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Toward automated biochemotype annotation for large compound libraries.

Combinatorial chemistry allows scientists to probe large synthetically accessible chemical space. However, identifying the sub-space which is selectively associated with an interested biological target, is crucial to drug discovery and life sciences. This paper describes a process to automatically annotate biochemotypes of compounds in a library and thus to identify bioactivity related chemotypes (biochemotypes) from a large library of compounds. The process consists of two steps: (1) predicting all possible bioactivities for each compound in a library, and (2) deriving possible biochemotypes based on predictions. The Prediction of Activity Spectra for Substances program (PASS) was used in the first step. In second step, structural similarity and scaffold-hopping technologies are employed. These technologies are used to derive biochemotypes from bioactivity predictions and the corresponding annotated biochemotypes from MDL Drug Data Report (MDDR) database. About a one million (982,889) commercially available compound library (CACL) has been tested using this process. This paper demonstrates the feasibility of automatically annotating biochemotypes for large libraries of compounds. Nevertheless, some issues need to be considered in order to improve the process. First, the prediction accuracy of PASS program has no significant correlation with the number of compounds in a training set. Larger training sets do not necessarily increase the maximal error of prediction (MEP), nor do they increase the hit structural diversity. Smaller training sets do not necessarily decrease MEP, nor do they decrease the hit structural diversity. Second, the success of systematic bioactivity prediction relies on modeling, training data, and the definition of bioactivities (biochemotype ontology). Unfortunately, the biochemotype ontology was not well developed in the PASS program. Consequently, "ill-defined" bioactivities can reduce the quality of predictions. This paper suggests the ways in which the systematic bioactivities prediction program should be improved.

Chemistry, Pharmaceutical↗

Things to come: postmodern digital knowledge management and medical informatics.

The overarching informatics grand challenge facing society is the creation of knowledge management systems that can acquire, conserve, organize, retrieve, display, and distribute what is known today in a manner that informs and educates, facilitates the discovery and creation of new knowledge, and contributes to the health and welfare of the planet. At one time the private, national, and university libraries of the world collectively constituted the memory of society's intellectual history. In the future, these new digital knowledge management systems will constitute human memory in its entirety. The current model of multiple local collections of duplicated resources will give way to specialized sole-source servers. In this new environment all scholarly scientific knowledge should be public domain knowledge: managed by scientists, organized for the advancement of knowledge, and readily available to all. Over the next decade, the challenge for the field of medical informatics and for the libraries that serve as the continuous memory for the biomedical sciences will be to come together to form a new organization that will lead to the development of postmodern digital knowledge management systems for medicine. These systems will form a portion of the evolving world brain of the 21st century.

Artificial Intelligence↗

Update on inflation of journal prices: Brandon/Hill list journals and the scientific, technical, and medical publishing market.

OBJECTIVE: The original study of journal prices, using the "Brandon/ Hill Selected List of Books and Journals for the Small Medical Library," was first published in 1980 and periodically updated. This research continues to measure price increases for these titles for the periods 1996 to 1999 and 1999 to 2002. METHODOLOGY: The 111 journal titles that have appeared in each published list from 1967 to 2001 were included in the study. Institutional subscription price data were gathered for each journal for the years 1996, 1999, and 2002 and were compared to the Consumer Price Index (CPI) for the same years. RESULTS: The average journal price continues to rise significantly and is independent of the CPI. The study found that prices have jumped 51.9% from 1996 to 1999 and 32% from 1999 to 2002, which is consistent with nearly every recent journal price study. CONCLUSION: The unprecedented rise in journal prices negatively affects the purchasing power of medical libraries. This paper examines the economic and technological pressures on the science, technology, and medical journals market that contribute to high prices and identifies a number of initiatives in the biological and health sciences that utilize alternative models for disseminating scientific research.

Costs and Cost Analysis↗

Recent progress in biomolecular engineering.

