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Rapid urbanisation, population growth and the effects of climate change drive the need for sustainable urban water management (SUWM) in Asian cities. The complexity of this challenge calls for the integration of knowledge from different disciplines and collaborative approaches. This paper identifies key issues and sets the stage for interdisciplinary research on SUWM in Asia. It reports on the initial stages of a SUWM research programme being undertaken at Monash University, Australia, and proposes a framework to guide the process of interdisciplinary research in urban water management. Three key themes are identified: (1) Technology and Innovation, (2) Urban Planning and Design, and (3) Governance and Society. Within these themes 12 research projects are being undertaken across Indonesia, China, India and Bangladesh. This outward-looking, interdisciplinary approach guides our research in an effort to transgress single-discipline solutions and contribute on-ground impact to SUWM practices in Asia.

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BACKGROUND: Human patient simulators are frequently used for airway management training and research. However, little is known about their fidelity and validity. The use of these simulators as a benchmark model remains highly questionable. The objective of this study was to evaluate the validity and fidelity of two patient simulators (compared to actual patients) for anaesthesia residents performing three airway management techniques. METHODS: Endotracheal intubation, laryngeal mask airway insertion and mask ventilation were performed by anaesthesia residents on 80 patients undergoing elective surgery. The anaesthesia residents also used these three techniques to secure the airways of two human patient simulators in a randomised crossover study. The durations, difficulties, realism and success rates of the procedures were assessed. RESULTS: Although the performance of endotracheal intubation was comparable in patients and both manikins, no chest rise was visible in 35% (HAL) and 32.5% (SimMan) of the manikins after inserting a laryngeal mask airway. This result was not observed in patients (P<0.001). Furthermore, effective mask ventilation was not possible in 60% of the cases using HAL, compared with 0% of cases using SimMan and 2.5% of patients (P<0.001). CONCLUSION: Patient simulators are not a valid alternative to human patients for conducting scientific evaluations of supraglottic airway management techniques. HAL and SimMan do have adequate validity for endotracheal intubation, but the fidelity and validity are low when a laryngeal mask is used or if mask ventilation is performed. Therefore, previous simulation-based airway device evaluation studies must be interpreted with great caution.

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OBJECTIVE: Achieving joint regeneration in rheumatoid arthritis (RA) represents a future challenge. Autologous synovial mesenchymal stem cells (MSCs) could be therapeutically exploited. However, the inflammatory milieu in the RA synovium could adversely affect endogenous MSC function. To test this hypothesis, the frequency and multipotency of RA synovial MSCs was evaluated in relation to existing synovial inflammation. METHODS: Synovial inflammation was measured using the arthroscopic visual analogue score (VAS) and further validated using immunohistochemistry and flow cytometry. Highly proliferative clonogenic in vivo MSCs were enumerated following fluorescence-activated cell sorting and expansion for 20 population doublings. MSC multipotency was quantified following standard in vitro culture expansion and trilineage differentiation assays. Real-time PCR, flow cytometry and ELISA were used to evaluate pro- and anti-chondrogenic molecules in standard polyclonal synovial MSCs. RESULTS: The arthroscopic VAS significantly correlated with synovial macrophage infiltration. In RA, synovial MSC chondrogenesis was inhibited in direct relation to VAS (r = -0.777, p<0.05) and reduced compared with control osteoarthritis (OA)-MSCs (p<0.05). In vivo, MSCs resided in the synovial fibroblastic/stromal fraction (CD45(-)CD31(-)) and were reduced in frequency in relation to VAS (r = -0.695, p<0.05). In RA-MSCs, CD44 levels correlated negatively with inflammation and positively with chondrogenesis (r = -0.830 and r = 0.865, respectively). Cytokine production and Sox9 expression was similar in RA-MSCs and OA-MSCs. CONCLUSIONS: There is a negative relationship between synovial MSC chondrogenic and clonogenic capacities and the magnitude of synovitis in RA. Effective suppression of joint inflammation is therefore necessary for the development of autologous MSC treatments aimed at cartilage regeneration in RA.

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OBJECTIVE: The study was undertaken to determine the effect of advice to discontinue hormone replacement therapy (HRT) on 100 women who were well established on treatment without side-effects. METHOD: The study was retrospective from November 2003 to April 2004, in a single gynecological practice in London, UK. One hundred consecutive long-term estrogen and testosterone hormone implant users were assessed as to their knowledge of recent studies regarding risks of long-term HRT and whether they wished to discontinue hormones. RESULTS: All women receiving estrogen and testosterone implants, for a mean duration of 17.65 years (range 10-28 years), felt well informed concerning the Women's Health Initiative Study and the Million Women Study but only three women were happy to discontinue. The reasons given for the continuation of therapy were that they felt well and their quality of life had greatly improved. The mean estradiol and testosterone levels were 921 pmol/l and 1.91 nmol/l, respectively. CONCLUSIONS: The high rate of continuation of hormone treatment indicates that, despite the recent adverse publicity, these women feel well informed and were not willing to discontinue with their hormone therapy if they felt well. A regular discussion of the risks and benefits of HRT remains mandatory.

