%). Pharmacy assistants alone provided advice in 58% of sales. Two thirds of purchases were for self use. In two thirds of cases, customers had a particular brand in mind; this was highly correlated with previous purchases. Pharmacy staff were highly influential in first time purchases. Conclusions: This study reports a high level of involvement and influence of pharmacy staff in medicine selection.

Effects of patient-focused care on seclusion in a psychiatric intensive care unit

The objective of the study was to evaluate whether the introduction of patient-focused nursing care affected the number of seclusions and the length of time patients spent in seclusion, in an acute psychiatric unit. The study used a pre-intervention–post-intervention design and was conducted in an eight-bed locked unit within a large regional general hospital in Queensland, Australia. The medical records of all people who were secluded as part of their management while in hospital, during two 6-month periods, were retrospectively reviewed. Changes to the ways in which nurses conducted their daily activities were implemented during the time between the data collection periods. There were no differences between the groups with respect to the number of times a patient was secluded. However, following implementation of patient-focused care, there was a reduction in the length of time for which patients were secluded. The only change in medication administration was that post-implementation, Haloperidol was used in fewer seclusion episodes. The findings indicate that changes to nursing practice may result in closer monitoring of patients and a reduction in the time patients spend secluded in acute inpatient psychiatric settings.

Audit of consultant physicians' reply letters for referrals to clinics in a tertiary teaching hospital

Background: Doctors referring patients to consultant physicians seek reply letters which both educate and assist in ongoing patient management. Highly desirable attributes in specialist letters include clearly stated and justified: (i) diagnostic formulations, (ii) management regimens, (iii) use of clinical investigations, (iv) prog-nostic statements, (v) contingency plans and (vi) follow-up arrangements. Aim: To explicitly evaluate the quality of reply letters for new patients referred to clinics at a tertiary teaching hospital. Methods: Letters were sampled from outpatient clinics of 10 different medical specialties at Princess Alexandra Hospital in Brisbane, Australia. Reply letters for new patient referrals between 1 August 2000 and 31 October 2000 were retrieved, from which data were abstracted to calculate the proportion of letters satisfying prespecified quality attributes. Results: Of 297 new patient referrals, reply letters were retrieved for 204 (69%). Of these, 147 (72%) referrals were accompanied by a referral letter, mostly (113/147; 77%) from general practitioners. For 120 referrals involving diagnostic issues, 69 (56%) letters stated a diagnostic formulation. Of 114 letters recommending further clinical investigations, 61 (53%) described a rationale for such testing. In 125 cases where therapy was a key issue, 83 (66%) letters recommended changes to current treatment for which reasons were specified in 46 (55%) cases, and contingency plans provided in 13 (16%). Prognosis was mentioned in only 18 (9%) cases. Follow-up arrangements were detailed in 123 (60%) letters. Assessments of patient understanding and likely adherence to therapy were stated in less than 15% of -letters. Conclusions: Opportunities exist for improving quality of consultant physicians' reply letters in terms of greater use of problem lists, contingency plans, prognostic statements and patient-centred assessments, as well as more frequent enunciation of consultants' reasoning behind requests for further tests and changes to current management. Use of structured letter templates may facilitate more consistent inclusion of key information to referring doctors.

Tuning the metal-to-metal charge transfer energy of cyano-bridged dinuclear complexes

The metal-to-metal charge transfer (MMCT) transitions of a series of Class II mixed valence dinuclear complexes bearing cyano bridging ligands may be varied systematically by variations to either the hexacyanometallate(II) donor or Co-III acceptor moieties. Specifically, the new dinuclear species trans-[(LCoNCFe)-Co-14S(CN)(5)](-) (L-14S = 6-methyl-1,11-diaza-4,8-dithia- cyclotetradecane-6-amine) and trans-[(LCoNCRu)-Co-14(CN)(5)]-(L-14 = 6-methyl-1,4,8,11-tetraazacyclotetradecane-6-amine) have been prepared and their spectroscopic and electrochemical properties are compared with the relative trans-[(LCoNCFe)-Co-14(CN)(5)](-). The crystal structures of Na{trans-[(LCoNCFe)-Co-14S(CN)(5)]}.51/2H(2)O.1/2EtOH, Na{trans-[(LCoNCRu)-Co-14(CN)(5)]}.3H(2)O and Na{trans-[(LCoNCRu)-Co-14(CN)(5)]}.8H(2)O are also reported. The ensuing changes to the MMCT energy have been examined within the framework of Hush theory, and it was found that the free energy change between the redox isomers was the dominant effect in altering the energy of the MMCT transition.

The late effects of poliomyelitis in Queensland

This paper reports an investigation of new health problems reported by Queensland residents with a prior history of poliomyelitis. 126 people with a past history of paralytic poliomyelitis were recruited from the waiting list for the trial Post Polio Clinic at Queen Elizabeth II Hospital, Brisbane. A self-administered postal questionnaire was used to examine a number of variables including acute poliomyelitis histories; presence, duration and severity of new symptoms consistent with the late effects of poliomyelitis; changes in functional status between the maximal recovery period and the time of the survey and the impact of post-polio symptoms on lifestyle and employment. The most frequent new symptoms reported were muscle weakness (87 per cent), unusual tiredness (79 per cent), joint pain (79 per cent), muscle pain (61 per cent) and muscle cramps (71 per cent). Subjects reported an increased reliance on assistive devices and a decreased level of independence with activities of daily living, particularly with mobility-related tasks. Eight three per cent of subjects had made lifestyle changes as a result of post-polio symptoms and 67 per cent of those subjects in the workforce reported making changes to their employment, such as reduced hours of work. (author abstract)