Publications by authors named "Sanner M"

87 Publications

Comparing 4 classification systems for drug-related problems: processes and functions.

Res Social Adm Pharm 2008 Dec 8;4(4):320-31. Epub 2008 Aug 8.

Department of Public Health and Caring Sciences, Uppsala Science Park, 751 85 Uppsala, Sweden.

Background: Counseling patients on drug-related problems (DRPs) is a new enterprise for pharmacists. Accordingly, a variety of classification systems have been created to document DRPs. This aroused our interest in finding out how classification systems differ.

Objective: The objective is to explore and describe the characteristics of 4 classification systems for DRPs to understand their similarities and differences with regard to processes and functions.

Methods: Four established classification systems were selected; they were Strand, Granada-II, Pharmaceutical Care Network Europe v5.0, and Apoteket. To gain experience of the use of the systems, an existing database containing documented problems that were identified during patient counseling at community pharmacies was used. The entries in the database were classified using the 4 selected classification systems, one at a time. In the following analysis, focus was set on what issues were classified and how they were classified in each system. Based on similarities and differences, 8 themes were identified and characteristics of the 4 systems were listed according to these themes. Characteristics of each system were thoroughly scrutinized and interpreted.

Results: The processes of selecting classification categories were different in all 4 systems, and as a result the contents of categories in systems were different. The systems had different characteristics and a decisive characteristic was whether the patients were involved in the classification of problems or not. Because of the different characteristics the systems had different functions.

Conclusions: To understand the usefulness of a classification system, both structure of categories and work process must be considered. The studied systems had different functions that revealed different aims embedded in the systems. To develop the counseling role of pharmacists, a limited number of classification systems would be beneficial. To get there, common aims and common systems must be developed.
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http://dx.doi.org/10.1016/j.sapharm.2007.10.006DOI Listing
December 2008

Shape complementarity of protein-protein complexes at multiple resolutions.

Proteins 2009 May;75(2):453-67

Department of Molecular Biology, The Scripps Research Institute 10550 North Torrey Pines Road, mail MB-5, La Jolla, California 92037, USA.

Biological complexes typically exhibit intermolecular interfaces of high shape complementarity. Many computational docking approaches use this surface complementarity as a guide in the search for predicting the structures of protein-protein complexes. Proteins often undergo conformational changes to create a highly complementary interface when associating. These conformational changes are a major cause of failure for automated docking procedures when predicting binding modes between proteins using their unbound conformations. Low resolution surfaces in which high frequency geometric details are omitted have been used to address this problem. These smoothed, or blurred, surfaces are expected to minimize the differences between free and bound structures, especially those that are due to side chain conformations or small backbone deviations. Despite the fact that this approach has been used in many docking protocols, there has yet to be a systematic study of the effects of such surface smoothing on the shape complementarity of the resulting interfaces. Here we investigate this question by computing shape complementarity of a set of 66 protein-protein complexes represented by multiresolution blurred surfaces. Complexed and unbound structures are available for these protein-protein complexes. They are a subset of complexes from a nonredundant docking benchmark selected for rigidity (i.e. the proteins undergo limited conformational changes between their bound and unbound states). In this work, we construct the surfaces by isocontouring a density map obtained by accumulating the densities of Gaussian functions placed at all atom centers of the molecule. The smoothness or resolution is specified by a Gaussian fall-off coefficient, termed "blobbyness." Shape complementarity is quantified using a histogram of the shortest distances between two proteins' surface mesh vertices for both the crystallographic complexes and the complexes built using the protein structures in their unbound conformation. The histograms calculated for the bound complex structures demonstrate that medium resolution smoothing (blobbyness = -0.9) can reproduce about 88% of the shape complementarity of atomic resolution surfaces. Complexes formed from the free component structures show a partial loss of shape complementarity (more overlaps and gaps) with the atomic resolution surfaces. For surfaces smoothed to low resolution (blobbyness = -0.3), we find more consistency of shape complementarity between the complexed and free cases. To further reduce bad contacts without significantly impacting the good contacts we introduce another blurred surface, in which the Gaussian densities of flexible atoms are reduced. From these results we discuss the use of shape complementarity in protein-protein docking.
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http://dx.doi.org/10.1002/prot.22256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928789PMC
May 2009

Two perspectives on organ donation: experiences of potential donor families and intensive care physicians of the same event.

J Crit Care 2007 Dec 5;22(4):296-304. Epub 2007 Jul 5.

Department of Public Health and Caring Sciences, Health Services Research Unit, Uppsala University, SE-751 85 Uppsala, Sweden.

