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Biomedical subjects

J Duncan

Publications and source records attributed to J Duncan.

At least 19 recordsLinked to original sources
PubMed2006

Activation of NF-kappaB transcription factor in the preterm ovine brain and placenta after acute LPS exposure.

Intrauterine infection may be causally related to inflammation and injury of the fetal brain, however the mechanisms by which this occurs are unclear. We have investigated whether nuclear factor (NF)-kappaB, a transcription factor for proinflammatory cytokines, is activated in the fetal brain after acute LPS-exposure. At 95 days of gestation (term = approximately 147 days), 5 fetuses received a single intravenous bolus dose of LPS (1 microg/kg); 6 fetuses served as controls. Fetal blood samples were taken hourly for 6 hr post LPS-exposure to assess physiological status. Ewes and fetuses were then euthanased, placental and brain tissue examined histologically, and NF-kappaB activation assessed in several regions of the fetal brain using an electromobility shift assay (EMSA). Oxidative stress was measured using lipid peroxidation and 8-isoprostane biochemical assays and brain cytokine concentrations analysed by enzyme linked immunosorbent assay (ELISA). LPS-exposed fetuses (relative to controls) were hypoxemic and the haematocrit and lactate levels had increased. In the brains of LPS-exposed fetuses compared to controls, NF-kappaB binding activity was elevated in the hippocampus and the thalamus/basal ganglia; 8-isoprostane levels were elevated overall (P < 0.05) in the parietal/occipital/temporal lobes and thalamus/basal ganglia. TNF-alpha and IL-6 concentrations were not elevated, however, there was a tendency for an elevation of IFN-gamma concentrations in the thalamus/basal ganglia. IFN-gamma concentration was elevated (P < 0.05) in the plasma 4 hr after LPS-exposure. In the placenta, NF-kappaB binding activity was increased (P < 0.05). We conclude that acute systemic administration of LPS leads to increased binding activity of NF-kappaB subunits in specific regions of the fetal brain and in the placenta, but that there is no clear-cut relationship between this elevation and vulnerability to endotoxic damage.

Animals↗
PubMed2006

Expression of drug pathway proteins is independent of tumour type.

Current clinicopathological staging systems have the advantage of standardized criteria for assessing tumour stage, and a relationship between advancing tumour stage and poor prognosis has been established for most cancers. However, these tools have not led to clear criteria for therapy selection in individual patients. Indeed, the concept of therapy based on anatomical location seems quaint. Therefore, a representative drug pathway (irinotecan) was evaluated across common tumour types to test the hypothesis that pharmacological proteins are expressed independent of anatomical location. Many enzymes are involved in controlling the disposition of irinotecan, including the cellular target (TOP1), metabolism enzymes (CES2, UGT1A1, CYP3A4, CYP3A5), and cellular transporters of the anti-cancer agent (ABCB1, ABCC1, ABCC2, ABCC3, ABCC5, ABCG2). These 11 proteins were evaluated in tissue microarrays containing colon, breast, prostate, ovary, and lung cancers; brain tumours; melanoma; lymphoma; and selected normal tissues. A total of 255 tumours and 37 normal tissue samples were evaluable for all proteins. Linear discriminant analysis designed to predict the tissue type from the protein expression levels revealed a 49.6% misclassification rate, indicating that protein expression of this drug pathway is not associated with tissue type. Cluster analysis identified a variety of tumours with the same pharmacological profile. The anatomy independence of drug pathways stimulates efforts to move away from our traditional approaches to the selection of cancer therapy.

Adenocarcinoma↗
PubMed2005

Assessment of fluorescent amplified fragment length polymorphism analysis for epidemiological genotyping of Legionella pneumophila serogroup 1.

This study assessed the reproducibility and epidemiological concordance of double-enzyme fluorescent amplified fragment length polymorphism (fAFLP) analysis for genotyping of Legionella pneumophila serogroup (sg) 1. fAFLP fragment analysis was performed on three different sequencing platforms (one gel- and two capillary-based) in different laboratories with a well-characterised set of 50 strains of L. pneumophila sg 1. fAFLP data were analysed with the Pearson correlation similarity coefficient, using a range of parameters, and dendrogram outputs were converted to arbitrary types after selection of a specified percentage similarity threshold. The results obtained were compared with those obtained by the standard non-fluorescent AFLP method and were found to be broadly concordant. Using optimised settings for each fAFLP method to analyse the panel of 50 strains, epidemiological concordance (E) and reproducibility (R) values of 1.00 were obtained, and the number of types ranged from nine to 15, compared with E=1.00 and R=1.00, with 16 types, for the non-fluorescent AFLP protocol. The study demonstrated the potential of fAFLP for typing strains of L. pneumophila sg 1 on all three platforms; however, inter-platform comparison of fAFLP data was not achieved. fAFLP analysis may have a role in the fingerprinting of multiple isolates during Legionella outbreak investigations, but further work is required before type designations and identification libraries can be developed.

