What's related? Generalizing approaches to related articles in medicine.

INTRODUCTION: We did formative evaluations of several variations to the computation of related articles for non-bibliographic resources in the medical domain. METHODS: A binary model and several variations of the vector space model were used to measure similarity between documents. Two corpora were studied, using a human expert as the gold standard. RESULTS: Variations in term weights and stopword choices made little difference to performance. Performance was worse when documents were characterized by title words alone or by MeSH terms extracted from document references. DISCUSSION: Further studies are needed to evaluate these methods in medical information retrieval systems.

Versatile user interface using UMLS Metathesaurus.

One of the obstacles for a successful search in the biomedical field is that different vocabularies are used by different databases but more than one database is usually needed to respond adequately to a healthcare professional's query. A typical searcher usually is unfamiliar with these vocabularies and the sophisticated measures to narrow or broaden a search. As a result, a failed search is often due to using "inappropriate" search terms. We have developed a highly interactive and versatile user interface, SHINE Refined Search (SHINE RS). It uses medical concepts from the UMLS Metathesaurus as the building block to help searchers find "appropriate" search terms for their queries. The results of our preliminary usability assessment are promising and demonstrate the potential to improve retrieval results.

Analysis of information needs of users of the Stanford Health Information Network for Education.

OBJECTIVE: To examine the information needs of users of the Stanford Health Information Network for Education (SHINE), an integrated information retrieval (IR) system. METHODS: A subset of queries from the SHINE log were categorized into one or more of 33 categories. RESULTS: Drugs and infectious disease accounted for 25% of categorizations, and otherwise the distribution of categorizations was quite broad. CONCLUSIONS: Attention should be paid to the selection of drug information resources in medical knowledge information retrieval systems. The distribution of query categorizations also suggests that IR systems include a wide range of knowledge resources.

New paradigms for medical decision support and education: the Stanford Health Information Network for Education.

The information needs of physicians are complex and ever increasing in a world of rapidly expanding medical knowledge and a practice environment where physicians are required to know and do more with shrinking resources. Current strategies for providing clinical decision support and continuing medical education have failed, in part, because they have not provided timely, easy access to information that is current, integrated with other information and the physician's workflow, and relevant to specific questions that occur during the patient encounter. Meeting these challenges involves understanding the nature of medical knowledge, the different information needs of physicians, the clinical decision-making process, and the constraints of the physicians work environment, as well as the traditional barriers to physician education. We explore the nature of some of these challenges and propose one solution in the form of a highly integrated web-based technology--The Stanford Health Information Network for Education.

The Stanford Health Information Network for Education: integrated information for decision making and learning.

Although multiple decision support systems have been built for physicians, efficient delivery of valid and complete medical knowledge remains an elusive goal. In this paper we describe a new project, the Stanford Health Information Network for Education (SHINE). SHINE unifies core medical resources in an intuitive interface to support clinical decision making. Included in the description is a novel paradigm for continuing medical education (CME).

Effects of lymphokines and mitogens on a histamine derivative-induced intracellular calcium mobilization and inositol phosphate production.

Histamine trifluoromethyl-toluidine derivative (HTMT), a novel immunosuppressive agent, stimulates H1, H2 and HTMT receptors in lymphocytes. HTMT receptors are different from the classical H1, H2 or H3 receptors. Stimulation of HTMT receptors results in increased intracellular concentrations of calcium ([Ca2+]i) and inositol phosphate (IP) in human peripheral blood lymphocytes. In the present study, we investigated the effects of lymphokines [interleukin-4 (IL-4), interleukin-2 (IL-2)] and other pharmacologic agents [lipopolysaccharide (LPS), phorbol 12-myristate 13-acetate (PMA)] on HTMT-induced Ca2+ and IP responses in non-rosetted cells. HTMT caused enhanced [Ca2+]i and IP responses when the cells were pretreated with IL-4. The effects of IL-4 were concentration dependent and became maximal after the cells were incubated with IL-4 for 48 hr. Inhibitors of protein synthesis, but not of RNA synthesis, blocked the effects of IL-4 on HTMT-induced responses. LPS was more potent than IL-4 in augmenting CA2+ mobilization induced by HTMT. However, the effects of LPS were not altered by inhibitors of either protein synthesis or RNA transcription. This indicated that LPS may act differently than IL-4 on the HTMT response. IL-2 and PMA did not affect HTMT-induced [Ca2+]i and IP responses. The effects of IL-4 and LPS were agonist specific. They did not affect the Ca2+ mobilization induced by PAF. The data indicate that the response to HTMT can be regulated by IL-4 and LPS. Although the in vivo importance of these receptors is not yet clear, the receptor is likely a contributor to immune and/or inflammatory regulation.

