Biomedical subjects

Mark Graham

Publications and source records attributed to Mark Graham.

At least 19 recordsLinked to original sources

PubMed2026

Anti-inflammatory and phosphorylation effects of CFTR modulator triple therapy in cystic fibrosis.

CFTR modulators like elexacaftor-tezacaftor-ivacaftor (ETI) improve morbidity in cystic fibrosis (CF), but their systemic effects on young children are not yet clear. We hypothesize that ETI has anti-inflammatory effects and reverse disease-associated molecular signatures in children with CF. This exploratory pilot study evaluates the cellular mechanisms of ETI on peripheral immune cells in children (<12 years) with CF using a multi-omics approach. Seventeen children with CF (median age 8.7 years, 26% female) and 12 controls (median age 9.6 years, 42% female) were included for blood RNA-sequencing, proteomics and phosphoproteomics. Baseline pathway enrichment analysis revealed systemic inflammation, transmembrane transporter deficiencies, reduced protein kinase, and GTPase activity. Three months post-ETI, anti-inflammatory effects, epigenetic modulation, and increased protein kinase activity were observed, indicating partial reversal of cellular abnormalities. ETI modified systemic inflammatory, epigenetic, and phosphorylation pathways in young children with CF, offering insights into CF pathology and potential biomarkers for treatment monitoring.

cystic fibrosis↗

PubMed2006

Subcellular compartmentalization of glutathione: correlations with parameters of oxidative stress related to genotoxicity.

Glutathione (GSH) is a major component of the antioxidant defence system of mammalian cells and is found in subcellular pools within the cytoplasm, nucleus and mitochondria. To evaluate the relationships between these pools and parameters of oxidative stress related to genotoxicity, wild type (WT) and 8-oxo-2'-deoxyguanosine glycosylase 1 (OGG1)-null (mOGG1(-/-)) mouse embryonic fibroblasts (MEF) were treated with buthionine sulphoximine (BSO; 0-1000 microM, 24 h), an inhibitor of GSH biosynthesis. BSO treatment resulted in a concentration-dependent depletion of GSH from the cytoplasm, but depletion of mitochondrial and nuclear GSH occurred only at concentrations > or =100 microM. GSH levels were correlated with reactive oxygen species (ROS), lipid peroxidation (measured as the increase in the genotoxic end-product malondialdehyde (MDA)) and oxidative DNA modifications, measured as both frank DNA strand-breaks (FSB) and oxidized purine lesions (OxP) using the alkaline comet assay with formamidopyrimidine DNA glycosylase (FPG) modification; this system allowed for the identification of BSO-induced DNA modifications as primarily mutagenic 8-oxo-2'-deoxyguanosine lesions. A number of significant correlations were observed. First, negative linear correlations were observed between mitochondrial GSH and ROS (r = -0.985 and r = -0.961 for WT and mOGG1(-/-) MEF, respectively), and mitochondrial GSH and MDA (r = -0.967 and r = -0.963 for WT and mOGG1(-/-) MEF, respectively). Second, positive linear correlations were observed between ROS and MDA (r = 0.996 and r = 0.935 for WT and mOGG1(-/-) MEF, respectively), and ROS and OxP (r = 0.938 and r = 0.981 for WT and mOGG1(-/-) MEF, respectively). Finally, oxidative DNA modifications displayed a negative linear correlation with nuclear GSH (r = -0.963 and -0.951 between nuclear GSH and FSB and OxP, respectively, for WT MEF and r = -0.960 between nuclear GSH and OxP in mOGG1(-/-) MEF), thus, demonstrating the genotoxic potential of compounds that deplete GSH. The findings highlight the critical roles of the mitochondrial and nuclear GSH pools in protecting cellular components, particularly DNA, from oxidative modification.

Animals↗

PubMed2006

Size of residual lymph node metastasis after neoadjuvant chemotherapy in locally advanced breast cancer patients is prognostic.