During the next decade or so, there will be significant and impressive advances in biomolecular engineering, especially in our understanding of the biological roles of various biomolecules inside the cell. The advances in high throughput screening technology for discovery of target molecules and the accumulation of functional genomics and proteomics data at accelerating rates will enable us to design and discover novel biomolecules and proteins on a rational basis in diverse areas of pharmaceutical, agricultural, industrial, and environmental applications. As an applied molecular evolution technology, DNA shuffling will play a key role in biomolecular engineering. In contrast to the point mutation techniques, DNA shuffling exchanges large functional domains of sequences to search for the best candidate molecule, thus mimicking and accelerating the process of sexual recombination in the evolution of life. The phage-display system of combinatorial peptide libraries will be extensively exploited to design and create many novel proteins, as a result of the relative ease of screening and identifying desirable proteins. Even though this system has so far been employed mainly in screening the combinatorial antibody libraries, its application will be extended further into the science of protein-receptor or protein-ligand interactions. The bioinformatics for genome and proteome analyses will contribute substantially toward ever more accelerated advances in the pharmaceutical industry. Biomolecular engineering will no doubt become one of the most important scientific disciplines, because it will enable systematic and comprehensive analyses of gene expression patterns in both normal and diseased cells, as well as the discovery of many new high-value molecules. When the functional genomics database, EST and SAGE techniques, microarray technique, and proteome analysis by 2-dimensional gel electrophoresis or capillary electrophoresis in combination with mass spectrometer are all put to good use, biomolecular engineering research will yield new drug discoveries, improved therapies, and significantly improved or new bioprocess technology. With the advances in biomolecular engineering, the rate of finding new high-value peptides or proteins, including antibodies, vaccines, enzymes, and therapeutic peptides, will continue to accelerate. The targets for the rational design of biomolecules will be broad, diverse, and complex, but many application goals can be achieved through the expansion of knowledge based on biomolecules and their roles and functions in cells and tissues. Some engineered biomolecules, including humanized Mab's, have already entered the clinical trials for therapeutic uses. Early results of the trials and their efficacy are positive and encouraging. Among them, Herceptin, a humanized Mab for breast cancer treatment, became the first drug designed by a biomolecular engineering approach and was approved by the FDA. Soon, new therapeutic drugs and high-value biomolecules will be designed and produced by biomolecular engineering for the treatment or prevention of not-so-easily cured diseases such as cancers, genetic diseases, age-related diseases, and other metabolic diseases. Many more industrial enzymes, which will be engineered to confer desirable properties for the process improvement and manufacturing of high-value biomolecular products at a lower production cost, are also anticipated. New metabolites, including novel antibiotics that are active against resistant strains, will also be produced soon by recombinant organisms having de novo engineered biosynthetic pathway enzyme systems. The biomolecular engineering era is here, and many of benefits will be derived from this field of scientific research for years to come if we are willing to put it to good use.

Animals↗

Comparison of holdings of NLM (CATLINE) with those of resource libraries.

The collection development practices of the National Library of Medicine (NLM), with the goal of comprehensive acquisition of biomedical monographs, are compared with those of the resource libraries of the TALON (Region IX) Regional Medical Library. Holdings of two resource libraries in the TALON region, The University of Texas Health Science Center at San Antonio and The University of Texas Medical Branch at Galveston, and of the TALON Union Catalog of Monographs were compared with the NLM CATLINE data base for four subject classes and selected imprint years. Foreign-language coverage is lacking in Region IX, with English-language coverage is lacking in Region IX, with English-language coverage ranging between 70 and 88% of titles listed in CATLINE. Absent English-language material tends to be ephemeral or otherwise out of scope for the resource libraries. Between 7.1 and 18.8% of monographs acquired in each subject class by the two recource libraries are lacking in CATLINE; this represents between 2 and 8% of the CATLINE titles for each class.

Book Collecting↗

Augmented reality in surgery.

OBJECTIVE: To evaluate the history and current knowledge of computer-augmented reality in the field of surgery and its potential goals in education, surgeon training, and patient treatment. DATA SOURCES: National Library of Medicine's database and additional library searches. STUDY SELECTION: Only articles suited to surgical sciences with a well-defined aim of study, methodology, and precise description of outcome were included. DATA SYNTHESIS: Augmented reality is an effective tool in executing surgical procedures requiring low-performance surgical dexterity; it remains a science determined mainly by stereotactic registration and ergonomics. Strong evidence was found that it is an effective teaching tool for training residents. Weaker evidence was found to suggest a significant influence on surgical outcome, both morbidity and mortality. No evidence of cost-effectiveness was found. CONCLUSIONS: Augmented reality is a new approach in executing detailed surgical operations. Although its application is in a preliminary stage, further research is needed to evaluate its long-term clinical impact on patients, surgeons, and hospital administrators. Its widespread use and the universal transfer of such technology remains limited until there is a better understanding of registration and ergonomics.

