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PubMed2005

New approaches to mechanism analysis for drug discovery using DNA microarray data combined with KeyMolnet.

We have developed a comprehensive information platform, named KeyMolnet, for drug discovery and life science research in the post-genome era. Using KeyMolnet, we show new approaches to research into the biological mechanism in DNA microarray analysis. Thanks to the DNA microarray technology, it is now possible to obtain very large quantities of gene expression data at a time. However, it is still difficult to extract meaningful information from such large quantities of data and to analyze the relationship between gene expression data and biological function. We therefore developed an advanced tool that can generate molecular networks upon demand, and beyond signaling "cross-talks," can connect them to physiological phenomena and medical and drug information. Here we show the methods of mechanism analysis using the DNA microarray data and KeyMolnet, as well as the possible mechanism of inducing apoptosis in the human promyelocytic leukemia cell line, HL-60, treated with 12-O-tetradecanoylphorbol 13-acetate (TPA), using the time series of gene expression data from DNA microarray experiments. KeyMolnet enables practical approaches to research into biological mechanisms, which in turn contribute to new discoveries in the medical, pharmaceutical and life sciences.

Apoptosis↗
PubMed2000

Pentoxifylline for sickle-cell disease.

OBJECTIVE: To review the use of pentoxifylline for the prevention and treatment of acute vasoocclusive episodes (VOEs) in sickle-cell disease (SCD). DATA SOURCES: Searches of MEDLINE (1965-April 2000), International Pharmaceutical Abstracts (1970-April 2000), and Science Citation Index Expanded (1989-April 2000) were performed using the key search terms sickle-cell disease, pentoxifylline, oxypentifylline, and Trental. DATA SYNTHESIS: Patients with SCD commonly suffer from painful VOEs. Pentoxifylline may be useful in this condition due to its ability to increase red blood cell deformability and inhibit platelet aggregation. Laboratory evidence, an animal model, and case reports suggest a benefit, but available clinical studies are methodologically poor, and data analysis is often inappropriate or absent. Limited data suggest that pentoxifylline is beneficial for treatment of a VOE in progress, but no data exist demonstrating a reduction in the number of VOEs with chronic pentoxifylline therapy. CONCLUSIONS: Documentation of the efficacy of pentoxifylline for VOE prevention and treatment of SCD is poor, further studies are needed before its routine use is recommended.

Anemia, Sickle Cell↗
PubMed2003

Overview of bioinformatics and its application to oral genomics.

The "informatics revolution" in both bioinformatics and dental informatics will eventually change the way we practice dentistry. This convergence will play a pivotal role in creating a bridge of opportunity by integrating scientific and clinical specialties to promote the advances in treatment, risk assessment, diagnosis, therapeutics, and oral health-care outcome. Bioinformatics has been an emerging field in the biomedical research community and has been gaining momentum in dental medicine. This area has created a steady stream of large and complex genomic data, which has transformed the way a clinical or basic science researcher approaches genomic research. This application to dental medicine, termed "oral genomics", can aid in the molecular understanding of the genes and proteins, their interactions, pathways, and networks that are responsible for the development and progression of oral diseases and disorders. As the result of the Human Genome Project, new advances have prompted high-throughput technologies, such as DNA microarrays, which have become accepted tools in the biomedical research community. This manuscript reviews the two most commonly used microarray technologies, basic microarray data analysis, and the results from several ongoing oral cancer genomic studies.

Carcinoma, Squamous Cell↗
PubMed2003

Information-seeking behavior in complementary and alternative medicine (CAM): an online survey of faculty at a health sciences campus.

