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Biomedical subjects

L Murphy

Publications and source records attributed to L Murphy.

At least 19 recordsLinked to original sources
PubMed2006

Efficacy of repeated high-dose hepatitis B vaccine (80 microg) in patients with chronic liver disease.

Patients with chronic liver disease (CLD) respond poorly to standard hepatitis B (HBV) vaccine given as sequential 20 microg IM shots because of an overall impaired immune response. Many of these patients go on to liver transplantation and are at risk of acquiring recurrent or de novo HBV infection. To evaluate the efficacy and safety of high-dose (80 microg) IM HBV vaccination in patients with CLD who had previously failed to respond to a standard three-dose schedule of 40 microg IM vaccine given monthly. A retrospective review was undertaken at our institution of 79 patients with CLD who were treated with high-dose (80 microg) HBV vaccinations. All had previously failed a three-dose course of 40 microg HBV vaccine. An HBV vaccine response was defined as an anti-HBs titer greater than 100 mIU/ml. Liver enzymes, creatinine, age, prothrombin time, total vaccine dose, and MELD score were recorded. No adverse events were reported. Seventy-two per cent (57/79) of the subjects had an adequate response after receiving a mean total dose of 220 mug vaccine (range 80-800 microg). Twenty-eight per cent (22/79) of the subjects did not respond after receiving a mean total dose of 420 microg vaccine (range 240-720 microg). Non-responders had more severe hepatic disease defined as a higher mean total bilirubin level (p = 0.003) and a lower mean albumin level (p < 0.05). Age, prothrombin time, MELD score, and creatinine were not statistically significant between the responders and non-responders. Repeated high-dose (80 microg) HBV vaccination, in patients who do not respond to standard HBV vaccine doses, is safe and effective in the majority of patients with CLD.

Adult↗
PubMed2005

Establishing a master's degree programme in bioinformatics: challenges and opportunities.

The development of the Bioinformatics MS degree program at the University of Illinois, the challenges and opportunities associated with such a process, and the current structure of the program is described. This program has departed from earlier University practice in significant ways. Despite the existence of several interdisciplinary programs at the University, a few of which grant degrees, this is the first interdisciplinary program that grants degrees and formally recognises departmental specialisation areas. The program, which is not owned by any particular department but by the Graduate College itself, is operated in a franchise-like fashion via several departmental concentrations. With four different colleges and many more departments involved in establishing and operating the program, the logistics of the operation are of considerable complexity but result in significant interactions across the entire campus.

Biomedical Engineering↗
PubMed2004

Atrial fibrillation and thrombosis: immunohistochemical differences between in situ and embolized thrombi.

BACKGROUND/OBJECTIVE: Thromboembolism secondary to atrial fibrillation accounts for approximately one-fourth of all strokes. Although considerable resources have been targeted to pharmacologic prophylaxis, neither the cellular nor the biochemical composition of atrial thrombi is known. Quantitative immunohistochemistry was undertaken to define the composition of atrial thrombi and to explore morphological differences between atrial appendage thrombi and those that embolize. PATIENTS/METHODS: Serial sections of thrombi obtained during valve replacement surgery or embolectomy from 22 patients with atrial fibrillation were stained with antibodies against fibrin, integrin beta3, or tissue factor and analyzed with NIH-image. RESULTS: Thrombi showed distinct regions staining for either fibrin or platelets and on average, the fibrin-rich regions predominated (P < 0.0001). The platelet content of embolized thrombi was nearly twice that of atrial thrombi (P = 0.02). Non-staining amorphous material comprised nearly half of atrial thrombi in situ, but was rare in embolized thrombi (P < 0.001). Tissue factor colocalized to areas rich in platelets and granulocytes. CONCLUSIONS: The abundance of fibrin relative to platelets underscores the enhanced efficacy of warfarin prophylaxis in clinical trials. The finding of tissue factor localized to platelet-leukocyte clusters suggests its blood-borne origin. Compositional differences between in situ and embolized thrombi suggest directions for investigating propensity for embolization.

Aged↗
PubMed2002

Sequence of Plasmodium falciparum chromosomes 1, 3-9 and 13.

Since the sequencing of the first two chromosomes of the malaria parasite, Plasmodium falciparum, there has been a concerted effort to sequence and assemble the entire genome of this organism. Here we report the sequence of chromosomes 1, 3-9 and 13 of P. falciparum clone 3D7--these chromosomes account for approximately 55% of the total genome. We describe the methods used to map, sequence and annotate these chromosomes. By comparing our assemblies with the optical map, we indicate the completeness of the resulting sequence. During annotation, we assign Gene Ontology terms to the predicted gene products, and observe clustering of some malaria-specific terms to specific chromosomes. We identify a highly conserved sequence element found in the intergenic region of internal var genes that is not associated with their telomeric counterparts.