BACKGROUND: The prognostic significance of micrometastasis after neoadjuvant chemotherapy for locally advanced breast cancer is unknown. We examined the residual lymph node metastasis size in patients after treatment with neoadjuvant chemotherapy to determine the relevance of metastasis size on outcome. METHODS: Stage II/III breast cancer patients treated with neoadjuvant chemotherapy at our institution from 1991 to 2002 were included. We examined the relationship of postneoadjuvant chemotherapy lymph node metastasis size and number with distant disease-free survival (DDFS) and overall survival (OS). RESULTS: In 122 patients with a median follow-up of 5.4 years, we found not only that patients with an increasing number of residual positive nodes had progressively worse DDFS and OS (P < .0001 for both) compared with patients with negative nodes, but also that the size of the largest lymph node metastasis was associated with worse DDFS and OS (P < .0001 for both) in both univariate and multivariate analysis. Compared with negative nodes, even lymph node micrometastasis (<2 mm) was associated with worsened DDFS and OS (adjusted P = .02 and P = .005, respectively). CONCLUSIONS: Residual micrometastatic disease in the axillary lymph nodes after neoadjuvant chemotherapy is predictive of worse prognosis than negative nodes. In this study, the lymph node metastasis size and the number of involved lymph nodes were independent powerful predictors of DDFS and OS.

Adult↗

PubMed2006

miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting.

Current understanding of microRNA (miRNA) biology is limited, and antisense oligonucleotide (ASO) inhibition of miRNAs is a powerful technique for their functionalization. To uncover the role of the liver-specific miR-122 in the adult liver, we inhibited it in mice with a 2'-O-methoxyethyl phosphorothioate ASO. miR-122 inhibition in normal mice resulted in reduced plasma cholesterol levels, increased hepatic fatty-acid oxidation, and a decrease in hepatic fatty-acid and cholesterol synthesis rates. Activation of the central metabolic sensor AMPK was also increased. miR-122 inhibition in a diet-induced obesity mouse model resulted in decreased plasma cholesterol levels and a significant improvement in liver steatosis, accompanied by reductions in several lipogenic genes. These results implicate miR-122 as a key regulator of cholesterol and fatty-acid metabolism in the adult liver and suggest that miR-122 may be an attractive therapeutic target for metabolic disease.

AMP-Activated Protein Kinases↗

PubMed2006

Delivery of a healthy baby after first-trimester maternal exposure to lapatinib.

We report the case of a woman who conceived while being treated on a phase I clinical trial with lapatinib, a dual inhibitor of epidermal growth factor receptor (EGFR) and HER2/neu, for metastatic breast cancer. Despite approximately 11 weeks of exposure to lapatinib in the first and second trimesters, the pregnancy was uncomplicated and resulted in the delivery of a healthy baby. Although concomitant cancer and pregnancy is relatively rare, the increasing use of biologic agents among fertile women, sometimes for as long as a year in the adjuvant setting increases the probability that some women will conceive while taking a growth factor pathway inhibitor. As with systemic chemotherapy given during pregnancy, there exists the potential for teratogenicity or fetal demise from exposure of the developing embryo to inhibitors of EGFR and HER2/neu. Despite the positive outcome of this case, continued caution is warranted with the use of EGFR and HER2/neu inhibitors in pregnancy.

Adult↗

PubMed2005

Accumulation of selenium and lack of severe effects on productivity of American dippers (Cinclus mexicanus) and spotted sandpipers (Actitis macularia).

Selenium has been found at elevated concentrations in water, sediments, and aquatic biota in the Elk River (British Columbia, Canada) and some of its tributaries downstream of several coal mines. Selenium water concentrations in those areas exceed Canadian and British Columbia guidelines and are above levels at which adverse effects to fish and waterfowl could occur. We compared selenium concentrations in the eggs of two riverine waterbirds, American dippers and spotted sandpipers, with measures of productivity: the number of eggs laid, egg hatchability, and nestling survival. In American dippers, the mean egg selenium concentration from the exposed areas, 1.10 +/- SE 0.059 microg/g wet weight, was indistinguishable from the reference areas, 0.96 +/- SE 0.059 microg/g wet weight. For spotted sandpipers, the mean egg selenium concentration in the exposed areas, 2.2 +/- 0.5 microg/g wet weight, was significantly higher than in the reference areas, 1.2 +/- 0.14 microg/g wet weight, but less than reported thresholds for waterfowl and other shorebirds. There were no significant differences in egg hatchability between dippers in reference and exposed areas, but reduced hatchability was apparent for sandpipers in exposed locations. Despite the slightly reduced hatchability in sandpipers, overall productivity was higher than regional norms for both species; thus, selenium did not affect the number of young recruited to local populations. We did not observe teratogenic effects in either species, although none was expected at these concentrations. Despite moderately high selenium concentrations in the water, mean egg selenium concentrations were less than predicted from uptake models. We hypothesise that the relatively low uptake of selenium into the eggs of the two waterbirds in this study is likely due to their lotic environment's low biological transformation and uptake rates.

