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Biomedical subjects

J Harrington

Publications and source records attributed to J Harrington.

At least 19 recordsLinked to original sources
PubMed2006

Ex vivo expansion of mafosfamide-purged PBPC products.

BACKGROUND: Multiple studies have demonstrated that 'purging' of autografts with 4-hydroperoxycyclophosphamide (4HC) or the related compound mafosfamide (Mf), to eradicate residual leukemia, produces the best results associated with autologous blood and marrow transplantation for AML. However, 4HC purging results in prolonged aplasia. Therefore, we evaluated the potential of ex vivo expansion of Mf-treated CD34+ cells from mobilized PBPC. METHODS: CD34+ cells were isolated from PBPC products and treated with 30 microg/mL Mf. The Mf-treated CD34+ cells were washed and cultured for 14 days in StemLine II-defined media containing recombinant human (rh) SCF, G-CSF and thrombopoietin (Tpo). RESULTS: Treatment with Mf resulted in 90% killing of progenitor cells (GM-CFC) but maintenance of SCID-repopulating cells (SRC). Ex vivo culture of the Mf-treated CD34+ cells resulted in decreased cell numbers (10-20% of the starting cell dose) during the first week. Nevertheless, in the second week of culture the total cell numbers expanded to approximately 20-fold above starting cell numbers and progenitor cells returned to approximately pre-treatment levels. DISCUSSION: These studies demonstrate the potential of ex vivo culture to expand both total cell numbers and progenitor cells following treatment of PBPC CD34+ cells with Mf. Clinical studies are currently being initiated to evaluate the engraftment potential of these purged and expanded products.

Adjuvants, Immunologic↗
PubMed2005

Outgrowth of a transformed cell population derived from normal human BM mesenchymal stem cell culture.

BACKGROUND: Human mesenchymal stem cells (hMSC) have been isolated and characterized extensively for a variety of clinical applications. Yet it is unclear how the phenomenon of hMSC plasticity can be safely and reasonably exploited for therapeutic use. METHODS: We have generated mesenchymal stem cells (MSC) from normal human BM and identified a novel cell population with a transformed phenotype. This cell population was characterized by morphologic, immunophenotypic, cytogenetic analyzes and telomerase expression. Its tumorigenicity in NOD/SCID mice was also studied. RESULTS: A subpopulation of cells in hMSC culture was noted to appear morphologically distinct from typical MSC. The cells were spherical, cuboidal to short spindle in shape, adherent and exhibited contact independent growth. Phenotypically the cells were CD133(+), CD34(-), CD45(-), CD90(low), CD105(-), VEGFR2(+). Cytogenetic analysis showed chromosome aneuploidy and translocations. These cells also showed a high level of telemerase activity compared with typical MSC. Upon transplantation into NOD/SCID mice, multiple macroscopic solid tumors formed in multiple organs or tissues. Histologically, these tumors were very poorly differentiated and showed aggressive growth with large areas of necrosis. DISCUSSION: The possible explanations for the origin of this cell population are: (1) the cells represent a transformed population of MSC that developed in culture; (2) abnormal cells existed in the donor BM at rare frequency and subsequently expanded in culture. In either case, the MSC culture may provide a suitable environment for transformed cells to expand or propagate in vitro. In summary, our data demonstrate the potential of transformed cells in hMSC culture and highlight the need for karyotyping as a release criteria for clinical use of MSC.

AC133 Antigen↗
PubMed2005

Development of homogeneous high-affinity agonist binding assays for 5-HT2 receptor subtypes.