The aim was to explore how relatives and physicians understood cases where organ donation had been requested and what factors were salient for the decision on donation. Physicians of 25 deceased patients and 20 relatives were interviewed. The material was analyzed using qualitative methods. Eleven patients had declared their wishes on donation before death; in 14 cases the relatives had to decide. Half of these relatives accepted donation and half refused. The donation request was of secondary importance to the families; they were totally occupied by the death and initially tried to avoid the request by regarding "no" as a nonresponse. They needed support to relieve their immediate reactions of uneasiness, start rational thought processes, and reach well-grounded answers. The basis for requesting donation was good; relatives, with regard to circumstances, had been well prepared for the death by continuous information from the physicians and had confidence in staff, accepted that the question was raised, and understood the death criteria. However, about half the physicians experienced conflicts regarding prerequisites of procuring organs and dealing with relatives. Three different approaches were displayed: prodonation, neutral, and ambivalent. Only physicians with a prodonation approach received acceptance for donation.
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http://dx.doi.org/10.1016/j.jcrc.2007.03.002DOI Listing
December 2007

Protein-ligand docking with multiple flexible side chains.

J Comput Aided Mol Des 2008 Sep 22;22(9):673-9. Epub 2007 Nov 22.

Department of Molecular Biology, TPC26, The Scripps Research Institute, 10550 North Torrey Pine Rd, La Jolla, CA, 92037-1000, USA.

In this work, we validate and analyze the results of previously published cross docking experiments and classify failed dockings based on the conformational changes observed in the receptors. We show that a majority of failed experiments (i.e. 25 out of 33, involving four different receptors: cAPK, CDK2, Ricin and HIVp) are due to conformational changes in side chains near the active site. For these cases, we identify the side chains to be made flexible during docking calculation by superimposing receptors and analyzing steric overlap between various ligands and receptor side chains. We demonstrate that allowing these side chains to assume rotameric conformations enables the successful cross docking of 19 complexes (ligand all atom RMSD < 2.0 A) using our docking software FLIPDock. The number of side receptor side chains interacting with a ligand can vary according to the ligand's size and shape. Hence, when starting from a complex with a particular ligand one might have to extend the region of potential interacting side chains beyond the ones interacting with the known ligand. We discuss distance-based methods for selecting additional side chains in the neighborhood of the known active site. We show that while using the molecular surface to grow the neighborhood is more efficient than Euclidian-distance selection, the number of side chains selected by these methods often remains too large and additional methods for reducing their count are needed. Despite these difficulties, using geometric constraints obtained from the network of bonded and non-bonded interactions to rank residues and allowing the top ranked side chains to be flexible during docking makes 22 out of 25 complexes successful.
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http://dx.doi.org/10.1007/s10822-007-9148-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828239PMC
September 2008

A dynamical study of antibody-antigen encounter reactions.

Phys Biol 2007 Oct 2;4(3):172-80. Epub 2007 Oct 2.

Dipartimento di Fisica, Università di Firenze, V. G. Sansone 1, 50019 Firenze, Italy.

The effects of internal dynamics in diffusion-driven encounters between macro-molecules represent a problem of broad relevance in molecular biology. In this view, we investigate a typical antigen-antibody reaction chain, based on a coarse-grained mechanical model parameterized directly upon results from single-molecule experiments. We demonstrate that the internal dynamics is a crucial factor in the encounter process. To describe our numerical results, we formulate a simple, intuitive theoretical framework, and we develop it analytically. This enables us to show that the inner dynamics of antibody molecules results in a cooperative behavior of their individual sub-units. Along the same lines, we also investigate the case of double binding to multi-valent antigens. Our results quantify the enhancement of avidity afforded by the double binding in excellent agreement with the available experimental data.
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http://dx.doi.org/10.1088/1478-3975/4/3/004DOI Listing
October 2007

FLIPDock: docking flexible ligands into flexible receptors.

Proteins 2007 Aug;68(3):726-37

Department of Molecular Biology, TPC26, The Scripps Research Institute, La Jolla, CA 92037-1000, USA.

Conformational changes of biological macromolecules when binding with ligands have long been observed and remain a challenge for automated docking methods. Here we present a novel protein-ligand docking software called FLIPDock (Flexible LIgand-Protein Docking) allowing the automated docking of flexible ligand molecules into active sites of flexible receptor molecules. In FLIPDock, conformational spaces of molecules are encoded using a data structure that we have developed recently called the Flexibility Tree (FT). While the FT can represent fully flexible ligands, it was initially designed as a hierarchical and multiresolution data structure for the selective encoding of conformational subspaces of large biological macromolecules. These conformational subspaces can be built to span a range of conformations important for the biological activity of a protein. A variety of motions can be combined, ranging from domains moving as rigid bodies or backbone atoms undergoing normal mode-based deformations, to side chains assuming rotameric conformations. In addition, these conformational subspaces are parameterized by a small number of variables which can be searched during the docking process, thus effectively modeling the conformational changes in a flexible receptor. FLIPDock searches the variables using genetic algorithm-based search techniques and evaluates putative docking complexes with a scoring function based on the AutoDock3.05 force-field. In this paper, we describe the concepts behind FLIPDock and the overall architecture of the program. We demonstrate FLIPDock's ability to solve docking problems in which the assumption of a rigid receptor previously prevented the successful docking of known ligands. In particular, we repeat an earlier cross docking experiment and demonstrate an increased success rate of 93.5%, compared to original 72% success rate achieved by AutoDock over the 400 cross-docking calculations. We also demonstrate FLIPDock's ability to handle conformational changes involving backbone motion by docking balanol to an adenosine-binding pocket of protein kinase A.
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http://dx.doi.org/10.1002/prot.21423DOI Listing
August 2007

