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Biomedical subjects

D Dwyer

Publications and source records attributed to D Dwyer.

At least 19 recordsLinked to original sources
PubMed2001

Early response gene expression during differentiation of cultured Leishmania donovani.

The promastigote form of the unicellular parasite, Leishmania donovani, must differentiate into the amastigote form to establish an infection in a mammalian host. Identification of genes whose expression changes during differentiation could help reveal mechanisms of Leishmania gene regulation and identify targets for controlling the diseases caused by this human pathogen. Two genomic clones were isolated, P9 that is more highly expressed in promastigotes than in axenic amastigotes and A14 that is preferentially expressed in axenic amastigotes. Analysis of the DNA sequences revealed open reading frames that would encode 55.5 kDa and 100 kDa proteins, respectively, with no homology to known proteins. The mRNA level for these genes during 24 h time courses of parasite differentiation in culture was compared to two genes known to be differentially expressed, c-lpk2 and mkk. Changes in RNA level occurred within 2 h for each gene and continued in advance of morphological changes. The expression levels of these four genes in axenic amastigotes correlated with results from animal-derived parasites.

Animals↗
PubMed2001

A national agenda for public health informatics.

The American Medical Informatics Association 2001 Spring Congress brought together the public health and informatics communities to develop a national agenda for public health informatics. Discussions on funding and governance; architecture and infrastructure; standards and vocabulary; research, evaluation, and best practices; privacy, confidentiality, and security; and training and workforce resulted in 74 recommendations with two key themes: (1) all stakeholders need to be engaged in coordinated activities related to public health information architecture, standards, confidentiality, best practices, and research and (2) informatics training is needed throughout the public health workforce. Implementation of this consensus agenda will help promote progress in the application of information technology to improve public health.

Congresses as Topic↗
PubMed2001

The role of non-nucleoside reverse transcriptase inhibitors in children with HIV-1 infection.

Over 1.4 million of the worlds' children are infected with HIV-1, mostly acquired in the perinatal period. Antiviral therapeutic options for children with HIV-1 infection have lagged behind those for infected adults. However, we now know that prevention of perinatal HIV-1 transmission to children is possible and that combination therapy for the management of infected children is efficacious. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are developing a more prominent role in combination therapy regimens, particularly as alternatives to protease inhibitors. They also have a role in preventing perinatal transmission, where it has been shown that only 2 doses of the NNRTI nevirapine can significantly reduce mother-to-child transmission of HIV-1. This has major therapeutic implications, particularly in areas where combination therapy is not readily available. Palatable paediatric formulations of NNRTIs are available or are being developed. Whilst pharmacokinetic data regarding the use of antiretrovirals in children remain scarce, published clinical trials have demonstrated the efficacy of NNRTIs when used as part of combination regimens in the management of HIV-1 infected children. The toxicity profile of NNRTIs is relatively favourable; however, severe skin rash, hepatotoxicity and central nervous system adverse effects with various NNRTIs can lead to treatment cessation. The development of class resistance with single step mutations in the reverse transcriptase gene remains a major therapeutic problem with this class of antiretrovirals. Novel NNRTIs under development are of interest either because of improved pharmacodynamics, reduced toxicity profiles or because of action against NNRTI-mutation containing resistant virus. There are no data available yet on the use of these drugs in the paediatric population.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Neo-self antigens and the expansion of B-1 cells: lessons from atherosclerosis-prone mice.

The pathogenesis of atherosclerosis involves an inflammatory process that is modulated by the immune system, and within these complex responses we have discerned a possible role for an archetypic B-1 clone. We speculate that due to their immunogenicity and in vivo distribution the "neo"-self determinants created in oxidatively modified LDL are highly stimulatory for certain B-1 cell clones. These neo-self determinants, which can be created chemically, by somatic processes, may in fact represent the molecular analogues of somatic maturation, or even aging. These changes, including those on non-protein antigens induced by oxidative metabolism, amongst others, create neo-determinants against which the host no doubt can not develop rigorous B-cell tolerance. The onset of expression of these oxidative neo-determinants relatively late in development may well serve a useful function for the highly evolved mammalian immune system, as targeting by evolutionarily selected B-1 clones may facilitate the amplification of other useful antibody-mediated physiologic functions. As in the case of the T15 clone, these antibodies may aid in protection against common microbial pathogens. Hence we postulate that during the evolution of the adaptive immune system the neo-self antigenic milieu may have been exploited for the natural selection of primordial clonal specificities. The T15 B-1 clone may then illustrate a common paradigm in which there has been natural selection based on utility for the defense of the individual from environmental threats, as well as for possible "housekeeping" role(s) and the maintenance of cellular homeostasis.