The serotonin (5-hydroxytryptamine) 5-HT2 receptor subfamily consists of three members, 5-HT2A, 5-HT2B, and 5-HT2C. These receptors share high homology in their amino acid sequence, have similar signaling pathways, and have been indicated to play important roles in feeding, anxiety, aggression, sexual behavior, mood, and pain. Subtype-selective agonists and antagonists have been explored as drugs for hypertension, Parkinson's disease, sleep disorders, anxiety, depression, schizophrenia, and obesity. In this study, we report the development of homogeneous agonist binding assays in a scintillation proximity assay (SPA) format to determine the high-affinity binding state of agonist compounds for the human 5-HT2C, 5-HT2A, and 5-HT2B receptors. The 5-HT2 agonist 1-(4- [125I]iodo-2,5-dimethoxyphenyl)-2-aminopropane ([125I]DOI) was used to label the high-affinity sites for the 5-HT2A and 5-HT2C receptors. The high-affinity sites for the 5-HT2B receptor were labeled with [3H]lysergic acid diethylamide. Total receptor expression was determined with the 5-HT2 antagonist [3H]mesulergine for the 5-HT2B and 5-HT2C receptors, and [3H]ketanserin for the 5-HT2A receptor. The agonist high-affinity binding sites accounted for 2.3% (5-HT(2C) receptor), 4.0% (5-HT2A receptor), and 22% (5-HT2B receptor) of the total receptor population. Competition binding studies using known agonists indicated high Z' values of the agonist binding assays in SPA format (Z' > 0.70). The Ki values of 5-HT, (R)(-)DOI, and VER-3323 for the 5-HT2A, 5-HT2B, and 5-HT2C receptors by SPA format were equivalent to published data determined by filtration binding assays. These results indicate that agonist binding assays in SPA format can be easily adapted to a high throughput assay to screen for selective 5-HT2C receptor agonists, as well as for selectivity profiling of the compounds.

Amphetamines↗
PubMed2004

Ex vivo expansion of cord blood mononuclear cells on mesenchymal stem cells.

BACKGROUND: Cord blood (CB) cells are being used increasingly as a source of hematopoietic cells to support high dose chemotherapy. However, CB units contain low numbers of cells, including CD34+ cells, and thus their use is associated with significant delays in engraftment of neutrophils and platelets. Exvivo expansion of CB has been proposed to increase the numbers of cells available. We and others have reported the requirement of CD34 selection for optimal expansion of CB products'; however, the selection of frozen CB products in clinical trials results in significant loss of CD34+ cells, with a median recovery of 50, but less than 40% recovery in more than one-third of products. In the present studies we evaluated the potential of mesenchymal stem cells (MSC) to support ex vivo expansion of unselected CB products. METHODS: Mononuclear cells (MNC) from CB products were isolated and cultured on preformed MSC layers in T150 flasks containing 50 mL Stemline II media plus hematopoietic growth factors. Various culture conditions were compared for optimal expansion of the CB MNC. RESULTS: Ex vivo expansion of CB MNC on MSC resulted in 10- to 20-fold expansion of total nucleated cells, seven- to 18-fold expansion of committed progenitor cells, two- to five-fold expansion of primitive progenitor cells and 16- to 37-fold expansion of CD34+ cells. DISCUSSION: These studies demonstrated significant expansion of CB products without CD34 cell selection using culture conditions that are clinically applicable. Our current focus is to initiate clinical trials to evaluate the in vivo potential of CB cells expanded with these conditions.

Antigens, CD34↗
PubMed2004

How great is the risk of abuse in infants born to drug-using mothers?

UNLABELLED: This prospective, cohort study reports early child protection and surveillance process markers for children born to self-proclaimed drug-using mothers. BACKGROUND: A strong association is reported between maternal drug use and child abuse in North American studies. There are no systematic data describing this association for the UK population. Given the heterogeneous nature of drug cultures and associated behaviour it is difficult to generalize from US data to the UK population. METHODS: The study group consisted of all women referred to a hospital-based antenatal clinic for pregnant drug users. Infants of non-drug users were matched for social class and gestational age. At 18 months the Bristol and surrounding area child protection registers and child health surveillance records were searched. Infants were coded as to whether they were the subject of an enquiry, case conference, registration, registration with subsequent deregistration, or taken into care. RESULTS: There were 68 infants of drug users and 127 infants of non-drug users. Most (81%) of drug users were heroin and/or methadone users; half were using/had used intravenously. Child health surveillance uptake for both groups is lower than that reported for the Avon population as a whole during the study period, consistent with the relatively deprived populations represented. There is no statistically significant difference between the drug users and non-drug users. The overall risk of child protection proceedings was higher in children of drug users than in children of non-drug users. However, closer inspection of the data shows most of the excess risk is explained by the small group taken into care and the much larger group for whom the concerns were relatively shortlived as shown by their subsequent deregistration during the study period. CONCLUSIONS: Maternal drug use does not necessarily lead to unacceptable standards of parenting. More UK-based research is needed to inform the risk assessment process for child protection.

