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Background Obtaining family consent to organ donation is a significant obstacle to improving further Australian deceased organ donation rates. Currently, neither the consent rates for donors eligible to donate after circulatory death, nor factors that influence decision to decline or consent to donation in general are known in Australia. Methods This study at four university teaching hospitals in Melbourne, Victoria, examined consecutive patients where organ donation was discussed with the family Results A total of 123 cases were identified; the family consent rate was 52.8%, and 34.1% proceeded to donation. Consent to donation was related to potential donor factors such as country of birth, cultural background in Australia, a non-religious or Christian background and registration on the Australian Organ Donor Register. Family-related factors included being English speaking and having knowledge of the deceased's wishes about organ donation. Family of donation after circulatory death-eligible donors were less likely to consent to donation than the family of donation after brain death-eligible donors, although not reaching statistical significance. Among consented potential donors, those eligible for donation after brain death and with a shorter length of stay were more likely to proceed to donating organs for transplantation. Conclusion Despite a small sample size, these findings describe current consent and donation rates and associated factors and may assist in improving conversations about organ donation.

To improve organ donation processes and outcomes, many Australian hospitals have introduced donation after cardiac death (DCD) following the 2010 publication of the National Protocol for DCD. As emergency clinicians play a significant role in identifying potential DCD donors, it is critical to assess their support and knowledge. Although many support DCD, most are unaware of the protocol or procedures regarding DCD. Education is needed and desired by many emergency clinicians.

Objectives: In 2010 the Australian Organ and Tissue Authority introduced a nationally consistent indicator, the GIVE Clinical Trigger, for early identification of potential organ and tissue donors in EDs and intensive care units. This national survey of emergency clinicians aimed to assess emergency clinicians’ perceptions and use of the Trigger. Methods: National cross-sectional survey of Australasian College for Emergency Medicine (ACEM) fellows and trainees and members of the College of Emergency Nursing Australia (CENA); online questionnaire; 12 items addressing implementation of the GIVE Trigger; graded and free-text responses. Results: Five hundred and ninety-nine (20.2%) of 2969 ACEM members and 212 (20.7%) of 1026 CENA members responded. Four hundred and seventy-four respondents (62.7%) were familiar with the Trigger; 472 (63.8%) agreed it was easy to recognise patients who activated the Trigger; 490 (64.9%) had sufficient time to use the Trigger; 511 (67.7%) felt they had the necessary competence and knowledge to identify a potential donor; 464 (61.5%) felt competent and 501 (66.4%) felt comfortable referring a potential donor when identified. Overall 587 (77.7%) ED clinicians supported the use of the Trigger, but most (587 [77.7%]) perceived barriers to its use; 628 (80%) had never activated the Trigger and 557 (71%) had never referred a potential donor to relevant authorities. Conclusion: Most Australian emergency clinicians are familiar with and support the GIVE Clinical Trigger, and feel they have the necessary skills to use the Trigger; however, most perceive barriers to its use and have not yet used the Trigger.

Objective: The ED is emerging as a priority for efforts to improve rates of organ and tissue donation (OTD) in Australia, but little is known of ED clinicians' attitudes, education or practices in the area. We aimed to determine the attitudes and OTD-related educational background and practices of Australian ED clinicians. Methods: This was a national cross-sectional survey of members of the Australasian College for Emergency Medicine (ACEM) and the College of Emergency Nursing Australasia (CENA); online questionnaire of 133 items, graded responses using Likert and ordinal multi-category scales, plus open-ended qualitative questions. Results: Of 2969 ACEM members, 599 (20.2%) responded; of 1026 CENA members, 212 (20.7%) responded. Respondents were broadly representative of the membership, with male trainee specialists underrepresented. Most ED staff supported OTD, although many were not certain that facilitating OTD was their role, or that the ED was the right place to identify donors. Around a quarter of medical and nursing staff had received no education regarding OTD. Having received education was related to professional status, cultural background, place of work and years of experience, and was significantly associated with attitude towards OTD and whether staff participated in OTD-related tasks. Conclusions: More education on OTD is needed and requested by ED clinicians in Australia, particularly on OTD after cardiac death, management of a donor, brain death and obtaining consent. Postgraduate curricula should reflect this need for more OTD-related education in emergency medicine and nursing.