BACKGROUND: The amount of reliable information available for complementary and alternative medicine (CAM) is limited, and few authoritative resources are available. OBJECTIVE: The objective is to investigate the information-seeking behavior of health professionals seeking CAM information. METHODS: Data were gathered using a Web-based questionnaire made available to health sciences faculty affiliated with the University of California, San Francisco. RESULTS: The areas of greatest interest were herbal medicine (67%), relaxation exercises (53%), and acupuncture (52%). About half the respondents perceived their CAM searches as being only partially successful. Eighty-two percent rated MEDLINE as a useful resource, 46% personal contacts with colleagues, 46% the Web, 40% journals, and 20% textbooks. Books and databases most frequently cited as useful had information about herbs. The largest group of respondents was in internal medicine (26%), though 15% identified their specialties as psychiatry, psychology, behavioral medicine, or addiction medicine. There was no correlation between specialty and patterns of information-seeking behavior. Sixty-six percent expressed an interest in learning more about CAM resources. CONCLUSIONS: Health professionals are frequently unable to locate the CAM information they need, and the majority have little knowledge of existing CAM resources, relying instead on MEDLINE. Medical librarians need to educate health professionals in the identification and use of authoritative CAM resources.

California↗
PubMed2006

V-cluster algorithm: a new algorithm for clustering molecules based upon numeric data.

Clustering molecules based on numeric data such as, gene-expression data, physiochemical properties, or theoretical data is very important in drug discovery and other life sciences. Most approaches use hierarchical clustering algorithms, non-hierarchical algorithms (for examples, K-mean and K-nearest neighbor), and other similar methods (for examples, the Self-Organization Mapping (SOM) and the Support Vector Machine (SVM)). These approaches are non-robust (results are not consistent) and, computationally expensive. This paper will report a new, non-hierarchical algorithm called the V-Cluster (V stands for vector) Algorithm. This algorithm produces rational, robust results while reducing computing complexity. Similarity measurement and data normalization rules are also discussed along with case studies. When molecules are represented in a set of numeric vectors, the V-Cluster Algorithm clusters the molecules in three steps: (1) ranking the vectors based upon their overall intensity levels, (2) computing cluster centers based upon neighboring density, and (3) assigning molecules to their nearest cluster center. The program is written in C/C++ language, and runs on Window95/NT and UNIX platforms. With the V-Cluster program, the user can quickly complete the clustering process and, easily examine the results by use of thumbnail graphs, superimposed intensity curves of vectors, and spreadsheets. Multi-functional query tools have also been implemented.

Algorithms↗
PubMed2006

WHO systematic review of prevalence of chronic pelvic pain: a neglected reproductive health morbidity.

BACKGROUND: Health care planning for chronic pelvic pain (CPP), an important cause of morbidity amongst women is hampered due to lack of clear collated summaries of its basic epidemiological data. We systematically reviewed worldwide literature on the prevalence of different types of CPP to assess the geographical distribution of data, and to explore sources of variation in its estimates. METHODS: We identified data available from Medline (1966 to 2004), Embase (1980 to 2004), PsycINFO (1887 to 2003), LILACS (1982 to 2004), Science Citation index, CINAHL (January 1980 to 2004) and hand searching of reference lists. Two reviewers extracted data independently, using a piloted form, on participants' characteristics, study quality and rates of CPP. We considered a study to be of high quality (valid) if had at least three of the following features: prospective design, validated measurement tool, adequate sampling method, sample size estimation and response rate >80%. We performed both univariate and multivariate meta-regression analysis to explore heterogeneity of results across studies. RESULTS: There were 178 studies (459975 participants) in 148 articles. Of these, 106 studies were (124259 participants) on dysmenorrhoea, 54 (35973 participants) on dyspareunia and 18 (301756 participants) on noncyclical pain. There were only 19/95 (20%) less developed and 1/45 (2.2%) least developed countries with relevant data in contrast to 22/43 (51.2%) developed countries. Meta-regression analysis showed that rates of pain varied according to study quality features. There were 40 (22.5%) high quality studies with representative samples. Amongst them, the rate of dysmenorrhoea was 16.8 to 81%, that of dyspareunia was 8 to 21.8%, and that for noncyclical pain was 2.1 to 24%. CONCLUSION: There were few valid population based estimates of disease burden due to CPP from less developed countries. The variation in rates of CPP worldwide was due to variable study quality. Where valid data were available, a high disease burden of all types of pelvic pain was found.