Child Abuse↗
PubMed2003

Social diversity of Irish adults nutritional intake.

OBJECTIVE: The first health and lifestyle survey of Irish adults was carried out in 1998 and aimed to describe the health-related lifestyle behaviours of a cross-section of various population strata residing in the Republic of Ireland. This paper reports on the social variation in nutrient intake. DESIGN: A self-administered postal questionnaire, including a 149 food item semiquantitative food frequency section, from which nutrient intakes were estimated based on McCance and Widdowson food composition tables. SETTING: Community-based adults aged 18 years and over residing in the Republic of Ireland on the Register of Electors. SUBJECTS: A stratified sample of adults on the Register of Electors received the questionnaire, of which 6539 (62%) were returned. RESULTS: The contribution of fat to total energy intake increased with decreasing socioeconomic grouping, a finding reflective of the higher consumption levels of foods high in fat by respondents from socially disadvantaged groups. Energy from carbohydrates was greatest among those from socially advantaged groups, and was close to the recommended 50% of the total energy intake. Conversely, energy from protein decreased with increasing social status group. The mean intake of vitamins and minerals was generally close to or above the recommended values. Significant variation was observed among females across the different levels of education, whereas living with someone appeared to influence the micronutrient intake of males. The reported diets of males and females over the age of 65 years were lacking in vitamin D. Mean calcium levels among males were borderline and females over the age of 65 years had mean dietary iron levels below the recommended intake. CONCLUSIONS: For the first time, quantification of nutrient intake in the different social groups in Ireland has been undertaken. A healthy balance of energy derived from fat, protein and carbohydrate is best achieved among respondents from higher social positions. The positive relation observed with healthy food intake and increasing education level was also present in macronutrient intake and a clear gender and social support interplay was seen in the nutrient intake levels.

Adolescent↗
PubMed2002

Effects of age, size and condition of elephant seals (Mirounga leonina) on their intravenous anaesthesia with tiletamine and zolazepam.

Southern elephant seals (Mirounga leonina) were caught as part of a long-term demographic study on Macquarie Island. Over 18 months, 1033 seals were caught by hand and anaesthetised intravenously with a 1:1 mixture of tiletamine and zolazepam. Assessments were made of the effects of variations in the body condition and age at capture of the seals on the characteristics of their anaesthesia, including induction time and weighted recovery time. The size and condition of the seals were assessed by morphometric and ultrasound measurements. Weighted recovery times decreased as the body condition and age of the seals increased, but there were no residual effects of sex. There were no fatalities, and no periods of apnoea longer than five minutes were recorded. In individual seals there was a significant increase in weighted recovery time with successive captures.

Age Factors↗
PubMed2001

The relation between vertebral endplate shape and lumbar disc herniations.

STUDY DESIGN: Blinded review of selected and un-selected computed tomographic myelograms. OBJECTIVE: To determine whether shape of the vertebral body endplate margins is a risk factor for the development of symptomatic lumbar disc herniations. The law of LaPlace for a fluid-filled tube suggests that anular tension could be related to endplate shape and a propensity for disc herniation. SUMMARY OF BACKGROUND DATA: It was hypothesized that the law of Laplace could apply to the lumbar spine because of to the cylindrical shape of the lumbar disc and its high water content in nonelderly individuals. It was further hypothesized that differences in the radius of the curvature could place stresses on the anulus that would make posterior disc herniations more likely with "rounder" endplates. METHODS: Ninety-seven contrast computed tomography scans were reviewed at transitional L4-L5 and L5-S1 in patients under 60 years of age, without previous spine surgery and without spondylolisthesis. Determinations of disc herniations and measurements of endplates were performed by blinded observers. A ratio of these measurements was used to determine the relative circularity of the endplate. Height, weight, body mass index, and disc endplate size and shape were related to the presence of disc herniation. RESULTS: By multiple logistic regression, only endplate shape was strongly related to disc herniations. Endplate area was a less significant factor in men. CONCLUSIONS: The shape of the vertebral body margin at the endplate is an important factor contributing to the development of disc herniations at L4-L5 and L5-S1.

