Search PubMed⌕ Search

Biomedical subjects

C Harrison

Publications and source records attributed to C Harrison.

At least 19 recordsLinked to original sources
PubMed2003

Studies of micro-, kappa-, and delta-opioid receptor density and G protein activation in the cortex and thalamus of monkeys.

The aim of this study was to investigate the relative density of micro -, kappa-, and delta-opioid receptors (MOR, KOR, and DOR) and guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding stimulated by full agonists in cortical and thalamic membranes of monkeys. The binding parameters [Bmax (femtomoles per milligram)/Kd (nanomolar)] were as follows: [3H][d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) (MOR; 80/0.7), [3H]U69593 [(5alpha,7alpha,8beta)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl) benzeneacetamide] (KOR; 116/1.3), and [3H][d-Pen2,d-Pen5]-enkephalin (DPDPE) (DOR; 87/1.3) in the cortex; [3H]DAMGO (147/0.9), [3H]U69593 (75/2.5), and [3H]DPDPE (22/2.0) in the thalamus. The relative proportions of MOR, KOR, and DOR in the cortex were 28, 41, and 31% and in the thalamus were 60, 31, and 9%. Full selective opioid agonists, DAMGO (EC50 = 532-565 nM) and U69593 (EC50 = 80-109 nM) stimulated [35S]GTPgammaS binding in membranes of cortex and thalamus, whereas SNC80 [(+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethyl-benzamide] (DOR; EC50 = 68 nM) was only active in cortical membranes. The magnitudes of [35S]GTPgammaS binding stimulated by these agonists were similar in the cortex, ranging from 17 to 25% over basal binding. In the thalamus, DAMGO and U69593 increased [35S]GTPgammaS binding by 44 and 23% over basal, respectively. Opioid agonist-stimulated [35S]GTPgammaS binding was blocked selectively by antagonists for MOR, KOR, and DOR. The amount of G protein activated by agonists was highly proportional to the relative receptor densities in both regions. These results distinguish the ability of opioid agonists to activate G proteins and provide a functional correlate of ligand-binding experiments in the monkey brain. In particular, the relative densities of opioid receptor binding sites in the two brain areas reflect their functional roles in the pharmacological actions of opioids in the central nervous system of primates.

Animals↗
PubMed2003

Early optical emission from the gamma-ray burst of 4 October 2002.

Observations of the long-lived emission--or 'afterglow'--of long-duration gamma-ray bursts place them at cosmological distances, but the origin of these energetic explosions remains a mystery. Observations of optical emission contemporaneous with the burst of gamma-rays should provide insight into the details of the explosion, as well as into the structure of the surrounding environment. One bright optical flash was detected during a burst, but other efforts have produced negative results. Here we report the discovery of the optical counterpart of GRB021004 only 193 seconds after the event. The initial decline is unexpectedly slow and requires varying energy content in the gamma-ray burst blastwave over the course of the first hour. Further analysis of the X-ray and optical afterglow suggests additional energy variations over the first few days.

Journal Article↗
PubMed2002

Hermansky-Pudlak syndrome: infrequent bleeding and first report of Turkish and Pakistani kindreds.

Hermansky-Pudlak syndrome (HPS) is a rare disorder characterised by oculocutaneous albinism, a bleeding tendency, and lipofuscinosis. This retrospective study reviews the clinical history and haematological features of 23 cases of HPS. Information was gathered from patient notes and by direct interview. Thirteen of the 23 children were of Turkish origin, 12 being members of four kindreds from the Turkish/Kurdish border. Four children originated from Pakistan. Haemorrhage was uncommon; two experienced significant bleeding (intracranial and retinal haemorrhage in one and menorrhagia in another), and twelve minor symptoms. Results of laboratory evaluation of platelet function were not predictive of bleeding; in particular the PFA-100 analyser was not sensitive to the HPS defect. The most sensitive test of platelet fuction was quantitation of platelet nucleotides. The occurrence of Turkish and Pakistani kindreds with HPS is novel and follow up for long term complications described in Puerto Rican patients as well as genetic analysis is ongoing.

