Tuesday, March 15, 2011

New Drug Shown Effective in Blocking HIV Entry

A research team led by Dr. Pin-Fang Lin at Bristol-Myers Squibb, Wallingford, CT has discovered a small molecule compound that can block HIV-1’s entrance into cells (Lin, P.-F. et al., PNAS 100:11013-11018, Sep. 16, 2003). Most of the drugs currently available for treating HIV infection affect replication of viral nucleic acids or the synthesis of viral proteins.
The compound, BMS-378806, binds to the envelope protein, gp120, of HIV-1 and inhibits interactions between gp120 and the CD4 receptor molecule on CD4+ T cells, a necessary step for HIV-1 to infect host cells.
The inhibitory effect of compound BMS-378806 is selective for HIV-1. It is inactive against HIV-2 (a less virulent, primarily West African virus similar to HIV-1), simian immunodeficiency virus, and other viruses tested. The compound exhibits other encouraging pharmacokinetic amenities such as low protein binding and minimal impairment of the compound by human serum. Tests in animals showed that the compound is safe, with acceptable toxicity profiles.
The compound targets a specific HIV-1 protein that does not exist in human cells. It is a novel approach for HIV-1 therapies. It represents a hope that HIV-1 can be stopped before it infects cells. This class of drugs can be used in combination with other drugs to achieve maximum deterrence of HIV-1 infection.

Three trials with strong financial supporters test Viread as a preventive drug for HIV infection

Three clinical trials starting this year will test the effectiveness of Viread (tenofovir disoproxil fumarate) in preventing HIV. Viread, a nucleotide reverse transcriptase inhibitor, is currently approved to treat patients already infected with HIV. Clinical studies showed that Viread is relatively less toxic and less prone to the development of resistance towards it. Gilead Sciences, Foster City, CA makes and markets Viread since 2001 with estimated sales of $550 to $570 million in 2003.
Several years ago, a research team headed by Dr. Roberta Black at the University of Washington’s Regional Primate Research Center in Seattle, published a report in Science demonstrating Viread’s effectiveness in preventing simian immunodeficiency virus (SIV) infection in monkeys (Tsai CC et al., Science 270:1197-1199, Nov. 17, 1995). The effectiveness of Viread [then called (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA)] was tested both pre- and post-exposure in preventing SIV in macaques as a model for HIV prevention in humans. Viread was administered beginning 48 hours before, 4 hours after, or 24 hours after virus inoculation. The once daily treatment was continued for 4 weeks. Virologic, immunologic, and clinical parameters of the macaques were monitored for up to 56 weeks. Viread prevented SIV infection in all macaques without toxicity, whereas all control macaques became infected. The results indicated that Viread was able to prevent the SIV infections in monkeys and suggested that it may have similar effects on HIV in humans.
The Bill and Melinda Gates Foundation will pay $6.5 million to test Viread in 2,000 people in Cambodia, Ghana, and other countries. The U.S. National Institutes of Health has awarded a $2.1 million grant to the University of California to evaluate Viread in 960 Cambodian women including many at-risk prostitutes. The U.S. Centers for Disease Control is paying $3.5 million for testing in 400 uninfected gay and bisexual men.
HIV has so far infected about 40 million people worldwide and is spreading rampantly in parts of Africa and Asia. Because it does not have to be taken repeatedly, a vaccine would be a more effective means to slow the rate of transmission but development has proven elusive and no vaccine is predicted to be available for at least the next decade. At the present time, a drug may be the best means to slow the spread of HIV.

Recent Advances in Biopolymers and Biomedical Materials

In this overview of recently published scientific literature, the authors provide a snapshot of current research trends in biopolymers and biomedical polymers. During experimentation to improve product benefits, the personal care industry eagerly formulates with new and different materials and ideas. Sometimes these new materials are generated within the industry while other times, they are borrowed from other sectors. In reviewing the current scientific literature, the authors hope to encourage readers to innovate by technology transfer and by gaining a better understanding of biopolymers at a time when they are escalating in importance.