Case-mix adjustment using objective measures of severity: the case for laboratory data.

OBJECTIVE: We evaluate the use of routinely gathered laboratory data to subclassify surgical and nonsurgical major diagnostic categories into groups homogeneous with respect to length of stay (LOS). DATA SOURCES AND STUDY SETTING: The source of data is the Combined Patient Experience database (COPE), created by merging data from computerized sources at the University of California San Francisco (UCSF) Medical Center and Stanford University Medical Center for a total sample size of 73,117 patient admissions. STUDY DESIGN: The study is cross-sectional and retrospective. All data were extracted from COPE consecutive admissions; the unit of analysis is an admission. The outcome variable LOS proxies hospital resource utilization for an inpatient stay. Nine (candidate) predictor variables were derived from seven lab tests (WBC, Na, K, C02, BUN, ALB, HCT) by recording the whole-stay minimum or maximum test result. DATA COLLECTION/EXTRACTION METHODS: Patient groups were formed by first assigning to major diagnostic categories (MDCs) all 73,117 admissions. Each MDC was then partitioned into medical and surgical subgroups (sub-MDCs). The 13 sub-MDCs selected for study define a study population of 32,599 patients that represents approximately 45 percent of inpatients. Within each of the 13 sub-MDCs, patients were randomly assigned to one of two data sets in a ratio of 2:1. The first set was used to create, the second to validate, three different LOS predictors. Predictive accuracies of individual DRG classes were compared with those of two alternative classification schemes, one formed by recursive partitioning (the sub-MDC) using only lab test results, the other by partitioning with both lab test results and individual DRGs. PRINCIPAL FINDINGS: For the eight largest sub-MDCs (81 percent of study population), individual DRGs explained 23 percent of the within sub-MDC variance in LOS, laboratory data classes explained 31 percent, and classes derived by considering individual DRGs and laboratory data explained 37 percent. (Each result is a weighted average R2. The average number of LOS classes into which the eight largest sub-MDCs were partitioned were 20, 10, and 10, respectively. Within six of the eight, partitioning on the basis of laboratory data alone explained more within sub-MDC variance than did partitioning into individual DRGs. CONCLUSIONS: Routine lab test data improve the accuracy of LOS prediction over that possible using DRG classes. We note that the improvements do not result from overfitting the data, since the numbers of LOS classes we use to predict LOS are considerably fewer than the numbers of individual DRGs.

A histamine derivative increases intracellular calcium mobilization and oxidative metabolism in HL-60 cells.

Past work in our laboratory has shown that a derivative of histamine, histamine-trifluoromethyl-toluidide (HTMT), has surprising tissue specificity on lymphocytes and can produce remarkable immunosuppression. This study focuses on the effects of HTMT on Ca2+ mobilization and oxidative metabolism in undifferentiated and DMSO-differentiated HL-60 cells. HTMT caused two phases of increases in intracellular calcium concentrations ([Ca2+]i) in HL-60 cells. The responses were dose dependent, with similar EC50 values (1.7 x 10(-5) M for undifferentiated and 1.5 x 10(-5) M for differentiated cells). The increase in [Ca2+]i in differentiated cells was much greater than in undifferentiated cells. The maximum responses were observed after the undifferentiated cells were incubated with DMSO for 7 days. The increase in [Ca2+]i induced by HTMT in both types of cells was competitively antagonized by high concentrations of histamine but not by classic histamine receptor antagonists (H1, H2, or H3). The inhibitory effects of histamine on [Ca2+]i accumulation in differentiated cells were partially reversed by histamine H2 receptor antagonist ranitidine, whereas in undifferentiated cells, the effects of histamine on Ca2+ mobilization were not affected by ranitidine. Other cAMP elevating agents did not inhibit increases in [Ca2+]i in undifferentiated cells but did affect [Ca2+]i in differentiated cells. The enhanced response in [Ca2+]i mobilization after differentiation of HL-60 cells appeared to be the result of an increase in the expression/function of receptors for HTMT. One interesting feature of this regulation was the fact that cAMP per se did not regulate HTMT induced Ca2+ mobilization in undifferentiated cells but inhibited the mobilization in differentiated cells. HTMT caused the generation of reactive oxygen species in both undifferentiated and differentiated HL-60 cells as measured by chemoluminescence and the levels of generation correlated with the mobilization of [Ca2+]i. In addition, the EC50s for the HTMT induced calcium mobilization and the generation of reactive oxygen species were similar, as was the case for histamine induced inhibition (Ki) in both cell types. The data imply a second messenger role for Ca2+ in HTMT induced neutrophil activation.