Insulin receptor substrate (IRS) proteins comprise a family of adaptor molecules that integrate extracellular signals from insulin and other ligands to intracellular effectors such as phosphoinositide 3-kinase and mitogen-activated protein kinase. The predominant forms of IRS protein in humans, IRS1 and IRS2, are widely expressed. Despite structural similarities, IRS1 and IRS2 display distinct signalling modalities, and mice lacking these proteins present with distinct phenotypes. Transforming growth factor (TGF)-β1 is the primary cytokine shown to induce epithelial–mesenchymal transition. Recent data have demonstrated a role for IRS1 in TGF-β1-induced epithelial–mesenchymal transition in lung epithelial cells. In the present study, we report data showing that TGF-β1 signals via IRS2 in kidney epithelial cells. Small interfering RNA (siRNA)-mediated targeting of IRS2 increased E-cadherin expression, although it did not alter TGF-β1-mediated E-cadherin repression. Phosphorylation of the downstream target of IRS2/Akt signalling, FoxO3a, was induced on Ser253 and, to a lesser extent, on Thr32. Transfection of FoxO3aThr32Ala mutant for 24 h greatly reduced FoxO3a phosphorylation on Ser253 but over-expression of FoxO3a Ser253Ala did not effect Thr32 phosphorylation, suggesting that a distinct order of phosphorylation of FoxO3a is required for physiological function in cells. Transfection of FoxO3a Ser253Ala mutant partially inhibited TGF-β1-mediated E-cadherin repression at 24 h. Taken together, these data highlight novel roles for IRS2 and FoxO3a in the regulation of kidney epithelial cells by E-cadherin.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a serine lipase that is associated with low density lipoprotein (LDL) in human plasma. Substrates include oxidised phosphatidylcholine (PC), which is hydrolysed by Lp-PLA2 to lyso-PC and oxidised fatty acids. Both products are bioactive and proinflammatory, and implicated in monocyte infiltration into the developing plaque, deposition of foam cells, and plaque progression and instability. Lp-PLA2 has recently been shown to be a risk factor for coronary events in previously asymptomatic, hypercholesterolaemic men. A series of azetidinones was designed as potent and selective inhibitors of this enzyme; SB-222657 inhibited release of the chemotactic cleavage products from oxidised LDL, and SB-244323 reduced atherosclerotic plaque development in a 3 month rabbit study. A series of pyrimidones has been designed from a screening hit, and nanomolar inhibitors identified. Oral efficacy in inhibiting plasma Lp-PLA2 in rabbits has been demonstrated with a variety of structural classes.

A mild, base mediated conversion of an azetidin-2-one to the [1,4]-diazapinedione system is reported and a putative mechanistic pathway is proposed.

1. Octimibate is a potent inhibitor of human platelet aggregation, and appears to act (at least in part) through the prostacyclin receptor, as described in the preceding paper. Here, the vascular effects, both in vitro and in vivo, of octimibate have been compared to those of the stable prostacyclin (PGI2) mimetic, iloprost. Since octimibate shows extensive species variation and is potent at inhibiting platelet aggregation in primates, all of the experiments reported here have been carried out with primate tissue or in vivo in cynomolgus monkeys. 2. Activation of adenylyl cyclase in human lung membranes appears to involve stimulation of the vascular PGI2 receptor. Octimibate, as well as iloprost, stimulates adenylyl cyclase in this preparation. The EC50 values for iloprost and octimibate are 50 nM and 340 nM respectively. These values are similar to those seen with human platelet membranes. As with platelets, the maximal activation achievable with octimibate is 60% of that seen with iloprost. This result suggests that octimibate is a partial agonist for stimulation of adenylyl cyclase. 3. Iloprost (10-100 nM) relaxes human coronary and mesenteric artery precontracted with KCl, and also relaxes cynomolgus monkey aorta precontracted with phenylephrine. Octimibate appears to be a partial agonist for relaxation of human coronary artery precontracted with KCl; the intrinsic activity of octimibate (10 microM) is 0.15 compared to iloprost, and octimibate surmountably antagonizes the relaxant effects of iloprost with a Kp of 200 nM. Octimibate (up to 10 microM) evokes only weak relaxation of human mesenteric artery (precontracted with KCl) and cynomolgus monkey aorta (precontracted with phenylephrine). 4. The effects of iloprost and octimibate were compared in vivo in cynomolgus monkeys. In addition to inhibiting ex vivo platelet aggregation, both compounds cause hypotension with little effect on heart rate. The dose-response curves for inhibition of ex vivo platelet aggregation and a fall in mean arterial blood pressure were compared. The dose-separation (i.e., the relative differences in effective concentrations) for the two responses is similar with both iloprost and octimibate. 5. Since the pern; beral resistance vessels are intimately involved in regulation of systemic arterial blood pressure, the effects of both agents were tested on human peripheral resistance vessels (150-400pm diameter) in vitro. These vessels are relaxed by both iloprost and octimibate following precontraction with KCI. The IC50 value for iloprost is 44nM, and 1.7 microM octimibate evokes 50% of the maximal relaxation obtained with iloprost. Thus, the relative potencies of the two compounds in relaxing human subcutaneous resistance vessels are similar to their relative potencies in inhibiting platelet responses. This result correlates with the lack of platelet versus vascular selectivity seen with the in vivo monkey studies. 6. These results suggest that octimibate, a partial agonist at the prostacyclin receptor, is unable to discriminate between platelet and vascular prostacyclin receptors in primates.

