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D Young

Publications and source records attributed to D Young.

At least 145 records · Page 8Linked to original sources
PubMed1999

Correlation between IL-3 receptor expression and growth potential of human CD34+ hematopoietic cells from different tissues.

CD123 (alpha-subunit of IL-3 receptor) expression on primitive and committed human hematopoietic cells was studied by multicolor sorting and single-cell culture. The sources of cells included fetal liver (FLV), fetal bone marrow, umbilical cord blood, adult bone marrow and mobilized peripheral blood. Three subsets of CD34+ cells were defined by the levels of surface CD123: CD123negative, CD123low, and CD123bright. Coexpression of lineage markers showed that a majority of CD34+CD123bright cells were myeloid and B-lymphoid progenitors, while erythroid progenitors were mainly in the CD34+CD123negative subset. The CD34+CD123low subset contained a heterogeneous distribution of early and committed progenitor cells. Single CD34+ cells from the CD123 subsets were cultured in a cytokine cocktail of stem cell factor, interleukin 3 (IL-3), IL-6, GM-CSF, erythropoietin, insulin-like growth factor-1, and basic fibroblast growth factor. After 14 days of incubation, a higher cloning efficiency (CE) was observed in the CD34+CD123negative and CD34+CD123low fractions (37+/-23% and 44+/-23%, respectively) than in the CD34+CD123bright fraction (15+/-21%). Using previously published criteria that colonies containing dispersed, translucent cells (dispersed growth pattern, DGP) were derived from primitive cells and that colonies composed solely of clusters were from committed cells, early precursors were distributed evenly in the CD34+CD123negative and CD34+CD123low subsets. When CD38 and CD90 (Thy-1) were used for further characterization of CD34+ cells from FLV, CE increased from 37+/-23% in CD123negative to 70+/-19% in CD123negativeCD38- and from 44+/-23% in CD123low to 66+/-19% in CD123lowCD38-. No significant increase in CE or DGP progenitors was observed when CD34+ cells were sorted by CD90 and CD123. We concluded that: A) high levels of CD123 were expressed on B-lymphoid and myeloid progenitors; B) early erythroid progenitors had little or no surface CD123, and C) primitive hematopoietic cells are characterized by CD123negative/low expression.

ADP-ribosyl Cyclase↗
PubMed1999

The American brachytherapy society survey of brachytherapy practice for carcinoma of the cervix in the United States.

PURPOSE: The purpose of this study was to survey the brachytherapy practice for cervical cancer in the United States. METHODS: The Clinical Research Committee of the American Brachytherapy Society (ABS) performed a retrospective survey of individual physicians of the ABS and American Society of Therapeutic Radiologists and Oncologists regarding the details of the brachytherapy techniques they personally used in the treatment of cervical cancer patients for the year 1995. The replies (some of which may have been an estimate only) were tabulated. The scope of this survey did not allow us to verify the data by chart audits. RESULTS: A total of about 3500 questionnaires were mailed out; 521 responses were received. Of these responders, 206 (40%) did not perform any brachytherapy for carcinoma of the cervix in 1995. Of the other 315 responders reporting a total of 4892 patients treated in 1995, 88% used low dose rate (LDR) while 24% used high dose rate (HDR). There was a wide variation in the doses used. For LDR treatments, the median total external beam radiation therapy (EBRT) dose was 45 and 50 Gy and the LDR dose was 42 and 45 Gy for early and advanced cancers, respectively. For HDR treatments, the median EBRT dose was 48 and 50 Gy and the median HDR dose was 29 and 30 Gy for early and advanced cancers, respectively. The median dose per fraction was 6 Gy for a median of five fractions. Interstitial brachytherapy was used as a component of the treatment in 6% of the patients by 21% of responders. Very few responders treated with pulsed or medium dose rates. CONCLUSION: This retrospective survey showed the current brachytherapy practice pattern in the treatment of cervical cancer in the United States and can serve as a basis for future prospective national brachytherapy data registry. There was wide variation in the practice pattern, emphasizing the urgent need for consensus on these issues.

