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J Plumb

Publications and source records attributed to J Plumb.

At least 19 recordsLinked to original sources
PubMed2006

Upregulation of ADAM-17 expression in active lesions in multiple sclerosis.

ADAM-17, a disintegrin and metalloproteinase, is the major proteinase responsible for the cleavage of membrane-bound tumour necrosis factor (TNF) as well as being an active sheddase of other cytokines, cytokine receptors, growth factors and adhesion molecules. TNF is a major proinflammatory cytokine that has been identified as having a pathogenic role in inflammatory diseases within the CNS including multiple sclerosis (MS). Here we report the cellular origin and distribution of ADAM-17 expression within clinically and neuropathologically confirmed MS and normal control white matter, assessed by immunohistochemistry, western blotting and PCR. ADAM-17 expression was associated with the blood vessel endothelium, activated macrophages/microglia and parenchymal astrocytes in MS white matter. Increased levels of ADAM-17 immunoreactivity were displayed in active lesions with evidence of recent myelin breakdown. Further studies into the functional role of ADAM-17 in the pathogenesis of MS and other inflammatory conditions are required.

ADAM Proteins↗
PubMed2006

Expression of ADAMTS-1, -4, -5 and TIMP-3 in normal and multiple sclerosis CNS white matter.

ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) -1, -4 and -5 proteases have been identified in the CNS at the mRNA level. These glutamyl endopeptidases, inhibited by tissue inhibitor of metalloproteinases (TIMP)-3, are key enzymes in the degradation of the aggregating chondroitin sulphate proteoglycans (CSPGs), and may therefore play a role in CNS extracellular matrix (ECM) changes in multiple sclerosis (MS). We have investigated ADAMTS and TIMP-3 expression in normal and MS CNS white matter by real-time RT-PCR, western blotting and immunohistochemistry. We report for the first time the presence of ADAMTS-1, -4 and -5 in normal and MS white matter. Levels of ADAMTS-1 and -5 mRNA were decreased in MS compared to normal tissue, with no significant change in ADAMTS-4 mRNA levels. Protein levels of ADAMTS-4 were significantly higher in MS tissue compared to normal tissue. Immunohistochemical studies demonstrated that ADAMTS-4 was associated predominantly with astrocytes with increased expression within MS lesions. TIMP-3 mRNA was significantly decreased in MS compared to controls. These studies suggest a role for ADAMTS-4 in the pathogenesis of MS. Further studies on the activity of ADAMTS-4 will enable a better understanding of its role in the turnover of the ECM of white matter in MS.

ADAM Proteins↗
PubMed2005

Differential expression of ADAMTS-1, -4, -5 and TIMP-3 in rat spinal cord at different stages of acute experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is an animal model of inflammatory demyelination, a pathological event common to multiple sclerosis (MS). During CNS inflammation there are alterations in the extracellular matrix (ECM). A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS)-1, -4 and -5 are proteases present in the CNS, which are able to cleave the aggregating chondroitin sulphate proteoglycans, aggrecan, phosphacan, neurocan and brevican. It is therefore important to investigate changes in their expression in different stages of EAE induction. We have investigated expression of ADAMTS-1, -4, -5 and tissue inhibitor of metalloproteinase (TIMP)-3, by real-time RT-PCR. We have also examined protein expression of ADAMTS-1, -4 and -5 by western blotting and immunocytochemistry in spinal cord from animals at different stages of disease progression. Our study demonstrated a decrease in ADAMTS-4 mRNA and protein expression. TIMP-3 was decreased at the mRNA level although protein levels were increased in diseased animals compared to controls. Our study identifies changes in ADAMTS expression during the course of CNS inflammation which may contribute to ECM degradation and disease progression.

ADAM Proteins↗
PubMed2005

Using smart card technology to monitor the eating habits of children in a school cafeteria: 1. Developing and validating the methodology.

OBJECTIVE: The aim of the study was to test the feasibility of using smart card technology to track the eating behaviours of nearly a thousand children in a school cafeteria. METHODS: Within a large boys' school a smart card based system was developed that was capable of providing a full electronic audit of all the individual transactions that occurred within the cafeteria. This dataset was interfaced to an electronic version of the McCance and Widdowson composition of foods dataset. The accuracy of the smart card generated data and the influence of portion size and wastage were determined empirically during two 5-day trials. RESULTS: The smart card system created succeeded in generating precise data on the food choices made by hundreds of children over an indefinite time period. The data was expanded to include a full nutrient analysis of all the foods chosen. The accuracy of this information was only constrained by the limitations facing all food composition research, e.g. variations in recipes, portion sizes, cooking practices, etc. Although technically possible to introduce wastage correction factors into the software, thereby providing information upon foods consumed, this was not seen as universally practical. CONCLUSION: The study demonstrated the power of smart card technology for monitoring food/nutrient choice over limitless time in environments such as school cafeterias. The strengths, limitations and applications of such technology are discussed.