False-reactive microbiologic screening test results in Swedish blood donors-how big is the problem? A survey among blood centers and deferred donors.

Transfusion 2007 Jan;47(1):80-9

Department of Medicine, Infectious Diseases Unit, Karolinska Institutet, Karolinska University Hospital-Solna, Stockholm, Sweden.

Background: Screening of blood donors for markers of transfusion-transmissible infectious agents leads to a varying number of false-reactive test results and sometimes thereby temporary or permanent deferral of donors and also to loss of collected units.

Study Design And Methods: Data on false-reactive screening test results in 2002 and 2003 were collected from 19 blood centers in Sweden. A questionnaire was sent to donors deferred because of false-reactive screening test results to investigate their perception of the information and their reaction to the deferral.

Results: Testing of 21,189 samples from new donors and 423,543 donations from regular and/or repeat donors produced 1,059 false-reactive test results, mostly from hepatitis C virus antibody testing, and 299 deferrals. Six different human immunodeficiency virus tests led to between 0.02 and 0.2 percent false-reactive results. The deferral rate varied considerably between different counties. Of 204 deferred donors contacted, 180 (88%) answered the questionnaire. More than 80 percent were worried about their test results and worry was more common among those who did not feel sufficiently informed.

Conclusion: The results imply that there is a need for a more standardized approach to the screening of blood donors and donations with the aim of minimizing the number of false-reactive screening test results. They also emphasize the importance of appropriate information and support to deferred donors.
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http://dx.doi.org/10.1111/j.1537-2995.2007.01067.xDOI Listing
January 2007

Hierarchical and multi-resolution representation of protein flexibility.

Bioinformatics 2006 Nov 18;22(22):2768-74. Epub 2006 Sep 18.

Department of Molecular Biology, TPC26, The Scripps Research Institute La Jolla, CA, USA.

Motivation: Conformational rearrangements during molecular interactions are observed in a wide range of biological systems. However, computational methods that aim at simulating and predicting molecular interactions are still largely ignoring the flexible nature of biological macromolecules as the number of degrees of freedom is computationally intractable when using brute force representations.

Results: In this article, we present a computational data structure called the Flexibility Tree (FT) that enables a multi-resolution and hierarchical encoding of molecular flexibility. This tree-like data structure allows the encoding of relatively small, yet complex sub-spaces of a protein's conformational space. These conformational sub-spaces are parameterized by a small number of variables and can be searched efficiently using standard global search techniques. The FT structure makes it straightforward to combine and nest a wide variety of motion types such as hinge, shear, twist, screw, rotameric side chains, normal modes and essential dynamics. Moreover, the ability to assign shapes to the nodes in a FT allows the interactive manipulation of flexible protein shapes and the interactive visualization of the impact of conformational changes on the protein's overall shape. We describe the design of the FT and illustrate the construction of such trees to hierarchically combine motion information obtained from a variety of sources ranging from experiment to user intuition, and describing conformational changes at different biological scales. We show that the combination of various types of motion helps refine the encoded conformational sub-spaces to include experimentally determined structures, and we demonstrate searching these sub-spaces for specific conformations.
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http://dx.doi.org/10.1093/bioinformatics/btl481DOI Listing
November 2006

Obstacles to organ donation in Swedish intensive care units.

Intensive Care Med 2006 May 21;32(5):700-7. Epub 2006 Mar 21.

Department of Public Health and Caring Sciences, Unit of Health Services Research, Uppsala University, and Department of Anaesthesiology and Intensive Care, Orebro University Hospital, Sweden.

Objective: To identify obstacles to organ donation in Swedish intensive care units.

Design: A survey exploring attitudes and experiences of organ donation activities was sent to half of all anaesthetists and all neurosurgeons in Sweden (n=644). Total response rate was 67%; 69% from the anaesthetists and 54% from the neurosurgeons.

