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Biomedical subjects

C Harrison

Publications and source records attributed to C Harrison.

At least 37 records · Page 2Linked to original sources
PubMed2000

A bioethics education program in pediatric rheumatology.

The medical care of children by pediatric rheumatologists may be ethically very complex. Medical trainees and members of the multidisciplinary health care team must be sensitive to and knowledgeable about ethical issues relevant to the care of their patients, and capable of ethical reasoning. Members of the Bioethics Department and the Division of Rheumatology at the Hospital for Sick Children have cooperatively developed a Bioethics Education Program with a curriculum tailored to meet the needs of the health care team. The quarterly ethics seminars are case based and interdisciplinary. Topics addressed include the nature of the patient-practitioner relationship, research with child participants, the developing autonomy of the child, the child's "best interests," and consent

Bioethics↗
PubMed1999

The effect of C-terminal truncation of the recombinant delta-opioid receptor on Ca2+i signaling.

We have previously shown a stimulatory coupling of the recombinant delta-opioid receptor to phospholipase C leading to production of inositol (1,4,5) triphosphate [Ins(1,4,5)P3] that is affected by truncation of the C-terminus of the receptor. Using a C-terminal mutant of the delta-opioid receptor lacking the final 37 amino acids (CHOdelta37), we examined its coupling to intracellular calcium ion concentration ([Ca2+]i) compared to the full length wild type receptor (CHOdeltaWT) in transfected Chinese hamster ovary (CHO) cells. D-[Pen2,5]enkephalin (DPDPE) mediated increases in [Ca2+]i were measured fluorimetrically in fura-2 loaded whole cell suspensions. DPDPE produced time- and concentration-dependent increases in [Ca2+]i in CHOdeltaWT and CHOdelta37. In both cell types the DPDPE simulated increase in [Ca2+]i was naloxone reversible and pertussis toxin and thapsigargin sensitive. Removal of the C-terminus resulted in a rightward shift of the Ca2+ release concentration-response curve [pEC50 = 8.43 +/- 0.13 and 6.08 +/- 0.25 for CHOdeltaWT and CHOdelta37, respectively]. These data indicate that the C-terminus of the recombinant delta-opioid receptor is important in [Ca2+]i coupling and may be attributed to the effect of C-terminus truncation on phospholipase C coupling reported previously.

Amino Acid Sequence↗
PubMed1999

The effects of endomorphin-1 and endomorphin-2 in CHO cells expressing recombinant mu-opioid receptors and SH-SY5Y cells.

1 Endomorphin-1 and -2 (E-1/E-2) have been proposed as endogenous ligands for the mu-opioid receptor. The aims of this study are to characterize the binding of E-1/E-2 and the subsequent effects on cyclic AMP formation and [Ca2+]i levels in SH-SY5Y and Chinese hamster ovary (CHO) cells expressing endogenous and recombinant mu-opioid receptors. 2 E-1 displaced [3H]-diprenorphine ([3H]-DPN) binding in CHO micro and SH-SY5Y membranes with pKi values of 8.02+/-0.09 and 8.54+/-0.13 respectively. E-2 displaced [3H]-DPN binding in CHOmu and SH-SY5Y cells with pKi values of 7.82+/-0.11 and 8.43+/-0.13 respectively. E-1/E-2 bound weakly to CHOdelta and CHOkappa membranes, with IC50 values of greater than 10 microM. 3 In CHOmu cells, E-1/E-2 inhibited forskolin (1 microM) stimulated cyclic AMP formation with pIC50 values of 8.03+/-0.16 (Imax = 53.0+/-9. 3%) and 8.15+/-0.24 (Imax = 56.3+/-3.8%) respectively. In SH-SY5Y cells E1/E2 inhibited forskolin stimulated cyclic AMP formation with pIC50 values of 7.72+/-0.13 (Imax=46.9+/-5.6%) and 8.11+/-0.31 (Imax = 40.2+/-2.8%) respectively. 4 E-1/E-2 (1 microM) increased [Ca2+]i in fura-2 loaded CHOmu cell suspensions in a thapsigargin sensitive and naloxone reversible manner. Mean increases observed were 106+/-28 and 69+/-6.7 nM respectively. In single adherent cells E-1/E-2 (1 microM) increased [Ca2+]i with a mean 340/380 ratio change of 0.81+/-0.09 and 0.40+/-0.08 ratio units respectively. E-1/E-2 failed to increase intracellular calcium in CHOdelta, CHOkappa and SH-SY5Y cells. 5 These data show that E-1/E-2 bind with high affinity and selectivity to mu-opioid receptors and modulate signal transduction pathways typical of opioids. This provides further evidence that these two peptides may be endogenous ligands at the mu-opioid receptor.