DNA Fingerprinting↗
PubMed2004

Tannery effluent as a carbon source for biological sulphate reduction.

Tannery effluent was assessed as a carbon source for biological sulphate reduction in a pilot-scale upflow anaerobic sludge blanket (UASB), stirred tank reactor (STR) and trench reactor (TR). Sulphate removals of between 60-80% were obtained in all three reactors at total sulphate feed levels of up to 1800 mg l(-1). Sulphate removal in the TR (400-500 mg SO4 l(-1) day(-1)) and UASB (up to 600 mg SO4 l(-1) day(-1)) were higher than those obtained in the STR (250 mg SO4 l(1) day(-1)). A change in operation mode from a UASB to a STR had a large impact on chemical oxygen demand (COD) removal efficiencies. COD removal rates decreased by 25% from 600-700 mg COD l(-1) day(-1) to 200-600 mg COD l(-1) day(-1). The TR had an average COD removal rate of 500 mg COD l(-1) day(-1). Large quantities of sulphide were produced in the reactors (up to 1500 mg l(-1)). However due to the elevated pH in the reactor, only a small amount was in the form of H2S and thus the odour problem normally associated with biological sulphate reduction was not present.

Bioreactors↗
PubMed2004

The use of micro-algal biomass as a carbon source for biological sulphate reducing systems.

An upflow anaerobic digestor was fed dried algal biomass as a carbon source to establish the feasibility of using micro-algal biomass as the sole carbon source for biological sulphate reduction. The effect of the COD:SO4 ratio on substrate consumption and sulphate removal efficiencies were assessed by varying the organic carbon content of the media. Similar COD removal efficiencies were obtained irrespective of the influent COD:SO4 ratios, which were 8.1, 11.2 and 15.0. However, the rates of COD removal did differ with influent COD:SO4 ratios. The percentage sulphate removed decreased as the ratio of COD:SO4 increased. Not all of the COD was used for sulphate reduction, with only 31% being accounted for.

Biomass↗
PubMed2004

Pseudodominant inheritance of spondylocostal dysostosis type 1 caused by two familial delta-like 3 mutations.

Spondylocostal dysostoses (SCD) are a heterogeneous group of disorders of axial skeletal malformation characterized by multiple vertebral segmentation defects and rib anomalies. Sporadic cases with diverse phenotypes, sometimes including multiple organ abnormalities, are relatively common, and monogenic forms demonstrating autosomal recessive (AR) and, more rarely, autosomal dominant (AD) inheritance have been reported. We previously showed that mutations in delta-like 3 (DLL3), a somitogenesis gene that encodes a ligand for the notch signaling pathway, cause AR SCD with a consistent pattern of abnormal segmentation. We studied an SCD family previously reported to show AD inheritance, in which the phenotype is similar to that in AR cases. Direct DLL3 sequencing of individuals in two generations identified the affected father as homozygous for a novel frameshift mutation, 1440delG. His two affected children were compound heterozygotes for this mutation and a novel missense mutation, G504D, the first putative missense mutation reported in the transmembrane domain of DLL3. Their two unaffected siblings were heterozygotes for the 1440delG mutation. Pseudodominant inheritance has been confirmed, and the findings raise potential consequences for genetic counseling in relation to the SCD disorders.

Adult↗
PubMed2003

Novel mutations in DLL3, a somitogenesis gene encoding a ligand for the Notch signalling pathway, cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis.

The spondylocostal dysostoses (SCD) are a group of disorders characterised by multiple vertebral segmentation defects and rib anomalies. SCD can either be sporadic or familial, and can be inherited in either autosomal dominant or recessive modes. We have previously shown that recessive forms of SCD can be caused by mutations in the delta-like 3 gene, DLL3. Here, we have sequenced DLL3 in a series of SCD cases and identified 12 mutations in a further 10 families. These include 10 novel mutations in exons 4-8, comprising nonsense, missense, frameshift, splicing, and in frame insertion mutations that are predicted to result in either the truncation of the mature protein in the extracellular domain, or affect highly conserved amino acid residues in the epidermal growth factor-like repeats of the protein. The affected cases represent diverse ethnic backgrounds and six come from traditionally consanguineous communities. In all affected subjects, the radiological phenotype is abnormal segmentation throughout the entire vertebral column with smooth outlines to the vertebral bodies in childhood, for which we suggest the term "pebble beach sign". This is a very consistent phenotype-genotype correlation and we suggest the designation SCD type 1 for the AR form caused by mutations in the DLL3 gene.

Adult↗
PubMed2002

The role of the vertical meridian in visual memory for objects.

