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D Harris

Publications and source records attributed to D Harris.

At least 37 records · Page 2Linked to original sources
PubMed2002

End-to-end performance measurement of Internet based medical applications.

We present a method to obtain an end-to-end characterization of the performance of an application over a network. This method is not dependent on any specific application or type of network. The method requires characterization of network parameters, such as latency and packet loss, between the expected server or client endpoints, as well as characterization of the application's constraints on these parameters. A subjective metric is presented that integrates these characterizations and that operates over a wide range of applications and networks. We believe that this method may be of wide applicability as research and educational applications increasingly make use of computation and data servers that are distributed over the Internet.

Evaluation Studies as Topic↗
PubMed2001

A superfamily of variant genes encoded in the subtelomeric region of Plasmodium vivax.

The malarial parasite Plasmodium vivax causes disease in humans, including chronic infections and recurrent relapses, but the course of infection is rarely fatal, unlike that caused by Plasmodium falciparum. To investigate differences in pathogenicity between P. vivax and P. falciparum, we have compared the subtelomeric domains in the DNA of these parasites. In P. falciparum, subtelomeric domains are conserved and contain ordered arrays of members of multigene families, such as var, rif and stevor, encoding virulence determinants of cytoadhesion and antigenic variation. Here we identify, through the analysis of a continuous 155,711-base-pair sequence of a P. vivax chromosome end, a multigene family called vir, which is specific to P. vivax. The vir genes are present at about 600-1,000 copies per haploid genome and encode proteins that are immunovariant in natural infections, indicating that they may have a functional role in establishing chronic infection through antigenic variation.

Adult↗
PubMed2001

Gene discovery in Plasmodium chabaudi by genome survey sequencing.

The first genome survey sequencing of the rodent malaria parasite Plasmodium chabaudi is presented here. In 766 sequences, 131 putative gene sequences have been identified by sequence similarity database searches. Further, 7 potential gene families, four of which have not previously been described, were discovered. These genes may be important in understanding the biology of malaria, as well as offering potential new drug targets. We have also identified a number of candidate minisatellite sequences that could be helpful in genetic studies. Genome survey sequencing in P. chabaudi is a productive strategy in further developing this in vivo model of malaria, in the context of the malaria genome projects.

Amino Acid Sequence↗
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

Mechanism of GnRH receptor signaling on gonadotropin release and gene expression in pituitary gonadotrophs.

Gonadotropin releasing hormone (GnRH), the first key hormone of reproduction, is synthesized and secreted from the hypothalamus in a pulsatile manner and stimulates pituitary gonadotrophs (5-10% of the pituitary cells) to synthesize and release gonadotropin luteinizing hormone (LH) and follicle stimulating hormone (FSH). Gonadotrophs consist of 60% multihormonal cells (LH+FSH) and 18% LH- and 22% FSH-containing cells. LH and FSH, members of the glycoprotein hormone family, stimulate spermatogenesis, folliculogenesis, and ovulation. Although GnRH plays a pivotal role in gonadotropin synthesis and release, other factors such as gonadal steroids and gonadal peptides exert positive and negative feedback mechanisms, which affect GnRH actions. GnRH actions include activation of phosphoinositide turnover as well as phospholipase D and A2, mobilization and influx of Ca2+, activation of protein kinase C (PKC) and mitogen-activated protein kinase (MAPK). A complex crosstalk between the above messenger molecules mediates the diverse actions of GnRH. Understanding the signaling mechanisms involved in GnRH actions is the basis for our understanding of basic reproductive functions in general and gonadotropin synthesis and release in particular.

Animals↗
PubMed2001

Calculation of the electronic structure and spectra of model cytochrome P450 compound I.

The electronic structure and spectra of the oxyferryl (Fe=O) compound I P450 heme species, the transient putative active intermediate of cytochrome P450s, have been calculated employing a full protoporphyrin IX heme model representation. The principal aim of this work was to compare the computed spectra of this species with the observed transient spectra attributed to it. Computations were made using both nonlocal density functional theory (DFT) and semiempirical INDO/CI methods to characterize the electronic structure of the compound I P450 species. Both methods resulted in a similar antiferromagnetic doublet as the ground state with a ferromagnetic quartet excited state partner, slightly higher in energy. The INDO/ROHF/CI semiempirical method was used to calculate the spectrum of the protoporphyrin IX P450 compound I heme species in its lowest energy antiferromagnetic doublet state at the DFT optimized geometry. As a reference, the spectrum of the ferric resting form of the protoporphyrin IX P450 heme species was also calculated. The computed shifts in the Soret and Q bands of compound I relative to the resting state were both in good agreement with the corresponding experimentally observed shifts in the transient spectra of cytochrome P450cam (Biochem. Biophys. Res. Commun. 201 (1994) 1464) and chloroperoxidase (Biochem. Biophys. Res. Commun. 94 (1980) 1123) both ascribed to their common compound I heme site. This consistency provides additional, independent support for the assignment of compound I as the origin of the reported observed transient spectra.

Cytochrome P-450 Enzyme System↗
PubMed2001

Evaluating a telemedicine system to assist in the management of dermatology referrals.