Child↗
PubMed2005

Using smart card technology to monitor the eating habits of children in a school cafeteria: 2. The nutrient contents of all meals chosen by a group of 8- to 11-year-old boys over 78 days.

OBJECTIVE: The aim of the study was to test the abilities of the newly created smart card system to track the nutrient contents of foods chosen over several months by individual diners in a school cafeteria. METHODS: From the food choice and composition of food data sets, an Access database was created encompassing 30 diners (aged 8-11 years), 78 days and eight nutrients. Data were available for a total of 1909 meals. RESULTS: Based upon population mean values the cohort were clearly choosing meals containing higher than the recommended maximum amounts for sugar and lower than the recommended minimum amounts of fibre, iron and vitamin A. Protein and vitamin C contents of meals chosen were well above minimum requirements. Over the 1909 meals, nutrient requirements were met 41% of the time. CONCLUSIONS: The system created was very effective at continually monitoring food choices of individual diners over limitless time. The data generated raised questions on the common practice of presenting nutrient intakes as population mean values calculated over a few days. The impact of heavily fortified foods on such studies in general is discussed.

Child↗
PubMed2005

Using smart card technology to monitor the eating habits of children in a school cafeteria: 3. The nutritional significance of beverage and dessert choices.

OBJECTIVE: The consumption patterns of beverages and desserts features highly in the current debate surrounding children's nutrition. The aim of this study was to continuously monitor the choice of beverages and desserts made by nearly 1000 children in a school cafeteria. METHODS: A newly developed smart card system was used to monitor the food choices of diners (7-16-year-old boys) in a school cafeteria over 89 days. A wide variety of beverages and desserts were on offer daily. RESULTS: Despite coming from an affluent, well-educated demographic group, the boys' choices of beverages and desserts mirrored those of children in general. Buns and cookies were over 10 times more popular than fresh fruits and yogurts. Sugary soft-drinks were over 20 times more popular than fresh fruit drinks and milk combined. Appropriate choices could, over a month, reduce intake of added sugar by over 800 g and fat by over 200 g. CONCLUSION: The smart card system was very effective at monitoring total product choices for nearly 1000 diners. In agreement with a recent national school meal survey, where choice is extensive, children show a preference for products high in fat and/or sugar. The consequences of these preferences are discussed.

Adolescent↗
PubMed2003

CD83-positive dendritic cells are present in occasional perivascular cuffs in multiple sclerosis lesions.

Multiple sclerosis (MS) has a wide spectrum of clinical courses, characterized by multifocal central nervous system (CNS) damage, postulated to be mediated by CNS antigen-specific T cells. Dendritic cells (DC), the most potent antigen-presenting cell, play a pivotal role in the decision between T-cell activation or anergy. Monoclonal antibodies to CD1a (immature DC) and CD83 (mature DC) were used to screen lesions with evidence of recent demyelinating activity and chronic plaque and normal appearing white matter (NAWM) tissue sections from 12 MS cases by immunocytochemistry. No CD1a-positive cells were detected in the MS or control CNS tissue blocks investigated. CD83-positive cells were not detected in tissues from any of the control cases or in the majority of perivascular cuffs in the MS tissue sections. However; in eight of the MS tissue blocks with evidence of recent demyelination, and in one block each from chronic plaque and NAWM, small numbers of distinct CD83-positive cells were present within occasional perivascular cuffs. In one area only of MS NAWM were CD83-positive cells detected in the tissue parenchyma, in an area of intense immunological activity. DC in MS tissue may originate in the peripheral circulation as monocytes or immature DC and migrate to areas of plaque in response to signals received from CNS-produced chemokines.

Antigens, CD↗
PubMed2002

Cost-effectiveness of eformoterol Turbohaler versus salmeterol Accuhaler in children with symptomatic asthma.