Brachytherapy↗
PubMed1999

Altered blood pressure course during normal pregnancy and increased preeclampsia at high altitude (3100 meters) in Colorado.

OBJECTIVE: Our purpose was to determine the case incidences of preeclampsia at low and high altitudes and whether maternal blood pressure course during pregnancy differs between low and high altitudes. STUDY DESIGN: This was a retrospective cohort study of pregnancies in sociodemographically matched communities at low and high altitudes in Colorado; each community had a small hospital served by family practitioners and was located >100 miles from major urban areas. Included were consecutive singleton pregnancies of women without chronic disease that resulted in live-born infants at >28 weeks' gestation during an 18-month period (n = 116 at 1260 m, n = 93 at 3100 m). Clinic and hospital medical records were searched and data pertaining to hypertensive complications of pregnancy and serial blood pressure measurements were abstracted. RESULTS: Despite similar maternal risk factors, the case incidences of preeclampsia were 16% at 3100 m and 3% at 1260 m. As in sea-level pregnancies, mean blood pressure fell until week 20 in normotensive pregnancy at 1260 m. Mean pressure rose linearly, however, in normotensive women at 3100 m and in women with preeclampsia at both 1260 m and 3100 m. High altitude acted independently of known risk factors and yielded an odds ratio for preeclampsia of 3.6 (95% confidence interval 1. 1-11.9). Birth weight was 285 g lower at 3100 m despite similar gestational ages. CONCLUSION: The normal pregnancy-associated fall in blood pressure was absent at 3100 m, even in women who remained normotensive. The incidence of preeclampsia was increased at high altitude. Residence at high altitude interferes with the normal vascular adjustments to pregnancy, increasing the incidence of preeclampsia, and is perhaps analogous to other conditions that decrease uteroplacental oxygen delivery.

Adolescent↗
PubMed1999

Neuronal death and survival in two models of hypoxic-ischemic brain damage.

Two unilateral hypoxic-ischemia (HI) models (moderate and severe) in immature rat brain have been used to investigate the role of various transcription factors and related proteins in delayed neuronal death and survival. The moderate HI model results in an apoptotic-like neuronal death in selectively vulnerable regions of the brain while the more severe HI injury consistently produces widespread necrosis resulting in infarction, with some necrosis resistant cell populations showing evidence of an apoptotic type death. In susceptible regions undergoing an apoptotic-like death there was not only a prolonged induction of the immediate early genes, c-jun, c-fos and nur77, but also of possible target genes amyloid precursor protein (APP751) and CPP32. In contrast, increased levels of BDNF, phosphorylated CREB and PGHS-2 were found in cells resistant to the moderate HI insult suggesting that these proteins either alone or in combination may be of importance in the process of neuroprotection. An additional feature of both the moderate and severe brain insults was the rapid activation and/or proliferation of glial cells (microglia and astrocytes) in and around the site of damage. The glial response following HI was associated with an upregulation of both the CCAAT-enhancer binding protein alpha (microglia only) and NFkappaB transcription factors.

Animals↗
PubMed1999

Mobilization of peripheral blood progenitor cells for human immunodeficiency virus-infected individuals.