Female↗
PubMed2000

Reading aloud begins when the computation of phonology is complete.

Naming latency experiments in which monosyllabic items are read aloud are based on the assumption that the vocal response is not initiated until the phonology of the entire syllable has been computed. Recently, this assumption has been challenged by A. H. Kawamoto, C. T. Kello, R. Jones, and K. Bame (1998), who argued instead that the reading-aloud response begins as soon as the initial phoneme is computed. This view would be refuted by evidence of anticipatory coarticulation effects on the initial phoneme due to the nature of the following vowel in the speeded reading-aloud task. The authors provide such evidence.

Humans↗
PubMed2000

A pilot study of the relationship between problem-solving skills and outcome in major depressive disorder.

Three methods of assessing problem-solving skills are described in the literature: questionnaires, self-report inventories and verbal assessment of the resolution of problem scenarios. These three approaches were used to assess problem-solving ability in a sample of 20 patients with unipolar major depressive disorder, who were treated with antidepressant medication alone at a hospital out-patient clinic. It was found that baseline deficits in problem-solving skills were significantly associated with prognosis at 3- and 6-month follow-up. Self-ratings of perceived self-control and confidence rather than subjective problem-solving effectiveness were important predictors of final outcome. Differences in perceived and actual problem-solving ability emerged over time. The reasons for these differences in subjective and observer assessments are unclear. The data appear to demonstrate that problem-solving deficits in depression represent both state and trait phenomena.

Adolescent↗
PubMed1999

Acoustic evidence for dynamic formant trajectories in Australian English vowels.

The extent to which it is necessary to model the dynamic behavior of vowel formants to enable vowel separation has been the subject of debate in recent years. To investigate this issue, a study has been made on the vowels of 132 Australian English speakers (male and female). The degree of vowel separation from the formant values at the target was contrasted to that from modeling the formant contour with discrete cosine transform coefficients. The findings are that, although it is necessary to model the formant contour to separate out the diphthongs, the formant values at the target, plus vowel duration are sufficient to separate out the monophthongs. However, further analysis revealed that there are formant contour differences which benefit the within-class separation of the tense/lax monophthong pairs.

Adult↗
PubMed1998

Management of acquired rectourinary fistulas: outcome according to cause.

PURPOSE: Acquired rectourinary fistulas, an infrequent complication of pelvic conditions, remain a therapeutic problem for which neither a widely accepted classification nor long-term outcome data are available. This study was designed to provide a new etiologic classification system and examine the success of various surgical therapies. It also looked at the need for permanent fecal or urinary diversion or radical excision depending on the cause of the fistula, i.e., benign vs. malignancy-related. METHODS: A retrospective analysis was made of 41 patients treated for acquired rectourinary fistulas between 1980 and 1995. Acquired rectourinary fistulas were classified as 1) benign but caused by Crohn's disease, trauma, perirectal sepsis, or iatrogenic injury; and 2) malignancy-related fistulas secondary to neoplasm, radiation, surgery, or combined tumor and treatment effects. Surgical interventions were classified as repair, excision, fecal diversion, and urinary diversion. RESULTS: Thirty-seven males and 4 females with acquired rectourinary fistula were identified with a mean age of 62 (range, 28-90) years. Nineteen patients had fistulas involving their urethras, and 22 patients had fistulas involving the bladder. Eight patients were not treated surgically; one was not treated because of an advanced malignancy, three because of patient preference, three because of sepsis, and one because of a poor general condition. Of the remaining 33 patients, nine had benign fistulas of which two were the result of Crohn's disease, two were the result of trauma, two were from an iatrogenic response, and three were from perirectal sepsis. Twenty-four patients had malignancy-related fistulas, and five patients had neoplasm at their fistula sites. The remaining 19 patients had malignancy-related fistulas that were the result of cancer treatments. Of the 19 malignancy-related fistulas, 5 were from radiation, 9 were from surgical trauma, and 5 were from radiation and surgical trauma. Forty-nine percent of the patients had undergone attempts at fistula treatment before referral. A resolution of symptoms after initial and reoperative surgery occurred more often in patients with benign fistulas (44 and 100 percent; mean, 1.8 surgeries per patient) compared with malignancy-related fistulas (21 and 88 percent; mean, 2.1 surgeries per patient). The rates of permanent fecal, urinary, and fecal plus urinary diversion were also lower for benign fistulas (11, 0, and 33 percent) compared with malignancy-related fistulas (13, 8, and 54 percent). Permanent diversion was avoided in 56 percent of the benign fistulas but in only 25 percent of the malignancy-related fistulas. The rates of excisional and radical (ileal conduit) surgery were lower for benign fistulas than for malignancy-related fistulas (44 and 11 percent vs. 50 and 54 percent). CONCLUSION: Successful management of rectourinary fistulas typically requires aggressive reoperative therapy with permanent diversion more often required for malignancy-related fistulas. Better outcomes can be anticipated for benign fistulas.

