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Proteomics in rheumatology: a new direction for old diseases.

OBJECTIVES: Completion of the human genome project has stimulated scientists to begin looking for the next step in unraveling normal and abnormal functions within biological systems. Consequently, there is new focus on the role of proteins in these processes. Proteomics is a rapidly growing field that may provide a valuable approach to evaluate the field of rheumatology. The objectives of this article is to provide an overview of biophysical techniques, as "re-invented" research tools, as applied to the investigation of rheumatoid arthritis and osteoarthritis. METHODS: MEDLINE search of articles in English-language journals from 1966 to 2004. The index words "Rheumatoid/osteoarthritis/connective tissue disorders" and the following co-indexing terms were used: "mass spec," "NMR," "SPR" and "Proteomics." Papers identified were reviewed, abstracted, and summarized. The authors' own work in the field is also presented. RESULTS: As we move into the postgenomics era, new and exciting tools are being developed to study protein expression and protein interactions and identify new biomarkers for disease diagnosis and prognosis. Proteomics is an emerging field with widespread potential applications to rheumatic disease. CONCLUSIONS: In this review the biophysical techniques of nuclear magnetic resonance, mass spectroscopy, and surface plasmon resonance as proteomic tools in the study of rheumatoid and osteoarthritis were reviewed. What is emerging is the identification of new biomarkers with clinical and therapeutic relevance.

Arthritis, Rheumatoid↗

In vitro and in vivo imaging of cell migration: two interdepending methods to unravel metastasis formation.

Metastasis development requires the migratory activity of tumor cells. It is therefore important to understand the molecular mechanisms of this migration in order to prevent metastasis development, which is the pernicious step in most solid tumor diseases. A lot of methods have been invented to investigate tumor cell migration, but not all are equally suited and no method alone is able to deliver a complete picture of tumor cell migration. We herein suggest a combination of three-dimensional in vitro and in vivo methods for the investigation of tumor cell migration and summarize the knowledge, which has been reached so far.

Animals↗

Imprinted X-chromosome inactivation: enlightenment from embryos in vivo.

There are two forms of X chromosome inactivation (XCI) in the laboratory mouse, random XCI in the fetus and imprinted paternal XCI limited to the extraembryonic tissues supporting the fetal life in utero. Imprinted XCI has been studied extensively because it takes place first in embryogenesis and it may hold clues to the mechanism of control of XCI in general and to the evolution of random' XCI. Classical microscopic and biochemical studies of embryos in vivo provide a basis for interpreting the multifaceted information yielded by various inventive approaches and for planning further experiments.

Animals↗

Appropriation and commercialization of the Pasteur anthrax vaccine.

Whereas Pasteur patented the biotechnological processes that he invented between 1857 and 1873 in the agro-food domain, he did not file any patents on the artificial vaccine preparation processes that he subsequently developed. This absence of patents can probably be explained by the 1844 patent law in France that established the non-patentable status of pharmaceutical preparations and remedies, including those for use in veterinary medicine. Despite the absence of patents, the commercial exploitation of the anthrax vaccine in the 1880s and 1890s led to a technical and commercial monopoly by Pasteur's laboratory as well as the founding of a commercial company to diffuse the vaccine abroad. Pasteur repeatedly refused to transfer his know-how and anthrax vaccine production methods to foreign laboratories, on the grounds that he wished to control the quality of the vaccines produced. Indeed, it was relatively difficult to transfer a method that was not yet perfectly stabilized in the early 1880s. Pasteur also wanted to maintain the monopoly of his commercial company and to increase the profits from vaccine sales so that the Institut Pasteur could be financially independent. The 'Pasteur anthrax vaccine' operating licences are described and analysed in detail in this article.

Anthrax↗

Twins: A cloning experience.

Drawing upon qualitative interviews with monozygotic (identical) twins sharing 100% of their genes, and with dizygotic (fraternal) twins and singletons as control groups, this paper explores what it means to be genetically identical. (The twins interviewed were from the TwinsUK register in London.) In the context of the ongoing debate on human reproductive cloning, it examines questions such as: To what extent do identical twins perceive their emotional and physical bond to be a result of their genetic makeup? What would they think if they had been deliberately created genetically identical? How would they feel about being genetically identical to a person who was born a few years earlier or later? First, our respondents ascribed no great significance to the role of genes in their understanding of what it means to be identical twins. Second, the opinion that human reproductive cloning would "interfere with nature", or "contradict God's will", was expressed by our respondents exclusively on the abstract level. The more our respondents were able to relate a particular invented cloning scenario to their own life-worlds, the lower the prevalence of the argument. Third, for all three groups of respondents, the scenario of having been born in one of the other groups was perceived as strange. Fourth, the aspect that our respondents disliked about cloning scenarios was the potential motives of the cloners. Without equating monozygotic twins directly with "clones", these results from "naturally" genetically identical individuals add a new dimension to what a future cloning situation could entail: The cloned person might possibly (a) perceive a close physical and emotional connection to the progenitor as a blessing; (b) suffer from preconceptions of people who regard physical likeness as a sign of incomplete individuality; and (c) perceive the idea of not having been born a clone of a particular person as unpleasant.