Gene therapy is becoming one of the most promising modalities for the treatment of acquired immunodeficiency syndrome. The purpose of this study was to investigate the mobilization and collection of peripheral blood progenitor cells from human immunodeficiency virus (HIV)-infected individuals using granulocyte colony-stimulating factor (G-CSF). A total of 10 patients (9 male, 1 female; median age 36.5 years) with varying circulating CD4+ cell counts (13.9-1467/microL) were administered 10 microg/kg G-CSF daily for 6 days. Peripheral white blood cells (WBCs), CD34+ cell counts, lymphocyte subsets, and plasma viremia were monitored before each G-CSF injection. An average sixfold increase in WBCs was observed, which stabilized on day 4 or thereafter. The level of CD34+ cells was increased by 20-fold, and did not differ between days 5 and 6. Smaller increases in CD4+, CD8+, and CD4+CD8+ cells were observed. HIV viral load, as measured by RNA copy number in plasma, was not significantly altered by G-CSF administration. The leukapheresis product (LP), collected on day 7, contained an average of 6.25+/-4.52 (mean +/- standard deviation) x 10(10) WBCs and 3.08+/-2.98 x 10(6) CD34+ cells/kg. The levels of different CD34+ cell subsets were similar to those in the LPs of G-CSF-mobilized healthy individuals from an earlier study. Primitive hematopoietic cells (CD38- and CD38-HLA-DR+ cells) were detected in LPs (1.19+/-0.46% and 0.87+/-0.23%, respectively, of CD34+ cells). All parameters (WBC counts, lymphocyte populations, CD34+ cells, and HIV-1 RNA copies) measured 3 weeks after leukapheresis returned to baseline values. The administration of G-CSF was well tolerated by the HIV patients; side effects included bone pain, headache, flulike symptoms, and fatigue. There were no correlations between baseline CD4+ cell count and the WBCs, mononuclear cells, or CD34+ cells collected in the LP. Similarly, no correlation existed between baseline CD4+ and CD34+ cells, peak CD34+ cells, or days to achieve peak CD34+ cell counts after G-CSF mobilization. Our results showed that: (1) maximal mobilization can be achieved after 4 days of G-CSF administration; (2) therapeutic quantities of hematopoietic cells can be collected and used for gene therapy; and (3) G-CSF administration is well tolerated and does not cause a clinically significant increase in viremia.

Adult↗
PubMed1999

Biochemical and anatomical characterization of forepaw adjusting steps in rat models of Parkinson's disease: studies on medial forebrain bundle and striatal lesions.

Deficits in forepaw adjusting steps in rats have been proposed as a non-drug-induced model of the akinesia associated with Parkinson's disease. The present study examined the relationship between contralateral forepaw adjusting steps and dopamine depletion after medial forebrain bundle lesions with 6-hydroxydopamine. Depletion of striatal dopamine by >80% resulted in dramatic reductions in the ability of rats to make adjusting steps, but rats with < 80% dopamine depletion had no detectable deficit. The deficit in forepaw adjusting steps was evident by three days after lesions and did not recover for up to 13 weeks. Compared to apomorphine-induced rotation, the deficit in adjusting steps was evident at milder dopamine depletion. Discrete striatal lesions were also utilized to localize the striatal subregions that mediate forepaw adjusting steps. Forepaw adjusting steps were reduced after lesions of dorsolateral, ventrolateral or ventrocentral striatum, but not after lesions of dorsomedial, dorsocentral or ventromedial striatum. The reductions in adjusting steps after the discrete striatal lesions were not as severe as after medial forebrain bundle lesions. Furthermore, none of the discrete striatal lesions resulted in rotation after apomorphine administration, although a few resulted in increase in amphetamine-induced rotation. Administration of L-3,4-dihydroxyphenylalanine partially reversed the reductions of forepaw adjusting steps in both sets of lesion experiments. Together, these results suggest that forepaw adjusting step deficits in the rat provide a good model for the akinesia of Parkinson's disease both in medial forebrain bundle and striatal lesions, and would be a useful tool for investigating the efficacy of various therapeutic strategies.

Adaptation, Physiological↗
PubMed1999

Artificial neural networks applied to the in vitro-in vivo correlation of an extended-release formulation: initial trials and experience.

Artificial neural networks applied to in vitro-in vivo correlations (ANN-IVIVC) have the potential to be a reliable predictive tool that overcomes some of the difficulties associated with classical regression methods, principally, that of providing an a priori specification of the regression equation structure. A number of unique ANN configurations are presented, that have been evaluated for their ability to determine an IVIVC from different formulations of the same product. Configuration variables included a combination of architectural structures, learning algorithms, and input-output association structures. The initial training set consisted of two formulations and included the dissolution from each of the six cells in the dissolution bath as inputs, with associated outputs consisting of 1512 pharmacokinetic time points from nine patients enrolled in a crossover study. A third formulation IVIVC data set was used for predictive validation. Using these data, a total of 29 ANN configurations were evaluated. The ANN structures included the traditional feed forward, recurrent, jump connections, and general regression neural networks, with input-output association types consisting of the direct mapping of the dissolution profiles to the pharmacokinetic observations, mapping the individual dissolution points to the individual observations, and using a "memorative" input-output association. The ANNs were evaluated on the basis of their predictive performance, which was excellent for some of these ANN models. This work provides a basic foundation for ANN-IVIVC modeling and is the basis for continued modeling with other desirable inputs, such as formulation variables and subject demographics.