The synthesis of analogues of SB-253514, a novel natural product derived inhibitor of lipoprotein associated phospholipase A2 (Lp-PLA2), is described together with their ability to inhibit Lp-PLA2.

Summary— A pericaliceal haemangioma associated with papillary necrosis caused haematuria which led to nephrectomy. Seven similar vascular lesions were found on review of the surgical histopathology records from the last 25 years at the St Peter's Hospitals, Institute of Urology, London. In 4 of these there was histological evidence of damage to the renal papilla adjacent to the vascular abnormality; a possible mechanism for these changes is discussed. In all 8 cases the patients presented with haematuria and, in 5, abnormalities were seen on renal radiological investigation. Nephrectomy was performed in 5 instances and the remaining 3 patients were treated by partial nephrectomy. The presence of a vascular malformation was considered pre-operatively in 2 patients and in the remainder the diagnosis was first made on laboratory examination. In all patients haematuria ceased post-operatively and in 5 cases where follow-up information was available there has been no evidence of bilateral involvement.

Direct computer experiments are conducted on electron diffusion in a simple cubic lattice where the disorder corresponds to the Anderson model. Results for the onset of total localisation are in good agreement with other numerical estimates and it is found that the critical value of the parameterW/ZV is (17.7/6). A random structurally disordered system is also investigated with hopping integrals given by V(r) = -V0 exp (-r/a) and found that localisation occurs at the critical value a = 3 ± 0.3. Thisis in agreement with the only other numerical estimate but is substantiallydifferent from theoretical calculations. Es werden direkte Computerexperimente der Elektronendiffusion im primitiven kubischen Gitter durchgefuhrt, wo die Fehlordnung dem Andersonmodell entspricht. Ergebnisse fur das Einsetzen der Gesamtlokalisierung befinden sich in guter Ubereinstimmung mit anderen numerischen Berechnungen, und es wird ein kritischer Wert des Parameters W/ZV von 17,7/6 gefunden. Ein strukturell statistisch fehlgeordnetes System wird ebenfalls untersucht, wobei die Hoppingintegrale durch V(r) = -V0 exp (-r/a) gegeben sind, und es wird gefunden, das Lokalisierung beim kritischen Wert a = 3 ± 0,3 auftritt. Dies befindet sich in Ubereinstimmung mit der einzigen anderen numerischen Berechnung, ist jedoch wesentlich verschieden von theoretischen Berechnungen.

Summary A method of simultaneous bilateral ureterocolic anastomosis based on that devised by Davalos is described, and a short account is given of four patients on whom it was employed satisfactorily.

The key step in the synthesis of L-3,5-dibromo-3′-[6-oxo-1,6-dihydropyridazin-3-yl)methyl]-thyronine, SK&F L-94901 (1), a novel, selective, and potent thyromimetic, is the formation of the hindered diaryl ether moiety. This paper describes an investigation into the formation of the required diaryl ether by copper-catalysed reaction both of symmetrical iodonium salts (2a) and (10) and mixed iodonium salts (2b–e) with protected dibromotyrosine (5). The importance of the counter-ion of the iodonium salt is discussed. This work is extended to a large-scale synthesis of SK&F L-94901 (1).

Thermal decomposition of vinyl azides (1a–c) gives isoquinolines (3), benzazepines (4), or aziridines (5) and (6) by preferential reaction at the unsaturated substituent; removal of this unsaturation as in the epoxides (1d,1e) leads exclusively to 4-substituted indoles.

Photolysis of the azidocinnamates (1) gives trimers of the azirines (2); X-ray crystallographic analysis establishes the triazatricyclononene structure (6) for these trimers.

Iodine has a marked catalytic effect on the thermolysis of azidocinnamates; indoles, isoquinolines, 1,2-dihydroisoquinolines, or enamines are isolated depending on the conditions.