Animals↗
PubMed2000

Endurance training in Wistar rats decreases receptor sensitivity to a serotonin agonist.

There is mounting evidence that increased brain serotonin during exercise is associated with the onset of CNS-mediated fatigue. Serotonin receptor sensitivity is likely to be an important determinant of this fatigue. Alterations in brain serotonin receptor sensitivity were examined in Wistar rats throughout 6 weeks of endurance training, running on a treadmill four times a week with two exercise tests per week to exhaustion. Receptor sensitivity was determined indirectly as the reduction in exercise time in response to a dose of a serotonin (1A) agonist, m-chlorophenylpiperazine (m-CPP). The two groups of controls were used to examine (i) the effect of the injection per se on exercise performance and (ii) changes in serotonin receptor sensitivity associated with maturation. In the test group, undrugged exercise performance significantly improved by 47% after 6 weeks of training (4518 +/- 729 to 6640 +/- 903 s, P=0.01). Drugged exercise performance also increased significantly from week 1 to week 6 (306 +/- 69-712 +/- 192 s, P = 0.04). Control group results indicated that the dose of m-CPP alone caused fatigue during exercise tests and that maturation was not responsible for any decrease in receptor sensitivity. Improved resistance to the fatiguing effects of the serotonin agonist suggests desensitization of central serotonin receptors, probably the 5-HT1A receptors. Endurance training appears to stimulate an adaptive response to the fatiguing effects of increased brain serotonin, which may enhance endurance exercise performance.

Adaptation, Physiological↗
PubMed2000

Multistate outbreak of hemolysis in hemodialysis patients traced to faulty blood tubing sets.

BACKGROUND: Hemolysis associated with hemodialysis is rare. The most frequent causes of hemodialysis-associated hemolysis are chemical contamination, heat, or mechanical injury of erythrocytes from occluded or kinked hemodialysis blood lines. When patients in three states developed hemolysis while undergoing hemodialysis between May 13 and 23, 1998, an investigation was initiated. METHODS: A case-patient was defined as any patient at healthcare facilities A (Nebraska), B (Maryland), or C (Massachusetts) during May 13 through 23, 1998 (epidemic period), who had hemolysis diagnosed > or =48 hours after undergoing hemodialysis. To identify case-patients and to determine background rates, the medical records of patients from facilities A, B, and C who were undergoing hemodialysis during the epidemic and pre-epidemic (that is, May 5 through 19, 1998) periods were reviewed. Experiments simulating hemodialysis with the same lot numbers of hemodialysis blood tubing cartridge sets used on case- and control-patients were conducted. RESULTS: The rates of hemolysis among patients at facilities A, B, and C were significantly higher during the epidemic than the pre-epidemic period (13 out of 118 vs. 0 out of 118, P < 0.001; 12 out of 298 vs. 0 out of 298, P = 0.001; and 5 out of 62 vs. 0/65, P = 0.03, respectively). All case-patients had hemolysis. Twenty (66%) had hypertension. Eighteen (60%) had abdominal pain, and 10 (36%) were admitted to an intensive care unit. There were two deaths. The only commonality among the three outbreaks was the use of the same lot of disposable hemodialysis blood tubing from one manufacturer. Examination of the implicated hemodialysis blood tubing cartridge sets revealed narrowing of an aperture through which blood was pumped before entering the dialyzers. In vitro experiments with the hemodialysis blood tubing revealed that hemolysis was caused by increased pressure on erythrocytes as they passed through the partially occluded hemodialysis blood tubing. CONCLUSIONS: Our investigation traced the multiple hemolysis outbreaks to partially occluded hemodialysis blood tubing produced by a single manufacturer. On May 25, 1998, the manufacturer issued a voluntary nationwide recall of the implicated lots of hemodialysis blood tubing cartridge sets.

Adult↗
PubMed2000

Pacing your patients.

Explore the source record for details and available documents.

Cardiac Pacing, Artificial↗
PubMed1999

The reliability of muscle biopsies taken from vastus lateralis.