Forecasting↗

Intramuscular arteether for treating severe malaria.

BACKGROUND: Quinine and artemisinin drugs are used in severe malaria, but quinine resistance is increasing. Arteether is a recently developed artemisinin derivative that is oil soluble, has a long elimination half life, and is more stable than other derivatives. OBJECTIVES: To compare intramuscular arteether with other antimalarial drugs to treat severe malaria. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group Specialized Register (August 2004), CENTRAL (The Cochrane Library Issue 3, 2004), MEDLINE (1966 to August 2004), EMBASE (1980 to August 2004), U.S. National Library of Medicine (NLM) Gateway (1953 to 1965), Web Science Citation (1981 to August 2004), LILACS (August 2004), Google search engine (August 2004), conference proceedings, and reference lists. We also contacted researchers, organizations, and pharmaceutical companies to help identify trials. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials of intramuscular arteether in adults and children with severe malaria. DATA COLLECTION AND ANALYSIS: We independently assessed the methodological quality of the trials and extracted data, and analysed data using Review Manager 4.2. MAIN RESULTS: Two small trials (n = 194) met the inclusion criteria. Both trials compared arteether with quinine in children with cerebral malaria and reported on similar outcomes. There was no statistically significant difference in the number of deaths (relative risk 0.75, 95% confidence interval 0.43 to 1.30; n = 194, 2 trials), neurological complications (relative risk 1.18, 95% confidence interval 0.31 to 4.46; n = 58, 1 trial), or other outcomes including time to regain consciousness, parasite clearance time, and fever clearance time. The meta-analyses lack statistical power to detect important differences. REVIEWERS' CONCLUSIONS: More trials with a larger number of participants are needed before a firm conclusion about the efficacy and safety of arteether can be reached.

Adult↗

Vaccines for preventing malaria (pre-erythrocytic).

BACKGROUND: Vaccines against all stages of the malaria parasite are in development, mainly for Plasmodium falciparum, which causes the most serious form of malaria. Pre-erythrocytic vaccines act to prevent or delay a malaria attack by attacking the sporozoite and liver stages before the parasite reaches the bloodstream. OBJECTIVES: To assess the efficacy and safety of pre-erythrocytic malaria vaccines against any type of human malaria. SEARCH STRATEGY: In March 2006, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2006, Issue 1), MEDLINE, EMBASE, LILACS, and the Science Citation Index. We also searched conference proceedings and reference lists of articles, and contacted organizations and researchers in the field. SELECTION CRITERIA: Randomized controlled trials comparing pre-erythrocytic vaccines with placebo, control vaccine, or routine antimalarial control measures in people of any age receiving an artificial challenge or natural exposure to malaria infection. DATA COLLECTION AND ANALYSIS: Both authors independently assessed trial quality and extracted data. Results of meta-analyses were expressed as relative risks with 95% confidence intervals (CI) using an intention-to-treat analysis. MAIN RESULTS: Nine safety and efficacy trials, and two safety trials, with over 3000 participants were included. In semi-immune children, RTS,S vaccine reduced clinical episodes of malaria by 26% (95% CI 13% to 37%) and severe malaria by 58% (95% CI 15% to 79%) for up to 18 months. Prevalence of parasitaemia was also reduced by 26% (95% CI 11% to 38%) at six months after immunization. RTS,S also reduced clinical malaria episodes by 63% (95% CI 18% to 83%) in semi-immune adult men in the second year of follow up after a booster dose. No severe adverse events were judged to be related to RTS,S vaccine, although the frequencies of injection site pain, swelling, arm motion limitation, headache, and malaise were increased in the vaccine groups. There was no evidence for effect of the CS-NANP vaccines (307 participants, 3 trials), CS102 peptide vaccine (14 participants, 1 trial), or the ME-TRAP vaccine (372 participants, 1 trial). AUTHORS' CONCLUSIONS: RTS,S vaccine was effective in preventing a significant number of clinical malaria episodes, including good protection against severe malaria in children for 18 months. No severe adverse events were attributable to the vaccine. Progression of this vaccine towards licensing is justified while efforts to increase its efficacy continue. The other vaccines do not look promising and further research is a priority.