Bleeding Time↗
PubMed2002

Health-related quality of life before and after solid organ transplantation. Measurement consideration, reported outcomes, and future directions.

The initial focus in organ transplantation clinical research was demonstrating acceptable technical and survival outcomes. Both patient and graft survival have reached well-documented, laudable levels, and solid organ (liver, heart, kidney, lung) transplantation procedures are now relatively common. As with any complex medical procedure that entails relatively high risk, financial costs, and life-long follow-up care, reliable and valid assessments of the "quality" of the extended life years are of interest to patients, their families, policy makers, and payers. This review focuses on health-related quality of life (HRQOL) and functional performance in adults following solid organ transplantation, with an emphasis on: 1) instruments and methods; 2) outcomes in liver, heart, kidney, and lung transplant recipients; and 3) future research directions. Practical considerations for developing longitudinal HRQOL assessment strategies are reviewed. The current emphasis on modeling demographic and clinical factors that promote or limit optimal HRQOL is illustrated. These lines of research will help identify potential interventions designed to promote better HRQOL in organ transplant recipients.

Health Status↗
PubMed2001

The structure of anti-Gal immunoglobulin genes in naïve and stimulated Gal knockout mice.

BACKGROUND: Naturally occurring antibodies (Nabs) that bind to terminal galactose alpha1,3-galactose carbohydrate structures (Gal) are present in humans and Old World monkeys but are negatively regulated in other mammalian species because they express Gal epitopes on their cell surfaces. A Gal knockout mouse (Gal-/-) model, generated by homologous disruption of alpha1,3-galactosyltransferase gene, is capable of producing natural anti-Gal Abs. METHODS: To study the genetic control of the anti-Gal response, we have generated anti-Gal hybridomas from Gal-/- mice and analyzed VH genes of anti-Gal Abs from naïve animals and from mice stimulated by rat heterotopic heart transplantation. RESULTS: Six immunoglobulin (Ig)M anti-Gal hybridomas derived from naïve Gal-/- mice exhibited anti-Gal binding activity with some cross-reactivity to related carbohydrate structures. These naïve anti-Gal Abs used five different VH genes in a germline configuration. Anti-Gal IgM hybridomas isolated after a rat heterotopic heart xenograft (4 days) utilized germline VH gene segments from the VH7183 family and exhibited less cross-reactivity. In contrast to mice 4 days after xenograft, we have predominantly isolated IgG anti-Gal hybridomas from mice 21 days after rat heterotopic heart xenografts, indicating an isotype switch. Nine of the IgG anti-Gal hybridomas secreted IgG3 subclass and one produced IgG1. Sequence analysis of the VH gene usage from the induced anti-Gal IgG antibodies demonstrated a restricted gene utilization (VHJ606-V14A). CONCLUSION: Our results demonstrate that the anti-Gal response in naïve Gal-/- mice is encoded by multiple germline progenitors. In response to a xenograft, the induced anti-Gal Abs exhibited a restricted gene usage and somatic mutations, indicating a positive selection.

Animals↗
PubMed2001

Temperature-dependent activation of recombinant rat vanilloid VR1 receptors expressed in HEK293 cells by capsaicin and anandamide.

Capsaicin activates vanilloid (VR1) receptors found on sensory neurons. These ligand-gated ion channels are also sensitive to low pH, elevated temperature and the endocannabinoid, anandamide. In this study, we have measured capsaicin- and anandamide-induced elevations in intracellular calcium concentrations ([Ca(2+)](i)) in fura-2 loaded HEK293 cells stably expressing the rat VR1 receptor at 22, 37 and 50 degrees C. Both capsaicin and anandamide produced a concentration-dependent elevation in [Ca(2+)](i) at all temperatures. pEC(50) values were 7.74 and 5.69 at 22 degrees C and 6.90 and 5.15 at 37 degrees C for capsaicin and anandamide, respectively. At 50 degrees C, the pEC(50) value for capsaicin was 6.36 but the response to anandamide did not saturate. Responses to both agonists were sensitive to ruthenium red and capsazepine at all temperatures. This temperature-dependent reduction in potency may result from desensitization.