Chronic Disease↗
PubMed1995

Appropriate use of heparin. Empiric vs nomogram-based dosing.

BACKGROUND: A study involving two groups of patients with cardiovascular disease was conducted to compare empiric (clinician-directed) heparin therapy with therapy based on a nomogram-determined dosage. The comparison was based on (1) the average weight-referenced infusion rate yielding a therapeutic activated partial thromboplastin time (APTT) and (2) the time required to reach a therapeutic APTT (55 to 95 seconds) after empiric or nomogram-based heparin therapy was initiated. METHODS: Data were collected for patients admitted to the cardiology service at a university health science center in two phases: phase 1 (April 1 through June 30, 1992), involving 95 patients receiving heparin therapy, with 88 patients included in the data analysis, and phase 2 (March 11 through June 11, 1993), involving 156 patients receiving heparin therapy, with 45 patients receiving nomogram-guided therapy included in the data analysis. RESULTS: In phase 1, 66 patients (75.0%) achieved a therapeutic APTT some time during their heparin therapy, with an average time to therapeutic APTT of 20.7 + 19.1 hours. Regression analysis demonstrated a statistically significant relationship between the heparin infusion rate at the time of the patient's first therapeutic APTT and the patient's total body weight (r2 = .3043). An initial infusion rate based on total body weight (13 U/kg per hour) was therefore used as the basis for the nomogram in phase 2. In phase 2, 41 patients (91.1%) achieved a therapeutic APTT at some time during their heparin therapy, with an average time to therapeutic APTT of 13.1 + 11.9 hours, statistically significantly shorter than that in phase 1. A greater proportion of patients in phase 2 compared with patients in phase 1 reached the therapeutic range within 12 hours (62.2% vs 34.1%) and within 24 hours (77.8% vs 54.5%). CONCLUSIONS: Use of a weight-based nomogram to determine the initial and maintenance heparin infusion rates was associated with a higher percentage of patients admitted to the cardiology service reaching the targeted therapeutic APTT range at a time earlier in the course of therapy compared with empiric dosing.

Adult↗
PubMed2004

Effectiveness of intermediate care in nursing-led in-patient units.

BACKGROUND: The Nursing led inpatient Unit (NLU) is one of a range of services that have been considered in order to manage more successfully the transition between hospital and home for patients with extended recovery times. OBJECTIVES: To determine whether nursing-led inpatient units are effective in preparing patients for discharge from hospital compared to usual inpatient care. SEARCH STRATEGY: We searched The Cochrane Library, the Specialized Register of the Cochrane Effective Practice and Organisation of Care (EPOC) group, MEDLINE, CINAHL, EMBASE, BNI and HMIC databases. Citation searches were undertaken on the science and social science citation indices. Authors were contacted to identify additional data. SELECTION CRITERIA: Controlled trials and interrupted time series designs that compared the NLU to usual inpatient care managed by doctors. Patients over 18 years of age following an acute hospital admission for a physical health condition. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed study quality. MAIN RESULTS: Ten random or quasi-random controlled trials reported on a total of 1896 patients. There was no statistically significant effect on inpatient mortality ( OR 1.10, 95% CI 0.56 to 2.16) or mortality to longest follow up (OR 0.92, 95% CI 0.65 to 1.29) but higher qaulity studies showed a larger non-significant increase in inpatient mortality (OR 1.52, 95% CI 0.86 to 2.68). Discharge to institutional care was reduced for the NLU (OR 0.44 95% CI 0.22 to 0.89) and functional status at discharge increased (SMD 0.37, 95% CI 0.20 to 0.54) but there was a near significant increase in inpatient stay (WMD 5.13 days 95% CI -0.5 days to 10.76 days). Early readmissions were reduced (OR 0.52 95% CI 0.34 to 0.80). One study compared a NLU for the chronically critically ill with ICU care. Mortality (OR 0.62 95% CI 0.35 to 1.10) and length of inpatient stay differ did not differ (WMD 2 days, 95% CI 10.96 to -6.96 days). Early readmissions were reduced (OR 0.33 95% CI 0.12 to 0.94). Costs of care on the NLU were higher for UK studies but lower for US based studies. REVIEWERS' CONCLUSIONS: There is some evidence that patients discharged from a NLU are better prepared for discharge but it is unclear if this is simply a product of an increased length of inpatient stay. No statistically significant adverse effects were noted but the possibility of increased early mortality cannot be discounted. More research is needed.