It is widely believed that, in human and nonhuman primates, visual memories of objects are stored in the temporal lobe. Electrophysiological results in monkeys, however, indicate that when a visual scene contains two or more objects, with at least one object in each visual hemifield, neurons in the temporal lobe of each hemisphere respond only to the objects that are in the contralateral visual hemifield, and their activity is unaffected by the objects in the ipsilateral hemifield. Putting these two premises together predicts that object memory should fail, or at least suffer a substantial decrement, when an object is presented for learning and retention as part of such a scene, but crosses the vertical meridian between the learning trial and the retention test. The effect of this change should be much greater than the effect of an equal retinal translation that crosses the horizontal rather than the vertical meridian. An experiment with normal human subjects verified this prediction under conventional conditions of tachistoscopic viewing, with a single constant fixation spot. A further condition in the same experiment, however, tested the same retinal translations in a more naturalistic condition, where the retinal changes were produced by varying the position on the display screen of the fixation spot rather than of the objects. Here, there was no significant special effect of crossing the vertical meridian. We conclude that visual memories are not stored exclusively in the temporal lobe.

Adult↗
PubMed2001

Insights into psoriasis and other inflammatory diseases from large-scale gene expression studies.

Approximately 2% of the Caucasian population is affected by psoriasis (PS); a chronic inflammatory skin disease triggered by both genetic and environmental risk factors. In addition to a major contribution from the HLA class I region, PS susceptibility loci have been mapped to a number of regions including 1q21, 3q21, 4qter, 14q31-q32, 17q24-q25, 19p13.3 and 20p. Some of these overlap with loci implicated in other autoimmune/inflammatory diseases. Global gene expression studies are beginning to provide insights into the etiology of these and other complex diseases. We used Affymetrix oligonucleotide arrays comprising approximately 12 000 known genes to initiate a more comprehensive analysis of the transcriptional changes that occur in involved and uninvolved skin of 15 psoriatic patients versus six normal controls. Expression levels of the transcripts detected on the arrays were first used to determine the relationship of samples to each other using hierarchical clustering. This analysis clearly differentiated involved psoriatic skin from uninvolved and normal skin. Clusters of differentially expressed genes with similar expression patterns in the same samples were then identified. Six out of 32 clusters contained a total of 177 transcripts that were differentially expressed in involved psoriatic skin versus normal skin. These differences were independent of the gender, age, skin site and HLA class I status of the patient. Ten of the 177 genes were also differentially expressed in uninvolved skin, and several mapped to regions previously shown to harbor psoriasis susceptibility loci.

Autoimmune Diseases↗
PubMed2001

Comparison of a virtual microscope laboratory to a regular microscope laboratory for teaching histology.

Emerging technology now exists to digitize a gigabyte of information from a glass slide, save it in a highly compressed file format, and deliver it over the web. By accessing these images with a standard web browser and viewer plug-in, a computer can emulate a real microscope and glass slide. Using this new technology, the immediate aims of our project were to digitize the glass slides from urinary tract, male genital, and endocrine units and implement them in the Spring 2000 Histology course at the University of Iowa, and to carry out a formative evaluation of the virtual slides of these three units in a side-by-side comparison with the regular microscope laboratory. The methods and results of this paper will describe the technology employed to create the virtual slides, and the formative evaluation carried out in the course. Anat Rec (New Anat) 265:10-14, 2001.

Computer-Assisted Instruction↗
PubMed2001

Recurrent transfusion-related acute lung injury.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a rare condition that is commonly associated with the transfusion of donor plasma containing WBC antibodies. Biologically active lipids that accumulate during storage of RBCs and platelets may also cause TRALI. There has been only one previously reported case of recurrent TRALI. CASE REPORT: A patient received a transfusion 2 days after undergoing hysterectomy; she developed TRALI after receiving the transfusion. The patient recovered after being on ventilation for 6 days but received an additional transfusion and had a second episode of TRALI, which required further ventilation. RESULTS: Laboratory investigation of the first episode of TRALI suggested the presence of HLA-A2 (N = 1) and granulocyte-specific IgM antibodies (N = 2) in the sera from three of the donors. All three sera reacted in crossmatch studies with the patient's granulocytes and lymphocytes. Lymphocyte-specific IgG antibodies were detected in the patient's serum. There was no evidence to suggest the involvement of WBC antibodies in the second episode of TRALI. Antibody screening of the donors' samples and both forward and reverse crossmatch studies were negative. CONCLUSION: The first episode of TRALI seems to be due to the action of HLA-A2 and granulocyte-specific IgM antibodies. The second episode may have been due to the action of lipid neutrophil-priming agents in the donors' units in association with the patient's underlying pulmonary condition (i.e., recovering from lung injury). TRALI can recur if a patient requires further transfusion support shortly after an initial episode of TRALI.