Animals↗
PubMed2002

Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2).

Streptomyces coelicolor is a representative of the group of soil-dwelling, filamentous bacteria responsible for producing most natural antibiotics used in human and veterinary medicine. Here we report the 8,667,507 base pair linear chromosome of this organism, containing the largest number of genes so far discovered in a bacterium. The 7,825 predicted genes include more than 20 clusters coding for known or predicted secondary metabolites. The genome contains an unprecedented proportion of regulatory genes, predominantly those likely to be involved in responses to external stimuli and stresses, and many duplicated gene sets that may represent 'tissue-specific' isoforms operating in different phases of colonial development, a unique situation for a bacterium. An ancient synteny was revealed between the central 'core' of the chromosome and the whole chromosome of pathogens Mycobacterium tuberculosis and Corynebacterium diphtheriae. The genome sequence will greatly increase our understanding of microbial life in the soil as well as aiding the generation of new drug candidates by genetic engineering.

Bacterial Proteins↗
PubMed2002

The genome sequence of Schizosaccharomyces pombe.

We have sequenced and annotated the genome of fission yeast (Schizosaccharomyces pombe), which contains the smallest number of protein-coding genes yet recorded for a eukaryote: 4,824. The centromeres are between 35 and 110 kilobases (kb) and contain related repeats including a highly conserved 1.8-kb element. Regions upstream of genes are longer than in budding yeast (Saccharomyces cerevisiae), possibly reflecting more-extended control regions. Some 43% of the genes contain introns, of which there are 4,730. Fifty genes have significant similarity with human disease genes; half of these are cancer related. We identify highly conserved genes important for eukaryotic cell organization including those required for the cytoskeleton, compartmentation, cell-cycle control, proteolysis, protein phosphorylation and RNA splicing. These genes may have originated with the appearance of eukaryotic life. Few similarly conserved genes that are important for multicellular organization were identified, suggesting that the transition from prokaryotes to eukaryotes required more new genes than did the transition from unicellular to multicellular organization.

Base Sequence↗
PubMed2001

Metabolites of a tobacco-specific lung carcinogen in nonsmoking women exposed to environmental tobacco smoke.

BACKGROUND: Environmental tobacco smoke (ETS) is associated with lung cancer in nonsmokers. Most epidemiologic studies find a higher risk for lung cancer in nonsmoking women married to smokers than in those married to nonsmokers. We measured metabolites of a tobacco-specific lung carcinogen in urine from healthy, nonsmoking women exposed to ETS. METHODS: We recruited women and their partners through advertisements. Couples completed questionnaires on smoking history and demographics, and both partners provided 100 mL of urine; 23 women had male partners who smoked in the home (i.e., exposed women), and 22 women had male partners who did not smoke (i.e., unexposed women). Urine samples were analyzed for nicotine, for cotinine, for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronide (NNAL-Gluc), as well as for creatinine. NNAL and NNAL-Gluc are metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Unpaired Student's t tests were conducted on log-transformed values. All statistical tests are two-sided. RESULTS: Urinary levels of nicotine, cotinine, NNAL, and NNAL-Gluc were statistically significantly higher in exposed women than in unexposed women. Geometric means for these compounds in exposed versus unexposed women, respectively, were as follows: nicotine, 0.050 nmol/mg of creatinine (95% confidence interval [CI] = 0.033 to 0.076) versus 0.008 nmol/mg of creatinine (95% CI = 0.004 to 0.014); cotinine, 0.037 nmol/mg of creatinine (95% CI = 0.022 to 0.061) versus 0.007 nmol/mg of creatinine (95% CI = 0.004 to 0.011); NNAL, 0.013 pmol/mg of creatinine (95% CI = 0.007 to 0.024) versus 0.004 pmol/mg of creatinine (95% CI = 0.002 to 0.007); and NNAL-Gluc, 0.027 pmol/mg of creatinine (95% CI = 0.016 to 0.045) versus 0.004 pmol/mg of creatinine (95% CI = 0.003 to 0.006). CONCLUSIONS: Nonsmoking women exposed to ETS take up and metabolize the tobacco-specific lung carcinogen NNK, which could increase their risk of lung cancer. Within couples, the NNAL plus NNAL-Gluc level in exposed women compared with that of their smoking partners averaged 5.6%. Notably, epidemiologic studies have estimated the excess risk for lung cancer in nonsmoking women exposed to ETS as 1%-2% of that in smokers.