Alberta↗

PubMed2005

Energy substrate requirements for survival of rat retinal cells in culture: the importance of glucose and monocarboxylates.

The process of metabolic coupling has been described as a means of providing additional fuel for neurons during periods of intense activity. This process has been suggested to occur in the mammalian retina, but whether retinal neurons can metabolise glial-derived monocarboxylates remains uncertain. The present study therefore sought to define the preferred energy substrates for maintenance of different retinal cells in culture, in order to clarify whether metabolic coupling can potentially occur in this tissue. All cells in rat retinal cultures were detrimentally affected by glucose deprivation. The effect on some neurons, however, could be partially reversed by 5 mm pyruvate or lactate. Furthermore, the glycolytic inhibitor, iodoacetic acid, caused a dose-dependent loss of all retinal cells in culture, whereas the mitochondrial inhibitor, 2,4-dinitrophenol, only led to a decrease in the number of neurons. Finally, inhibition of transporters for glucose or monocarboxylates caused the respective loss of glia or neurons from cultures. These data together demonstrate that, although cells do preferentially metabolise glucose, monocarboxylates such as lactate or pyruvate do play an important role in neuronal maintenance. These data therefore give partial support to the notion that metabolic coupling may occur in the retina.

Animals↗

PubMed2005

Monocarboxylate transporter expression remains unchanged during the development of diabetic retinal neuropathy in the rat.

PURPOSE: To determine the effect of diabetes on monocarboxylate transporter (MCT) expression in the rat retina. METHODS: Diabetes was induced in Wistar rats by a single intraperitoneal injection of streptozotocin (62.5 mg/kg). Rats were killed after 10 weeks, and the retinal levels of PKCalpha, bFGF, glial fibrillary acidic protein (GFAP), caspase-3, and MCT1, -2, and -4 were assessed with immunoblot analysis and RT-PCR. Hippocampal samples were used as a comparison. In other animals, the retinas were processed histologically and sections stained for the breakdown of DNA (TUNEL procedure) and for the distribution of MCT1, -2, and -4. RESULTS: Diabetic rats exhibited cataract formation, elevated blood glucose levels, and polydipsia. Retinal levels and distribution of MCT1, 2, and -4 were similar in the diabetic and age-matched control groups; however, the early retinopathy markers bFGF and PKCalpha were significantly elevated in the diabetic retinas but not in the hippocampal samples. ERG recordings showed decreased oscillatory potentials in the diabetic group, and TUNEL staining was most evident in the photoreceptor layer. Activated caspase-3 levels were elevated in the diabetic retina. CONCLUSIONS: The expression of retinal MCT1, -2, and -4 is unaffected after 10 weeks of diabetes in rats. It appears unlikely that diabetic retinal neuropathy is a result of a hyperglycemic induction of altered MCT expression.

Animals↗

PubMed2004

Expression of monocarboxylate transporters in rat ocular tissues.

The aim of the present study was to determine the distribution of monocarboxylate transporter (MCT) subtypes 1-4 in the various structures of the rat eye by using a combination of conventional and real-time RT-PCR, immunoblotting, and immunohistochemistry. Retinal samples expressed mRNAs encoding all four MCTs. MCT1 immunoreactivity was observed in photoreceptor inner segments, Muller cells, retinal capillaries, and the two plexiform layers. MCT2 labeling was concentrated in the inner and outer plexiform layers. MCT4 immunolabeling was present only in the inner retina, particularly in putative Muller cells, and the plexiform layers. No MCT3 labeling could be observed. The retinal pigment epithelium (RPE)/choroid expressed high levels of MCT1 and MCT3 mRNAs but lower levels of MCT2 and MCT4 mRNAs. MCT1 was localized to the apical and MCT3 to the basal membrane of the RPE, whereas MCT2 staining was faint. Although MCT1-MCT4 mRNAs were all detectable in iris and ciliary body samples, only MCT1 and MCT2 proteins were expressed. These were present in the iris epithelium and the nonpigmented epithelium of the ciliary processes. MCT4 was localized to the smooth muscle lining of large vessels in the iris-ciliary body and choroid. In the cornea, MCT1 and MCT2 mRNAs and proteins were detectable in the epithelium and endothelium, whereas evidence was found for the presence of MCT4 and, to a lesser extent, MCT1 in the lens epithelium. The unique distribution of MCT subtypes in the eye is indicative of the pivotal role that these transporters play in the maintenance of ocular function.