Adult↗

Vaccines for preventing malaria (blood-stage).

BACKGROUND: A malaria vaccine is needed because of the heavy burden of mortality and morbidity due to this disease. This review describes the results of trials of blood (asexual)-stage vaccines. Several are under development, but only one (MSP/RESA, also known as Combination B) has been tested in randomized controlled trials. OBJECTIVES: To assess the effect of blood-stage malaria vaccines in preventing infection, disease, and death. SEARCH STRATEGY: In March 2006, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2006, Issue 1), MEDLINE, EMBASE, LILACS, and the Science Citation Index. We also searched conference proceedings and reference lists of articles, and contacted organizations and researchers in the field. SELECTION CRITERIA: Randomized controlled trials comparing blood-stage vaccines (other than SPf66) against P. falciparum, P. vivax, P. malariae, or P. ovale with placebo, control vaccine, or routine antimalarial control measures in people of any age receiving a challenge malaria infection. DATA COLLECTION AND ANALYSIS: Both authors independently assessed trial quality and extracted data. Results for dichotomous data were expressed as relative risks (RR) with 95% confidence intervals (CI). MAIN RESULTS: Five trials of MSP/RESA vaccine with 217 participants were included; all five reported on safety, and two on efficacy. No severe or systemic adverse effects were reported at doses of 13 to 15 microg of each antigen (39 to 45 microg total). One small efficacy trial with 17 non-immune participants with blood-stage parasites showed no reduction or delay in parasite growth rates after artificial challenge. In the second efficacy trial in 120 children aged five to nine years in Papua New Guinea, episodes of clinical malaria were not reduced, but MSP/RESA significantly reduced parasite density only in children who had not been pretreated with an antimalarial drug (sulfadoxine-pyrimethamine). Infections with the 3D7 parasite subtype of MSP2 (the variant included in the vaccine) were reduced (RR 0.38, 95% CI 0.26 to 0.57; 719 participants) while those with the other main subtype, FC27, were not (720 participants). AUTHORS' CONCLUSIONS: The MSP/RESA (Combination B) vaccine shows promise as a way to reduce the severity of malaria episodes, but the effect of the vaccine is MSP2 variant-specific. Pretreatment for malaria during a vaccine trial makes the results difficult to interpret, particularly with the relatively small sample sizes of early trials. The results show that blood-stage vaccines may play a role and merit further development.

Antigens, Protozoan↗

[Pott triad and Schmorl nodules. A historical overview of kyphosis with special reference to tuberculous spondylitis and Scheuermann disease].

This report provides an overview of the history of the different types of kyphosis (arcuated and angulated forms). Especially tuberculous spondylitis and Scheuermann's disease are pointed out from among the large group of kyphotic diseases. Therefore, Beckhterew's disease, the combination of rickets and kyphosis as well as the dysraphic diseases and constitutional kyphosis caused by faulty posture are only mentioned. These two special types of kyphosis (Scheuermann's disease and tuberculous spondylitis) are presented from the first description with diagnostic findings, the ideas of pathogenesis and aspects of treatment through to the different periods of medical history. This article describes the way of thinking and discussing of opinion leaders at the beginning of the century and the influence of new techniques and developments (asepsis, antisepsis, anesthesia, bacteriology, X-ray, antibiotics) on the differential diagnosis and therapy. It is impossible to give a complete overview of all aspects during the centuries concerning tuberculous spondylitis or arcuated kyphosis. The authors of this article have focussed their studies on developments from the first descriptions until World War II, based mainly on literature from German journals and historical books from the library of the German Museum for Orthopedic History and Science.

Eponyms↗

[Transition from malum coxae senile to the arthrosis deformans concept. A summary of the best known theories and classifications].