Cloning, Organism↗

Robotics in colorectal surgery: telemonitoring and telerobotics.

Surgery has just passed through the laparoscopic surgery revolution, with validation of the advantages for the patient evaluated painstakingly; however, laparoscopy is a transition phase to fully information-based surgery, which only can be accomplished when hand motions are converted to information through robotic surgery systems. The main advantage is using such systems to integrate the entire surgical process. The components that will allow such a transition exist in other industries that use robotics, so it is more a matter of applying these engineering principles to surgery, rather than inventing new technologies. Robotics cannot only improve the performance of surgery, but is providing access to surgical expertise in remote and underserved areas through telementoring, teleconsultation, and telesurgery. Colorectal surgeons should seize the opportunity to begin to use surgical robotic systems in those niche areas and procedures that have proven to be of significant benefit to the patient and are cost-effective. Over time, with the development of even more advanced systems it will become more advantageous to use robotics on a routine basis.

Colon↗

Advances in surgical nutrition.

Dr. Stanley Dudrick invented total parenteral nutrition in 1968, providing a desperately needed therapy to those patients who could not eat. It has since saved thousands of patients worldwide. Nutrition interventions (NI) in surgical/trauma and critically ill patients have evolved dramatically during the last 20 years from a supportive therapy to a clear therapeutic role. Like any other form of therapy, NI will benefit patients when adequately indicated and prescribed. NI, however, may cause significant side effects and harm when poorly ordered. This article reviews the indications for the prescription of the different forms of NI available to the clinician caring for the surgical patient.

Caloric Restriction↗

Cellular and molecular mechanisms of atherosclerosis with mouse models.

Recently, there has been an explosion in the number of in vivo studies using genetically engineered mouse models. Atherosclerosis research using mice began with the invention of traditional atherosclerotic mice including low-density lipoprotein receptor knockout (LDLR(-/-)) and apolipoprotein E knockout (apoE(-/-)) mice, which provided tremendous progress in atherosclerosis research. Since then, a number of modified atherosclerotic mouse models have been reported to generate lesions that more closely characterize human atherosclerotic lesions. Those modifications include inflammation, hypertension, proteinases and extracellular matrix, glucose metabolism, and immune systems. This article focuses on various kinds of mouse models with atherosclerosis and their contributions to the current advances of research.

Animals↗

Molecular chaperones: assisting assembly in addition to folding.

The common perception that molecular chaperones are involved primarily with assisting the folding of newly synthesized and stress-denatured polypeptide chains ignores the fact that this term was invented to describe the function of a protein that assists the assembly of folded subunits into oligomeric structures and only later was extended to embrace protein folding. Recent work has clarified the role of nuclear chaperones in the assembly of nucleosomes and has identified a cytosolic chaperone required for mammalian proteasome assembly, suggesting that the formation of other oligomeric complexes might be assisted by chaperones.

Animals↗

The neural code for written words: a proposal.

How is reading, a cultural invention, coded by neural populations in the human brain? The neural code for written words must be abstract, because we can recognize words regardless of their location, font and size. Yet it must also be exquisitely sensitive to letter identity and letter order. Most existing coding schemes are insufficiently invariant or incompatible with the constraints of the visual system. We propose a tentative neuronal model according to which part of the occipito-temporal 'what' pathway is tuned to writing and forms a hierarchy of local combination detectors sensitive to increasingly larger fragments of words. Our proposal can explain why the detection of 'open bigrams' (ordered pairs of letters) constitutes an important stage in visual word recognition.

Age Factors↗

Understanding SAGE data.

