The Phox Homology (PX) domain-dependent, 3-phosphoinositide-mediated association of sorting nexin-1 with an early sorting endosomal compartment is required for its ability to regulate epidermal growth factor receptor degradation

Recent studies have shown that phox homology (PX) domains act as phosphoinositide-binding motifs. The majority of PX domains studied show binding to phosphatidylinositol 3-monophosphate (Ptdlns(3)P), an association that allows the host protein to localize to membranes of the endocytic pathway. One issue, however, is whether PX domains may have alternative phosphoinositide binding specificities that could target their host protein to distinct subcellular compartments or allow their allosteric regulation by phosphoinositides other than PtdIns(3)P. It has been reported that the PX domain of sorting nexin 1 (SNX1) specifically binds phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P-3) (Zhong, Q., Lazar, C. S., Tronchere, H., Sato, T., Meerloo, T., Yeo, M., Songyang, Z., Emr, S. D., and Gill, G. N. (2002) Proc. Natl. Acad. Sci. U. S. A. 99,6767-6772). In the present study, we have shown that whereas SNX1 binds PtdIns(3,4,5)P-3 in protein:lipid overlay assays, in liposomes-based assays, binding is observed to PtdIns(3)P and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P-2) but not to PtdIns(3,4,5)P-3. To address the significance of PtdIns(3,4,5)P-3 binding, we examined the subcellular localization of SNX1 under conditions in which plasma membrane PtdIns(3,4,5)P-3 levels were significantly elevated. Under these conditions, we failed to observe association of SNX1 with this membrane. However, consistent with the binding to PtdIns(3)P and PtdIns(3,5)P-2 being of more physiological significance was the observation that the association of SNX1 with an early endosomal compartment was dependent on a 3-phosphoinositide-binding PX domain and the presence of PtdIns(3)P on this compartment. Finally, we somal association of SNX1 is important for its ability to regulate the targeting of internalized epidermal growth factor receptor for lysosomal degradation.

Social structure in migrating humpback whales (Megaptera novaeangliae)

Although largely solitary, humpback whales exhibit a number of behaviours where individuals co-operate with one another, for example during bubble net feeding. Such cases could be due to reciprocal altruism brought on by exceptional circumstances, for example the presence of abundant shoaling fish. An alternative explanation is that these behaviours have evolved through kin selection. With little restriction to either communication or movement, diffuse groups of relatives could maintain some form of social organization without the need to travel in tight-nit units. To try to distinguish between these hypotheses, we took advantage of the fact that migrating humpback whales often swim together in small groups. If kin selection is important in humpback whale biology, these groups should be enriched for relatives. Consequently, we analysed biopsy samples from 57 groups of humpback whales migrating off Eastern Australia in 1992. A total of 142 whales were screened for eight microsatellite markers. Mitochondrial DNA sequences (371 bp) were also used to verify and assist kinship identification. Our data add support to the notion that mothers travel with their offspring for the first year of the calf's life. However, beyond the presence of mother-calf/yearling pairs, no obvious relatedness pattern was found among whales sampled either in the same pod or on the same day. Levels of relatedness did not vary between migratory phases (towards or away from the breeding ground), nor between the two sexes considered either overall or in the north or south migrations separately. These findings suggest that, if any social organization does exist, it is formed transiently when needed rather than being a constant feature of the population, and hence is more likely based on reciprocal altruism than kin selection.

The politics of suffering: Progress, modernity and the adolescent crisis

A concern for progress is central to the public agendas of modern societies. Political actors compete with one another mainly with regard to their respective claims to bring about a better future, particularly in the economic and technological spheres. The focus on progress has, however, deeper roots which date back to the aspirations of the Enlightenment. Around that time, the belief arose that systematic improvements are made possible by the structural features of modern society and culture, improvements that will gradually release humanity from much of the suffering characterising its historical past. This article argues the persistence of a culture of progress, rather than easing suffering, in fact enhances and mobilises it for the pursuit of superficial forms of gain. It is also claimed the attempt by Habermas' critical theory to develop a broader and more satisfactory conception of progress fails to address this problem. The article suggests an alternative and more fundamental critique of progressive ideas is required. It reflects upon these abstract theoretical questions in connection with the concrete example of the 'adolescent crisis' and the role ideas of progress play within it.

Expression of MUC1 splice variants in benign and malignant ovarian tumours

MUC1 is expressed on the surface of ovarian cancer cells. Nine different splice variants of MUC1 have been described, but no study has reported on the expression of MUC1 iso-forms in human ovarian cancer. Our study compares patterns of expression of MUC1 splice variants of malignant and benign ovarian tumours. Ovarian tissue samples were taken from patients with benign ovarian tumours (n = 34) and from patients who had surgery for primary (n = 47) or recurrent (n = 8) ovarian cancer. RT-PCR for MUC1 splice variants A, B, C, D, X, Y, Z, REP and SEC was performed and their expression compared to clinical and histopathologic parameters. Variants A, D, X, Y and Z were more frequently expressed in malignant than in benign tumours. All primary ovarian cancer cases were positive for variant REP but negative for variant SEC. No significant association of the expression of MUC1 splice variants with the response to chemotherapy or patient survival could be demonstrated. Expression of MUC1 splice variants A, D, X, Y, Z and REP is associated with the presence of malignancy, whereas expression of MUC1/SEC is associated with the absence of malignancy. (C) 2002 Wiley-Liss, Inc.