A Biomedical Look At Spaceflight

Mary Roach, author of previous entertaining books Bonk (a history of sex research) and Stiff (a history of cadaver research), has turned her considerable talents in translating decades of research into a readable review of human (and animal) spaceflight experimentation.
The title of her new book, Packing for Mars: The Curious Science of Life in the Void, is a bit of a misnomer — only the last chapter is devoted to the medical advances needed for a trip to Mars. However, it is a great layman’s history of the biomedical results of both the American and Russian space programs.
Through my own research and academic career I’ve been peripherally involved with many of the recent studies she mentions in the book, and I know many of the people she interviewed, so I give her credit for taking some fairly complicated concepts and distilling them to relevant anecdotes and asides.
Her characterizations of the individuals I know is spot on and I can hear their voices in the quotes she uses. Roach breaks the book down roughly into large projects, rather than by physiological areas or research fields, such as cadaver tests for the next space capsule, space food packaging, simulated environments, microgravity flights, Japanese astronaut selection, porn filmed partially in microgravity, and nausea experiments.
Each chapter typically focuses on some large effort and builds context by peppering in the results from other studies and an interviews with experts in the field. The resulting chapters are pretty independent and, aside from a transition paragraph at the end of each, could probably be read in any order. This style of writing is familiar to anyone who has read Roach’s other books.
Roach accurately notes NASA and the space program’s role in the development of medical technology, although the NASA Public Affairs Office may put it differently when promoting the positive benefits of space flight; NASA sees medical technology as a means, not an end. She mentions that most medical technology that helps increase efficiency, redundancy, reliability, or decrease size, mass, and power requirements were worked on or considered by NASA and related agencies at some point. Not because NASA’s charter includes helping the world, but because it helps get more stuff off the ground with the constraints inherent in spaceflight.
The book includes interviews with researchers in the National Space Biomedical Research Institute (NSBRI), a group we have mentioned many times here on Medgadget, which functions as NASA’s academic research arm. NSBRI researchers tend to be a little easier to talk to about the topics Roach covers in the book, mostly because they don’t have to go through NASA Public Affairs. [Disclosure: My thesis work has been partially funded by both NASA and NSBRI, so I have a sense of the bureaucratic issues, and there are many.]
Overall, I would recommend this book to anyone interested in what the body goes through in spaceflight, and how we are preparing for those challenges. Regardless of familiarity with the subject matter, Mary Roach’s book is informative and entertaining, showing a well-thought out perspective on medical research in spaceflight.
Link: Packing for Mars: The Curious Science of Life in the Void
*This blog post was originally published at Medgadget*

Biomedical Autism Treatment – Exercise and Autism

I want to talk a little bit about the role of exercise and treatment of Autism. Some recent information has come out that discusses how exercise impacts depression. What research seems to be finding is that for individuals who get regular exercise, which means at least 30 minutes per day, 3 to 5 times per week, they had significantly reduced rates of depressive issues, by 45%. And given that in our country we primarily treat depression using ant-depressive medications, this new information is very significant. Just simply getting enough aerobic exercise each week, 30 minutes a day and between 3 and 5 days per week, can reduce depression significantly.

Over the course of treating children in my practice for years, I too have seen the benefits of children with Autism who get regular exercise. They seem to function better, that can mean better behavior, better attention, better focusing, less anxiety, etc. And yet for children, the definition of exercise can be different than that of an adult. Going to a park and letting them run and play on the equipment can be great exercise. They have the opportunity to run, climb and swing. Another wonderful activity for kids is riding their bike. Swimming is also a great activity, as is just about anything that lets them be physically active. I really do encourage parents to let their children get out in the fresh air and natural sun light, especially now that summer is here and the days are getting longer. Let your child explore, play and run if that is something that they seem interested in.

We see more and more children who spend most of their time inside, usually stuck on the computer or stuck on video games or watching movies. And many children with Autism spend many hours a day in therapy sessions. After their therapy sessions they can tend to be anxious, hyper, agitated, and have trouble sleeping. What can make a world of difference is making sure your child also gets some exercise. A nightly walk after dinner can be a great place to start. And remember, it is not all about supplements, it is not just about medications, it is not just about a diet. Sometimes a change in attitude comes from good physical exertion and physical exercise, it can put your child with Autism in a better mental state.

Who’s afraid of the recent biomedical heritage?