Health Care Costs↗
PubMed1983

Review: putative mutagens and carcinogens in foods. I. Nitrate/nitrite ingestion and gastric cancer mortality.

Published figures for per capita daily levels of nitrate ingestion in the 1970s are compared with gastric cancer mortality estimates for the same period. A strong positive correlation is observed in 12 countries, not only when the data are analyzed as a linear-linear function, as illustrated in this paper, but also when the relationship is analyzed as a function of (nitrate)2. This correlation supports the concept that important components of gastric cancer induction are the in vivo bacterial reduction of nitrate to nitrite and the intragastric formation of mutagenic/carcinogenic nitroso, and possibly nitro compounds. Data are summarized from a recent National Academy of Sciences [1981] study that enumerates by individual dietary sources the mean ingestion of nitrate and nitrite by the United States population at the present time. The ingestion figures are used to calculate the probable current gastric nitrite load in US adults with normal gastric acidity. Similar calculations are provided for past years (1925, 1936-1937, and 1971-1972). Since 1925, there has been an approximately threefold decrease in gastric cancer mortality in the US, and this decline is paralleled by an approximately fourfold decrease in average gastric nitrite load. The excessive ingestion of nitrate/nitrite in the US in past years is attributed to the very high content of nitrate and nitrite in cured meats. Several ways compatible with current US farming and marketing practices that are capable of reducing the gastric nitrite load even further are pointed out.

Animals↗
PubMedDate not supplied

Radiotherapy for basaloid squamous cell carcinoma of the head and neck.

Basaloid squamous cell carcinoma (BSCC) of the head and neck is a recently described high-grade variant of squamous cell carcinoma. It is a biologically virulent neoplasm with a propensity for nodal, as well as systemic, metastases. Because of the limited number of published reports, we reviewed data from patients of the University of Virginia Health Sciences Center and identified 16 cases of BSCC. The intent of this study was to determine the role of radiotherapy in the treatment of BSCC and better define the clinical features of this entity. Radiotherapy alone, or in combination with surgery, resulted in excellent local control rates. Distant metastases, chiefly pulmonary, occurred in more than half of the patients.

Carcinoma, Squamous Cell↗
PubMedDate not supplied

Overview of randomized clinical trials of total parenteral nutrition for malnourished surgical patients.

The past decade has seen a maturation of the art and science of perioperative nutritional support. We now have sufficient data to make informed and reasonable judgments regarding when we should and should not provide perioperative TPN. These judgments can be considered medically sound and fiscally responsible. The following guidelines are proposed: (1) Postoperative TPN should be considered when oral or enteral feeding is not anticipated within 7 to 10 days in previously well-nourished patients or within 5 to 7 days in previously malnourished or critically ill patients. (2) Preoperative TPN should be considered in patients who cannot or should not eat or receive enteral feedings if the operation must be delayed for more than 3 to 5 days. (3) Preoperative TPN should be considered in the most severely malnourished surgical candidates if an operative delay is not contraindicated. In patients with only mild to moderate degrees of malnutrition preoperative TPN is not indicated.

Humans↗
PubMed1990

Immunomodulatory characteristics of a novel antiproliferative protein, suppressin.