We conducted an economic evaluation in a UK setting based on a 12-week prospective randomized open-label parallel-group comparison of eformoterol Turbohaler 12 microg b. i.d. with salmeterol Accuhaler 50 microg b. i.d. in children aged 6-17 with symptomatic asthma receiving inhaled corticosteroids and short-acting beta2-agonists. The principal effectiveness measure was percentage of symptom-free days with no short-acting beta2-agonist use during the study period. Asthma-related medication, unscheduled physician contacts and hospitalizations were collected prospectively and cost to the UK NHS calculated using year 2,000 prices. The economic evaluation included 73 patients in the eformoterol group and 72 patients in the salmeterol group. The mean age of patients was 11.6 years (eformoterol) and 11.8 years (salmeterol). The mean percentage of symptom-free days with no short-acting beta2-agonist use was 39% in the eformoterol group and 30% in the salmeterol group. Mean per patient daily cost was 1.15 pounds in the eformoterol group and 1.39 pounds in the salmeterol group. Both cost and effectiveness differences favoured eformoterol (P < 0.05; one-sided). Sensitivity analysis confirmed the results to be robust to changes in effectiveness, price and resource utilisation parameters. Eformoterol delivered by Turbohaler was found to be significantly more effective and less expensive than salmeterol Accuhaler in this study.

Adolescent↗
PubMed2001

Exposures and outcomes of children with urticaria seen in a pediatric practice-based research network: a case-control study.

OBJECTIVES: (1) To determine the duration, outcome, and associated findings of urticaria in children seen by general pediatricians; (2) to compare the exposure to foods, medications, insect stings or bites, and the presence of other symptoms in children with urticaria with controls; (3) to determine general pediatricians' management of urticaria. DESIGN: Case-control. PARTICIPANTS: Children with urticaria seen by Utah Pediatric Practice Based Research Network members between August 1, 1999, and August 31, 2000. Control patients were matched for age and sex. MAIN OUTCOME MEASURES: Duration of urticaria; associated symptoms; personal and family history of atopy; medications; ingestion of peanuts, nuts, shellfish, tomatoes, strawberries, or eggs; being stung by an insect; suspected cause, diagnostic studies; treatment. RESULTS: Fifty-two cases and 47 controls were enrolled. The mean duration of urticaria was 8.9 days (range, 1-50 days). Seventeen patients (33%) and 1 control patient were taking antibiotics (odds ratio [OR], 22.3; 95% confidence interval [CI], 2.8-176; chi(2), P<.001). Fourteen patients and 5 controls had gastrointestinal symptoms (OR, 3.1; 95% CI, 1.02-9.4; chi(2), P =.04). There were no differences between cases and controls for other symptoms, personal or family history of atopy, ingestion of the foods listed, insect sting, or other medications. A cause was suspected in 28 patients (54%): a "viral illness" (19%), antibiotics (15%), or a combination (35%). CONCLUSIONS: Patients were more likely than controls to be taking an antibiotic and were more likely to have a personal or family history of atopy or to report ingesting foods commonly associated with urticaria. A viral illness was the most common cause suspected by pediatricians.

Adolescent↗
PubMed2000

Targeting transgene expression to airway epithelia and submucosal glands, prominent sites of human CFTR expression.

Targeting therapeutic gene expression to disease-affected tissues is an essential component of effective and safe gene therapy. After birth, CFTR gene expression in human lungs is localized predominantly in the epithelial cells lining the upper airways, especially in the ducts and serous tubules of the submucosal glands. We have developed a K18 expression cassette, based on the DNA control elements of the human cytokeratin 18 gene. Temporal and spatial analyses of transgenic mice demonstrated that this expression cassette targets transgene expression to almost all cell types in which CFTR is expressed. Airway epithelium expression started as early as 11.5 days of gestational age and continued into the adulthood of the transgenic mice. In these adult mice, the pattern of the reporter expression strikingly matched that of the human cytokeratin 18 and human CFTR genes. The transgene expression was epithelium-specific and undetectable in connective tissue, muscle, bone, cartilage, blood, and endothelial cells. Significantly, high levels of expression were detected in tracheal submucosal glands. Together, these results suggest that our K18 expression cassette has a high potential for clinical application in gene therapy for patients with cystic fibrosis.

Animals↗
PubMed2000

A human epithelium-specific vector optimized in rat pneumocytes for lung gene therapy.