The purpose of this study was to examine whether a single biopsy sample of vastus lateralis could provide an accurate estimate of capillary density (CD) which is indicative of the entire muscle, or whether capillary density is distributed unevenly and varies with muscle depth. Whole muscle cross sections of vastus lateralis were excised post mortem (n=11) for analysis of capillary density at three muscle depths, (superficial, mid and deep regions). Muscle thickness varied widely (17-79 mm) across subjects. The distribution of CD throughout the depth of the muscle was homogeneous in 8 subjects, but in 3 subjects it was heterogeneous (p<0.05). In 3 of these subjects there was a significant (p<0.05) effect of sample depth on CD. These data indicate that tissue from a single biopsy will not adequately represent the CD of the entire vastus lateralis in some individuals. Single biopsies from unspecified muscle depth, have routinely been used to estimate CD and fibre type in vastus lateralis. The present study indicates that a more reliable method of analysis would be to use the tissue from two needle biopsies taken at the superficial and deep portions of the muscle from a group of at least 10 subjects. Sampling theory analysis supported this conclusion.

Adolescent↗
PubMed1999

Genetic dissection of cell growth arrest functions mediated by the Epstein-Barr virus lytic gene product, Zta.

Expression of the Epstein-Barr virus (EBV) latency-associated genes activates cell cycle progression and drives immortalization of the infected cell. In contrast, progression of the EBV replication program occurs most efficiently in growth-arrested cells. Previous studies showed that the EBV-encoded immediate-early transcription factor, Zta, can induce expression of the cyclin-dependent kinase inhibitors, p21 and p27, the tumor suppressor, p53, and cell growth arrest. Moreover, Zta-mediated induction of growth arrest occurs independently of its transcriptional transactivation function. Here we show that substitution of Zta's basic DNA binding domain with the analogous region of the Zta homologue, c-Fos, abrogates Zta's ability to induce growth arrest and to induce p21, p27, or p53 expression, suggesting that protein-protein interactions between this region of Zta and key cell cycle control proteins are involved in signaling cell cycle arrest. We also show that despite the crucial role for Zta's basic domain in eliciting cell growth arrest, its amino terminus is required for efficient induction of p27 and it modulates the level of p53 induction. Last, we provide evidence that Zta-mediated inductions of p21, p27, and p53 occur, at least in part, through distinct pathways. Therefore, Zta interacts with multiple growth arrest pathways, a property which may have evolved partly as a means to ensure that lytic replication occurs in a growth-arrested setting in multiple different tissues in various states of differentiation.

Amino Acid Sequence↗
PubMed1999

Persistent CCR5 utilization and enhanced macrophage tropism by primary blood human immunodeficiency virus type 1 isolates from advanced stages of disease and comparison to tissue-derived isolates.

Viral phenotype, tropism, coreceptor usage, and envelope gene diversity were examined in blood isolates collected from 27 individuals at different stages of human immunodeficiency virus type 1 (HIV-1) disease and tissue derived isolates from 10 individuals with AIDS. The majority (89%) of blood and all tissue HIV-1 isolates from all stages of infection were non-syncytium inducing and macrophage (M) tropic. Tropism and productive infection by HIV isolates in both monocytes and monocyte-derived macrophages (MDM) increased in advanced disease (HIV tropism for monocytes, 1 of 6 from categories I and II versus 11 of 21 [P = 0.05] from category IV and II [CD4 < 250]; and high-level replication in MDM, 1 of 6 from categories I and II versus 16 of 21 from categories IV and II [P = 0. 015]). There was a high level of replication of blood and tissue isolates in T lymphocytes without restriction at any stage. Overall, the level of replication in MDM was 5- to 10-fold greater than in monocytes, with restriction in the latter occurring mainly at entry and later stages of replication. Only three blood isolates were identified as syncytium inducing, and all had a dualtropic phenotype. There was a significant increase of HIV envelope gene diversity, as shown by a heteroduplex mobility assay, in advanced disease; this may partly underlie the increase of HIV replication in MDM. Unlike blood isolates (even those from patients with advanced disease), tissue isolates displayed greater similarities (90%) in productive infection between MDM and monocytes. The majority (87%) of all isolates, including those from patients with advanced disease, used CCR5, and only 5 of 37 isolates showed expanded coreceptor usage. These results indicate that in the late stage of disease with increasing viral load and diversity, CCR5 utilization and M-tropism persist in blood and tissue and the replicative ability in macrophages increases. This suggests that these characteristics are advantageous to HIV and are important to disease progression.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Inducible expression of suicide genes in Leishmania donovani amastigotes.