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STUDY DESIGN: This prospective study examined the efficacy and somatic tolerance as well as the perception of the different phases of medical abortion with mifepristone and misoprostol. The subjective influence of counseling and accompanying on perception and psychic sequelae was evaluated. METHOD: The somatic data of the patients who had a medical abortion at Basel University Hospital of Gynecology and Obstetrics from December 1, 1999, to October 31, 2000, were identified in the case records. A questionnaire at the time of the abortion and a structured interview by telephone 6 months later were used to assess the perception of the abortion. RESULTS: Abortion with mifepristone and misoprostol was successful in 95.2% of cases. Counseling and accompanying were considered supportive by 90.4 and 73.7%, respectively. The psychological workup was without problems in 95.5%. CONCLUSION: Medical abortion with mifepristone and misoprostol was successful in 95.2%. Our concept of counseling and accompanying was well received and resulted in an uneventful psychological workup in most cases.

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Sodium valproate (VPA) is clinically employed as an anticonvulsant and, to a lesser extent, as a mood stabilizer. While the incidence of toxicity associated with the clinical use of valproate is low, serious hepatotoxicity makes up a significant percentage of these rare adverse effects, with fatalities occurring mainly in children receiving polypharmacy. Previous studies have highlighted the different pharmacological effects of acute valproate exposure, a combination of which are likely to underpin its observed broad-spectrum anticonvulsant efficacy. However, limited studies have been undertaken to investigate the subacute effects of this compound and how genomic effects may underlie the observed hepatotoxic effects. Investigation into the mild hepatoxicity observed in rats exposed to high doses of VPA may provide important information on the human situation. Male Sprague-Dawley rats were dosed with 500 mg/kg/day sodium valproate: after necropsy, mRNA was subjected to suppression PCR subtractive hybridization, identifying 8 up-regulated and 14 down-regulated mRNA species. The down-regulation of several mRNA species coding for enzymes involved in cellular energetics (e.g., succinate dehydrogenase, aldolase B) was of particular interest, as mitochondrial dysfunction is a key feature of valproate hepatotoxicity. In vitro studies were then undertaken to examine the dose and time dependence of these changes and also their effect on the overall energy levels within the cell. We demonstrate that, both in vivo and in vitro, valproate exposure in rats results in a significant decrease in pathways involved in cellular energy homeostasis. These changes may provide insight into the rare human hepatoxicity associated with this compound.

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The measurement of the nuchal translucency is an important marker to detect a vast number of fetal anomalies. Lately the nuchal translucency has been used increasingly as a screening method to find chromosomal anomalies especially for trisomy 21. Beside a high incidence of chromosomal defects one assumes a high risk of rare syndromes and other associated anomalies such as heart defects, skeletal anomalies, cerebral anomalies, diaphragmatic hernias, as well as of an intrauterine death. In view of abortion rate, detection rate of chromosomal anomalies, other fetal anomalies and rare syndromes we evaluated in this study the pregnancy outcome after nuchal translucency measurement, and discuss a concept for its management.

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PATIENTS AND METHODS: 26 consecutive patients with early hydrocephalus (median age at shunting 2.5 months) were followed up to the age of 3 years, prospectively. The work-up included: regular evaluation of psychomotor development and CT/MRI prior and 6 months following surgery. The latter with measurement of the area of the ventricles (degree of hydrocephalus) and the area of the hemispheres in cm(2) (area of hemispheres minus area of ventricles = parenchymal area and degree of brain mass) at the level of the slice with the largest area of the ventricles. RESULTS: 16 (62 %) had normal development (= Group A) and 10 (38 %) moderate or severe retardation (= Group B). The mean ventricular surface was 25.4 cm(2) in Group A and 31.2 cm(2) in Group B prior to surgery (p = 0.1) and 8.9 versus 14.1 cm(2) postsurgery (p = 0.2). The percentage decrease postoperatively was 59.9, versus 57.1 % (p = 0.4). The percentage of ventricular surface in relation to the hemispheres prior to surgery was 42.2 versus 51.4 % (p = 0.1) and post-surgery 12.8 versus 22.4 % (p = 0.1). The mean parenchymal surface was 34.9 cm(2) in Group A and 29.0 cm(2) in Group B prior to surgery (p = 0.3) and 60.9 versus 48.1 cm(2) post surgery (p = 0.07). Percentage increase was 87.3 % versus 77.3 % (p = 0.9). The absolute increase was 26.0 versus 19.0 cm(2) postoperatively (p = 0.2). In contrast to these mean values and their distribution with no significant differences in Group A and B there was some correlation between development and percentage of ventricular surface in relation to the hemispheres prior to surgery: more than 40 % is a critical value, because most of the later retarded children belonged to this radiological subgroup and only half of the later normal patients. After surgery, there was a distinct correlation between developmental outcome and parenchymal surface and its absolute increase in cm(2): most of those who had a normal outcome had a parenchymal surface of more than 40 cm(2) in the third trimenon and an increase of 20 cm(2) and more within six months post surgery, whereas this was the case in only 40 - 50 % of the retarded patients. CONCLUSIONS: In most young infants with hydrocephalus there is more brain mass than the ventricular enlargement suggests. The prognostic value of quantitative evaluation of neuroimaging should not be overestimated. Nevertheless, some prognostication in this age group is possible prior to surgery by measurement of ventricular area in relation to the hemispheres and after surgery by measurement of the parenchymal area and its increase in cm(2).