The disease of degenerative arthritis has been known for thousands of years. Paleopathology has provided findings of ancient degenerative alterations. Furthermore, physicians in classical antiquity described several forms of joint diseases. A challenging problem was the therapy, which was limited at that time. For centuries all joint diseases were subsumed under the term"rheumatism." In 1683 Thomas Sydenham, who suffered himself from gout, first differentiated this joint disease from the larger group of rheumatic joint diseases. Another early classification was undertaken by John Haygarth in 1779. He differentiated gout from malum coxae senilis and the chronic rheumatic diseases. The different theories and the resulting classifications were influenced by different disciplines such as surgery, internal medicine, pathology, anatomy, neurology, microbiology, and radiology. This investigation includes the time period from the early nineteenth century until 1925 when the word "arthrosis" was first used in a medical publication. This investigation is based on research at the library of the German Museum for Orthopedic History and Science as well on the systematic search for articles in different German journals such as Zeitschrift für Orthopddie and Fortschritte auf dem Gebiet der Röntgenstrahlen. It includes almost all important books and publications about degenerative arthritis for this time period. In the past there were many different descriptions for degenerative arthritis. The establishment of X-rays and new methods in histology and microbiology and the aspect of biomechanical theories led to a better understanding of the different diseases. The authors tried to construct new classifications without the knowledge of the causal and formal pathogenesis. This is the reason for the large number of different classifications, which had to be revised after a short period of time. This publication gives an overview about the most important articles and books which led to the classification currently in use.

Aged↗

Maté: a risk factor for oral and oropharyngeal cancer.

Maté is a tea-like beverage consumed mainly in Argentina, Uruguay, Paraguay, southern Brazil and to a lesser degree in other areas of the world such as Germany, Syria, Lebanon and Northern Israel. It is brewed from the dried leaves and stemlets of the perennial tree Ilex paraguarensis ("yerba mate") a species that belongs to the Aquifoliaceae family. Maté consumption has been associated with an increased rate of oral and oropharyngeal cancers. The purpose of this study is to review the literature and discuss the role of Maté consumption in the development of oral and oropharyngeal cancer and the potential carcinogenic mechanisms. A review of the relevant literature linking Maté consumption with oral and oropharyngeal cancer and the carcinogenicity of Maté was performed. The search was performed using Medline, library catalogues, OCLC first search and ISI web of science databases. Case control studies on Maté drinking populations and, in vivo and in vitro studies on the carcinogenicity of Maté were reviewed. The populations reviewed in many of these studies also used alcohol and tobacco products confounding the influence of Maté as an independent risk factor. There is evidence in the literature that Maté consumption is in itself carcinogenic and plays a role in the development of cancers of the oral cavity and oropharynx. Although the exact mechanism of carcinogenesis is still unknown, available information suggests that Maté drinking should be considered one of the risk factors for oral and oropharyngeal cancer.

Alcohol Drinking↗

Understanding uncertainty and minimizing families' anxiety at the time of transfer from intensive care.

When general ward registered nurses (RN) receive patients from an intensive care unit (ICU) they report that much of their time in the initial phases revolves around meeting family needs (Farvis, 2002). Families experience anxiety when leaving the security of the close monitoring seen in ICU (Leith, 1999) and their anxiety reduces their ability to play a key role in the patient's recovery (McShane, 1991; Leske, 1992) as it can impair their decision-making (Cagan, 1988; Halm et al., 1993). By reducing a family's anxiety, they may be more able to cope with the necessary transition to a general ward and support the patient's recovery. A literature search from 1990 onwards was performed within the CINAHL, Medline and Cochrane databases using the key words: intensive care, family, General System Theory, uncertainty, anxiety and transfer. Further articles were retrieved from citation references from the Web of Science or through the reference lists of retrieved literature. Library catalogues were searched using the same key words for books and book chapters. von Bertalanffy's General System Theory provides a framework for understanding the importance of family in a critical illness situation. Critical illness permits little or no time to adapt, thus reducing the family's ability to cope with the situation. Transfer out of ICU is a significant anxiety-producing event for families. Uncertainty in illness is reported in other illness situations to reduce family's adaptation to illness events, but has not been researched with an ICU cohort of families. Seven out of the top 10 needs of ICU families are information needs, highlighting the importance of communication regarding progress and future plans. Nurses require an increased awareness that transfer anxiety exists for families and to be knowledgeable about ways to reduce its occurrence. Research is required to evaluate the efficacy of interventions to reduce anxiety for families and examine the level of uncertainty in illness in this cohort.