Serial analysis of gene expression (SAGE) is a method for identifying and quantifying transcripts from eukaryotic genomes. Since its invention, SAGE has been widely applied to analyzing gene expression in many biological and medical studies. Vast amounts of SAGE data have been collected and more than a thousand SAGE-related studies have been published since the mid-1990s. The principle of SAGE has been developed to address specific issues such as determination of normal gene structure and identification of abnormal genome structural changes. This review focuses on the general features of SAGE data, including the specificity of SAGE tags with respect to their original transcripts, the quantitative nature of SAGE data for differentially expressed genes, the reproducibility, the comparability of SAGE with microarray and the future potential of SAGE. Understanding these basic features should aid the proper interpretation of SAGE data to address biological and medical questions.

Data Interpretation, Statistical↗

David B. Pall, PhD (1914-2004).

In this edition of the Pioneers and Pathfinders Series, the contributions of David B. Pall, PhD, to transfusion medicine are discussed. With the aid of Dr Pall's unpublished personal history and assistance from family members and the company he founded, we are able to provide perspective to several remarkable scientific advances. For those of us in transfusion medicine, the discovery of the world's first leukoreduction filter prevails as his most significant invention. However, to the rest of the world, Dr Pall pioneered filtration with applications in aerospace, microelectronics, general industry, and most recently, contamination control. The almost 60-year-old Pall Corporation continues to preserve his legacy.

Blood Component Transfusion↗

Struan Sutherland--Doyen of envenomation in Australia.

Struan Sutherland (1936-2002) was the doyen of medical research in the field of envenomation and the ultimate authority on the medical management of envenomated victims in Australia for almost 3 decades. In 1981 as Head of Immunology Research of Commonwealth Serum Laboratories (CSL), he produced an antivenom against the Sydney Funnel-web Spider (Atrax robustus)-an accomplishment that had defied numerous previous attempts. Struan also invented the pressure-immobilisation technique of first-aid for snake bite. This ingenious, simple but safe and effective technique revolutionised first-aid management of snake bite and of some other types of envenomation. It made redundant the use of tourniquets and other dangerous first-aid treatments. Similarly, he helped to develop a snake venom detection kit, which enables doctors working at a victim's bedside to ascertain which snake was responsible and which antivenom should be administered. He had a very wide range of research interests and was a prodigious researcher publishing over 200 scientific and medical articles, numerous chapters in books and the standard Australian medical textbook on the management of envenomation, Australian Animal Toxins. He made major contributions to the understanding of the venoms of Australia's remarkable range of fauna including snakes, spiders, Blue-ringed octopus, ants, jellyfish and stinging fish. Struan served the medical fraternity and the public selflessly. He was always available to doctors, or to anybody, to give advice at any hour of the day or night, on management of envenomated victims. Members of the Australian Venom Research Unit, which he founded in 1994 at The University of Melbourne, now continue this 24-h advisory service.

Animals↗

The Jellyfish hunter--Jack Barnes: a pioneer medical toxinologist in Australia.

Dr Jack Handyside Barnes (1922-1985) was one of the small and elite group of Pacific marine toxinologists whose work was characterised by an uncompromising rugged persona, a focussed resolve to solve challenging problems of human clinical envenomation, and who conducted curiosity-driven research under conditions of scientific isolation. He was a pioneering advocate for the preservation of marine heritage, particularly that of the Great Barrier Reef. A former military commando who later became a general medical practitioner with extensive surgical and obstetric skills, in 1947 he was appointed the Medical Superintendent of Thursday Island in the Torres Strait. Later (from January 1953), he worked indefatigably as a general medical practitioner in Cairns, in tropical North Australia. For four decades (1945-1985), Jack Barnes undertook detailed laboratory, clinical and field research into invertebrate envenomation, particularly medusan toxinology. In 1960 he discovered the species responsible for the Irukandji syndrome, a small carybdeid named Carukia barnesi in his honour. He invented the research technique for the extraction of venom from the world's most venomous creature, the Pacific box Jellyfish, Chironex fleckeri. By 1960, he had published taxonomic details of nematocyst structure and clinical envenomation details consequent upon stings by Physalia, Cyanea, Chironex, Chiropsalmus and Carukia. This paper is a précis of the chronology of his life, contributions and influence.

Animals↗

Efficacy of cutting balloon for anastomotic stricture of the hepatic vein.