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The addition of angiotensin II (AII) and angiotensin III (AIII) to isolated tissue baths produced the same maximal contractile response of rabbit aortic strips. AIII was about 10 times less potent, the slope of its concentration-response curve was less steep and its rate of onset slower than that of AII. The responses of both AII and AIII were inhibited with equal potency by the surmountable AII antagonist Phe4, Tyr8-AII and its unsurmountable analog Sar1, Leu8-AII but the kinetic patterns of inhibition by both were less well defined with the agonist AIII than with AII. The addition of AIII to tissues which had exhibited a maximal response to AII did not increase the level of contraction, in contrast to the case when norepinephrine was added to tissues contracted by AII. Both AII and AIII displaced [125I]AII binding from rabbit adrenal membranes; AIII was 6 times less potent than AII but displayed competitive kinetics as an inhibitor of [125I]AII binding. In further studies two binding sites for [125I]AII were identified in adrenal membranes, having KD values of 2.0 +/- 0.2 and 19.6 +/- 2.3 nM, respectively. Each site was inhibited by both AII and AIII and the ratio of the apparent Ki values for the two hormones was not significantly different. The Hill coefficient for the high affinity site was, however, lower for AIII than AII. We interpret our data to suggest that AII and AIII act on the same receptors. AIII apparently binds less efficiently than does AII in both rabbit adrenal membranes and rabbit aortic strips.

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Fenoldopam (SK&F 82526) is a potent and selective dopamine DA-1 agonist with demonstrated renal vasodilator and antihypertensive activities in experimental animals and humans. Fenoldopam is a racemic mixture of two enantiomers, SK&F R-82526 and SK&F S-82526. The R-enantiomer is uniformly reported to be more potent than the racemate; in contrast, there is controversy regarding potency of the S-enantiomer. In these studies, the renal and systemic hemodynamic activities of fenoldopam and its enantiomers are characterized in anesthetized, phenoxybenzamine-treated dogs. The results show that the renal and systemic vasodilator activities of fenoldopam are properties of the R-enantiomer; the S-enantiomer is essentially inactive. The renal and systemic vasodilator properties of SK&F R-82526 are antagonized in a competitive fashion by the DA-1 antagonist, SK&F R-83566, but not the DA-2 antagonist, domperidone. Ganglionic blockade did not attenuate renal vasodilation associated with SK&F R-82526. Thus, the mechanism of SK&F R-82526-associated vasodilation, like that previously established for fenoldopam, is via stimulation of postganglionic DA-1 receptors.

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The purpose of this study was to define in a systematic experimental manner the minimal amino acid domain(s) present in the angiotensin II molecule that are required for binding to, as well as activation of, its receptor at physiological concentrations. Although removal of the C-terminal phenylalanine residue markedly reduced affinity for the rabbit adrenal cortical receptor, sequential additions of amino acids beginning with phenylalanine did not result in a molecule with significant receptor affinity until the hexapeptide stage was reached. Similar receptor affinities were obtained with the other two possible 6 amino acid fragments in the molecule. None of the possible pentapeptide fragments were active, as was also the case with representative 4, 3 and 2 amino acid sequences. Of the three hexapeptides, only the one containing phenylalanine as the C-terminal amino acid displayed agonist activity on the rabbit aortic strip. The other two behaved as competitive antagonists. These results indicate that 6 amino acids constitute the minimal receptor binding domain present in the angiotensin II molecule and that phenylalanine is crucial at the C-terminus for activating the receptor.

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Angiotensin II (AII) labeled with 125I binds to rabbit adrenal cortical membranes over a concentration range from 0.5 to 20 nM at an apparent single site with a KD of 5 nM. This binding was inhibited in a surmountable fashion with respect to AII by the peptide analogs sarcosine1 (Sar1),Leu8AII and Phe4, Tyr8 AII when added to the incubation media concomitant with AII addition. With a 30-min preincubation, however, the former inhibitor displayed nonsurmountable kinetics whereas the profile of the latter was unaffected. In rabbit aortic strips with the same preincubation time, the Sar1Leu8AII analog was a nonsurmountable antagonist of the contractile effect of AII whereas the inhibition produced by Phe4,Tyr8AII was surmountable by increasing agonist (AII) concentrations. The inhibitory effect of the former was maintained after repeated washing of the tissue whereas that of the latter was readily reversible. Addition of Phe4,Tyr8AII to the bath 5 min before preincubation protected the tissue from the prolonged AII inhibition by Sar1,Leu8AII. These findings indicate different kinetic modes of AII inhibition by these two antagonists. Phe4,Tyr8AII behaves as a reversible, competitive inhibitor of AII binding, whereas Sar1,Leu8AII combines with the AII receptor in a slowly dissociable manner and is therefore not readily displaced by AII.

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