Adult↗
PubMed2001

Massive gene decay in the leprosy bacillus.

Leprosy, a chronic human neurological disease, results from infection with the obligate intracellular pathogen Mycobacterium leprae, a close relative of the tubercle bacillus. Mycobacterium leprae has the longest doubling time of all known bacteria and has thwarted every effort at culture in the laboratory. Comparing the 3.27-megabase (Mb) genome sequence of an armadillo-derived Indian isolate of the leprosy bacillus with that of Mycobacterium tuberculosis (4.41 Mb) provides clear explanations for these properties and reveals an extreme case of reductive evolution. Less than half of the genome contains functional genes but pseudogenes, with intact counterparts in M. tuberculosis, abound. Genome downsizing and the current mosaic arrangement appear to have resulted from extensive recombination events between dispersed repetitive sequences. Gene deletion and decay have eliminated many important metabolic activities including siderophore production, part of the oxidative and most of the microaerophilic and anaerobic respiratory chains, and numerous catabolic systems and their regulatory circuits.

Animals↗
PubMed2001

Probiotic impact on microbial flora, inflammation and tumour development in IL-10 knockout mice.

BACKGROUND: The enteric bacterial flora has been implicated in the pathogenesis of enterocolitis and colon cancer in C57BL/6 IL-10 knockout mice. Probiotic Lactobacilli modify the enteric flora and are thought to have a beneficial effect on enterocolitis. We conducted a controlled feeding trial in IL-10 knockout mice using the probiotic Lactobacillus salivarius ssp. salivarius UCC118. AIM: To determine the effect of probiotic consumption on the gastrointestinal microflora, tumour development and colitis in IL-10 knockout mice. METHODS: Twenty IL-10 knockout mice were studied (10 consumed probiotic organisms in milk and 10 consumed unmodified milk) for 16 weeks. Faecal microbial analysis was performed weekly to enumerate excretion of the probiotic UCC118, total lactobacilli, Clostridium perfringens, bacteroides, coliforms, bifidobacteria and enterococci. At sacrifice, the small and large bowel were microbiologically and histologically assessed. RESULTS: L. salivarius UCC118 was detected in faeces from all mice in the probiotic fed group, but not the control group. Faecal coliform and enterococci levels were significantly reduced in probiotic fed animals compared to the controls (P < 0.05). At sacrifice, a significant reduction in C. perfringens numbers was observed in the test mice (P < 0.05). There were no fatalities in the test group compared to two deaths from fulminant colitis in the control group. Only one test mouse developed colonic adenocarcinoma compared to five in the control group. Test animal mucosal inflammation consistently scored lower than that of the control mice. CONCLUSION: In this placebo controlled trial, modification of enteric flora in IL-10 knockout mice by probiotic lactobacilli was associated with reduced prevalence of colon cancer and mucosal inflammatory activity.

Animals↗
PubMed2001

In vitro selection criteria for probiotic bacteria of human origin: correlation with in vivo findings.

The enteric flora comprises approximately 95% of the total number of cells in the human body and can elicit immune responses while protecting against microbial pathogens. However, the resident bacterial flora of the gastrointestinal tract may also be implicated in the pathogenesis of diseases such as inflammatory bowel disease (ulcerative colitis and Crohn disease). The objectives of the Probiotic Research Group based at University College Cork were to isolate and identify lactic acid bacteria exhibiting beneficial probiotic traits, such as bile tolerance in the absence of deconjugation activity, acid resistance, adherence to host epithelial tissue, and in vitro antagonism of pathogenic microorganisms or those suspected of promoting inflammation. To isolate potentially effective probiotic bacteria, we screened the microbial population adhering to surgically resected segments of the gastrointestinal tract (the environment in which they may subsequently be reintroduced and required to function). In total, 1500 bacterial strains from resected human terminal ilea were assessed. From among these organisms, Lactobacillus salivarius subsp. salivarius strain UCC118 was selected for further study. In mouse feeding trials, milk-borne L. salivarius strain UCC118 could successfully colonize the murine gastrointestinal tract. A human feeding study conducted in 80 healthy volunteers showed that yogurt can be used as a vehicle for delivery of strain UCC118 to the human gastrointestinal tract with considerable efficacy in influencing gut flora and colonization. In summary, we developed criteria for in vitro selection of probiotic bacteria that may reflect certain in vivo effects on the host such as modulation of gastrointestinal tract microflora.