We investigated the immunoregulatory properties of a recently described inhibitor of lymphocyte proliferation, suppressin (SPN). It was determined that preincubation of murine leukocytes with SPN enhances natural killer cell (NK) activity. In addition, SPN potentiates interferon-gamma (IFN-gamma) augmentation of NK activity. Furthermore, preincubation of murine leukocytes with SPN induces the production of IFN-alpha/beta. The IFN-alpha/beta produced is active in NK assays as well as vesicular stomatitis virus neutralization assays. In vivo, SPN increases the time of survival of C57BL/6 mice injected with EL-4 lymphoma cells. Interestingly, SPN inhibits immunoglobulin (IgA, IgG, and IgM) production in response to the mitogen, concanavalin A in a dose-dependent manner. Collectively, the above data indicate SPN may have numerous applications in clinical science including tumor surveillance and autoimmune diseases such as arthritis.

Animals↗
PubMed2006

Temporal representation and reasoning in medicine: Research directions and challenges.

OBJECTIVE: The main aim of this paper is to propose and discuss promising directions of research in the field of temporal representation and reasoning in medicine, taking into account the recent scientific literature and challenging issues of current interest as viewed from the different research perspectives of the authors of the paper. BACKGROUND: Temporal representation and reasoning in medicine is a well-known field of research in the medical as well as computer science community. It encompasses several topics, such as summarizing data from temporal clinical databases, reasoning on temporal clinical data for therapeutic assessments, and modeling uncertainty in clinical knowledge and data. It is also related to several medical tasks, such as monitoring intensive care patients, providing treatments for chronic patients, as well as planning and scheduling clinical routine activities within complex healthcare organizations. METHODOLOGY: The authors jointly identified significant research areas based on their importance as for temporal representation and reasoning issues; the subjects were considered to be promising topics of future activity. Every subject was addressed in detail by one or two authors and then discussed with the entire team to achieve a consensus about future fields of research. RESULTS: We identified and focused on four research areas, namely (i) fuzzy logic, time, and medicine, (ii) temporal reasoning and data mining, (iii) health information systems, business processes, and time, and (iv) temporal clinical databases. For every area, we first highlighted a few basic notions that would permit any reader--including those who are unfamiliar with the topic--to understand the main goals. We then discuss interesting and promising directions of research, taking into account the recent literature and underlining the yet unresolved medical/clinical issues that deserve further scientific investigation. The considered research areas are by no means disjointed, because they share common theoretical and methodological features. Moreover, subjects of imminent interest in medicine are represented in many of the fields considered. CONCLUSIONS: We propose and discuss promising subjects of future research that deserve investigation to develop software systems that will properly manage the multifaceted temporal aspects of information and knowledge encountered by physicians during their clinical work. As the subjects of research have resulted from merging the different perspectives of the authors involved in this study, we hope the paper will succeed in stimulating discussion and multidisciplinary work in the described fields of research.

Artificial Intelligence↗
PubMed2004

Vascular disease and inflammation.

The past decade has witnessed a dramatic shift in the understanding of the causes of atherosclerotic vascular disease. What was once considered to be a process of abnormal lipid deposition in the vascular wall is now understood to be a dynamic inflammatory process from inception through plaque growth, rupture and ultimately thrombosis. This article reviews the basic science research that supports this growing body of epidemiologic data and discusses the inflammatory markers that predict future clinical events,as well as the pharmacologic success in therapies that specifically target inflammation.

Animals↗
PubMed2006

Cancer risk assessment for 1,3-butadiene: dose-response modeling from an epidemiological perspective.