Computer Simulation↗
PubMed1999

Pharmacokinetics of aminolevulinic acid after intravesical administration to dogs.

PURPOSE: To examine the stability and systemic absorption of aminolevulinic acid (ALA) in dogs during intravesical administration. METHODS: Nine dogs received an intravesical dose of ALA either with no prior treatment, after receiving ammonium chloride for urinary acidification, or after receiving sodium bicarbonate for urinary alkalinization. Urine and blood samples collected during and after administration were monitored for ALA using an HPLC assay developed in our laboratories. Concentrations of pyrazine 2,5-dipropionic acid, the major ALA degradation product, and radiolabeled inulin, a nonabsorbable marker for urine volume, were also determined. RESULTS: Less than 0.6% of intravesical ALA doses was absorbed into plasma. Urine concentrations decreased to 37% of the initial concentration during the 2 hour instillation. Decreases in urinary ALA and radiolabeled inulin concentrations were significantly correlated, indicating that urine dilution accounted for over 80% of observed decreases in urinary ALA. ALA conversion to pyrazine 2,5-dipropionic acid was negligible. CONCLUSIONS: These studies demonstrate that ALA is stable and poorly absorbed into the systemic circulation during intravesical instillation. Future studies utilizing intravesical ALA for photodiagnosis of bladder cancer should include measures to restrict fluid intake as a means to limit dilution and maximize ALA concentrations during instillation.

Administration, Intravesical↗
PubMed1999

Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective.

The mammalian brain has a high degree of plasticity, with dentate granule cell neurogenesis and glial proliferation stimulated by an enriched environment combining both complex inanimate and social stimulation. Moreover, rodents exposed to an enriched environment both before and after a cerebral insult show improved cognitive performance. One of the most robust associations of environmental enrichment is improved learning and memory in the Morris water maze, a spatial task that mainly involves the hippocampus. Furthermore, clinical evidence showing an association between higher educational attainment and reduced risk of Alzheimer and Parkinson-related dementia indicates that a stimulating environment has positive effects on cerebral health that may provide some resilience to cerebral insults. Here we show that in addition to its effects on neurogenesis, an enriched environment reduces spontaneous apoptotic cell death in the rat hippocampus by 45%. Moreover, these environmental conditions protect against kainate-induced seizures and excitotoxic injury. The enriched environment induces expression of glial-derived neurotrophic factor and brain-derived neurotrophic factor and increases phosphorylation of the transcription factor cyclic-AMP response element binding protein, indicating that the influence of the environment on spontaneous apoptosis and cerebral resistance to insults may be mediated through transcription factor activation and induction of growth factor expression.

Animals↗
PubMed1999

Mobilization of blood-derived stem and progenitor cells in normal subjects by granulocyte-macrophage- and granulocyte-colony-stimulating factors.