Dual mode cooling house in the warm humid tropics

Passive techniques as an alternative to artificial cooling can bring important energy, environmental, financial, operational and qualitative benefits. However, regions such as the wet tropics can reach high levels of thermal stress in which passive means alone are unable to provide appropriate thermal comfort standards for some parts of the year. Despite a great accumulation of empirical information on the passive performance of houses for either free-running or conditioned modes, very little work has been done on the thermal performance of buildings that can operate with a mixed-running strategy in warm-humid climates. Buildings with such design features are able to balance the needs for comfort, privacy, and energy efficiency during different periods of the year. As free-running and conditioned modes are believed by many to be 'opposite' approaches, and have been presented as separate strategies, this paper demonstrates that not all parameters are directly opposite and a possible dual-mode integrated operation can be used for warm-humid locations for maximum comfort and minimum energy requirements. For this purpose, simulation runs using ESP-R (University of Strathclyde, ESRU, UK) were based on the climate data of Darwin (Australia) and on the ventilation styles of the house: free running and conditioned. Design features applicable to both, i.e. for a dual mode operation could be identified and the differences between conditioned and free running were demonstrated and proved not to be totally conflicting and therefore suitable for a dual mode operation. Different daily usage profiles (five use patterns were defined), and zoning of sleeping and living areas are presented. The dual mode use patterns compared to the base case house, for all the user possibilities, had improved performances of 17-52%, when compared to the free-running mode and 66-98% when compared to the conditioned mode. Simulation runs using other warm-humid climates (Miami, USA; Sao Luis, Brazil; Kuala Lumpur, Malaysia) were also conducted and compared to the results found for Darwin. (C) 2002 Elsevier Science Ltd. All rights reserved.

Comparison of two population pharmacokinetic programs, NONMEM and P-PHARM, for tacrolimus

Objectives: To compare the population modelling programs NONMEM and P-PHARM during investigation of the pharmacokinetics of tacrolimus in paediatric liver-transplant recipients. Methods: Population pharmacokinetic analysis was performed using NONMEM and P-PHARM on retrospective data from 35 paediatric liver-transplant patients receiving tacrolimus therapy. The same data were presented to both programs. Maximum likelihood estimates were sought for apparent clearance (CL/F) and apparent volume of distribution (V/F). Covariates screened for influence on these parameters were weight, age, gender, post-operative day, days of tacrolimus therapy, transplant type, biliary reconstructive procedure, liver function tests, creatinine clearance, haematocrit, corticosteroid dose, and potential interacting drugs. Results: A satisfactory model was developed in both programs with a single categorical covariate - transplant type - providing stable parameter estimates and small, normally distributed (weighted) residuals. In NONMEM, the continuous covariates - age and liver function tests - improved modelling further. Mean parameter estimates were CL/F (whole liver) = 16.3 1/h, CL/F (cut-down liver) = 8.5 1/h and V/F = 565 1 in NONMEM, and CL/F = 8.3 1/h and V/F = 155 1 in P-PHARM. Individual Bayesian parameter estimates were CL/F (whole liver) = 17.9 +/- 8.8 1/h, CL/F (cutdown liver) = 11.6 +/- 18.8 1/h and V/F = 712 792 1 in NONMEM, and CL/F (whole liver) = 12.8 +/- 3.5 1/h, CL/F (cut-down liver) = 8.2 +/- 3.4 1/h and V/F = 221 1641 in P-PHARM. Marked interindividual kinetic variability (38-108%) and residual random error (approximately 3 ng/ml) were observed. P-PHARM was more user friendly and readily provided informative graphical presentation of results. NONMEM allowed a wider choice of errors for statistical modelling and coped better with complex covariate data sets. Conclusion: Results from parametric modelling programs can vary due to different algorithms employed to estimate parameters, alternative methods of covariate analysis and variations and limitations in the software itself.

Cyclosporin monitoring in Australasia: 2002 update of consensus guidelines

Therapeutic drug monitoring of cyclosporin (CsA) has been established as part of the routine clinical treatment of patients following organ transplantation for more than 20 years, and based on contemporary knowledge, many consensus guidelines have been published to assist clinics and laboratories attain optimal strategies for patient care. This article addresses the newer directions in CsA monitoring, with particular reference to the Australasian situation that has evolved since the 1993 Australasian guideline (1). These changes have included the introduction of alternative assay methodologies, changed CsA formulation from Sandimmun to Neoral throughout Australasia, and alternatives to trough concentration (C0) monitoring, especially 2-hour concentration (C2) monitoring and associated validated dilution protocols to accurately quantitate the higher whole blood CsA concentrations. The revision was prepared following a recent survey of all Australasian CsA-monitoring laboratories (2) where discordant practices were evident.