Analgesics, Opioid↗
PubMed1999

Effects of antigen dose and immunization regimens on antibody responses to a cytomegalovirus glycoprotein B subunit vaccine.

The purpose of this phase I study was to evaluate the safety and immunogenicity of 2 doses of cytomegalovirus glycoprotein B (CMV gB)/MF59 vaccine at 3 different immunization schedules. Ninety-five volunteers were randomized to 6 groups. Antibodies to gB represent the majority of the CMV-specific neutralizing response. Three groups received 5 microgram of gB antigen combined with MF59 (a proprietary adjuvant) and 3 groups received a 30-microgram dose at 0, 1, and 2 months; 0, 1, and 4 months; or 0, 1, and 6 months. The vaccine was well tolerated, and there was no significant difference in antibody production between the 2 doses. The vaccine induced highest antibody titers when given at 0, 1, and 6 months. A low dose of CMV gB/MF59 may be the preferred dose for future studies.

Adjuvants, Immunologic↗
PubMed1999

Stemming the tide: reducing cardiovascular disease and renal failure in Australian Aborigines.

An epidemic of cardiovascular disease (CVD) and end stage renal disease (ESRD) has developed among Aborigines in the Northern Territory; CVD deaths increased over the 1980s (tripling among women!), and are now more than five times those of non-Aboriginal people, while ESRD rates are increasing more than 20-fold and are doubling every three to four years. Dialysis costs (>$75,000 per person/year) pose a crisis for health care budgets, but premature mortality is the greater human catastrophe. Health services are not meeting the challenge of timely diagnosis, prevention and containment. We screened 90% of adults (20+ years) in one community, with CVD mortality among the highest in Australia, and ESRD rates increased 60-fold. Seventy-five per cent of persons were smokers. Central obesity was common, but BMIs only modestly increased by Caucasian standards, 23% had hypertension (>140/90), 29% had diabetes or impaired glucose tolerance (IGT) (peaking at 65% of persons aged 40-49 years), high triglyceride and insulin levels were common, and 55% had albuminuria (albumin/creatinine ratio (ACR), >3.4 gm/moL). Progressive albuminuria predicted renal failure. ACR was correlated with age, BMI, blood pressure, lipid, glucose and insulin levels, heavy drinking and past and current skin infections, and, inversely with birth weight. ACR correlated strongly with a composite CV risk score, and in a two to five year follow-up, microalbuminuria (ACR 3.4-33) and overt albuminuria (ACR 34+) have both predicted increased rate of premature death from natural causes of lower ACRs. Thus albuminuria marks CV risk/disease. This implies that renal and CV disease share common risk factors, and should respond to the same interventions, and that this response might be monitored through ACR levels. Robust public health programmes could reduce all these reversible risk factors, lowering disease rates over the intermediate term, however, few such programmes are in place. Modification of disease in persons already afflicted is a parallel responsibility. To this end, in November 1995, we introduced a treatment programme with Coversyl (perindopril, Servier) for all persons in the study community with hypertension (>140/90), for all diabetics with ACR 3.4+ and for all nondiabetic, non-hypertensive persons with progressive overt albuminuria (ACR 34+). One-quarter of all adults, or 224 persons have enrolled; 162 have reached one year of treatment and 100 have passed two years. Compliance is reasonable and enthusiasm high. Average SBP has fallen 12 mmHg (24 mmHg in hypertensive persons), while average ACR and estimated glomerular filtration rate (GFR) have stabilised. This contrasts favourably with the pretreatment course (average 2.7 years) in the same persons, when SBP had increased by 3 mmHg, ACR had increased by 15% and GFR had decreased by 3.5 mL/min each year. Cautious estimates suggest a >50% fall in ESRD, and a reduction in all-cause and CV deaths, even at this early stage, although more extended observation is needed. These data predict a dramatic and rapid fall in morbidity, premature deaths and health care costs if these basic principles of medical care are extended to all Aboriginal people. A national, concerted, multi-disciplinary effort to implement a coherent, effective strategy to this end is of great urgency.

Adult↗
PubMed1999

Detection of enzootic babesiosis in baboons (Papio cynocephalus) and phylogenetic evidence supporting synonymy of the genera Entopolypoides and Babesia.