Results: Neurosurgeons had more experiences of caring for potential donors and requesting donation than anaesthetists. Twenty-seven percent of the anaesthetists were not confident with clinical neurological criteria for brain incarceration. Nine per cent found donation activities solely burdensome, and 14% wanted an external team to take over the donation request. A quarter regarded the request definitely as an extra load on the family, and more than half of the respondents had refrained from asking in emotionally strained situations. Forty-nine per cent had a neutral approach to relatives when requesting donation while 38% had a pro-donation approach. Thirty-six per cent terminated ventilator treatment for a potential donor without waiting for total brain infarction. Lack of resources in the ICUs resulted in not identifying a possible donor according to 29% of respondents. Knowing the prior wish of the deceased was regarded as the single most important factor that facilitated the work with organ donation for the intensivists.

Conclusions: The identified obstacles (neutral approach of donation request, ethical problems concerning the potential donor and the relatives, varying competence in diagnosing total brain infarction, and lack of intensive care bed resources) require tailored efforts in order to increase organ donation. Checking these factors can be used as a quality control when analysing donation activities at hospitals.
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http://dx.doi.org/10.1007/s00134-006-0126-5DOI Listing
May 2006

[Obstacles for recruiting organ donors in intensive care units can be overcomed. Identified obstacles are attitudes, ethics, resources and competence, as shown by an inquiry].

Lakartidningen 2005 Nov 7-13;102(45):3300-2, 3304-5

Institutionen för folkhälso- och värdvetenskap, enheten för hälso- och sjukvårdsforskning, Uppsala universitet, Sweden.

The aim of this study was to identify obstacles for recruiting organ donors in the ICU. All specialists in neurosurgery and half of the specialists in anaesthesiology in Sweden were surveyed. Response rate was 67%. The following obstacles were identified: A neutral approach of the physicians when requesting organ donation of the families instead of a pro-donation approach; ethical problems concerning non-therapeutic ventilation and requesting donation of grieving families; varying competence in diagnosing brain infarction; lack of resources at the ICU. Suggestions for organizational and educational improvements are given.
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January 2006

[Non-therapeutic ventilation of potential donor is ethically acceptable. It allows time to consider for both the family and the personnel].

Lakartidningen 2005 May 2-15;102(18-19):1411-2, 1414-6

Linköpings universitet.

In the debate on organ donation it has been argued that all medical care of patients in intensive care units should be undertaken solely for the good of the patient and that it is wrong to initiate non-therapeutic ventilation in order that such a patient may later become an organ donor. We argue against this view. We think the ethically relevant instant is not the time of death but the point where the physicians deem it pointless to undertake curative measures. We envisage two cases for such non-therapeutic ventilation. One is when a patient is deemed to be in a terminal state (for example after having suffered significant intra-cranial bleeding), and there are no curative measures to be taken. In this case the patient is unconscious and the decision for ventilator treatment must be taken with short notice. Here we recommend that such patients are put on ventilators and the relatives are consulted afterwards. The other case is when a patient, already ventilated, is in a terminal state, unconscious, and the physicians deem that curative measures no longer can be taken. In this case we recommend that ventilation be continued. In both cases, such a policy might provide more organs for transplantation. It could benefit many and it will hurt no one.
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June 2005

Living with a stranger's organ--views of the public and transplant recipients.

Ann Transplant 2005 ;10(1):9-12

Department of Public Health and Caring Sciences, Uppsala Science Park, Uppsala, Sweden.

This comprehensive article is based on three previous studies on people's reactions on receiving transplants of various kinds: a survey of the public, in-depth interviews with informants recruited from this survey and two other surveys, and in-depth interviews with heart and kidney recipients. The ideas and reactions of the public, when confronted with the issue of receiving a transplant in a hypothetic situation, vary from magical thinking to a conception of the body as an object in need of repair. The actual recipients show a similar variation in their reactions as the public. However, there are some differences between the two groups that probably depend on the patient selection for transplantation, reality factors, acclimatization factors, and defense strategies to master anxiety-provoking thoughts about the donor and transplant. The most constructive of the ideas about the donor seems to be identification with positive traits, such as generosity and solidarity.
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July 2005

The donation process of living kidney donors.

Nephrol Dial Transplant 2005 Aug 26;20(8):1707-13. Epub 2005 Apr 26.

Department of Public Health and Caring Sciences, Unit of Health Services Research, Uppsala University, Uppsala Science Park, SE-751 85 Uppsala, Sweden.

Background: The rates of both genetic and non-genetic living donors are increasing. However, previous research has almost exclusively explored the decision-making of genetic donors. Therefore, in this study both genetic and non-genetic donors are investigated with focus on their whole donation process.

Methods: Thirty-nine donors were interviewed the day before nephrectomy and 3 weeks afterwards. Twenty-three donors were genetic relatives, 16 were not. The interviews were analysed qualitatively, mainly by narrative structuring.