The dose-response assessment of the association between 1,3-butadiene (BD) and leukemia mortality among workers in the North American synthetic rubber industry is explored. Analyses are based on the most recent University of Alabama at Birmingham epidemiological study and exposure estimation. The U.S. EPA Science Advisory Board recommendations of using the most recent data and giving consideration to peak exposures to BD have been followed. If cumulative BD ppm-years is to be used as the predictor of the leukemia rate ratio, then the performance of that predictor is statistically significantly improved if the slope in the predictor is estimated with age and the cumulative number of BD peaks (where a BD peak is any exposure, regardless of duration, to a BD concentration above 100 ppm) added as categorical covariates. After age and the cumulative number of BD peaks are incorporated as categorical covariates in the Poisson regression model, the estimated concentration (EC(001)) corresponding to an excess risk of 0.001 as a result of continuous environmental exposure is 11.2 ppm; however, the estimated slope for BD cumulative ppm-years in the linear rate ratio for leukemia used to derive this EC(001) is not statistically significantly different from zero. Sensitivity analyses using alternative models indicate either essentially no risk or estimated EC(001) values of 9 and 77 ppm. Analyses suggesting the absence of a statistically significant low-dose risk versus cumulative BD ppm-years are presented. Sensitivity analyses of other malignant neoplasms of lymphatic and hematopoietic tissue (specifically, lymphoid and myeloid neoplasms) resulted in conclusions about the dose-response modeling methodology that were supportive of the methodology used for leukemia.

Aging↗
PubMed2006

Genome-wide profiling of segmental-regulated transcriptomes in human epididymis using oligo microarray.

Sperm maturation during passage through the epididymis depends on regionalized gene expression which maintains the progressively changing environment within the epididymal tubule. Towards defining the genes that drive the sequential maturation of spermatozoa, we profiled regionally regulated gene expression pattern in the epididymis of a fertile young male donor using Affymetrix human genome U133 plus 2.0 microarray representing approximately the whole human genome. Over 15000 transcripts, almost one-third of the total on the array were identified in whole epididymis. Among them, 65% were detected in all three regions of the epididymis, 410 or 2.6% were present only in one region and the remaining 32.4% were distributed in two regions. Region-specific transcripts observed in caput (264), corpus (61) and cauda (81) epididymides were further classified as empirically determined reported genes or ESTs. This study revealed for the first time, the expression in human epididymis of a number of region-specific genes. The original data will be made publicly available on the Shanghai Science and Technology Database (http://www.scbit.org/human_epididymis_transcriptomes).

Adult↗
PubMed2005

Brainstem origins for cortical 'what' and 'where' pathways in the auditory system.

We have developed a data-driven conceptual framework that links two areas of science: the source-filter model of acoustics and cortical sensory processing streams. The source-filter model describes the mechanics behind speech production: the identity of the speaker is carried largely in the vocal cord source and the message is shaped by the ever-changing filters of the vocal tract. Sensory processing streams, popularly called 'what' and 'where' pathways, are well established in the visual system as a neural scheme for separately carrying different facets of visual objects, namely their identity and their position/motion, to the cortex. A similar functional organization has been postulated in the auditory system. Both speaker identity and the spoken message, which are simultaneously conveyed in the acoustic structure of speech, can be disentangled into discrete brainstem response components. We argue that these two response classes are early manifestations of auditory 'what' and 'where' streams in the cortex. This brainstem link forges a new understanding of the relationship between the acoustics of speech and cortical processing streams, unites two hitherto separate areas in science, and provides a model for future investigations of auditory function.

Animals↗
PubMed2002

Learning and development in neural networks--the importance of prior experience.

Infants can discriminate between familiar and unfamiliar grammatical patterns expressed in a vocabulary that is distinct from that used earlier during familiarization (Cognition 70(2) (1999) 109; Science 283 (1999) 77). Various models have captured the data, although each required that discrimination be distinct, in terms of the computational process, from familiarization. This article describes a simple recurrent network (SRN), equipped only with the assumption that it should predict what comes next, which models the data without distinguishing between familiarization and discrimination. To accomplish this, the SRN requires pre-training on a range of sequences instantiating different structures and different vocabulary items to those used subsequently during familiarization and test. Pre-training enables the network to avoid replacing structure acquired during familiarization with structure experienced at test. An equivalent enabling condition may underpin infants' resistance to catastrophic interference between the different structures and vocabulary items to which they are exposed.

Cognition↗