BACKGROUND: It was previously reported that the combination of granulocyte-macrophage-colony-stimulating factor (GM-CSF) and granulocyte-CSF (G-CSF) for 4 days mobilized more primitive CD34+ subsets than did either G-CSF or GM-CSF alone. STUDY DESIGN AND METHODS: The studies determine the optimal number of days of growth factor dosing for mobilization and collection of peripheral blood progenitor cells, by increasing the days of administration of GM-CSF and/or G-CSF or employing the sequential administration of GM-CSF followed by G-CSF. Sixty normal subjects were given injections of G-CSF or GM-CSF alone; GM-CSF and G-CSF concurrently for 4, 5, or 6 days; or a sequential regimen of GM-CSF for 3 or 4 days followed by G-CSF for 2 or 3 days. A 10-L apheresis was performed 24 hours after the last dose. RESULTS: The three most efficacious mobilization regimens consisted of sequential GM-CSF for 3 days followed by G-CSF for either 2 or 3 days and G-CSF alone for 5 days. Each of these regimens resulted in the collection of significantly greater numbers of CD34+ cells by apheresis than any of the 4-day dosing regimens with G-CSF and/or GM-CSF (sequential GM-CSF/G-CSF: 3 days/2 days = 3.58 +/- 0.53 x 106 CD34+ cells/kg; GM-CSF/G-CSF: 3 days/3 days = 4.45 +/- 1.08 x 10(6) CD34+ cells/kg; G-CSF: 5 days = 3.58 +/- 0.97 x 10(6) CD34+ cells/kg; all p<0.05 vs. G-CSF and/or GM-CSF for 4 days). Clonogenic assays generally paralleled the level of CD34+ cells. Regimens containing GM-CSF resulted in a higher percentage of the cells from primitive CD34+/CD38-/HLA-DR+ subset than G-CSF alone. CONCLUSION: Compared with 4-day dosing regimens with G-CSF and/or GM-CSF, mobilization of CD34+ cells in normal subjects using sequential GM-CSF for 3 days followed by G-CSF for 2 or 3 days or using G-CSF alone for 5 days increased the number CD34+ cells that can be collected by a single 10-L apheresis 24 hours after the last dose of cytokine.

Antigens, CD34↗
PubMed1999

Genotypic analysis of Mycobacterium tuberculosis from medieval human remains.

Three medieval bone samples with osteological evidence of tuberculosis infection were analysed for the presence of DNA sequences from Mycobacterium tuberculosis using a series of PCRs. In each case amplification of IS6110 and part of the beta-subunit of RNA polymerase identified infection with a bacterium belonging to the M. tuberculosis complex. Amplification of the mtp40 genome fragment and the presence of a guanine residue at position 285 in the oxyR pseudogene, demonstrated the infecting strain to be similar to present day M. tuberculosis isolates rather than to Mycobacterium bovis. Spoligotyping, based on amplification of the direct repeat (DR) region of the mycobacterial genome, provided further evidence of similarity to M. tuberculosis and indicated a close relationship between isolates associated with two separate medieval burials. The study demonstrates the feasibility of amplifying multiple M. tuberculosis loci in ancient human remains and suggests important applications in the study of the palaeoepidemiology and virulence of tuberculosis in past populations.

Bacterial Typing Techniques↗
PubMed1999

Charge and length of hospital stay analysis of radical retropubic prostatectomy and transperineal prostate brachytherapy.

PURPOSE: For the treatment of clinically localized prostate cancer radical retropubic prostatectomy with its attendant hospital stay should be associated with higher charges than transperineal prostate brachytherapy. We report a comparative case series to determine patient charges and length of hospitalization of 2 modalities of monotherapy for localized prostate cancer. MATERIALS AND METHODS: A total of 35 consecutive patients with clinically localized prostate cancer underwent radical retropubic prostatectomy (16) or transperineal prostate brachytherapy (19) at the Arthur James Cancer Hospital and Research Institute. Complete charge and length of hospital stay data were collected for each patient. Total charges were calculated and the 2 modalities were compared. RESULTS: Charge data were available in 33 cases. Average total charges in the prostatectomy and brachytherapy groups were $15,097 and $21,025, respectively ($5,928 difference, p <0.0001). The difference increased further when outliers were excluded from study. Average length of hospital stay and average charge in the prostatectomy group were 3.8 days and $1,897. The higher charges for transperineal prostatic brachytherapy were due to dosimetry calculations, radioactive seeds and seed implantation. CONCLUSIONS: At our institution the average total charges for transperineal prostate brachytherapy are significantly higher than those for radical retropubic prostatectomy.

Brachytherapy↗
PubMed1999

General practice integration in Australia. Primary health services provider and consumer perceptions of barriers and solutions.