Results: All donors but one passed seven steps in the donation process. They included: (i) awareness of suffering; compassion and empathy; (ii) imminence of transplantation; recognition of oneself as potential donor; (iii) information acquisition and deliberation; (iv) attribution of responsibility to oneself; announcement of decision to donate; (v) examination; maintaining the decision; (vi) facing nephrectomy; and (vii) postoperative experiences. Two types of decision-making were displayed: immediate and later announcement of decision. Half the donors belonged to each type. Various relationship groups displayed different types. The examination period was the most stressful time, partly due to imperfect coordination and excessive time-wasting. One-third found postoperative pain the most painful experience ever. There was a lack of attention to regressive needs and to recognition of the deed.

Conclusions: The two types of decision-making seem similar in ethical requirements. It is not a genetic or non-genetic relationship per se that determines what kind of decision the donors make. Psychological support, especially during Steps 5 and 7, should be improved and the donors included in a structured donation programme. Possible health care ambivalence toward living donation should not affect the donors.
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http://dx.doi.org/10.1093/ndt/gfh861DOI Listing
August 2005

Tangible augmented interfaces for structural molecular biology.

IEEE Comput Graph Appl 2005 Mar-Apr;25(2):13-7

The Scripps Research Institute, USA.

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http://dx.doi.org/10.1109/mcg.2005.47DOI Listing
April 2005

Tangible interfaces for structural molecular biology.

Structure 2005 Mar;13(3):483-91

The Scripps Research Institute, La Jolla, California 92037, USA.

The evolving technology of computer autofabrication makes it possible to produce physical models for complex biological molecules and assemblies. Augmented reality has recently developed as a computer interface technology that enables the mixing of real-world objects and computer-generated graphics. We report an application that demonstrates the use of autofabricated tangible models and augmented reality for research and communication in molecular biology. We have extended our molecular modeling environment, PMV, to support the fabrication of a wide variety of physical molecular models, and have adapted an augmented reality system to allow virtual 3D representations to be overlaid onto the tangible molecular models. Users can easily change the overlaid information, switching between different representations of the molecule, displays of molecular properties, or dynamic information. The physical models provide a powerful, intuitive interface for manipulating the computer models, streamlining the interface between human intent, the physical model, and the computational activity.
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http://dx.doi.org/10.1016/j.str.2005.01.009DOI Listing
March 2005

A component-based software environment for visualizing large macromolecular assemblies.

Authors:
Michel F Sanner

Structure 2005 Mar;13(3):447-62

Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.

The interactive visualization of large biological assemblies poses a number of challenging problems, including the development of multiresolution representations and new interaction methods for navigating and analyzing these complex systems. An additional challenge is the development of flexible software environments that will facilitate the integration and interoperation of computational models and techniques from a wide variety of scientific disciplines. In this paper, we present a component-based software development strategy centered on the high-level, object-oriented, interpretive programming language: Python. We present several software components, discuss their integration, and describe some of their features that are relevant to the visualization of large molecular assemblies. Several examples are given to illustrate the interoperation of these software components and the integration of structural data from a variety of experimental sources. These examples illustrate how combining visual programming with component-based software development facilitates the rapid prototyping of novel visualization tools.
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http://dx.doi.org/10.1016/j.str.2005.01.010DOI Listing
March 2005

Discovery and SAR of 2-aminothiazole inhibitors of cyclin-dependent kinase 5/p25 as a potential treatment for Alzheimer's disease.

Bioorg Med Chem Lett 2004 Nov;14(22):5521-5

Neuroscience Medicinal Chemistry and Pharmacology, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.

High-throughput screening with cyclin-dependent kinase 5 (cdk5)/p25 led to the discovery of N-(5-isopropyl-thiazol-2-yl)isobutyramide (1). This compound is an equipotent inhibitor of cdk5 and cyclin-dependent kinase 2 (cdk2)/cyclin E (IC(50)=ca. 320nM). Parallel and directed synthesis techniques were utilized to explore the SAR of this series. Up to 60-fold improvements in potency at cdk5 and 12-fold selectivity over cdk2 were achieved.
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http://dx.doi.org/10.1016/j.bmcl.2004.09.006DOI Listing
November 2004

Swedish medical students' views of the changing professional role of medical doctors and the organisation of health care.

Adv Health Sci Educ Theory Pract 2004 ;9(1):5-14

Department of Public Health and Caring Sciences, Section for Health Services Research, Uppsala Science Park, SE-751 85 Uppsala, Sweden.