Animals↗

PubMed2004

Dendritic cells can be rapidly expanded ex vivo and safely administered in patients with metastatic breast cancer.

PURPOSE: Immunotherapy using either dendritic cells (DCs) or expanded cytotoxic T cells (CTLs) has received increased interest in the treatment of specific malignancies including metastatic breast cancer (MBC). DCs can be generated ex vivo from monocytes or CD34+ precursors. The ability to expand and safely administer CD34-derived DCs in patients with MBC that have received prior cytotoxic chemotherapy has not been evaluated. METHODS: We enrolled ten patients with MBC that had received prior chemotherapy for the treatment of metastatic disease on a phase I/II trial designed to test the safety and feasibility of administering ex vivo expanded DCs from CD34+ progenitor cells. RESULTS: Using a cocktail of multiple different cytokines, we could expand DCs 19-fold compared to the initial CD34-selected product, which allowed the administration of as many as six vaccine treatments per patient. Patients received three to six injections i.v. of DCs pulsed with either the wild type GP2 epitope from the HER-2/neu protein or an altered peptide ligand, isoleucine to leucine (I2L). Toxicity was mild, with no patients demonstrating grade III toxicity during the treatment. Two patients with subcutaneous disease had a partial response to therapy, while IFN-gamma-producing CD8+ T cells could be found in two other patients during treatment. CONCLUSIONS: This approach is safe and effective in generating a significant quantity of DCs from CD34-precursors.

Adult↗

PubMed2004

High-resolution axillary ultrasound is a poor prognostic test for determining pathologic lymph node status in patients undergoing neoadjuvant chemotherapy for locally advanced breast cancer.

BACKGROUND: The purpose of this study was to evaluate the efficacy of high-resolution axillary ultrasound in detecting axillary lymph node metastases after neoadjuvant chemotherapy in patients with locally advanced breast cancer. METHODS: Fifty-three patients with stage II or III breast cancer undergoing neoadjuvant chemotherapy who had a physical examination, high-resolution axillary ultrasound, and axillary lymph node dissection from January 1999 to September 2003 were included in this study. RESULTS: The positive predictive value of the postchemotherapy ultrasound for predicting pathologic nodal involvement was 83%, but the negative predictive value was only 52%. Postchemotherapy physical examination was also poor at predicting pathologic nodal involvement with a positive predictive value of 93% and a negative predictive value of only 58%. CONCLUSIONS: A negative post-neoadjuvant chemotherapy high-resolution axillary ultrasound or physical examination does not predict pathologic node status, and this test has limited value in this setting.

Adult↗

PubMed2004

Retinal ischemia: mechanisms of damage and potential therapeutic strategies.

Retinal ischemia is a common cause of visual impairment and blindness. At the cellular level, ischemic retinal injury consists of a self-reinforcing destructive cascade involving neuronal depolarisation, calcium influx and oxidative stress initiated by energy failure and increased glutamatergic stimulation. There is a cell-specific sensitivity to ischemic injury which may reflect variability in the balance of excitatory and inhibitory neurotransmitter receptors on a given cell. A number of animal models and analytical techniques have been used to study retinal ischemia, and an increasing number of treatments have been shown to interrupt the "ischemic cascade" and attenuate the detrimental effects of retinal ischemia. Thus far, however, success in the laboratory has not been translated to the clinic. Difficulties with the route of administration, dosage, and adverse effects may render certain experimental treatments clinically unusable. Furthermore, neuroprotection-based treatment strategies for stroke have so far been disappointing. However, compared to the brain, the retina exhibits a remarkable natural resistance to ischemic injury, which may reflect its peculiar metabolism and unique environment. Given the increasing understanding of the events involved in ischemic neuronal injury it is hoped that clinically effective treatments for retinal ischemia will soon be available.

Animals↗

PubMed2004

Effects of halothane, isoflurane, sevoflurane and desflurane on contraction of ventricular myocytes from streptozotocin-induced diabetic rats.