OBJECTIVE: To identify practical examples of barriers and possible solutions to improve general practice integration with other health service providers. METHOD: Twelve focus groups, including one conducted by teleconference, were held across Australia with GPs and non GP primary health service providers between May and September, 1996. Focus groups were embedded within concept mapping sessions, which were used to conceptually explore the meaning of integration in general practice. Data coding, organising and analysis were based on the techniques documented by Huberman and Miles. RESULTS: Barriers to integration were perceived to be principally due to the role and territory disputes between the different levels of government and their services, the manner in which the GP's role is currently defined, and the system of GP remuneration. Suggestions on ways to improve integration involved two types of strategies. The first involves initiatives implemented 'top down' through major government reform to service structures, including the expansion of the role of divisions of general practice, and structural changes to the GP remuneration systems. The second type of strategy suggested involves initiatives implemented from the 'bottom up' involving services such as hospitals (e.g. additional GP liaison positions) and the use of information technology to link services and share appropriate patient data. CONCLUSION: The findings support the need for further research and evaluation of initiatives aimed at achieving general practice integration at a systems level. There is little evidence to suggest which types of initiatives improve integration. However, general practice has been placed in the centre of the health care debate and is likely to remain central to the success of such initiatives. Clarification of the future role and authority of general practice will therefore be required if such integrative strategies are to be successful at a wider health system level.

Australia↗
PubMed1999

Increased leucine turnover and insulin resistance in men with advanced HIV infection.

BACKGROUND: The purpose of this study was to determine if patients with advanced HIV infection exhibit increased rates of leucine turnover and to determine dose effects of insulin on suppression of leucine turnover. We also wished to evaluate hepatic glucose production and re-examine peripheral insulin sensitivity in HIV infected adults. METHODS: Results from 9 males with advanced HIV disease (96-121% ideal body weight, NW-AIDS) and 3 males (80-88% ideal body weight, UW-AIDS) were compared to age and weight matched normal volunteers (NW-C and UW-C). Each subject underwent basal leucine turnover studies followed by insulin dose response studies using a step-up hyperinsulinemic euglycemic clamp (insulin dose: 10, 20 and 120 mU/m2/min) and the stable isotope [1-13C]leucine. Hepatic glucose production was measured using the stable isotope d-6,6(2)H2-glucose. Resting energy expenditure (REE) was measured by indirect calorimetry and a 24-hour food recall was obtained. Viral load, Karnofsky score, and CD4 counts were measured in AIDS subjects. RESULTS: All subjects with AIDS had higher rates of leucine appearance (leucine Ra) than controls. Although both AIDS and Controls demonstrated suppression of leucine Ra with insulin, suppression was less in AIDS subjects. There was a strong relationship between leucine Ra and viral load (r = 0.87, P = 0.02). The AIDS subjects exhibited peripheral insulin resistance when compared to controls. CONCLUSIONS: Our results suggest that patients with HIV have both peripheral insulin resistance and resistance to the anticatabolic effects of insulin.

Adult↗
PubMed1999

The concept mapping method. An alternative to focus group inquiry in general practice.

BACKGROUND: The concept mapping rationale and process are explained step by step. The concept mapping method produces a two dimensional conceptual map of ideas produced by the group which can be analysed at the level of individual statements, clusters of statements, and groups of similar clusters. An example of concept mapping conducted with four general practitioner (GP) groups from different practice types and demographic locations is provided. A total of 51 participating GPs were asked to complete an 'evaluation questionnaire' at the end of each group session. The majority of GP participants (68%) rated the method as highly useful. OBJECTIVE: To describe the concept mapping method and its interpretation for use in general practice research. To report on its perceived usefulness and acceptability by general practitioners. DISCUSSION: Concept mapping is a very useful method combining benefits from qualitative and quantitative approaches for exploring the breadth of a topic in its entirety, especially for abstract concepts. GPs found the concept mapping method to be efficient for group inquiry, rating it high on utility. There is scope to refine the method, reducing time spent in some stages of the session, and substituting more time on final analysis.

Australia↗