Medical students will influence future health care considerably. Their professional orientation while at medical school will be related to their future professional development. Therefore, it is important to study this group's view of the role of medical doctors, especially because Swedish health care is currently undergoing major changes and financial cut backs. Here, the theoretical framework was contemporary theories of competence development, which has shown that people's understanding of their work influences their actions. The aim of this study was to describe medical students' views of their future professional role in health care. In total, 57 fourth-year medical students at a Swedish university were asked to write a short essay about how they conceptualised their professional role in future health care. Fifty-three students (93%) replied. The essays were analysed qualitatively in three steps and four themes were subsequently identified: the professional role in change, organisation of health care, working conditions and the possibilities of having a balanced life. Some factors mentioned that would strongly influence the professional role were being team leader, increased specialisation, supporting the patient and computer science and technology. The students expressed ambiguous feelings about power and leadership. The results indicate that the students share a rather dark view of both the medical profession and health care, which seems to be related to stress and financial cut backs. Mentoring, time for reflection and changes in the curricula might be needed.
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http://dx.doi.org/10.1023/B:AHSE.0000012207.88241.8bDOI Listing
March 2004

Transplant recipients' conceptions of three key phenomena in transplantation: the organ donation, the organ donor, and the organ transplant.

Clin Transplant 2003 Aug;17(4):391-400

Department of Public Health and Caring Sciences, Unit of Health Services Research, Uppsala Science Park, Uppsala, Sweden.

Thirty-five heart and kidney transplant patients were interviewed on five separate occasions during the first 2 yr after transplantation. The aim was to explore their experiences of phenomena that distinguish the transplantation from other kinds of medical treatment. The selection of informants was designed to permit comparisons between recipients with heart and kidney transplants and with living and necro-transplants. The qualitative analysis of the informants' reactions was focused on three themes; nine categories emerged. The first theme concerned general aspects of the donation and the donor and was differentiated in four categories: joy and sorrow, gratefulness and indebtedness, guilt, and inequity. The second theme related to the donor as a unique individual and included three categories: recognition and identification with the donor, influences of the donor, and relationship to the living donor. The third theme pertained to incorporation of the transplant and included two categories related to the naturalness of having a transplant, and the benevolent transplant. The informants' reactions were discussed in terms of primary and secondary processes. All informants were in an emotionally charged situation after transplantation and warded off anxiety-provoking impulses, most intensively during the first 6 months. Avoidance, suppression, and denial were the most common defence mechanisms, all of which seemed to be supported by the medical context. Other, more constructive strategies are suggested. The recipients' own interpretations of causes to possible personality changes are discussed. There were few differences between heart and necro-kidney patients concerning the reactions to the donation, the donor, and the transplant; the dividing line was more prominent between recipients with living and necro-transplants.
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http://dx.doi.org/10.1034/j.1399-0012.2003.00065.xDOI Listing
August 2003

Cdk5 as a drug target for the treatment of Alzheimer's disease.

J Mol Neurosci 2002 Dec;19(3):267-73

CNS Discovery, Pfizer Global Research and Development, Groton, CT 06340, USA.

Cyclin-dependent kinase-5 (cdk5) is suggested to play a role in tau phosphorylation and contribute to the pathogenesis of Alzheimer's disease (AD). One of its activators, p25, is dramatically increased in AD brains where p25 and cdk5 are colocalized with neurofibrillary tangles. Several animal models have shown a correlation of p25/cdk5 activities with tau phosphorylation. Overexpression of p25/cdk5 in nueronal cultures not only leads to tau phosphorylation but also cytoskeletal abnormalities and neurodegeneration. Therefore, cdk5 kinase inhibitors are potential therapeutic agents for the treatment of AD. Availability of potent, selective, brain permeable cdk5 inhibitors and relevant animal models in which their efficacy can be treated will be critical in the development of these inhibitors.
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http://dx.doi.org/10.1385/JMN:19:3:267DOI Listing
December 2002

A Swedish survey of young people's views on organ donation and transplantation.

Transpl Int 2002 Dec 5;15(12):641-8. Epub 2002 Nov 5.

Department of Public Health and Caring Sciences, Uppsala Science Park, 751 85 Uppsala, Sweden.

The aim of this study is to explore young people's attitudes, beliefs, and knowledge on organ donation and transplantation. A survey was conducted among 1,447 students aged 15-18 years in four urban areas in Sweden. Although students looked upon organ transplantation favorably, only 50% were willing to donate their own organs, and only 20% the organs of their parents. Concerning organ donation, 75% of the students expressed some discomfort. There were significant gender differences. About 70% of the students indicated that transplantation issues should be included in the school curriculum. It is concluded that teenagers feel irresolution and discomfort regarding organ donation after death, but concurrently see organ transplantation as a highly valued service. One way that this mental conflict can be resolved is through education. Educational programs in school must address this ambivalence and both mediate facts and help students to work through the fear and discomfort associated with organ donation.
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http://dx.doi.org/10.1007/s00147-002-0474-1DOI Listing
December 2002

Model of the alphaLbeta2 integrin I-domain/ICAM-1 DI interface suggests that subtle changes in loop orientation determine ligand specificity.