Gene therapy vectors based on mammalian promoters offer the potential for increased cell specificity and may be less susceptible than viral promoters to transcription attenuation by host cytokines. The human cytokeratin 18 (K18) gene is naturally expressed in the lung epithelia, a target site for gene therapies to treat certain genetic pediatric lung diseases. Our original vector based on the promoter and 5' control elements of K18 offered excellent epithelial cell specificity but relatively low expression levels compared with viral promoters. In the present study, we found that adding a stronger SV40 poly(A) signal boosted primary rat lung epithelial cell expression but greatly reduced cell specificity. Addition of a 3' portion of the K18 gene to our vector as a 3' untranslated region (UTR) improved epithelial cell-specific expression by reducing expression in lung fibroblasts. The effect of the 3' UTR was not related to gross differences in cell-specific splicing. A deletion variant of this UTR further increased lung epithelial cell expression while retaining some cell specificity. These data illustrate the possibilities for using 3' UTR to regulate cell-specific transgene expression. Our improved K18 vector should prove useful for pediatric lung gene therapy applications.

Animals↗
PubMed1999

In vivo efficacy of XR9051, a potent modulator of P-glycoprotein mediated multidrug resistance.

Overexpression of P-glycoprotein (P-gp) is a potential cause of multidrug resistance (MDR) in tumours. We have previously reported that XR9051 (N-(4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phe nyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-pipera zinylidene)methylbenzamide) is a potent and specific inhibitor of P-gp, which reverses drug resistance in several murine and human MDR cell lines. In this study we have evaluated the in vivo efficacy of this novel modulator in a panel of murine and human tumour models and examined its pharmacokinetic profile. Efficacy studies in mice bearing MDR syngeneic tumours (P388/DX Johnson, MC26) or human tumour xenografts (A2780AD, CH1/DOXr, H69/LX) demonstrated that co-administration of XR9051 significantly potentiated the anti-tumour activity of a range of cytotoxic drugs. This modulatory activity was observed following parenteral and oral co-administration of XR9051. In addition, the combination schedules were well-tolerated. Following intravenous administration in mice, XR9051 is rapidly distributed and accumulates in tumours and other tissues. In addition, the compound is well-absorbed after oral administration. These data suggest that XR9051 has the potential for reversing clinical MDR mediated by P-glycoprotien.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Preparing the ground: contributions of the preclinical years to medical education for care near the end of life. Working Group on the Pre-clinical Years of the National Consensus Conference on Medical Education for Care Near the End of Life.

The preclinical years of medical education have rich potential for preparing medical students to provide optimal end-of-life care. Most of the opportunities and settings for this education already exist in the curricula of most medical schools, although they are underutilized for this purpose. In this report The Working Group on the Pre-clinical Years of the National Consensus Conference on Medical Education for Care Near the End of Life identifies the most promising settings and suggests how they might be used for maximum benefit in end-of-life education. Basic end-of-life care competencies are in five domains: (1) psychological, sociologic, cultural, and spiritual issues; (2) interviewing and communication skills; (3) management of common symptoms; (4) ethical issues; and (5) self-knowledge and self-reflection. A centralized group should oversee educational activities related to end-of-life care at each medical school. This group would identify and facilitate teaching opportunities in the preclinical curriculum: basic science courses; problem-based learning seminars; courses in interviewing, the doctor-patient relationship, and introduction to clinical medicine; courses in ethics, humanities, and the social-behavioral sciences; clinical preceptorships; and longitudinal experiences with patients. The group would also assess the potential impact of the "hidden curriculum."

Attitude to Death↗
PubMed1999

Hormonal regulation and genomic organization of the human amiloride-sensitive epithelial sodium channel alpha subunit gene.

To investigate the regulation of the amiloride-sensitive epithelial sodium channel (ENaC) expression, we have characterized the genomic structure and performed promoter analyses of the alpha subunit of the human (h) ENaC gene. Genomic clones containing the alphahENaC gene were isolated and subjected to restriction-mapping analysis. The alphahENaC gene was shown to be composed of 13 exons and 12 introns. Primer extension analysis confirmed that transcription initiation occurred at the beginning of the reported alphahENaC cDNA, but also indicated potential heterogenous initiation sites. Examination of a 3.1 kb 5' flanking sequence revealed a notable absence of CCAAT or TATA-like elements but suggested three GC boxes and several putative transcription factor binding sites, including a glucocorticoid response element (GRE) consensus. A 250 bp minimal promoter was capable of directing expression of a secreted alkaline phosphatase reporter. This promoter activity was enhanced 2.5- and 4-fold by upstream flanking sequences. Dexamethasone treatment induced levels of expression from the longer, GRE-containing promoter fragments from 8- to 20-fold, but not from the minimal promoter. Precise deletion of the 15-bp, dyad GRE sequence completely abolishes the response of reporter expression to dexamethasone induction. These experiments indicate that glucocorticoid augmentation of lung epithelial Na+ transport occurs, at least in part, by direct stimulation of transcription of the ENaC genes.