Anastomotic stricture of the hepatic vein is an annoying complication, especially in living donor liver transplantation. Balloon dilation has been utilized but is sometimes associated with recurrences. Recently, a cutting balloon was invented for treatment of arteriosclerosis. Herein we report the results of application of this device for treatment of anastomotic strictures of the hepatic vein in two living donor liver transplant recipients who underwent percutaneous dilation of the hepatic vein with a cutting balloon (8 x 10 mm, Atherotome, Boston Scientific). Case 1, a 26-year-old woman transplanted for subacute fulminant hepatitis, had been treated for an anastomotic stricture by balloon dilation on 15 occasions over a 2- to 3-month interval. Case 2, a 13-year-old boy transplanted for cryptogenic liver cirrhosis, had been treated for an anastomotic stricture by balloon dilation biannually. The cutting balloon was applied safely without severe complications. The first case showed a recurrent anastomotic stricture at 6 months after dilation. Follow-up at 6 months in the second case revealed a mild recurrence of the stricture. Anastomotic stricture of the hepatic vein jeopardizes the graft and the recipient. The reported treatments involve venoplastic surgery and expandable metallic stents. Application of a cutting balloon seemed to be a safe, convenient modality. However, its effect was not indefinite, so a cutting balloon of greater diameter or application of an expandable metallic stent may be considered for patients with multiple recurrences of their anastomotic stricture.

Adolescent↗

Kyoto islet isolation method: the optimized one for non-heart-beating donors with highly efficient islet retrieval.

The availability of pancreata for clinical cadaveric islet transplantation is restricted to non-heart-beating donors (NHBDs) in Japan. This forced us to modify the current standard islet isolation protocol that was made up for brain-dead donors and make it suitable for NHBDs. The Kyoto islet isolation method is the one with induction of several steps based on the ideas both already reported literally and invented originally by ourselves. Using this islet isolation method, we isolated islets from 13 human pancreata of NHBDs and transplanted 11 preparations to six type-1 diabetic patients. The rate to meet release criteria of Edmonton protocol was 84.6%. Establishment of this method allowed us to begin a clinical islet transplantation program in Japan and to continue to perform the preparation of islets from NHBDs with high rate to meet the release criteria of the Edmonton protocol.

Brain Death↗

Atomic force microscopy analysis of enveloped and non-enveloped viral entry into, and egress from, cultured cells.

Since its invention, the atomic force microscope has been used to image a wide variety of biological samples, including viruses. Viral entry into, and egress from, cultured cells has been extensively studied using numerous scientific techniques and to a limited extent using atomic force microscopy. One of the main structural differences that can exist between viruses is the absence, or presence, of an envelope and this factor has consequences for the mode of viral entry and egress. In this study, the entry into, and egress from, cultured cells of enveloped and non-enveloped viruses were investigated using atomic force microscopy. No significant cell surface changes were observed following infection with enveloped or non-enveloped viruses. Although roughness analysis of viral entry revealed cell smoothing post-infection, no differences between the roughness values of enveloped and non-enveloped viral entry were observed. Line analysis of viral entry revealed minor differences between cells infected with an enveloped rather than a non-enveloped virus. These differences may represent a distinction between the uptake processes of enveloped and non-enveloped viruses. Studies of viral egress revealed that infected cells were undergoing cytopathic changes. Whilst topographic, height and roughness differences clearly occurred between virally- and mock-infected cells, no significant differences were elucidated between enveloped and non-enveloped viral egress.

Animals↗

Breaking the spherical and chromatic aberration barrier in transmission electron microscopy.

Since the invention of transmission electron microscopy (TEM) in 1932 (Z. Physik 78 (1932) 318) engineering improvements have advanced system resolutions to levels that are now limited only by the two fundamental aberrations of electron lenses; spherical and chromatic aberration (Z. Phys. 101 (1936) 593). Since both aberrations scale with the dimensions of the lens, research resolution requirements are pushing the designs to lenses with only a few mm space in the pole-piece gap for the specimen. This is in conflict with the demand for more and more space at the specimen, necessary in order to enable novel techniques in TEM, such as He-cooled cryo electron microscopy, 3D-reconstruction through tomography (Science 302 (2003) 1396) TEM in gaseous environments, or in situ experiments (Nature 427 (2004) 426). All these techniques will only be able to achieve Angstrom resolution when the aberration barriers have been overcome. The spherical aberration barrier has recently been broken by introducing spherical aberration correctors (Nature 392 (1998) 392, 418 (2002) 617), but the correction of the remaining chromatic aberrations have proved to be too difficult for the present state of technology (Optik 57 (1980) 73). Here we present an alternative and successful method to eliminate the chromatic blur, which consists of monochromating the TEM beam (Inst. Phys. Conf. Ser. 161 (1999) 191). We show directly interpretable resolutions well below 1A for the first time, which is significantly better than any TEM operating at 200 KV has reached before.

Lenses↗