BACKGROUND: Teledermatology systems fall into two categories: live video or store-and-forward. In the former, video-conferencing equipment is used to connect a patient with a remote consultant. This method has been evaluated as an aid to dermatology, but it is expensive both in terms of capital and running costs. Video consultations are generally longer than conventional ones and harder to schedule. Some authors have considered store-and-forward as an alternative to live video: instead of a consultation, specialists could make a rapid inspection of a transmitted still image. OBJECTIVES: A study was conducted to evaluate the role of telemedicine in the dermatology outpatients department of a district general hospital (Whittington Hospital NHS Trust, London, U.K.). METHODS: One hundred and ninety-four patients were seen by one of two consultant dermatologists. A nurse used a video camera to store digital images of each patient's problem and compiled a history from the GP's referral letter. The images were reviewed 13 months later by both dermatologists; they recorded a provisional diagnosis and an assessment of how urgent an appointment would have been made given the information provided by the system. A third consultant graded the level of agreement between the telemedicine diagnoses and the face-to-face consultations. RESULTS: High levels of agreement were found between the diagnoses of the dermatologists using the system to inspect images and those of the dermatologist who saw the patients (77%). Consultants using the system recommended fewer urgent appointments (32% compared with 64%) and felt that in 31% of cases the patient did not need to be seen. In 15% of these cases (5% of the total), however, their diagnosis differed significantly from that of the consultant who saw the patient. Had the system been in use, 14% of patients conventionally assigned a non-urgent appointment would have been seen urgently. CONCLUSIONS: The images allowed a reasonably accurate diagnosis. The software was not reliable (six cases could not be viewed), or easy to use (it took approximately an hour to view 20 cases) but an improved version could be used in triaging outpatient appointments.

Correspondence as Topic↗
PubMed2001

Imaging and clinical characteristics of focal atrophy of segments 2 and 3 in primary sclerosing cholangitis.

BACKGROUND AND AIMS: Focal atrophy in primary sclerosing cholangitis (PSC) is usually thought to result from severe biliary stricture and focal biliary cirrhosis. Atrophy of the left lateral segments (segments 2 and 3) are striking when observed grossly. This type of atrophy may be subtle on cross-sectional imaging and by endoscopic retrograde cholangiopancreatography (ERCP) because of the peripheral location and compensatory hypertrophy of other parts of the liver. We examined 44 consecutive PSC patients to determine the incidence and clinical characteristics of this abnormality, and to correlate imaging studies with the gross appearance. METHODS: We reviewed all cases of PSC encountered over a 3 year period ascertained from the liver disease registry. Magnetic resonance imaging or CT images were re-examined for evidence of segment 2 and 3 atrophy. RESULTS: Four of 44 patients had focal segment 2 and 3 atrophy. These four had been confirmed laparoscopically or by inspection of the liver explant. The remaining segments of the liver were relatively spared of injury in two of the patients, and three of the four patients had preserved synthetic function without evidence of portal hypertension. While the abnormality is clearly visible on cross-sectional imaging, its peripheral location caused it to be an unobtrusive. Likewise, ERCP did not clearly reveal the abnormality on initial inspection. CONCLUSIONS: We conclude that focal atrophy of segments 2 and 3 is a sometimes early and subtle finding in PSC that may be overlooked in cross-sectional imaging or ERCP unless specifically sought.

Adult↗
PubMed2001

Fat-kidneyed.

Explore the source record for details and available documents.

Glomerulosclerosis, Focal Segmental↗
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↗
PubMed2001

Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia.

The mitogen-activated protein kinase (MAPK) pathway regulates growth and survival of many cell types, and its constitutive activation has been implicated in the pathogenesis of a variety of malignancies. In this study we demonstrate that small-molecule MEK inhibitors (PD98059 and PD184352) profoundly impair cell growth and survival of acute myeloid leukemia (AML) cell lines and primary samples with constitutive MAPK activation. These agents abrogate the clonogenicity of leukemic cells but have minimal effects on normal hematopoietic progenitors. MEK blockade also results in sensitization to spontaneous and drug-induced apoptosis. At a molecular level, these effects correlate with modulation of the expression of cyclin-dependent kinase inhibitors (p27(Kip1) and p21(Waf1/CIP1)) and antiapoptotic proteins of the inhibitor of apoptosis proteins (IAP) and Bcl-2 families. Interruption of constitutive MEK/MAPK signaling therefore represents a promising therapeutic strategy in AML.

Apoptosis↗
PubMed2001

Differentiation between bone infarction and acute osteomyelitis in children with sickle-cell disease with use of sequential radionuclide bone-marrow and bone scans.