Adult↗
PubMed1998

The Andover Working Group--accelerating the implementation of standards.

The Andover Working Group was formed with the objective to accelerate and broadly deliver standards-based solutions for healthcare which feature plug and play interoperability across the continuum of care. In this paper, organization and processes used by the Andover Working Group are discussed. A description of how multilateral message profiles, combined with object-oriented component middleware supporting application developments, systems integration and systems operation remove many of the barriers to deployment of systems of standards based applications is also given.

Diffusion of Innovation↗
PubMed1997

Significance of individual point mutations, T202C and C314T, in the human Lewis (FUT3) gene for expression of Lewis antigens by the human alpha(1,3/1,4)-fucosyltransferase, Fuc-TIII.

The Lewis alpha(1,3/1,4)-fucosyltransferase, Fuc-TIII, encoded by the FUT3 gene is responsible for the final synthesis of Lea and Leb antigens. Various point mutations have been described explaining the Lewis negative phenotype, Le(a-b-), on erythrocytes and secretions. Two of these, T202C and C314T originally described in a Swedish population, have not been found as single isolated point mutations so far. To define the relative contribution of each of these two mutations to the Lewis negative phenotype, we cloned and made chimeric FUT3 constructs separating the T202C mutation responsible for the amino acid change Trp68 --> Arg, from the C314T mutation leading to the Thr105 --> Met shift. COS-7 cells were transfected and the expression of Fuc-TIII enzyme activity and the presence of Lewis antigens were determined. There was no decrease in enzyme activity nor of immunofluorescence staining on cells transfected with the construct containing the isolated C314T mutation compared with cells transfected with a wild type FUT3 allele control. No enzyme activity nor immunoreactivity for Lewis antigens was detected in FUT3 constructs containing both mutations in combination. The T202C mutation alone decreased the enzyme activity to less than 1% of the activity of the wild type FUT3 allele. These results demonstrate, that the Trp68 --> Arg substitution in human Fuc-TIII is the capital amino acid change responsible for the appearance of the Le(a-b-) phenotype on human erythrocytes in individuals homozygous for both the T202C and C314T mutations.

Alleles↗
PubMed1997

Individual risk factors for early repetition of deliberate self-harm.

This study investigated individual factors associated with repetition of deliberate self-harm (DSH) within three months of a first-ever episode. Individuals from an 'at risk' population who repeated DSH (N = 25) were compared with a socio-demographically matched group of 'at risk' individuals who did not engage in a further episode of DSH (N = 18). In comparison with the 'single DSH' individuals, those in the 'repeated DSH' group demonstrated significantly higher levels of depression and hopelessness, were significantly less skilled at problem solving, were significantly less likely to report the availability of a confidante and significantly more likely to identify that the reason for their DSH was to communicate their desperation. The implications of these findings for risk assessment and interventions are noted.

Adaptation, Psychological↗