As biomedicine – the fusion of cell biology, molecular biology and information technology with clinical diagnostics and therapeutics – is emerging as a significant part of contemporary society and culture, it is time for university museums to take biomedicalization seriously. The Medical Museion at the University of Copenhagen is presently trying to resolve the museological problems that are raised in making sense of recent biomedical artefacts. Traditionally, museums deal with tangible material objects: good medical museum artefacts are concrete, sensual and spectacular, they are immediately understandable; they elicit memories, and evoke emotions. The emergence of recent biomedicine, however, challenges this classical notion of material objects as familiar, tangible, and sensuous. Today’s biomedical objects are abstract, non-tangible, and difficult to understand; they elicit few memories and hardly evoke any emotions. The challenges of recent biomedicine to university museums are illustrated with reference to three examples: gene microarray analysis, PET scanning, and molecular therapy. The paper concludes that medical museums today are caught in a paradox. On the one hand, biomedical research and technology fills more and more of our lives, from neonatal care to terminal intensive units. On the other hand, the whole idea of what constitutes a medical museum collection and what is displayable and easily understood by visitors in a medical museum exhibition becomes questionable.
Medicine is one of the oldest and most venerated ingredients of the world’s cultural and scientific heritage. Consequently medical artefacts feature prominently in many university museum collections. With respect to the historical time range covered, however, almost all museums deal with what might be called ‘modern medicine’, that is, they mainly contain artefacts and ideas that represent the medical practices of the modern era, from seventeenth century anatomical specimens to late-twentieth century mechanical medical instruments. With few exceptions, museums have not yet taken the rapidly growing biomedical culture of our present age into account, and so far no museum has made systematic efforts to document the recent biomedical heritage.
I suggest it is time for university museums to take biomedicine — that is, the fusion of cell biology, molecular biology and information technology with clinical diagnostics and therapeutics — seriously. The reason is, of course, that biomedicine is emerging as a significant formative part of contemporary society and culture. The discovery of the structure of DNA in 1953 and the subsequent rise of molecular biology have radically changed the research agendas, strategic decisions, and curricula of medical faculties over the last decades. A rapidly growing number of new molecular technologies have changed diagnostic and therapeutic methods beyond recognition; today’s clinical biochemical laboratory is a highly sophisticated and robotized molecular diagnostic system and gene therapy is becoming clinical reality. Digitalization too has changed biomedical research and clinical practices drastically in the last decades. Medical research is highly dependent on computerized methods. Clinical departments like neonatal wards or intensive care units are as digitalized as the cockpit in a modern aircraft. Diagnostic imaging tools like CT-, MR- and PET-scanning would be impossible without advanced digital technology.
This combined process of molecularization and digitalization of the laboratory and the clinic (in other words, biomedicalization) is embedded in a broader social and cultural context. The many (and often politically mediated) interactions between the transnational ‘biomedical-industrial complex’ and the steadily growing popular demand for better health care are turning biomedicine into a significant player on the global economic arena. Biomedicine has also entered the political scene. While some view its recent developments as a threat to basic human values, others see it as a key to the future of humankind. New technologies such as stem cell manipulation, cloning, and tissue engineering have raised both professional and popular expectations of the powers of biomedicine to combat, for example, cancer and degenerative diseases.
How can university museums accommodate to these material and discursive changes in the medical landscape? What consequences will the recent revolution in biomedical research and clinical development have for medical history collections and exhibitions? In the Medical Museion at the University of Copenhagen we are presently trying to resolve these and similar questions. In this paper I will discuss one of the museological problems raised, viz., how to handle the abstract and non-tangible character of many recent biomedical objects.