Anxiety↗

Comparative efficacy of thrombolytics in acute myocardial infarction: a systematic review.

BACKGROUND: The comparative clinical effectiveness of new (reteplase, tenecteplase) vs. older (alteplase, streptokinase) thrombolytic agents in the treatment of acute myocardial infarction is uncertain. AIM: To examine 30-35 day mortality and major adverse effects of thrombolytic agents in the treatment of acute myocardial infarction. DESIGN: Systematic review of randomized controlled trials comparing the clinical efficacy of included drug regimens. METHODS: We searched MEDLINE, EMBASE, Science Citation Index/Web of Science from 1980 to December 2001, and the Cochrane Library (2001, Issue 4). Reference lists of included studies and a number of medical journals were hand searched. Randomized controlled trials that compared any two of the included drugs provided to patients in the early stages of acute myocardial infarction, were included. Outcome measures included: mortality, bleeding, stroke, reinfarction, allergy and anaphylaxis. RESULTS: We found 14 studies, total study population 142 907. For available comparisons (all alteplase vs. streptokinase, reteplase vs. streptokinase or alteplase, tenecteplase vs. alteplase), meta-analysis showed no significant differences in mortality at 30-35 days. The GUSTO-I study showed an apparent benefit of accelerated alteplase over streptokinase, but its inclusion or exclusion made little difference. Total stroke and haemorrhagic stroke rates were lower for streptokinase than for all alteplase combined (total stroke, OR 1.29, 95%CI 1.13-1.46; haemorrhagic stroke OR 1.83, 95%CI 1.14-2.93). DISCUSSION: All thrombolytic drugs appear to be of similar efficacy in reducing mortality, and the apparent benefits of accelerated alteplase in GUSTO-I are consistent with this. Whether accelerated alteplase is sufficiently different from other regimens of administering alteplase to be excluded from a meta-analysis, and whether more weight should be placed on a meta-analysis than on a single trial, are matters for debate.

Fibrinolytic Agents↗

[Visual representation of biological structures in teaching material].

Parameters must be defined for presenting and handling scientific information presented in the form of teaching materials. Through library research and consultations with specialists in the health sciences and in graphic arts and design, this study undertook a comparative description of the first examples of scientific illustrations of anatomy and the evolution of visual representations of knowledge on the cell. The study includes significant examples of illustrations which served as elements of analysis.

Anatomy↗

[Bailey K. Ashford, more in his remembrance].

The military physician Bailey K. Ashford (Washington, D. C., September 18, 1873--San Juan, Puerto Rico, November 1, 1934) is mostly remembered for having identified in 1899 the cause of fatal anemia prevalent among Puertorican peasants, but he was also a distinguished investigator of other diseases, and organizer of mass medical services, in peace and in war. In spite of Ashford's own sober statements, the great influence of his scientific work in Puerto Rico and the impact of his personality in patients and colleagues have helped cast him as a mythical figure. His personal archives (kept at the library of the University of Puerto Rico's Medical Sciences Campus) make clear that his autobiography presents only a selection among the episodes that would form a complete biography.

History, 19th Century↗

Chemical biology of dynamic combinatorial libraries.

Dynamic combinatorial chemistry (DCC) is a recently introduced supramolecular approach to generate libraries of chemical compounds based on reversible exchange processes. The building elements are spontaneously and reversibly assembled to virtually encompass all possible combinations, allowing for simple one-step generation of complex libraries. The method has been applied to a variety of combinatorial systems, ranging from synthetic models to materials science and drug discovery, and enables the establishment of adaptive processes due to the dynamic interchange of the library constituents and its evolution toward the best fit to the target. In particular, it has the potential to become a useful tool in the direct screening of ligands to a chosen receptor without extensive prior knowledge of the site structure, and several biological systems have been targeted. In the vast field of glycoscience, the concept may find special perspective in response to the highly complex nature of carbohydrate-protein interactions. This chapter summarises studies that have been performed using DCC in biological systems, with special emphasis on glycoscience.

Carbohydrates↗