Animals↗
PubMed2001

Characterisation and comparison of novel ligands for the nociceptin/orphanin FQ receptor.

Studies of nociceptin/orphanin FQ (NC) have been hampered by the paucity of available ligands with activity at the nociceptin receptor (NCR). In this study we have compared the agonist profile of NC and a novel NCR agonist, Ro65-6570, in a series of radioligand binding studies and effects on forskolin-stimulated cAMP formation in Chinese hamster ovary (CHO) cells expressing the recombinant human NCR (CHOhNCR). In addition, we report the effects of three antagonists, [Nphe1]NC(1-13)NH2, J-113397 and III-BTD, on these responses. In radioligand binding studies Ro65-6570, [Nphe1]NC(1-13)NH2, J-113397 and III-BTD displaced [3H]NC with similar pKi values (8.4-8.8). This compares with a pK(D) of 10.2 for NC in a direct saturation experiment. [Nphe1]NC(1-13)NH2 and J-113397 showed at least 100-fold selectivity over classical opioid receptors. Both NC and Ro65-6570 produced a concentration-dependent inhibition of cAMP formation with pEC50 values of 9.56+/-0.06 and 8.68+/-0.04, respectively. Maximum inhibition achieved was 100%. [Nphe1]NC(1-13)NH2, J-113397 and III-BTD produced a parallel rightward shift in the concentration-response curves to both NC and Ro65-6570 with pK(B) values of approximately 6.5, approximately 7.5 and approximately 7.7, respectively. Importantly, all three antagonists were devoid of residual agonist activity. Collectively, these data indicate the value of Ro65-6570, [Nphe1]NC(1-13)NH2, J-113397 and III-BTD in studies of the physiological role played by NC. However, due to the relatively poor selectivity of Ro65-6570 and III-BTD caution should be exercised when using tissues that co-express micro-opioid receptors.

Animals↗
PubMed2001

Seroprevalence of Kaposi's sarcoma-associated herpesvirus infection among blood donors from Texas.

PURPOSE: Kaposi's sarcoma-associated herpesvirus (KSHV), a gammaherpesvirus recently discovered among AIDS patients with Kaposi's sarcoma, is a potential candidate for screening in blood and plasma donors. While a number of studies have assessed KSHV infection among U.S. blood donors, larger-scale population-based studies would be necessary to develop more refined estimates of the magnitude and variation of KSHV infection across different geographic regions of the U.S. blood supply. The goal of the present study, therefore, was to determine the seroprevalence of KSHV infection and to assess demographic correlates of KSHV infection among south Texas blood donors. METHODS: KSHV infection was determined using specific serologic assays that measure antibodies to KSHV latent and lytic antigens. RESULTS: The overall seroprevalence of KSHV in Texas blood donors (15.0%) is substantially higher than previously reported among blood donor and general population samples in the United States. This high rate of KSHV infection persisted across most of the sociodemographic subgroups under study but was particularly elevated among participants with less than a high school education. The infection rate also increased linearly with age. CONCLUSIONS: The elevated infection rate reported in the present study suggests that screening methods to detect KSHV infection in blood donors should be considered. In view of the etiologic role of KSHV for several malignancies, it would be important for future studies to directly assess the risk of KSHV transmission via blood transfusion.

Adolescent↗
PubMed2001

Determinants of outcome after intensified therapy of childhood lymphoblastic leukaemia: results from Medical Research Council United Kingdom acute lymphoblastic leukaemia XI protocol.

The single most important prognostic determinant in childhood acute lymphoblastic leukaemia (ALL) is effective therapy and changes in therapy may influence the significance of other risk factors. The effect of intensified therapy on the importance of currently recognized phenotypic and genotypic determinants of outcome was assessed in 2090 children enrolled on the Medical Research Council United Kingdom acute lymphoblastic leukaemia XI (MRC UKALL XI) protocol. Treatment allocation was not determined by risk factors. Multivariate analysis confirmed the dominant influence on prognosis of age, sex and presenting white cell count (WCC). After allowing for these features, blast karyotype, d 8 marrow blast percentage and remission status at the end of induction therapy were the only remaining significant predictors of outcome. Organomegaly, haemoglobin concentration, French--American--British type, body mass index, presence of central nervous system disease at diagnosis, immunophenotype and presence of TEL/AML1 fusion gene (examined in a subset of 659 patients) either had no significant effect on outcome or were significant only in univariate analysis. Among karyotype abnormalities with an independent influence on prognosis, high hyperdiploidy (> 50 chromosomes) was shown to be favourable, whereas near haploidy (23--29 chromosomes), presence of the Philadelphia chromosome, t(4;11) and abnormalities affecting the short arm of chromosome 9 [abn (9p)] were adverse risk factors. Early responders to therapy, determined by residual marrow infiltration after 8 d of induction therapy, had a good outcome, while the small proportion of patients who did not achieve a complete remission by the end of induction therapy had a poor outcome. A third block of late intensification was shown to improve event-free survival by 8% at 5 years. The effect of these risk factors was not significantly different between those randomized to the third intensification block and those not randomized to a third block.

Adolescent↗
PubMed2001

Hospital policy on appropriate use of life-sustaining treatment. University of Toronto Joint Centre for Bioethics/Critical Care Medicine Program Task Force.

OBJECTIVE: To describe the issues faced, and how they were addressed, by the University of Toronto Critical Care Medicine Program/Joint Centre for Bioethics Task Force on Appropriate Use of Life-Sustaining Treatment. The clinical problem addressed by the Task Force was dealing with requests by patients or substitute decision makers for life-sustaining treatment that their healthcare providers believe is inappropriate. DESIGN: Case study. SETTING: The University of Toronto Joint Centre for Bioethics/Critical Care Medicine Program Task Force on Appropriate Use of Life-Sustaining Treatment. PARTICIPANTS: The 24-member Task Force included physician and nursing leaders from five critical care units, bioethicists, a legal scholar, a health administration expert, a social worker, and a hospital public relations professional. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Our specific lessons learned include a) a policy focus on process; b) use of a negotiation and mediation model, rather than a hospital ethics committee model, for this process; and c) the policy development process is itself a negotiation, so we recommend equal involvement of interested groups including patients, families, and the public. CONCLUSIONS: This article describes the key issues faced by the Task Force while developing its policy. It will provide a useful starting point for other groups developing policy on appropriate use of life-sustaining treatment.

Hospital Administration↗
PubMed2000

Mechanisms of ordering in striped patterns.

We have studied the ordering dynamics of the striped patterns of a single layer of cylindrical block copolymer microdomains in a thin film. By tracking disclinations during annealing with time-lapse atomic force microscopy, we observe a dominant mechanism of disclination annihilation involving three or four disclinations (quadrupoles). Pairwise disclination annihilation events are suppressed as a result of the topological constraints in this system. The kinetic scaling laws with exponents observed here are consistent with topologically allowed annihilation events involving multiple disclinations. The results provide insight into two-dimensional pattern formation and may lead to the successful application of block copolymer lithography.

Journal Article↗
PubMed2000

Systematic implementation of an advance directive program in nursing homes: a randomized controlled trial.

CONTEXT: Although advance directives are commonly used in the community, little is known about the effects of their systematic implementation. OBJECTIVES: To examine the effect of systematically implementing an advance directive in nursing homes on patient and family satisfaction with involvement in decision making and on health care costs. DESIGN: Randomized controlled trial conducted June 1, 1994, to August 31, 1998. SETTING AND PARTICIPANTS: A total of 1292 residents in 6 Ontario nursing homes with more than 100 residents each. INTERVENTION: The Let Me Decide advance directive program included educating staff in local hospitals and nursing homes, residents, and families about advance directives and offering competent residents or next-of-kin of mentally incompetent residents an advance directive that provided a range of health care choices for life-threatening illness, cardiac arrest, and nutrition. The 6 nursing homes were pair-matched on key characteristics, and 1 home per pair was randomized to take part in the program. Control nursing homes continued with prior policies concerning advance directives. MAIN OUTCOME MEASURES: Residents' and families' satisfaction with health care and health care services utilization over 18 months, compared between intervention and control nursing homes. RESULTS: Of 527 participating residents in intervention nursing homes, 49% of competent residents and 78% of families of incompetent residents completed advance directives. Satisfaction was not significantly different in intervention and control nursing homes. The mean difference (scale, 1-7) between intervention and control homes was -0.16 (95 % confidence interval [CI], -0.41 to 0.10) for competent residents and 0.07 (95% CI, -0.08 to 0.23) for families of incompetent residents. Intervention nursing homes reported fewer hospitalizations per resident (mean, 0.27 vs 0.48; P = .001) and less resource use (average total cost per patient, Can $3490 vs Can $5239; P = .01) than control nursing homes. Proportion of deaths in intervention (24%) and control (28%) nursing homes were similar (P = .20). CONCLUSION: Our data suggest that systematic implementation of a program to increase use of advance directives reduces health care services utilization without affecting satisfaction or mortality.

Advance Directives↗
PubMed2000

Endomorphin-1 induced desensitization and down-regulation of the recombinant mu-opioid receptor.

1. Endomorphin-1 (E1) is a peptide with high affinity and selectivity for the mu-opioid receptor. The aim of this study was to determine if endomorphin-1 caused desensitization and down-regulation of the mu-opioid receptor expressed in Chinese hamster ovary cells. 2. Following 10 microM E1 pre-treatment, desensitization was assessed by measuring cyclic AMP inhibition, down-regulation was assessed by [(3)H]-diprenorphine ([(3)H]-DPN) binding and immuno-blotting. 3. Pre-treatment of CHO mu cells with 10 microM E1 for 11 and 18 h caused significant reduction in cyclic AMP inhibition. (11 h=39.0+/-16.7%, 18 h 47.0+/-11.1% reduction). 4. At 18 h E1 pre-treatment there was an enhancement (4.5 fold) of cyclic AMP production under forskolin stimulated conditions accompanied by a small rightward shift in the concentration-response curve (pEC(50) control=7.8+/-0.3, pEC(50) E1=7.3+/-0.2) when cells were re-challenged with E1. 5. In membranes prepared from untreated and 0.5 h E1 pre-treated cells, addition of GTP gamma S produced a significant rightward shift in the concentration response curves for E1 displacement of [(3)H]-DPN (0 h K(i) control=7.86+/-0.11, GTP gamma S=7.37+/-0.15; 0.5 h K(i) control=7.92+/-0.12, GTP gamma S=7.36+/-0.08) This was not observed in membranes prepared from cells that had been treated with E1 for 18 h (18 h K(i) control=7.69+/-0. 11, GTP gamma S=7.75+/-0.08). 6. In whole cells E1 treatment caused a rapid loss of cell surface receptors such that at 0.5 h there was a 30.5+/-1.5 reduction (this was unchanged for 18 h). In crude membranes a loss of receptors was also observed using radioligand binding or immuno-blotting protocols. 7. These data show that E1 causes desensitization and down-regulation of the rat mu-opioid receptor expressed in CHO cells. However, these two responses appear temporally distinct.

Animals↗
PubMed2000

MLL amplification in acute leukaemia: a United Kingdom Cancer Cytogenetics Group (UKCCG) study.

The MLL gene, located at 11q23, is frequently rearranged in acute leukaemia as either chimaeric fusion genes or partial tandem duplications. We report a series of 12 acute leukaemia cases with apparent amplification of the MLL gene ascertained using fluorescence in situ hybridisation (FISH). Seven cases showed intrachromosomal amplification of MLL, four cases showed extrachromosomal amplification as double minute chromosomes (dmin) and one case had separate subclones with dmin and homogenously staining region (hsr). Southern blot analysis of the MLL gene showed MLL gene rearrangement in three of the 10 successful cases. These cases do not naturally fall into either of the two recognised categories of MLL rearrangement and may represent a third variety of MLL gene abnormalities.

Acute Disease↗