Proteins 2002 Aug;48(2):151-60

Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204-5001, USA.

The interaction of the alphaLbeta2 integrin with its cellular ligand the intercellular adhesion molecule-1 (ICAM-1) is critical for the tight binding interaction between most leukocytes and the vascular endothelium before transendothelial migration to the sites of inflammation. In this article we have modeled the alphaL subunit I-domain in its active form, which was computationally docked with the D1 domain of the ICAM-1 to probe potential protein-protein interactions. The experimentally observed key interaction between the carboxylate of Glu 34 in the ICAM-1 D1 domain and the metal ion-dependent adhesion site (MIDAS) in the open alphaL I-domain was consistently reproduced by our calculations. The calculations reveal the nature of the alphaLbeta2/ICAM-1 interaction and suggest an explanation for the increased ligand-binding affinity in the "open" versus the "closed" conformation of the alphaL I-domain. A mechanism for substrate selectivity among alphaL, alphaM, and alpha2 I-domains is suggested whereby the orientation of the loops within the I-domain is critical in mediating the interaction of the Glu 34 carboxylate of ICAM-1 D1 with the MIDAS.
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http://dx.doi.org/10.1002/prot.10134DOI Listing
August 2002

Evolutionary analysis of HIV-1 protease inhibitors: Methods for design of inhibitors that evade resistance.

Proteins 2002 Jul;48(1):63-74

Department of Molecular Biology, The Scripps Research Institute, La Jolla, California.

Drug-resistant strains are rapidly selected during AIDS therapy because of the high rate of mutation in HIV. In this report, we present an evolutionary simulation method for analysis of viral mutation and its use for optimization of HIV-1 protease drugs to improve their robustness in the face of resistance mutation. We first present an analysis of the range of resistant mutants that produce viable viruses by using a volume-based viral fitness model. Then, we analyze how this range of mutant proteases allows development of resistance to an optimal inhibitor previously designed by computational coevolution techniques. Finally, we evaluate the resistance patterns of commercially available drugs, and we discuss how resistance might be overcome by optimizing the size of specific side-chains of these inhibitors.
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http://dx.doi.org/10.1002/prot.10130DOI Listing
July 2002

Tau protein phosphorylation as a therapeutic target in Alzheimer's disease.

Curr Top Med Chem 2002 Apr;2(4):395-415

CNS Discovery, Pfizer Global Research and Development, Groton, CT 06340, USA.

Neurofibrillary tangles (NFTs) are a distinguishing neuropathological feature found in postmortem brains of Alzheimer s disease (AD) and tauopathy patients. The density of these lesions correlates with severity of AD and their distribution follows a characteristic pattern of expansion as the disease progresses. The principle components of NFTs are highly phosphorylated forms of the microtubule-associated protein, tau. Tau phosphorylation is believed to initiate or facilitate dissociation from microtubules leading to microtubule destabilization, decay of cellular transport properties, and cell death. This review summarizes recent data and prevailing views on the roles of protein kinases and phosphatases in the regulation of tau phosphorylation in vitro and in vivo, taking into account data from human neurodegenerative diseases and from transgenic rodent models. Small molecule inhibitors of tau phosphorylation that serve as important research tools and possibly the basis of potential new therapeutics, are also described. Key challenges in developing effective therapeutic agents include identification of the relevant kinase(s) responsible for aberrant tau phosphorylation in AD, synthesis of inhibitors selectively targeting those kinases and establishment of appropriate animal models.
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http://dx.doi.org/10.2174/1568026024607526DOI Listing
April 2002

Automated docking to multiple target structures: incorporation of protein mobility and structural water heterogeneity in AutoDock.

Proteins 2002 Jan;46(1):34-40

Department of Molecular Biology, Scripps Research Institute, La Jolla, California 92037, USA.

Protein motion and heterogeneity of structural waters are approximated in ligand-docking simulations, using an ensemble of protein structures. Four methods of combining multiple target structures within a single grid-based lookup table of interaction energies are tested. The method is evaluated using complexes of 21 peptidomimetic inhibitors with human immunodeficiency virus type 1 (HIV-1) protease. Several of these structures show motion of an arginine residue, which is essential for binding of large inhibitors. A structural water is also present in 20 of the structures, but it must be absent in the remaining one for proper binding. Mean and minimum methods perform poorly, but two weighted average methods permit consistent and accurate ligand docking, using a single grid representation of the target protein structures.
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http://dx.doi.org/10.1002/prot.10028DOI Listing
January 2002

Exchanging spare parts or becoming a new person? People's attitudes toward receiving and donating organs.

Authors:
M A Sanner

Soc Sci Med 2001 May;52(10):1491-9

Department of Public Health and Caring Science, Social Medicine, Uppsala Science Park, Sweden.