Acute Disease↗
PubMed2001

Responses of neurons in macaque area V4 during memory-guided visual search.

In a typical scene with many different objects, attentional mechanisms are needed to select relevant objects for visual processing and control over behavior. To test the role of area V4 in the selection of objects based on non-spatial features, we recorded from V4 neurons in the monkey, using a visual search paradigm. A cue stimulus was presented at the center of gaze, followed by a blank delay period. After the delay, a two-stimulus array was presented extrafoveally, and the monkey was rewarded for detecting the target stimulus matching the cue. The array was composed of one 'good' stimulus (effective in driving the cell when presented alone) and one 'poor' stimulus (ineffective in driving the cell when presented alone). When the choice array was presented in the receptive field (RF) of the neuron, many cells showed suppressive interactions between the stimuli as well as strong attention effects. Within 150--200 ms of array onset, responses to the array were determined by the target stimulus. If the target was the good stimulus, the response to the array became equal to the response to the good stimulus presented alone. If the target was the poor stimulus, the response approached the response to that stimulus presented alone. Thus the influence of the nontarget stimulus was filtered out. These effects were reduced or eliminated when the poor stimulus was located outside the RF and, therefore, no longer competing for the cell's response. Overall, the results support a 'biased competition' model of attention, according to which objects in the visual field compete for representation in the cortex, and this competition is biased in favor of the behaviorally relevant object.

Animals↗
PubMed2001

The role of spatial configuration in tests of working memory explored with functional neuroimaging.

While the importance of the prefrontal cortex for "higher-order" cognitive functions is largely undisputed, no consensus has been reached regarding the fractionation of functions within this region. Several recent functional neuroimaging studies have suggested that the mid-ventrolateral frontal cortex may play an important role in various aspects of human memory. Thus, similar patterns of activation have been observed in this region during analogous spatial, verbal and visual span tasks. In the present study, however, activation was observed in a more dorsolateral region of the lateral frontal cortex during a modified version of the spatial span task, which differed only in the spatial configuration of the array employed. The results of a supplementary behavioral study, designed to investigate this effect further, suggest that in spatial memory tasks certain stimulus configurations may encourage subjects to adopt mnemonic strategies, which may depend upon dorsolateral, rather than ventrolateral, regions of the frontal cortex. These findings shed further light on the functional relationship between dorsal and ventral regions of the lateral frontal cortex and, more specifically, how the "executive" processes assumed to be dependent upon these regions might contribute to aspects of human memory.

Adult↗
PubMed2000

Understanding of prognosis among parents of children who died of cancer: impact on treatment goals and integration of palliative care.

CONTEXT: Parents' understanding of prognosis or decision making about palliative care for children who die of cancer is largely unknown. However, a more accurate understanding of prognosis could alter treatment goals and expectations and lead to more effective care. OBJECTIVES: To evaluate parental understanding of prognosis in children who die of cancer and to assess the association of this factor with treatment goals and the palliative care received by children. DESIGN, SETTING, AND PARTICIPANTS: Survey, conducted between September 1997 and August 1998, of 103 parents of children who received treatment at the Dana-Farber Cancer Institute and Children's Hospital, Boston, Mass, and who died of cancer between 1990 and 1997 (72% of those eligible and those located) and 42 pediatric oncologists. MAIN OUTCOME MEASURE: Timing of parental understanding that the child had no realistic chance for cure compared with the timing of physician understanding of this prognosis, as documented in the medical record. RESULTS: Parents first recognized that the child had no realistic chance for cure a mean (SD) of 106 (150) days before the child's death, while physician recognition occurred earlier at 206 (330) days before death. Among children who died of progressive disease, the group characterized by earlier recognition of this prognosis by both parents and physicians had earlier discussions of hospice care (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.01-1.06; P =.01), better parental ratings of the quality of home care (OR, 3.31; 95% CI, 1.15-9.54; P =.03), earlier institution of a do-not-resuscitate order (OR, 1.03; 95% CI, 1.00-1.06; P =.02), less use of cancer-directed therapy during the last month of life (OR, 2.80; 95% CI, 1.05-7.50; P =.04), and higher likelihood that the goal of cancer-directed therapy identified by both physician and parent was to lessen suffering (OR, 5.17; 95% CI, 1.86-14.4; P =.002 for physician and OR, 6.56; 95% CI, 1.54-27.86; P =.01 for parents). CONCLUSION: Considerable delay exists in parental recognition that children have no realistic chance for cure, but earlier recognition of this prognosis by both physicians and parents is associated with a stronger emphasis on treatment directed at lessening suffering and greater integration of palliative care. JAMA. 2000;284:2469-2475.

Adult↗