BACKGROUND: The differentiation of bone infarction from acute osteomyelitis in patients with sickle-cell disease is challenging, as the clinical presentations of the two conditions are similar and imaging and laboratory studies are of limited value. METHODS: A combination of radionuclide bone-marrow and bone scans was performed sequentially within a twenty-four-hour period (with one exception) to aid in the differentiation between bone infarction and osteomyelitis in seventy-nine consecutive episodes of acute bone pain in children with sickle-cell disease. RESULTS: Seventy cases of bone infarction were diagnosed on the basis of decreased uptake on the bone-marrow scan and abnormal uptake on the bone scan at the site of pain. Antibiotic administration was discontinued in sixty-six of the seventy cases after the imaging results were obtained, and the bone pain resolved. In four of the seventy-nine cases, there was normal uptake on the bone-marrow scan and abnormal uptake on the bone scan at the site of pain, findings that were suggestive of acute osteomyelitis. In three of these cases, osteomyelitis was proven by culture, and the symptoms in all four resolved with antibiotic treatment. In five of the seventy-nine cases, the bone-marrow and bone scans were normal and thought to indicate neither osteomyelitis nor bone infarction; in all of these cases, the symptoms resolved without the use of antibiotics. CONCLUSIONS: These findings suggest that osteomyelitis can be differentiated from bone infarction in children with sickle-cell anemia and acute bone pain by a combination of sequential bone-marrow and bone scintigraphy.

Acute Disease↗
PubMed2001

The decaying genome of Mycobacterium leprae.

Everything that we need to know about Mycobacterium leprae, a close relative of the tubercle bacillus, is encrypted in its genome. Inspection of the 3.27 Mb genome sequence of an armadillo-derived Indian isolate of the leprosy bacillus identified 1,605 genes encoding proteins and 50 genes for stable RNA species. Comparison with the genome sequence of Mycobacterium tuberculosis revealed an extreme case of reductive evolution, since less than half of the genome contains functional genes while inactivated or pseudogenes are highly abundant. The level of gene duplication was approximately 34% and, on classification of the proteins into families, the largest functional groups were found to be involved in the metabolism and modification of fatty acids and polyketides, transport of metabolites, cell envelope synthesis and gene regulation. Reductive evolution, gene decay and genome downsizing have eliminated entire metabolic pathways, together with their regulatory circuits and accessory functions, particularly those involved in catabolism. This may explain the unusually long generation time and account for our inability to culture the leprosy bacillus.

Evolution, Molecular↗
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

Both the structure and DNA binding function of the barrier-to-autointegration factor contribute to reconstitution of HIV type 1 integration in vitro.

Retroviral integration is mediated by viral preintegration complexes (PICs), and human immunodeficiency virus type 1 (HIV-1) PICs treated with high salt lose their in vitro integration activity. Barrier-to-autointegration factor (BAF) is a host protein that efficiently restores PIC activity, but the mechanism(s) by which BAF participates in HIV-1 integration remains largely unknown. Here we developed a gel shift assay to study BAF DNA binding, and analyzed 14 mutant proteins containing substitutions of conserved residues for binding and PIC reconstitution activities. Although wild-type BAF efficiently bound double-stranded DNA, binding to single-stranded DNA, RNA, or an RNA/DNA hybrid was not detected, suggesting that BAF associates with retroviral cDNA relatively late during reverse transcription. Although some of the BAF mutant proteins efficiently bound DNA, others were defective for binding. Mutants that bound DNA efficiently reconstituted HIV-1 integration, even though in one case binding was just 0.2% of wild-type BAF. Although misfolded mutants did not reconstitute integration, a structurally intact DNA binding-defective mutant displayed partial activity at high BAF concentration. We therefore conclude that both BAF protein structure and its DNA binding activity play roles in reconstituting HIV-1 integration in vitro.

Amino Acid Sequence↗
PubMed2000

Role of gap junctions in endothelium-derived hyperpolarizing factor responses and mechanisms of K(+)-relaxation.

We have examined the effects of ouabain (1 mM), the gap junction inhibitors, 18 alpha-glycyrrhetinic acid (100 microM), N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A; 10 microM) and palmitoleic acid (50 microM), and clotrimazole (10 microM) against endothelium-derived hyperpolarizing factor (EDHF)-mediated and K(+)-induced vasorelaxations in the rat mesentery. In the presence of indomethacin (10 microM) and 300-microM N(G)nitro-L-arginine methyl ester (L-NAME), carbachol caused EDHF-mediated relaxations (R(max)=85.3+/-4.0%). In the presence of ouabain, these responses were substantially reduced (R(max)=11.0+/-2.3%). 18 alpha-glycyrrhetinic acid, SR141716A, palmitoleic acid and clotrimazole also significantly inhibited these EDHF-mediated responses. K(+) caused vasorelaxation of preparations perfused with K(+)-free buffer (R(max)=73.7+/-2.4%), which were reduced by 10-microM indomethacin (R(max)=56.4+/-6.2%). K(+) vasorelaxation was essentially abolished by endothelial denudation. Both ouabain and 18 alpha-glycyrrhetinic acid opposed K(+) relaxations, however, neither SR141716A, clotrimazole nor palmitoleic acid had any effect. Direct cell-cell coupling via gap junctions was attenuated by ouabain, clotrimazole and palmitoleic acid. We conclude that: (i) that gap junctional communication plays a major role in EDHF-mediated relaxations, (ii) that K(+)-vasorelaxation is endothelium-dependent (thus, K(+) is unlikely to represent an EDHF), and (iii) that the inhibitory actions of ouabain and clotrimazole on gap junctions might contribute towards their effects against EDHF.

Animals↗