The Medical Museion is the continuation of the Medical History Museum in Copenhagen, founded by a private initiative in 1906. The rapidly expanding collections were taken over by the university in 1918, and thirty years later they were moved to their present location in the former Royal Academy of Surgeons and adjacent buildings. Today the University of Copenhagen owns one of the largest and most diversified medical history university collections in the world, including thousands of obstetric, radiological, opthamological, dental, and surgical instruments, several complete apothecaries and old pharmaceutical laboratories, an interesting assortment of microscopes, and a world-famous osteopathological collection from medieval leprosaria. Altogether the collections comprise approx. 60.000 registration units (a registration unit may contain many separate physical items so the number of individual objects probably exceeds a hundred thousand); in addition there are close to 100.000 iconographical items, a library of 30.000 volumes, and approx. 4000 archival units, including hospital patient records from the late eighteenth century and onwards. Only a small proportion of this material is displayed in the public exhibitions; most is kept in storage or in special ‘study collections’ for specialists.
Like most other medical university museums, the collecting and exhibition activities of the Medical History Museum were focused on ‘modern medicine’, especially on instruments that documented the triumph of the modern medical profession in the late nineteenth and first half of the twentieth century. But in recent years the museum has changed its orientation. The incentive for this move was the fact that the museum had stagnated since the 1970s; there were no research activities of any significance, the collections were run by amateur curators, and the exhibitions had not been revised for decades. A devastating report by The Danish State Board of Museums in 2000 raised negative headlines (‘Chaos in the museum’) in the Danish medical weekly, and induced the Faculty of Health Sciences to take its responsibility as owner. A year earlier, the chair in history of medicine had been filled to boost medical history research; in the following years three new museum positions were announced. Basic funding was increased as well, and in 2003 the faculty gave its unanimous support to a five-year plan for re-conceptualizing the former Medical-History Museum as a Medical Museion.
The Medical Museion concept is two-pronged. The basic idea is that research, teaching, collection activities and public outreach (including exhibitions) are closely integrated activities that mutually support each other. The classical notion of ‘museion’ has been chosen to symbolize the bridging of the gap between a traditional academic medical history research and teaching culture focusing on the production of texts (articles, books), and a traditional curatorial culture dealing with the acquisition, preservation and exhibition of material objects and images. In daily practice, this bridging means that both research and museum staff attend the weekly seminar dealing with all aspects of the institution, from registration systems and conservation methods to the history and philosophy of biology and the interaction between biomedicine and art; guest speakers include medical researchers, historians, ethnologists, museologists and artists. In other words, instead of making the traditional distinction between an academic university department and a museum, research, curating and acquisition are considered to be closely related forms of ‘inquiry’, and scholarly publishing, teaching and exhibitions are seen as closely related aspects of ‘presentation’.
The other main idea behind the Medical Museion concept is to shift the focus to the understanding, documentation and presentation of recent biomedicine in its social and cultural context. From the point of view of our university identity this shift of focus is advantageous as a growing number of conferences, monographs and research articles on different aspects of biomedicalization have appeared in the last decade. In other words, we are joining a growing trend among historians of science, historians of medicine, and scholars of science studies to investigate the recent history of biomedicine.
From the point of view of our museum identity, however, the new focus on recent biomedicine does raise some problems. With the exception of the Science Museum in London, very few museum institutions have taken the recent biomedical revolution seriously, and even fewer have begun to systematically acquire biomedical artefacts. Most medical history exhibitions still present medicine as it were in the period from the late eighteenth to the mid-twentieth centuries, that is, before molecular biology and information technologies began to change its face.
However, if (or rather when) museums begin to pay attention to recent biomedicine, they will be running into a major museological problem. This problem has to do with the object character of biomedical artefacts. Traditionally, museums are institutions that deal with material objects and material culture. The key-word here is tangibility — and medical museums are no exceptions, filled as they are with surgical instruments, microscopes, contraceptive devices, iron lungs, hospital beds, anatomical specimens, and so forth. Medical museum curators usually do not consider it a problem to define what an ‘object’ is, or what constitutes a ‘good’ museum object. Good objects are concrete, sensual and spectacular, like foot-driven dentist’s drills, siamese twins in jars, amputation saws, and trepanation instruments in handy travel sets. These and similar objects are considered ‘good’ objects because they are made of easily recognizable materials and resemble familiar tools; they are immediately understandable and also appeal to our fear of pain and death; they trigger the visitor’s attention, elicit memories, evoke emotions, and make us pause in front of the objects with a sense of curiosity and wonder. The lithoclast — an instrument invented in the early nineteenth century to crush bladder stones through the urethra (thus lowering the risk and pain of classical stone cutting) — is an archetypically ‘good’ medical history exhibition object. Young male visitors to the Medical Museion regularly turn pale when they realize how the instrument was used — before anaesthesia.