Cyclic AMP is not a direct regulator of calcium flux and hydrolysis of phosphoinositides in human lymphocytes.

The regulatory effects of adenosine 3',5'-cyclic monophosphate (cAMP) on Ca2+ flux and phosphatidylinositol (PI) turnover in human lymphocytes were studied. cAMP did not affect the intracellular accumulation of Ca2+ induced by phytohemagglutinin (PHA) and histamine-trifluoromethyl toluidide derivative (HTMT) in peripheral blood lymphocytes (PBL). In addition, cAMP also did not alter Ca2+ flux induced by PHA, anti-CD3, or PAF in T cells, or by anti-IgM and HTMT in non-rosetted cells. Similarly, cAMP did not inhibit IP accumulation induced by HTMT in PBL, anti-CD3 in T cells, and by anti-IgM or HTMT in non-rosetted cells. The only exception was the synthesis of IP induced by PHA in T cells that was inhibited by cAMP. Furthermore, prolonged treatment of T cells with cholera toxin inhibited Ca2+ accumulation in response to CD3. The degree of inhibition of Ca2+ and IP responses was not proportional to the levels of intracellular cAMP generated.

Histamine and its congener derivatives as immune modulators.

Our knowledge of the function of histamine as an immunoregulatory autacoid is expanding. The presence of histamine in many tissues in which the immune response takes place and its release during immune response lend credibility to the notion that histamine's role in the immune response could be an important one. In this report we present data that demonstrate the immune modulatory role of histamine. We also describe the synthesis and novel pharmacologic effects of congener derivatives of histamine. These new lymphocyte specific histamine H1 and/or H2 agonists make it feasible to assess the potential of histamine as a selective in vivo immune modulator.

Effects of histamine-trifluoromethyl-toluidide derivative (HTMT) on intracellular calcium in human lymphocytes.

We have studied the effects of histamine trifluoromethyl-toluidide derivatives on calcium mobilization in human peripheral blood lymphocytes using spectrofluorometric analysis. HTMT (compound 1) induced two phases of increase in intracellular calcium concentration--a rapid intracellular calcium concentration peak (10-60 sec), partial recovery (1-3 min) and a sustained moderate elevation that persisted for more than 5 min. The EC50 value was 1.9 X 10(-5) M. Pretreatment of lymphocytes with the agonist resulted in receptor desensitization that recovered after 15 min when the cells were drug free. The presence of extracellular ethylene glycol bis(beta-aminoethyl ether)N,N'-tetraacetic acid did not abrogate the early phase of the calcium rise, suggesting that the calcium appearing in the cytosol during the early phase was derived from intracellular stores. The increase in intracellular calcium concentration by this compound was competitively antagonized by high concentrations of histamine but not by classic histamine receptor antagonists (H1, H2 or H3). Other cyclic AMP elevating agents, with the exception of prostaglandin E2, did not affect the increase in calcium levels induced by compound 1. Compound 1 caused phosphatidylinositol metabolism resulting in inositol phosphate production, suggesting that inositol triphosphate may be the second messenger for the mobilization of intracellular Ca2+ by compound 1. The data imply a specific binding site for histamine trifluoromethyl toluidide derivative on lymphocytes that is different than the classic H1, H2 or H3 receptors.

Abnormal T suppressor cell function in juvenile rheumatoid arthritis.