Various clinically used volatile general anaesthetics (e.g. sevoflurane, halothane, isoflurane and desflurane) have been shown to have significant negative inotropic effects on normal ventricular muscle. However, little is known about their effects in ventricular tissue from diabetic animals. Streptozotocin (STZ)-induced diabetes is known to induce changes in the amplitude and time course of shortening and one report suggests that the inotropic effects of anaesthetics are ameliorated in papillary muscles from diabetic animals. The aim of these studies was to investigate this further in electrically stimulated (1 Hz) ventricular myocytes. Cells were superfused with either normal Tyrode (NT) solution or NT containing anaesthetic (1 mM) for a period of 2 min (at 30-32 degrees C). Myocytes from STZ rats were shown to have a significantly longer time to peak shortening (p > 0.001, n = 50) and the amplitude of shortening tended to be greater but this was not significant (p = 0.13, n = 50). Halothane, isoflurane, desflurane and sevoflurane significantly (p < 0.05) reduced the magnitude of shortening of control cells by 72.5 +/- 3.2%, 46.5 +/- 9.7%, 28.9 +/- 4.3% and 22.8 +/- 5.6%, respectively (n > 11 per group) but their steady-state negative inotropic effect was found to be no different in cells from STZ-treated rats (73.0 +/- 4.8%, 40.7 +/- 4.7%, 25.0 +/- 5.2% and 19.8 +/- 5.2%, respectively, n > 10 per group). Therefore, we conclude that the inotropic effects of volatile anaesthetics were not altered by STZ treatment.

Anesthetics, Inhalation↗

PubMed2004

Energy substrate requirements of rat retinal pigmented epithelial cells in culture: relative importance of glucose, amino acids, and monocarboxylates.

PURPOSE: To determine the metabolic conditions that provide maintenance of viability for cultured rat RPE cells and to determine whether monocarboxylates such as lactate or pyruvate, which are known to exist at high concentrations in the subretinal space, can provide an alternative energy source to maintain cells when other nutritive supplies are limited. METHODS: Cultured rat RPE cells (passage 2-4), in the absence of serum, were subjected to different metabolic challenges relating to glucose, amino acid, or oxygen deprivation. Lactate or pyruvate was added to some cells in each instance to determine whether cells could be maintained by using these substances as fuel sources for metabolic reactions. Cell viability was assessed after treatments, and in some cases proliferation rates and appearance of apoptosis-like DNA cleavage were also investigated by terminal deoxynucleotidyl-transferase UTP-linked nick-end labeling (TUNEL). Western blot analysis was used to determine the expression of transporters for glucose and monocarboxylates in these cells. RESULTS: RPE cell viability was partially reduced in the absence of glucose or with glycolytic inhibition. Lactate or pyruvate did not prevent these reductions. Inhibition of transaminase reactions with aminooxyacetic acid (AOAA) in the absence of glucose caused a complete loss of viability that was reversed by pyruvate or lactate. MCT inhibition was detrimental to RPE cell viability only at high concentrations (500 microM) in the presence of glucose but blocked the protective effect of pyruvate-lactate in the presence of AOAA at 1 microM. CONCLUSIONS: Rat RPE cells require glucose as their primary metabolic substrate in culture, but can metabolize glutamine in its absence. When glucose and glutamine are limiting, RPE cells can metabolize monocarboxylates such as lactate or pyruvate. These data provide evidence that such cells are able to withstand various types of insult brought about by nutrient deprivation, by altering their pathways of energy production.

Amino Acids↗

PubMed2004

Practical considerations for exploiting the World Wide Web to create infobuttons.

BACKGROUND: We are studying ways to provide automated, context-specific links (called "infobuttons") between clinical information systems (CIS) and other information resources available on the World Wide Web. As part of this work, we observed the information needs that arose when clinicians used a CIS and we classified those needs into generic questions. We then sought general methods for accessing information resources to answer the questions. METHODS: For each generic question, we identified a satisfactory resource and then developed a method for retrieving from it the information relevant to the question. We then studied these methods to characterize them into general approaches. RESULTS: We identified six general approaches and describe them in detail. These approaches range in complexity from simple, hard-coded links to intelligent agents and calculators. CONCLUSION: Web-based information resources can be exploited using a relatively small number of methods, although the specific methods require custom solutions. Standard methods for accessing Web-based resources would simplify the task of linking to CISs.

Decision Support Systems, Clinical↗

PubMed2003

The monocarboxylate transport inhibitor, alpha-cyano-4-hydroxycinnamate, has no effect on retinal ischemia.