The emergence of recent biomedicine, however, challenges this classical notion of material objects as familiar, tangible, and sensuous. Today’s biomedical objects are neither familiar, nor tangible; neither sensuous, nor emotionally evocative. To illustrate the challenges of recent biomedicine to university museums, I will shortly discuss three cases: gene microarray analysis, PET scanning, and molecular therapy.
Microarray analysis is one of the most sophisticated methods in post-genomic medicine. Based on the fact that the degree of hybridization between single-stranded oligonucleotide molecules is a measure of their similarity, it uses arrays of hundreds of thousands of specific oligonucleotide sequences as probes to map an unknown RNA/DNA-sample; this makes it possible to gauge the gene expression level of the entire genome (that is, which genes are ‘on’ and which are ‘off’) in one single run. The analytical power of the method has ushered a rapid growth of expectations in the biomedical research community and the pharmaceutical industry to use it as a major diagnostic and therapeutic tool, for example for individualized drug treatment: ‘The explosion in interest in DNA microarrays has almost been like a gold rush’, proclaims a textbook in the field.
The most widely used and best known microarray platform, the Affymetrix GeneChip®, was invented in the late 1980s and came into industrial production a few years later. By combining information technology and molecular biology the GeneChip embodies the very essence of biomedicine. It illustrates the restructuring of health-care in the advanced post-industrial societies towards increased individualisation of diagnostics and treatment. Also, by drawing on globally produced and globally available sequence data bases it epitomizes another salient aspect of the biomedical revolution, viz., its integration in the process of globalization. Furthermore, as one of the few biomedical technologies that has made it to the front-page of Financial Times, the GeneChip is an example of how cutting-edge university research often has given rise to successful private enterprises (the ‘Silicon Valley effect’) over the last decades. Finally it reminds us of Peter Sloterdijk’s point that biotechnology, for better or for worse, can make the old vision of eugenics come true. The Affymetrix GeneChip thus provides an ample focusing point for historians of recent biomedicine and biotechnology.
For museums curators, however, the GeneChip poses a problem. What is immediately available for display is just the handy 1 x 2 inch plastic casing where the hybridization reaction takes place. The ½ x ½ inch ‘chip’ inside, with some half million oligonucleotide molecular-sized probes attached to it, is not immediately visible, or intelligible. The result of the test is only visible indirectly; the genome data are produced by reading the hybridization pattern on the chip with a laser scanner (which looks like an advanced coffee machine) and the result is interpreted by a computer program. It is hardly necessary to say that the GeneChip technology, which is now revolutionizing medical diagnostics, makes poor museum objects because all the components of the platform are abstract, intangible and hardly evoke any memories or strong emotional reactions.
The PET (positron emission tomography) scanner, too, illustrates the problem of displaying new biomedical artefacts in a museum exhibition. The instrument is built to produce images representing the inner metabolism of the body; information that is indeed useful for diagnostic purposes. The patient is injected with glucose molecules marked with a short-lived isotope that emits positrons that can be measured by a detector. The ensuing data are then interpreted by a computer program to represent slices (tomography) of the spatial distribution of glucose metabolism in the body on a screen. For example, the screen image of metabolism in the brain of patients with Alzheimer’s disease is significantly different from that in ‘normal’ patient brains.
The PET-scanner is an impressive piece of combined digital and molecular technology which has already had great impact on medical diagnostics. An update of earlier imaging technologies, like X-ray, as it were — and as such it is a ‘must’ in any museum that wishes to document and exhibit significant features of recent university medicine. But whereas X-ray technology is relatively easily understood in terms of ‘modern medicine’ and does not create any problems for medical museum curators, the PET scanner poses at least two museological problems.