Base Sequence↗
PubMed1997

Development of an epithelium-specific expression cassette with human DNA regulatory elements for transgene expression in lung airways.

The efficient expression of therapeutic genes in target cells or tissues is an important component of efficient and safe gene therapy. Utilizing regulatory elements from the human cytokeratin 18 (K18) gene, including 5' genomic sequences and one of its introns, we have developed a novel expression cassette that can efficiently express reporter genes, as well as the human cystic fibrosis transmembrane conductance regulator (CFTR) gene, in cultured lung epithelial cells. CFTR transcripts expressed from the native K18 enhancer/promoter include two alternative splicing products, due to the activation of two cryptic splice sites in the CFTR coding region. Modification of the K18 intron and CFTR cDNA sequences eliminated the cryptic splice sites without changing the CFTR amino acid sequence, and led to enhanced CFTR mRNA and protein expression as well as biological function. Transgenic expression analysis in mice showed that the modified expression cassette can direct efficient and epithelium-specific expression of the Escherichia coli LacZ gene in the airways of fetal lungs, with no detectable expression in lung fibroblasts or endothelial cells. This is the first expression cassette which selectively directs lung transgene expression for CFTR gene therapy to airway epithelia.

Animals↗
PubMed1997

Anesthesia practices in the United States common to in vitro fertilization (IVF) centers.

PURPOSE: Our purpose was to characterize and describe anesthesia practice in programs performing IVF in the United States. METHODS: We used a telephone survey requiring respondents to be either the program director, a physician, or a nurse familiar with the practice. Two hundred seven (78%) Society of Assisted Reproductive Technology (SART) registered programs agreed to participate. Programs were divided by geographic region and type of practice (academic versus private). RESULTS: Ninety-one private (68%) and 41 academic (56%) programs used personnel provided by the Department of Anesthesiology. Conscious sedation was performed most commonly (95%). The remaining 5% used primarily either general, regional, or local anesthesia. Typical recovery times were 90 to 120 min. Average costs of anesthetic administration were $300- $400 and were similar among groups except for the Eastern academic programs, with a higher mean cost of $543. Programs using personnel from anesthesiology reported higher costs compared to programs utilizing their own staff ($391 +/- 15 vs $157 +/- 11; P < 0.05). Complications were infrequent (< 10%); no hospitalizations or serious life-threatening incidents were reported. CONCLUSIONS: A large number of programs safely used their own trained personnel to deliver anesthesia, and realized a significant reduction in cost.

Academic Medical Centers↗
PubMed1997

Identification and characterization of human genes encoding Hprp3p and Hprp4p, interacting components of the spliceosome.

Nuclear RNA splicing occurs in an RNA-protein complex, termed the spliceosome. U4/U6 snRNP is one of four essential small nuclear ribonucleoprotein (snRNP) particles (U1, U2, U5 and U4/U6) present in the spliceosome. U4/U6 snRNP contains two snRNAs (U4 and U6) and a number of proteins. We report here the identification and characterization of two human genes encoding U4/U6-associated splicing factors, Hprp3p and Hprp4p, respectively. Hprp3p is a 77 kDa protein, which is homologous to the Saccharomyces cerevisiae splicing factor Prp3p. Amino acid sequence analysis revealed two putative homologues in Caenorhabditis elegans and Schizosaccharomyces pombe. Polyclonal antibodies against Hprp3p were generated with His-tagged Hprp3p over-produced in Escherichia coli . This splicing factor can co-immunoprecipitate with U4, U6 and U5 snRNAs, suggesting that it is present in the U4/U6.U5 tri-snRNP. Hprp4p is a 58 kDa protein homologous to yeast splicing factor Prp4p. Like yeast Prp4p, the human homologue contains repeats homologous to the beta-subunit of G-proteins. These repeats are called WD repeats because there is a highly conserved dipeptide of tryptophan and aspartic acid present at the end of each repeat. The primary amino acid sequence homology between human Hprp4p and yeast Prp4p led to the discovery of two additional WD repeats in yeast Prp4p. Structural homology between these human and yeast splicing factors and the beta-subunit of G-proteins has been identified by sequence-similarity comparison and analysis of the protein folding by threading. Structural models of Hprp4p and Prp4p with a seven-blade beta-propeller topology have been generated based on the structure of beta-transducin. Hprp3p and Hprp4p have been shown to interact with each other and the first 100 amino acids of Hprp3p are not essential for this interaction. These experiments suggest that both Hprp3p and Hprp4p are components of human spliceosomes.

Amino Acid Sequence↗