Glial-derived monocarboxylate lactate is thought to be an important energy source for neurons during brain activation or in hypoxia-ischemia. Treatment with alpha-cyano-4-hydroxycinnamate (4-CIN), a monocarboxylate transporter inhibitor, has been recently reported to exacerbate delayed neuronal damage in a rat model of cerebral ischemia, an effect ascribed to inhibition of lactate/pyruvate transport. Since monocarboxylate transporters are abundant in the retina, we examined the effect of 4-CIN administration on the outcome of high intraocular pressure-induced retinal ischemia in rats. Retinal ischemic damage was assessed by changes in the electroretinogram (ERG), the retinal localization of choline acetyltransferase (ChAT) and neuronal nitric oxide synthase (nNOS) immunoreactivities, and the loss of retinal mRNA for Thy-1. Intraperitoneal or intravitreal administration of 4-CIN had no effect on the ERG or the localization of ChAT and nNOS immunoreactivities in either the control retina or a retina subjected to ischemia/reperfusion. In addition, intravitreal injection of 4-CIN had no effect on ischemia-induced reduction of retinal mRNA levels for Thy-1. These results provide no evidence to support the view that blockade of lactate uptake and/or pyruvate entry into mitochondria for oxidative metabolism has an influence on the outcome of retinal ischemia/reperfusion.

Animals↗

PubMed2003

Lansoprazole increases testosterone metabolism and clearance in male Sprague-Dawley rats: implications for Leydig cell carcinogenesis.

Leydig cell tumours (LCTs) are frequently observed during rodent carcinogenicity studies, however, the significance of this effect to humans remains a matter of debate. Many chemicals that produce LCTs also induce hepatic cytochromes P450 (CYPs), but it is unknown whether these two phenomena are causally related. Our aim was to investigate the existence of a liver-testis axis wherein microsomal enzyme inducers enhance testosterone metabolic clearance, resulting in a drop in circulating hormone levels and a consequent hypertrophic response from the hypothalamic-pituitary-testis axis. Lansoprazole was selected as the model compound as it induces hepatic CYPs and produces LCTs in rats. Male Sprague-Dawley rats were dosed with lansoprazole (150 mg/kg/day) or vehicle for 14 days. Lansoprazole treatment produced effects on the liver consistent with an enhanced metabolic capacity, including significant increases in relative liver weights, total microsomal CYP content, individual CYP protein levels, and enhanced CYP-dependent testosterone metabolism in vitro. Following intravenous administration of [14C]testosterone, lansoprazole-treated rats exhibited a significantly smaller area under the curve and significantly higher plasma clearance. Significant reductions in plasma and testicular testosterone levels were observed, confirming the ability of this compound to perturb androgen homeostasis. No significant changes in plasma LH, FSH, or prolactin levels were detected under our experimental conditions. Lansoprazole treatment exerted no marked effects on testicular testosterone metabolism. In summary, lansoprazole treatment induced hepatic CYP-dependent testosterone metabolism in vitro and enhanced plasma clearance of radiolabelled testosterone in vivo. These effects may contribute to depletion of circulating testosterone levels and hence play a role in the mode of LCT induction in lansoprazole-treated rats.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed2003

The classification of clinicians' information needs while using a clinical information system.

INTRODUCTION: Information needs are prevalent in clinical practice. They represent a potential source of medical errors. This study seeks to empirically determine the information needs of clinicians while using a clinical information system (CIS), and characterize those needs. In addition this paper will provide the framework necessary for the development of the solutions to these information needs. METHODS: Clinicians were observed while using a CIS. They were recorded on audiotape and the computer screen recorded on videotape. The types of question during these interactions were recorded. A classification of the questions provided the conceptual and architectural basis for the development of context-sensitive links to information resources, called infobuttons. RESULTS: There were 154 information needs. The questions were grouped into seven categories. Within these categories we were able to identify eleven specific repeated question patterns, accounting for 72 or 47% of users' questions. DISCUSSION: These findings are applicable to a number of settings and can be generalized to other institutions. The proposed infobuttons based on six categories, will be navigational ('how-to.' links), cross-reference ('what is the em leader ' links), domain knowledge buttons in the areas of laboratory, pharmacy, diagnosis, and definitions/general information. Using these groups we were able to identity eleven patterns of questions.

Clinical Medicine↗