One problem is that the PET scanner defies traditional museological display strategies. The directly visible and tangible ‘objects’ — the enclosing cabinet and the bed which the patient is placed on during the scanning procedure — are not at all important for the functionality of the scanner. The working material parts are either invisible and non-tangible (the isotope molecules) or non-intelligible (the detector and the computer hardware) and in addition do not make much sense without the resulting screen image. The ‘image’ in turn is indeed visible as long as the machine runs, but it is not tangible; it is the ephemeral result of the handling of signal data by the ‘text’ (that is, the computer programme code). The other problem (and this is why I have placed the words ‘object’, ‘image’ and ‘text’ between inverted commas) is that the PET scanner blurs the traditional categories of ‘object’, ‘image’ and ‘text’. How shall this artefact be classified? Does it belong among the physical museum objects? Or is it better placed (as an image) in the iconographical collection? Or even (as program code) in the archive?
My last example of how recent biomedicine is a challenge to university museums is the advent of molecular therapy. Traditionally, pharmacology is based on trial-and-error experience. The administered drug may not even be chemically characterized (as in folk herbal medicine) and physicians usually have no knowledge of the biochemical mechanism behind the effect; it just happens to work. Now, however, the biochemical mechanism that mediates between the active substance and the physiological response is being elucidated in a growing number of cases. A good example of molecular therapy is AstraZeneca’s Losec®, the world’s best-selling drug against ulcer and heart-burn in the 1990s. Earlier, ulcer patients were often treated with surgery; today they are given antibiotics against the Heliobacter infection and Losec to lower stomach acidity (often in the form of combination therapy).
The active substance in Losec is a synthetic molecule, omeprazol that specifically blocks the proton pump and hence acid production in the stomach. In other words, the omeprazol molecules work as a kind of specific biochemical microsurgery. It is thus a smart medical technology (and a major source of income for AstraZeneca) — but it is hardly a best-seller for medical museums. True, the Losec pill is tangible, but it looks very much like all other pills. The trillions of ‘molecular knives’ (omeprazol molecules) are intangible and invisible. The ion channels in the gastric lining are tangible on the microscopic level, but not visible to the naked eye. Furthermore, the most interesting ‘object’ is neither the pill nor the molecule, but the international network of scientists, medical doctors, advertising firms, and financial analysts who made a business success out of the omeprazol molecule. One could, of course, put the pill on a piece of black cloth under a spotlight and play a recorded deep voice telling the visitor that it gave AstraZeneca a 8 billion dollar revenue in the year 2000 only. But such stories are probably better told in books and magazines than in exhibitions. Likewise, the molecular and biological mechanisms of omeprazol may be better told in book pages and computer screens than in museums.
Microarray systems, PET scanners, and molecular therapies exemplify the problems involved in collecting and exhibiting recent biomedicine. Consequently I believe that medical museums today are caught in a paradox. On the one hand, biomedical research and technology fills more and more of our lives. On the other hand, the whole idea of what constitutes a medical museum collection and what is displayable in a medical museum exhibition is open to question, because medical diagnostics and treatment has become less visible and less sensuous. The biomedical ideas and artefacts of the last decades are very different from those presently gathered and displayed in museums. They are smaller (often microscopic), more abstract and mediated, less tangible (if not altogether intangible), and generally much less emotionally evocative than traditional ‘modern medical’ objects. And sometimes they are not even material artefacts in the classical sense, but ‘boundary artefacts’, that is simultaneously ‘material objects’, ‘texts’ and ‘images’, depending on the context of interpretation.
There may come a point when it becomes impossible to display such objects in a museum exhibition in any meaningful way. After all, who would come to the local university museum on a Sunday afternoon to read computer manuals, look at anonymous instrument plastic cabinets discretely labelled Perkin-Elmer or Hewlett-Packard, or watch video screens that represent repetitive patterns of DNA hybridization reactions? Will not those who are curious about the emergence of recent biomedicine and its impact on the world rather download the molecular images on their own computer or read about the global biomedical economy on a webpage or in a book or a magazine article instead? It makes sense to visit the local university museum to see lithoclasts, amputation saws, and siamese twins in jars? But why at all visit a museum if one wants to watch displays which elicudate the basic textbook principles of a PET scanner, a gene microarray or a ‘molecular knife’?
I believe this is a genuine museological problem and one that all museums with medical collections and exhibitions will have to solve in the near future — unless they want to restrict their activities to the safe realm of ‘modern medicine’. I am not pretending that the Medical Museion in Copenhagen has a solution in sight or even a smart way of circumventing it. But we are presently working on explicating and conceptualizing the problem, and with some help from our colleagues in the university museum world we will hopefully together be able to find solutions in the future.