The purpose of this study was to analyze T suppressor cell function in juvenile rheumatoid arthritis (JRA). JRA is a chronic inflammatory childhood disease of unknown etiology that is characterized by arthritis and immunoregulatory abnormalities. T suppressor cell precursors (CD8+, CD28-) were purified from the peripheral blood of 24 JRA patients, using a combination of monoclonal antibodies. These cells were treated with histamine or concanavalin A, agents that are known to induce suppressor activity. They were also tested for their ability to inhibit the proliferative response of autologous T cells to phytohemagglutinin. In some experiments, the accumulation of intracellular cAMP following histamine treatment was also measured. Twelve of 13 patients with clinically active JRA showed abnormal histamine-inducible T suppressor cell function, characterized by the failure of CD8+, CD28- T cells to mediate any detectable suppression. The failure of these cells to accumulate intracellular cAMP after histamine treatment was observed in 5 of 5 patients tested who had active disease. In contrast, 11 of 11 patients with clinically inactive JRA, 5 of 5 patients with cystic fibrosis, and 9 of 9 pediatric control subjects had normal histamine- and concanavalin A-inducible T suppressor cell function, and a normal cAMP response to histamine. These results suggest that patients with clinically active JRA have a reversible defect in T suppressor cell function that is associated with a failure of T suppressor cell precursors to accumulate intracellular cAMP following their exposure to selected immune stimuli.

In vitro pharmacological properties of a series of isoprenaline derivatives.

The p-trifluoromethylanilide congener of isoprenaline, tert-butyl N-[(S)[( 4-[(R)-6-[2-(3,4-dihydroxyphenyl-2- hydroxyethyl]amino]heptanamido]phenyl]methyl][(N-methylcarbamoy l) methyl]carbamoyl]methyl]carbamate (1S,4R)-4,7,7-trimethyl-3-oxo-2- oxabicyclo[2.2.1]heptane-1-carboxylate (1:1) (Ro 17-2218) was investigated for its effects in various pharmacological tests in vitro and compared to the parent compound. As Ro 17-2218 represented a mixture of four diastereomers, the pure isomers were synthesized. They had a purity of 97-98%. By pharmacological testing of the diastereomers the highest potency was found in the 6R,2'R-isomer Ro 17-8648, while the potency of the 6S,2'S-isomer, Ro 17-9651 was lower by three orders of magnitude. The amorphous hydrochloride Ro 17-8648/001 had 1/10 the potency of the respective crystalline camphanate Ro 17-8648/003. (R)-6-[(R)-[2-(3,4-Dihydroxyphenyl)-2-hydroxyethyl]amino]-N-[4- (trifluoromethyl) phenyl]heptan amide (Ro 17-8648/003) was found to have potent beta-agonist properties with clear beta 1-selectivity in radioligand binding studies. It exerted an extremely tight binding to membrane receptors. As a full beta-agonist it elicited positive inotropic effects in isolated cardiac tissues, with a potency 10-360 times that of isoprenaline and an extremely long duration of action. Electrophysiological studies in isolated guinea-pig papillary muscles confirmed the beta 1-receptor-mediated effects of the compound.

A subset of human rosetted lymphocytes contains previously unidentified histamine.

By sequential solid-phase immunoadsorption (panning) steps, we have isolated a subset of lymphocytes (comprising 3-7% of rosetted cells) that contains high concentrations of histamine. We have used a radioenzymatic assay for the determination of histamine and have located 117 ng of histamine/1 x 10(6) cells in Leu-5+ (OKT-11), Leu-15+ cells. This subset did not contain basophils and was negative for Leu-4 (OKT-3), Leu-3 (OKT-4), Leu-2 (OKT-8), and 9.3 antigens. The function of this subset of rosetted cells has not been determined.

Histamine regulates the generation of human cytolytic T lymphocytes.

Human cytolytic T lymphocytes (CTL) were generated in the presence and absence of histamine in order to define the role of this autacoid in immune regulation. Histamine (10(-8)-10(-4) M) suppressed the generation of class I specific CTL but, at 10(-4) M, actually increased class II specific cytolysis. Histamine acted at the level of CTL generation; histamine was not present in the cytolytic assay. When histamine was added to the cytolytic assay with CTL grown without histamine, the lytic ability of the effector cells was similar to that of controls. Histamine-induced suppression of class I specific cytolysis was blocked by continuous culture with the H2 antagonist ranitidine but not with the H1 antagonist pyrilamine. These data suggest that suppression was mediated by the H2 receptor. Continuous culture with histamine had no effect on T cell proliferation or the expression of cell surface molecules. Histamine-induced suppression of class I specific cytolysis was reversed by the addition of PHA to the cytotoxicity assay, showing that the cytolytic machinery was intact. These data provide evidence that histamine is involved in regulation of cytolytic T cells.