Animals↗
PubMed2001

From first base: the sequence of the tip of the X chromosome of Drosophila melanogaster, a comparison of two sequencing strategies.

We present the sequence of a contiguous 2.63 Mb of DNA extending from the tip of the X chromosome of Drosophila melanogaster. Within this sequence, we predict 277 protein coding genes, of which 94 had been sequenced already in the course of studying the biology of their gene products, and examples of 12 different transposable elements. We show that an interval between bands 3A2 and 3C2, believed in the 1970s to show a correlation between the number of bands on the polytene chromosomes and the 20 genes identified by conventional genetics, is predicted to contain 45 genes from its DNA sequence. We have determined the insertion sites of P-elements from 111 mutant lines, about half of which are in a position likely to affect the expression of novel predicted genes, thus representing a resource for subsequent functional genomic analysis. We compare the European Drosophila Genome Project sequence with the corresponding part of the independently assembled and annotated Joint Sequence determined through "shotgun" sequencing. Discounting differences in the distribution of known transposable elements between the strains sequenced in the two projects, we detected three major sequence differences, two of which are probably explained by errors in assembly; the origin of the third major difference is unclear. In addition there are eight sequence gaps within the Joint Sequence. At least six of these eight gaps are likely to be sites of transposable elements; the other two are complex. Of the 275 genes in common to both projects, 60% are identical within 1% of their predicted amino-acid sequence and 31% show minor differences such as in choice of translation initiation or termination codons; the remaining 9% show major differences in interpretation.

Animals↗
PubMed2000

Prevalence of small inversions in yeast gene order evolution.

Gene order evolution in two eukaryotes was studied by comparing the Saccharomyces cerevisiae genome sequence to extensive new data from whole-genome shotgun and cosmid sequencing of Candida albicans. Gene order is substantially different between these two yeasts, with only 9% of gene pairs that are adjacent in one species being conserved as adjacent in the other. Inversion of small segments of DNA, less than 10 genes long, has been a major cause of rearrangement, which means that even where a pair of genes has been conserved as adjacent, the transcriptional orientations of the two genes relative to one another are often different. We estimate that about 1,100 single-gene inversions have occurred since the divergence between these species. Other genes that are adjacent in one species are in the same neighborhood in the other, but their precise arrangement has been disrupted, probably by multiple successive multigene inversions. We estimate that gene adjacencies have been broken as frequently by local rearrangements as by chromosomal translocations or long-distance transpositions. A bias toward small inversions has been suggested by other studies on animals and plants and may be general among eukaryotes.

Candida albicans↗
PubMed2000

Photoproduction of straight phi(1020) mesons on the proton at large momentum transfer

The cross section for straight phi meson photoproduction on the proton has been measured for the first time up to a four-momentum transfer -t = 4 GeV2, using the CLAS detector at the Thomas Jefferson National Accelerator Facility. At low four-momentum transfer, the differential cross section is well described by Pomeron exchange. At large four-momentum transfer, above -t = 1.8 GeV2, the data support a model where the Pomeron is resolved into its simplest component, two gluons, which may couple to any quark in the proton and in the straight phi.

Journal Article↗
PubMed2000

From sequence to chromosome: the tip of the X chromosome of D. melanogaster.

One of the rewards of having a Drosophila melanogaster whole-genome sequence will be the potential to understand the molecular bases for structural features of chromosomes that have been a long-standing puzzle. Analysis of 2.6 megabases of sequence from the tip of the X chromosome of Drosophila identifies 273 genes. Cloned DNAs from the characteristic bulbous structure at the tip of the X chromosome in the region of the broad complex display an unusual pattern of in situ hybridization. Sequence analysis revealed that this region comprises 154 kilobases of DNA flanked by 1.2-kilobases of inverted repeats, each composed of a 350-base pair satellite related element. Thus, some aspects of chromosome structure appear to be revealed directly within the DNA sequence itself.

Animals↗
PubMed2000

Non-peptidic phenyl-based thrombin inhibitors: exploring structural requirements of the S1 specificity pocket with amidines.

We expand the structural requirements and structure-activity relationship of a novel class of non-peptidic aryl-based thrombin inhibitors through exploration of the S1 specificity pocket of thrombin using flexible and constrained amidines. The most active compound of this class is 11 with Ki = 69 nM, which is ca. 15-fold less potent than constrained guanidine 5.

Amidines↗