Anne O'Tate: A tool to support user-driven summarization, drill-down and browsing of PubMed search results

Background

PubMed is designed to provide rapid, comprehensive retrieval of papers that discuss a given topic. However, because PubMed does not organize the search output further, it is difficult for users to grasp an overview of the retrieved literature according to non-topical dimensions, to drill-down to find individual articles relevant to a particular individual's need, or to browse the collection.

Results

In this paper, we present Anne O'Tate, a web-based tool that processes articles retrieved from PubMed and displays multiple aspects of the articles to the user, according to pre-defined categories such as the "most important" words found in titles or abstracts; topics; journals; authors; publication years; and affiliations. Clicking on a given item opens a new window that displays all papers that contain that item. One can navigate by drilling down through the categories progressively, e.g., one can first restrict the articles according to author name and then restrict that subset by affiliation. Alternatively, one can expand small sets of articles to display the most closely related articles. We also implemented a novel cluster-by-topic method that generates a concise set of topics covering most of the retrieved articles.

Conclusion

Anne O'Tate is an integrated, generic tool for summarization, drill-down and browsing of PubMed search results that accommodates a wide range of biomedical users and needs. It can be accessed at [4]. Peer review and editorial matters for this article were handled by Aaron Cohen.

1. Background

Anne O'Tate was developed as a part of the Arrowsmith project [1-4], which has been developing informatics tools for advanced text mining of the biomedical literature. We sought to create a tool for carrying out PubMed searches [5] that did not require the user to progressively reformulate the initial query; that would assist the user in finding the most relevant articles quickly and efficiently; and that would summarize the salient features of a given set of articles – e.g., given a set of articles discussing gene X, to give a list of diseases that gene X has been studied in, or given a set of articles on disease Y, to give a list of symptoms that have been described in that disease. The present paper describes the current implementation of Anne O'Tate, which is used routinely by our group for conducting PubMed searches. The tool has been placed on the Arrowsmith homepage [4] as a free, public web-based service.

2. Implementation

2.1 Query interface

The PubMed query interface [5] was imported into the Anne O'Tate web page, so that when a user types in a query, it is sent to PubMed using the NCBI E-Utilities (ESearch and EFetch) [6] to obtain the PubMed IDs, and thereby takes advantage of the pre-processing that occurs within PubMed. Given the set of PubMed IDs, articles are looked up in a local MEDLINE/PubMed database; for articles not included in the local database, E-Utilities are used to download the records of those (generally very recent) articles. There is no restriction on the number of articles retrieved from PubMed and displayed initially to the user. However, to limit the computational load on the system, a limit was placed on the number of papers that are processed further (as discussed below). At present, the default limit is set to process further only the 25,000 most recent articles of a given query.

2.2 MEDLINE term database

A database of terms was created including all of the words and phrases [n-grams (n = 1,2,3)] that occur in the title of at least one article in MEDLINE. A simple tokenizer (to remove sentence delimiters and change the text to lower case) and a stemmer (to handle plurals) have been applied [7]. In total, 15.5 million terms were extracted. Document frequency is defined as the number of different articles in MEDLINE that contain the term in either title or abstract. Each term in an article is counted only once, even though it may occur several times in that article. We intend to update the term database yearly.

Semantic categories

Terms were run through the NIH MetaMap program (MMTx version 2.0) [8] to assign each term to one or more semantic categories, if possible, as defined by the Unified Medical Language System (UMLS). The 134 semantic categories were grouped into ~15 super-categories as outlined in [9]. (For example, a number of individual semantic categories such as Hazardous or Poisonous Substance, Hormone, and Immunologic Factor were subsumed under the super-category of Chemicals & Drugs.) Because MetaMap cannot optimally recognize terms out of context, and because at the time certain terms were poorly represented in the UMLS, including neuroanatomical terms and gene/protein names, the NeuroNames vocabulary [10] and a list of predicted gene and protein names extracted from Entrez Gene [11] were added as complementary semantic categories. Anne O'Tate allows users to restrict important words (see below) or MeSH terms to any of the 15 super-categories or to any of the individual semantic categories therein; alternatively, they can retain all terms that mapped to at least one semantic category while discarding terms that failed to map at all.

2.3 Anne O'Tate categories

1. Important words

Important words distinguish a specific literature L from the rest of MEDLINE. Important words of a literature should occur significantly more frequently within the literature than overall in MEDLINE. That is, they should show high enrichment, forming a literature-specific vocabulary that is similar to the concept of a domain sub-language [12]. At the same time, important words should ideally occur in a high proportion of the articles in literature L (i.e., should have high coverage).
To create a list of words that are highly enriched within a given retrieved literature L relative to MEDLINE as a whole, the null hypothesis is that L and a given word t are independent of each other, in which case the number of articles within that literature that contain the word will follow the hyper-geometric distribution. Words occurring one time in L were discarded from consideration. Given n, the number of articles in MEDLINE containing word t in title or abstract; and N, the number of articles in MEDLINE, we calculated the parameter Ent. This parameter is related to the probability that word t occurs at or above the observed document frequency (f) in L. Specifically, the Ent score is equal to the t-statistic; for example, Ent = 3 is equivalent to the statement that t is significantly enriched in L at p = 0.001). When N is large compared to |L|, Ent is approximately: