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Biomedical subjects

D Harris

Publications and source records attributed to D Harris.

At least 55 records · Page 3Linked to original sources
PubMed2000

Liposomal Bcl-2 antisense oligonucleotides enhance proliferation, sensitize acute myeloid leukemia to cytosine-arabinoside, and induce apoptosis independent of other antiapoptotic proteins.

The antiapoptotic proteins, Bcl-2 and Bcl-X(L), are expressed in most cases of acute myeloid leukemia (AML) and may contribute to drug resistance in AML. We tested the hypothesis that down-regulation of Bcl-2 alone by antisense oligodeoxynucleotides (Bcl-2-AS) induces apoptosis, even in the presence of other antiapoptotic genes. We tested Bcl-2-AS in myeloid leukemic HL-60 cells, in Bcl-2 and Bcl-X(L) overexpressing HL-60-DOX cells, and in primary AML samples. Down-regulation of Bcl-2 by Bcl-2-AS reduced the viability of HL-60 cells and, less effectively, HL-60-DOX cells and increased ara-C cytotoxicity in both cell lines. Incubation of primary AML blasts with Bcl-2-AS decreased Bcl-2 expression in CD34(+) blast cells after induction of apoptosis and enhancement of ara-C cytotoxicity in 11 of 19 primary AML samples. In 8 samples in which Bcl-2-AS did not induce apoptosis, baseline Bcl-2 levels were found to be strikingly high. The expression of other antiapoptotic proteins (Bcl-X(L), Bag-1, A1, and Mcl-1) did not prevent Bcl-2-AS-induced apoptosis. Bcl-2-AS also inhibited colony formation of AML progenitor cells. Low concentrations of Bcl-2-AS induced significant increases in S-phase cells (P =.04). Results establish Bcl-2 as a critical target for AS strategies in AML in which the baseline levels predict response to Bcl-2-AS. Bcl-2 exerts both antiapoptotic and antiproliferative functions in AML. Because early normal hematopoietic stem cells do not express Bcl-2, Bcl-2-AS therapy should be highly selective for AML cells. (Blood. 2000;95:3929-3938)

Acute Disease↗
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

Role of glutamine 151 of human immunodeficiency virus type-1 reverse transcriptase in substrate selection as assessed by site-directed mutagenesis.

A natural mutation at codon 151 (Gln --> Met; Q151M) of HIV-1 RT has been shown to confer resistance to the virus against dideoxy nucleoside analogues [Shirasaka, T., et al. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 2398], suggesting that Gln 151 may be involved in conferring sensitivity to nucleoside analogues. To understand its functional implication, we generated two mutant derivatives of this residue (Q151M and Q151N) and examined their sensitivities to ddNTPs and their ability to discriminate against rNTPs versus dNTP substrates on natural U5-PBS HIV-1 RNA template. We found that Q151M was highly discriminatory against all four ddNTPs but was able to incorporate rNTPs as efficiently as the wild type enzyme. In contrast, the Q151N mutant was only moderately resistant to ddNTPs but exhibited a higher level of discrimination against rNTPs. The fidelity of misinsertion was found to be highest for the Q151N mutant followed by Q151M and the wild type enzyme. These results point toward the importance of the amino acid side chain at position 151 in influencing the ability of the enzyme in recognition and discrimination against the sugar moieties of nucleotide substrates.

Asparagine↗
PubMed2000

A study of var gene transcription in vitro using universal var gene primers.

The polymorphic multigene family, var, encodes the variant antigen, Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), present on the surface of erythrocytes infected with the human malaria parasite, P. falciparum. PfEMP1 has been implicated in the pathology of malaria through its ability to bind to host endothelial receptors and uninfected erythrocytes. Understanding the relationship between host pathology, immune response and parasite variation is crucial, but requires a method of reliably detecting and differentiating all possible var genes. Several primer pairs used to date are biased and limited in their detection capacity. Here we describe a set of PCR primers that amplify the majority of var genes in the laboratory isolates 3D7 and A4, and appear to work equally well on all isolates tested. We use these universal primers to examine the relationship between var gene transcription as assessed by reverse transcriptase-PCR (RT-PCR) with that measured by Northern analysis of parasite RNA. Phenotypically selected young parasites have multiple transcripts detected by RT-PCR, but the full-length transcript appears to be homogeneous. In addition, we demonstrate that the choice of primers used for RT-PCR is crucial in data interpretation.

Amino Acid Sequence↗
PubMed2000

The Australian National Workplace Health Project: design and baseline findings.

BACKGROUND: This paper describes the study design, recruitment, measurement, and initial recruitment outcomes of Australia's largest workplace intervention trial, the National Workplace Health Project. METHODS: This was a cluster-randomized trial of socio-behavioral and environmental interventions focusing on key behaviors of physical activity, healthy food choices, cigarette smoking, and alcohol consumption, as well as motivational readiness for change. Twenty worksites were randomized separately for each intervention using a two-by-two factorial design. All participants underwent a health risk appraisal and measurements were made at baseline and at 1 and 2 years. RESULTS: The overall response rate for the baseline survey was 73% with 61% attending the health risk appraisal. The sample was predominantly male, English-speaking, married, blue-collar workers. Overall, 12% reported unsafe alcohol consumption, 26% were current smokers, 44% were physically inactive, 74% ate at most one piece of fruit per day, and 26% ate at most one serving of vegetables per day. Intervention and control conditions were similar at baseline for the primary outcomes, except that a higher proportion of the sociobehavioral intervention condition was more physically active (59%) than the corresponding control condition (53%). CONCLUSIONS: This study will permit the rigorous evaluation of the efficacy of sociobehavioral and environ mental intervention approaches to workplace health promotion. Although participants were randomized by worksite, intervention and control conditions were similar at baseline; any differences in the primary out come variables will be controlled for in the analysis.

Adult↗
PubMed2000

Phylogeography of Peromyscus furvus (Rodentia; muridae) based on cytochrome b sequence data.

We conducted phylogenetic analyses of cytochrome b sequence data to assess genetic variation within and among the three allopatric segments of the distribution of Peromyscus furvus from the Sierra Madre Oriental in eastern Mexico. We identified 24 unique haplotypes among the 54 individuals examined and genetic distances ranged up to 0.078 substitutions per site. Populations from the central portion of the range formed a monophyletic unit, whereas samples from the southern distributional unit were polyphyletic. Furthermore, the southernmost population sampled may represent a distinct species. This high degree of genetic differentiation among populations, currently recognized as conspecific, mirrors the result of other genetic studies of highland rodents in Mesoamerica. Together these studies indicate that the region, already considered hyperdiverse on the basis of species diversity and endemism, may contain considerably greater diversity than is currently appreciated.

Animals↗
PubMed2000

Education purchasers' views of nursing as an all graduate profession.

The issue of whether nursing should be an all graduate profession is one of the most important questions currently facing the nursing profession. The literature indicates that there are differing views on this issue but that there is little research on the performance of graduate nurses in practice. Purchasers of education have played an increasingly significant part in nurse education since the advent of Working Paper 10 (WP10) (DOH 1989). Purchasers hold the resources for nurse education and can now decide whether to commission for diploma or degree level student nurses, therefore they will have a major influence on the outcome of this debate. The aim of this paper is to discuss the views of the purchasers of education about this issue. A purposeful sample of 34 key stakeholders involved in commissioning and contracting for education was selected and asked for their views on whether nursing will or should become an all graduate profession. Key areas that were focused upon were the problems that might emerge from an all graduate nursing profession, the advantages of graduate level nurses within the NHS, what graduateness is and what it might mean for nursing. The results indicated that purchasers were convinced of the importance of nursing graduates but only as part of the workforce. Alternative ways of increasing the percentage of graduates rather than in pre-registration education were preferred with pathways of education linked to continuing professional development. Significantly, the participants were able to articulate the attributes of a degree level education for clinical practice including leadership, assertiveness, and reflective, critical skills.

Delivery of Health Care↗
PubMed2000

Effects of severe traumatic brain injury on visual memory.

The study aimed to clarify the effects of severe traumatic brain injury (TBI) on visual memory. Three groups of participants (14 late-recovery and 14 early-recovery TBI individuals and 18 controls) were administered the following: The Shum Visual Learning Test (SVLT), a test that measures the ability to remember visual patterns, an electronic maze test, a test that measures the ability to remember spatial positions, and the Rey Auditory Verbal Learning Test (RAVLT), a test of verbal memory and learning. The individuals with TBI (late- and early-recovery) were found to be impaired on the SVLT and the RAVLT but not on the electronic maze. Specifically, on the SVLT, they were found to learn at a slower rate and make more false-positive errors than the controls. The advantages of the SVLT over visual memory tests used in previous studies and the significance of findings of the present study were discussed.

Adolescent↗
PubMed2000

Stimulant psychosis: symptom profile and acute clinical course.

Nineteen patients seen at a psychiatric emergency service with amphetamine- or cocaine-induced psychotic disorder were assessed with structured interviews, chart review, and blood and urine testing. All had a predominance of positive symptoms from the Positive and Negative Syndrome Scale (PANSS). However, some subjects had substantial Negative Scale scores (26%), bizarre delusions (95%), and Schneiderian hallucinations (63%), mimicking a broad range of schizophrenic symptoms. Several PANSS scores were correlated with treatment intensity: Positive score with seclusion hours, General Psychopathology and Negative scores with hospitalization length, and General Psychopathology score with neuroleptic dose. Presenting symptoms may help in treatment planning.

Adult↗
PubMed2000

"No fear" curricular change: monitoring curricular change in the W. K. Kellogg Foundation's National Initiative on Community Partnerships and Health Professions Education.

PURPOSE: To assess the effect of the W. K. Kellogg Foundation's five-year (9/91 to 9/96) primary care curricular change initiative involving seven sites and 27 schools with respect to courses offered, graduates' specialty choices, and valued school features (e.g., reputation, research, productivity, school climate) and to track how well the schools possessed or developed the processes associated with enduring curricular change. METHOD: Information was collected via pre- and post-surveys of faculty and students, site visits, annual reports, and medical students' specialty match results. RESULTS: In general, the schools either possessed or developed the institutional, curricular design, and curriculum features associated with successful curricular change. Further, the initiative had a positive or neutral impact on most of the valued features: 199 courses were revised or developed, including 138 offered in the community, involving 141 interdisciplinary faculty. Comparing 1991-1997 data, the average percentage increases in students' selecting primary care from the involved schools were greater than the national percentages. In 1997, a larger percentage of project school graduates selected primary care than the national average. CONCLUSION: Medical schools can make major curricular changes and achieve intended outcomes (e.g., new and/ or revised courses, multidisciplinary instruction, instruction in the community, and changes in specialty choice), and this can occur without negatively impacting other valued school aspects.

Curriculum↗
PubMed2000

Effects of agronomic treatments on structure and function of ammonia-oxidizing communities.

The aim of this study was to determine the effects of different agricultural treatments and plant communities on the diversity of ammonia oxidizer populations in soil. Denaturing gradient gel electrophoresis (DGGE), coupled with specific oligonucleotide probing, was used to analyze 16S rRNA genes of ammonia oxidizers belonging to the beta subgroup of the division Proteobacteria by use of DNA extracted from cultivated, successional, and native deciduous forest soils. Community profiles of the different soil types were compared with nitrification rates and most-probable-number (MPN) counts. Despite significant variation in measured nitrification rates among communities, there were no differences in the DGGE banding profiles of DNAs extracted from these soils. DGGE profiles of DNA extracted from samples of MPN incubations, cultivated at a range of ammonia concentrations, showed the presence of bands not amplified from directly extracted DNA. Nitrosomonas-like bands were seen in the MPN DNA but were not detected in the DNA extracted directly from soils. These bands were detected in some samples taken from MPN incubations carried out with medium containing 1,000 microg of NH(4)(+)-N ml(-1), to the exclusion of bands detected in the native DNA. Cell concentrations of ammonia oxidizers determined by MPN counts were between 10- and 100-fold lower than those determined by competitive PCR (cPCR). Although no differences were seen in ammonia oxidizer MPN counts from the different soil treatments, cPCR revealed higher numbers in fertilized soils. The use of a combination of traditional and molecular methods to investigate the activities and compositions of ammonia oxidizers in soil demonstrates differences in fine-scale compositions among treatments that may be associated with changes in population size and function.

Agriculture↗
PubMed2000

Self-reported marijuana effects and characteristics of 100 San Francisco medical marijuana club members.

In order to assess the relationships between medical marijuana users' reasons for use, side effects, and drug use patterns, 100 participants were recruited from the San Francisco Cannabis Cultivator's Club. Users, averaging 14 years pre-illness use, perceived marijuana to be more effective than other treatments and to have less severe side effects. Urine drug assays showed recent use of other drugs, particularly stimulants. History of substance abuse or dependence and other psychiatric disorders was common. Those with greater past dependence on other drugs thought marijuana to be more effective but also reported worse side effects and quality of life. Quality of life was associated more with marijuana side effects rating than effectiveness. Patients reported potentially serious marijuana side effects on some questionnaires but not others. Inconsistencies in reporting made interpretation of results difficult. Physician supervision of medical marijuana use would allow more effective monitoring of therapeutic and unwanted effects, some unrecognized by patients.

Adult↗
PubMed1999

Phenylarsine oxide blocks interleukin-1beta-induced activation of the nuclear transcription factor NF-kappaB, inhibits proliferation, and induces apoptosis of acute myelogenous leukemia cells.

Arsenic compounds have recently been shown to induce high rates of complete remission in patients with acute promyelocytic leukemia (APL). One of these compounds, As(2)O(3), induces apoptosis in APL cells via a mechanism independent of the retinoic acid pathway. To test the hypothesis that arsenic compounds may be effective against other forms of acute myelogenous leukemia (AML), we studied the membrane-permeable arsenic compound phenylarsine oxide (PAO). Because interleukin-1beta (IL-1beta) plays a key role in AML cell proliferation, we first tested the effect of PAO on OCIM2 and OCI/AML3 AML cell lines, both of which produce IL-1beta and proliferate in response to it. We found that PAO inhibited the proliferation of both OCIM2 and OCI/AML3 cells in a dose-dependent fashion (0.01 to 0.1 micromol/L) and that IL-1beta partially reversed this inhibitory effect. We then measured IL-1beta levels in these cells by using an enzyme-linked immunosorbent assay and Western immunoblotting and found that PAO almost completely abolished the production of IL-1beta in these AML cells, whereas it did not affect the production of IL-1 receptor antagonist. Because PAO inhibits activation of the transcription factor NF-kappaB and because NF-kappaB modulates an array of signals controlling cellular survival, proliferation, and cytokine production, we also studied the effect of PAO on NF-kappaB activation in AML cells and found that PAO suppressed the IL-1beta-induced activation of NF-kappaB. Because inhibition of NF-kappaB may result in cellular apoptosis, we also tested whether PAO may induce apoptotic cell death in AML cells. We found that PAO induced apoptosis in OCIM2 cells through activation of the cystein protease caspase 3 and subsequent cleavage of its substrate, the DNA repair enzyme poly (ADP-ribose) polymerase. The PAO-induced apoptosis was caspase dependent, because it was completely blocked by the caspase inhibitor Z-DEVD-FMK. Finally, we tested the effect of PAO on fresh AML marrow cells from 7 patients with newly diagnosed AML and found that PAO suppressed AML colony-forming cell proliferation in a dose-dependent fashion. Taken together, our data showing that PAO is an effective in vitro inhibitor of AML cells suggest that this compound may have a role in future therapies for AML.

Acute Disease↗
PubMed1999

The complete nucleotide sequence of chromosome 3 of Plasmodium falciparum.