This study tests the feasibility of using the A2 gene regulatory system to create a Leishmania cell line in which attenuation is developmentally regulated when the parasite differentiates from promastigotes to amastigotes. The Leishmania donovani- inducible A2 gene regulatory system was used to differentially express in amastigotes two potential suicide genes: a truncated version of the L. donovani 3'-nucleotidase/nuclease expressed in the cytoplasm and the herpes simplex virus thymidine kinase gene. These genes were inserted between A2 noncoding regulatory sequences for up-regulation of expression in amastigotes. The accumulation of toxic products affected L. donovani cell replication and viability both in vitro and in vivo. The inducible expression of toxic gene products represents a valuable tool for the development of safe and effective vaccines.

Animals↗
PubMed1998

Serum antibodies to HIV-1 are produced post-measles virus infection: evidence for cross-reactivity with HLA.

Convalescent sera obtained from patients who were recently recovered from an acute measles virus infection were tested for the presence of anti-HIV-1 antibodies by Western blot analysis. While 16% (17/104) of control sera displayed reactive bands to a variety of HIV proteins, 62% (45/73) of convalescent sera demonstrated immunoreactive bands corresponding to HIV-1 Pol and Gag, but not Env antigens. This cross-reactivity appears to be the result of an active measles infection. No HIV-1 immunoblot reactivity (0/10) was observed in sera obtained from young adults several weeks after a combined measles, mumps, and rubella (MMR) vaccination. Interestingly, examination of anti-HLA typing sera specific for either class I and class II molecules revealed that 46% (19/41) of these sera contained cross-reactive antibodies to HIV-1 proteins. Absorption of measles sera with mixed lymphocyte reaction (MLR)-activated lymphocytes and/or HIV-1 recombinant proteins significantly decreased or removed the presence of these HIV-1-immunoreactive antibodies. Together, these findings suggest that the immune response to a natural measles virus infection results in the production of antibodies to HIV-1 and possibly autoantigens.

Absorption↗
PubMed1998

Effects of retention interval on latent inhibition and perceptual learning.

Repeated, non-reinforced preexposure to a context slowed development of conditioned freezing to that context when it was subsequently paired with footshock (latent inhibition) and enhanced discriminability of that context from a similar context (perceptual learning) whether assessed by a generalization test or by explicit discrimination training. Latent inhibition was eliminated by a delay between conditioning sessions and test (Experiments 1a and 1b) and reduced by a delay between preexposure and conditioning (Experiment 2). However, perceptual learning was unaffected by either of these intervals (Experiments 1b and 2). These results are discussed in terms their impact on theories that have latent inhibition as a possible mechanism of perceptual learning, and on theories of latent inhibition that consider the retardation of conditioned responding to be the result of an acquisition failure.

Animals↗
PubMed1998

Loss of latent inhibition of contextual conditioning following non-reinforced context exposure in rats.

Three experiments with rats demonstrated that preexposure to an experimental environment retarded the level of conditioned freezing observed on a test in that environment after it had been paired with mild footshock. Furthermore, Experiment 1 demonstrated that this latent inhibition effect could be abolished if preexposed rats were exposed to a second experimental environment following conditioning to the preexposed environment. Experiments 2 and 3 demonstrated that this second environment had to be similar, but not identical, to the preexposed environment, and that the influence of exposure to the second environment on latent inhibition could be abolished by exposure to that environment prior to footshock conditioning. These results are considered in terms of the Dickinson-Burke (1996) theory of retrospective revaluation, and their implications for experiments demonstrating a loss of latent inhibition across a delay are considered.

Animals↗
PubMed1998

Polymerase chain reaction and restriction fragment length polymorphism analysis of varicella-zoster virus isolates from the United States and other parts of the world.

A polymerase chain reaction (PCR) assay that identifies and differentiates wild-type (wt) and vaccine strains of varicella-zoster virus (VZV) was used to determine if VZV strains with restriction fragment length polymorphisms resembling those of the Japanese Oka vaccine strain were present in the wt pool outside of Japan. Virus samples (n = 114) from patients with chickenpox and zoster from various parts of the United States and Australia were analyzed. The assay correctly identified 113 samples as wt strain. The 1 sample identified as Oka vaccine strain came from a child with leukemia who developed a vaccine-associated rash after receiving the live attenuated varicella vaccine. At this point, there is no evidence that wt strains resembling the vaccine are circulating outside of Japan. This indicates that this PCR assay can be utilized to distinguish rashes due to vaccine and wt VZV.

Australia↗