The present study explored the public's feelings and ideas about receiving organs, and how this influenced their attitudes toward accepting a transplant themselves. Also the willingness to donate was examined in order to provide a complementary perspective. The main aim was to identify consistent attitude patterns that would include attitudes toward both receiving and donating organs and the motives behind this. Sixty-nine individuals with varying socio-demographic background, selected from samples who had responded to a questionnaire on receiving and donating organs and tissues, were interviewed in-depth. The approach to analyse the interviews was hermeneutic. Seven typical attitude patterns emerged. By an 'attitude pattern' was meant a specific set of attitudes and motives, that formed a consistent picture that was logical and psychologically meaningful. In the discussion, two different conceptions of the body were focused. One of them meant that the body was easily objectified and conceived as machine-like, and did not represent the self. This machine model paved the way for the understanding that body parts needed to be replaced by spare parts. The other conception meant that a new organ would transfer the donor's qualities, i.e. influence the identity of the recipient with regard to behaviour, appearance, and personality. This belief may be explained by 'analogy thinking' based on our everday experience of how mixed entities take on the qualities of all components. Another explanation would be a kind of magical thinking and 'the law of contagion', which is often connected to oral incorporation. The consequences of these conceptions when patients are confronted with the factual situation of a transplantation, were discussed.
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http://dx.doi.org/10.1016/s0277-9536(00)00258-6DOI Listing
May 2001

People's feelings and ideas about receiving transplants of different origins--questions of life and death, identity, and nature's border.

Authors:
M A Sanner

Clin Transplant 2001 Feb;15(1):19-27

Department of Public Health and Caring Sciences, Social Medicine, Uppsala, Sweden.

The aim of this study was to explore the public's feelings and ideas with regard to receiving transplants of different origins. Sixty-nine individuals with varying sociodemographic background, selected from samples who had responded to a questionnaire on receiving and donating organs, were interviewed in-depth. A wide variety of reactions was displayed. The feelings and ideas about receiving organs were summarized in ten categories: 1) the emergency situation; 2) the functioning of the transplant; 3) the influence of transplants on personality, behaviour, and appearance; 4) the influence of transplants on body image; 5) disgust; 6) cannibalism; 7) trespassing nature's border; 8) tradition; 9) ethical considerations; and 10) the debt of gratitude. Most individuals were willing to accept at least one organ. Animal organs were the least preferred. The hierarchy of organ preferences--with organs from a relative at the top and animal organs at the bottom was explained in terms of rational, magical, and analogy thinking. Finally, the consequences for the encounter between health care personnel and transplantation candidates were briefly discussed.
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http://dx.doi.org/10.1034/j.1399-0012.2001.150104.xDOI Listing
February 2001

Python: a programming language for software integration and development.

Authors:
M F Sanner

J Mol Graph Model 1999 Feb;17(1):57-61

Scripps Research Institute, La Jolla, CA 92037, USA.

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February 1999

Integrating computation and visualization for biomolecular analysis: an example using python and AVS.

Pac Symp Biocomput 1999 :401-12

Scripps Research Institute, La Jolla, CA-92037, USA.

One of the challenges in biocomputing is to enable the efficient use of a wide variety of fast-evolving computational methods to simulate, analyze, and understand the complex properties and interactions of molecular systems. Our laboratory investigates several areas including molecular visualization, protein-ligand docking, protein-protein docking, molecular surfaces, and the derivation of phenomenological potentials. In this paper we present an approach based on the Python programming language to achieve a high level of integration between these different computational methods and our primary visualization system AVS. This approach removes many limitations of AVS while increasing dramatically the inter-operability of our computational tools. Several examples are shown to illustrate how this approach enables a high level of integration and inter-operability between different tools, while retaining modularity and avoiding the creation of a large monolithic package that is difficult to extend and maintain.
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http://dx.doi.org/10.1142/9789814447300_0039DOI Listing
August 1999

The discovery of steroids and other novel FKBP inhibitors using a molecular docking program.

J Mol Biol 1999 Apr;287(5):853-8

Structural Biochemistry Unit, Edinburgh University, Michael Swann Building, Edinburgh, Kings Buildings, EH9 3JR, UK.

The molecular docking computer program SANDOCK was used to screen small molecule three-dimensional databases in the hunt for novel FKBP inhibitors. Spectroscopic measurements confirmed binding of over 20 compounds to the target protein, some with dissociation constants in the low micromolar range. The discovery that FK506 binding protein is a steroid binding protein may be of wider biological significance. Two-dimensional NMR was used to determine the steroid binding mode and confirmed the interactions predicted by the docking program.
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http://dx.doi.org/10.1006/jmbi.1999.2621DOI Listing
April 1999
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