Analysis of Plasmodium falciparum chromosome 3, and comparison with chromosome 2, highlights novel features of chromosome organization and gene structure. The sub-telomeric regions of chromosome 3 show a conserved order of features, including repetitive DNA sequences, members of multigene families involved in pathogenesis and antigenic variation, a number of conserved pseudogenes, and several genes of unknown function. A putative centromere has been identified that has a core region of about 2 kilobases with an extremely high (adenine + thymidine) composition and arrays of tandem repeats. We have predicted 215 protein-coding genes and two transfer RNA genes in the 1,060,106-base-pair chromosome sequence. The predicted protein-coding genes can be divided into three main classes: 52.6% are not spliced, 45.1% have a large exon with short additional 5' or 3' exons, and 2.3% have a multiple exon structure more typical of higher eukaryotes.

Animals↗
PubMed1999

P300 amplitude is related to clinical state in severely and moderately ill patients with schizophrenia.

BACKGROUND: Relationships between illness severity and neurobiologic abnormalities in schizophrenia were studied in subpopulations varying in clinical severity. METHODS: Auditory ERPs were collected from 28 severely ill, chronically hospitalized schizophrenic men from a state hospital; 29 moderately ill inpatient and outpatient schizophrenic men from a veterans hospital; and 30 healthy male subjects from the community as controls. Clinical symptoms were evaluated in patients using the Brief Psychiatric Rating Scale (BPRS). RESULTS: Both schizophrenic patient groups had smaller P300 amplitude than the control subjects. Severely ill patients had smaller P300s than moderately ill patients and scored higher on three BPRS factor scores as well as BPRS Total. Among severely ill patients, P300 amplitude was unrelated to clinical symptoms. Among moderately ill patients, P300 was related to Withdrawal/Retardation, Anxiety/Depression, and BPRS Total. After combining patients, Thinking Disturbance emerged as an additional correlate of P300. Group differences in P300 could not be accounted for by group differences in symptom severity using analysis of covariance. CONCLUSIONS: Reduced P300 amplitude marks the diagnosis of schizophrenia, but also reflects individual differences in severity, including positive symptoms. Previous failures to find relationships between positive symptoms and P300 may have been due to a restricted range of clinical severity.

Acute Disease↗
PubMed1999

The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1--a meta-analysis of 15 prospective cohort studies.

BACKGROUND: To evaluate the relation between elective cesarean section and vertical transmission of human immunodeficiency virus type 1 (HIV-1), we performed a meta-analysis using data on individual patients from 15 prospective cohort studies. METHODS: North American and European studies of at least 100 mother-child pairs were included in the meta-analysis. Uniform definitions of modes of delivery were used. Elective cesarean sections were defined as those performed before onset of labor and rupture of membranes. Multivariate logistic-regression analysis was used to adjust for other factors known to be associated with vertical transmission. RESULTS: The primary analysis included data on 8533 mother-child pairs. After adjustment for receipt of antiretroviral therapy, maternal stage of disease, and infant birth weight, the likelihood of vertical transmission of HIV-1 was decreased by approximately 50 percent with elective cesarean section, as compared with other modes of delivery (adjusted odds ratio, 0.43; 95 percent confidence interval, 0.33 to 0.56). The results were similar when the study population was limited to those with rupture of membranes shortly before delivery. The likelihood of transmission was reduced by approximately 87 percent with both elective cesarean section and receipt of antiretroviral therapy during the prenatal, intrapartum, and neonatal periods, as compared with other modes of delivery and the absence of therapy (adjusted odds ratio, 0.13; 95 percent confidence interval, 0.09 to 0.19). Among mother-child pairs receiving antiretroviral therapy during the prenatal, intrapartum, and neonatal periods, rates of vertical transmission were 2.0 percent among the 196 mothers who underwent elective cesarean section and 7.3 percent among the 1255 mothers with other modes of delivery. CONCLUSIONS: The results of this meta-analysis suggest that elective cesarean section reduces the risk of transmission of HIV-1 from mother to child independently of the effects of treatment with zidovudine.

Anti-HIV Agents↗