Crisis, change, and institutions in forest management: the Wet Tropics of northeastern Australia

This paper tests the four-phase heuristic model of change in resource management regimes developed by Gunderson et al. (1995. In: Barriers and Bridges to the Renewal of Ecosystems and Institutions. Columbia University Press, New York, pp. 489-533) by applying it to a case analysis of rainforest management in northeastern Australia. The model suggests that resource management regimes change in four phases: (i) crisis caused by external factors, (ii) a search for alternative management solutions, (iii) creation of a new management regime, and (iv) bureaucratic implementation of the new arrangements. The history of human use arid management of the tropical forests of this region is described and applied to this model. The ensuing analysis demonstrates that: (i) resource management tends to be characterized by a series of distinct eras; (ii) changes to management regimes are precipitated by crisis; and (iii) change is externally generated. The paper concludes by arguing that this theoretical perspective oil institutional change in resource management systems has wider utility. (C) 2002 Elsevier Science Ltd. All rights reserved.

Are tryptophan and 5-hydroxytryptophan effective treatments for depression? A meta-analysis

Objective: To review the literature regarding the effectiveness of 5-hydroxytryptophan (5-HT) and L-tryptophan in the treatment of unipolar depression. Methods: A systematic review of the literature from 1966 to 2000 using the search terms 'tryptophan', 5-hydroxytryptophan', '5-HTP', '5-HT' and 'depression'. We extracted and grouped data for meta-analysis by pooling odds ratios (OR) and relative risks where possible. Results: One hundred and eight studies were located of which only two studies, one of 5-HT and one of L-tryptophan, with a total of 64 patients met sufficient quality criteria to be included. These studies suggest 5-HT and L-tryptophan are better than placebo at alleviating depression (Peto OR = 4.1, 95% CI = 1.3-13.2). However, the small size of the studies, and the large number of inadmissible, poorly executed studies, casts doubt on the result from potential publication bias, and suggests that they are insufficiently evaluated to assess their effectiveness. Conclusions: A large body of evidence was subjected to very basic criteria for assessing reliability and validity, and was found to largely be of insufficient quality to inform clinical practice. More well-designed studies are urgently required to enable an assessment of what may be an effective class of agents.

Transport safety for older people: A study of their experiences, perceptions and management needs

With evidence of increasing accident risk due to age-related declines in health and cognition affecting driver performance, there is a need for research promoting safe mobility of older people. The present study aimed to identify transport options and licensing issues for a group of older people in an Australian community. Ninety-five participants aged 75 and over were interviewed about their driving status and accident record and tested for cognitive ability. After stratification on cognitive level and driver status (current, ex-driver or non-driver), 30 were selected for further in-depth interviews concerning demographics, licence status and impact of change, travel options available and used, and travel characteristics. Considerable reliance on the motor vehicle as the mode of transport and the decision to cease driving were major quality-of-life issues. There was little evidence of planning and support in making the decision to stop driving. Some differences in transport decisions on the basis of cognitive level were evident; however, people with severely compromised cognitive ability (and, therefore, unable to give informed consent) had been excluded. The study suggested the need for resources to assist older people/carers/health professionals to plan for the transition from driver to non-driver and to manage alternative transport options more effectively

The intuitive basis of implicature: relevance theoretic implicitness versus gricean implying

The notion of implicature was first introduced by Paul Grice (1967, 1989), who defined it essentially as what is communicated less what is said. This definition contributed in part to the proliferation of a large number of different species of implicature by neo-Griceans. Relevance theorists have responded to this by proposing a shift back to the distinction between "explicit" & "implicit" meaning (corresponding to "explicature" & "implicature," respectively). However, they appear to have pared down the concept of implicature too much, ignoring phenomena that may be better treated as implicatures in their overgeneralization of the concept of explicature. These problems have their roots in the fact that explicit & implicit meaning intuitively overlap & thus do not provide a suitable basis for distinguishing implicature from other types of pragmatic phenomena. An alternative conceptualization of implicature based on the concept of "implying" with which Grice originally associated his notion of implicature is thus proposed. From this definition, it emerges that implicature constitutes something else inferred by the addressee that is not literally said by the speaker. Instead, it is meant in addition to what the speaker literally says & is consequently defeasible like all other types of pragmatic phenomena. 1 Figure, 60 References. Adapted from the source document

General practitioner attitudes to case conferences: how can we increase participation and effectiveness?

Objectives: To identify general practitioners' views on the barriers to using case conferencing (as outlined in the Medical Benefits Schedule (MBS) Enhanced Primary Care package) and to develop a set of principles to encourage greater GP participation in case conferences. Design: Qualitative study, involving semistructured questions administered to focus groups of GPs, conducted between April and July 2001 as part of a broader study of case coordination in palliative care. Participants: 29 GPs from urban, regional, and rural areas of Queensland. Principal findings: Many of the GPs' work practices militated against participation in traditionally structured case conferences. GPs thought the range of MBS item numbers should be expanded to cover alternative methods of liaison (eg, phone consultations with other service providers). The onerous bureaucratic processes required to claim reimbursement were an additional disincentive. Conclusions: GPs would probably be more likely to participate in case conferences if they were initiated by specialist services and arranged more flexibly to suit GP work schedules.