Blood smear evaluation of two baboons (Papio cynocephalus) experiencing acute hemolytic crises following experimental stem cell transplantation revealed numerous intraerythrocytic organisms typical of the genus Babesia. Both animals had received whole-blood transfusions from two baboon donors, one of which was subsequently found to display rare trophozoites of Entopolypoides macaci. An investigation was then undertaken to determine the prevalence of hematozoa in baboons held in our primate colony and to determine the relationship, if any, between the involved species. Analysis of thick and thin blood films from 65 healthy baboons (23 originating from our breeding facility, 26 originating from an out-of-state breeding facility, and 16 imported from Africa) for hematozoa revealed rare E. macaci parasites in 31%, with respective prevalences of 39, 35, and 12%. Phylogenetic analysis of nuclear small-subunit rRNA gene sequences amplified from peripheral blood of a baboon chronically infected with E. macaci demonstrated this parasite to be most closely related to Babesia microti (97.9% sequence similarity); sera from infected animals did not react in indirect fluorescent-antibody tests with Babesia microti antigen, however, suggesting that they represent different species. These results support an emerging view that the genus Entopolypoides Mayer 1933 is synonymous with that of the genus Babesia Starcovici 1893 and that the morphological variation noted among intracellular forms is a function of alteration in host immune status. The presence of an underrecognized, but highly enzootic, Babesia sp. in baboons may result in substantial, unanticipated impact on research programs. The similarity of this parasite to the known human pathogen B. microti may also pose risks to humans undergoing xenotransplantation, mandating effective screening of donor animals.

Animals↗
PubMed1998

The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties.

Cytogenetics is considered one of the most valuable prognostic determinants in acute myeloid leukemia (AML). However, many studies on which this assertion is based were limited by relatively small sample sizes or varying treatment approach, leading to conflicting data regarding the prognostic implications of specific cytogenetic abnormalities. The Medical Research Council (MRC) AML 10 trial, which included children and adults up to 55 years of age, not only affords the opportunity to determine the independent prognostic significance of pretreatment cytogenetics in the context of large patient groups receiving comparable therapy, but also to address their impact on the outcome of subsequent transplantation procedures performed in first complete remission (CR). On the basis of response to induction treatment, relapse risk, and overall survival, three prognostic groups could be defined by cytogenetic abnormalities detected at presentation in comparison with the outcome of patients with normal karyotype. AML associated with t(8;21), t(15;17) or inv(16) predicted a relatively favorable outcome. Whereas in patients lacking these favorable changes, the presence of a complex karyotype, -5, del(5q), -7, or abnormalities of 3q defined a group with relatively poor prognosis. The remaining group of patients including those with 11q23 abnormalities, +8, +21, +22, del(9q), del(7q) or other miscellaneous structural or numerical defects not encompassed by the favorable or adverse risk groups were found to have an intermediate prognosis. The presence of additional cytogenetic abnormalities did not modify the outcome of patients with favorable cytogenetics. Subgroup analysis demonstrated that the three cytogenetically defined prognostic groups retained their predictive value in the context of secondary as well as de novo AML, within the pediatric age group and furthermore were found to be a key determinant of outcome from autologous or allogeneic bone marrow transplantation (BMT) in first CR. This study highlights the importance of diagnostic cytogenetics as an independent prognostic factor in AML, providing the framework for a stratified treatment approach of this disease, which has been adopted in the current MRC AML 12 trial.

Acute Disease↗
PubMed1998

The effect of nonoxynol-9 and chlorhexidine on HIV and sperm in vitro.

The effect of chlorhexidine and nonoxynol-9, either singly or in combination, on the replication and infectivity of HIV and the survival of both lymphocytes (MT2 cells) and human spermatozoa, was studied in vitro. Exposure of MT2 cells to 200 microg/ml nonoxynol-9 or 1 mg/ml chlorhexidine for one minute destroyed their viability. A combination of 60 microg/ml of nonoxynol-9 and chlorhexidine, however, killed MT2 cells under the same conditions. Nonoxynol-9 and chlorhexidine were both spermicidal, 268 microg/ml nonoxynol-9, or 2.063 mg/ml chlorhexidine caused complete immobilization of sperm after one minute. The same effect was achieved by a combination of 200 microg/ml nonoxynol-9 and 1.0 mg/ml chlorhexidine. The effect of chlorhexidine and nonoxynol-9 on the replication of HIV was estimated by the output of p24 (the HIV core protein) and the concentration of virus was determined by titration with MT2 cells. Separately, 300 microg/ml nonoxynol-9 alone completely inactivated HIV, while 1 mg/ml chlorhexidine was 80%-100% effective. Certain combinations of nonoxynol-9 and chlorhexidine were antagonistic in their inactivation of HIV, up to 400 microg/ml chlorhexidine partly neutralized the action of 200-500 microg/ml nonoxynol-9.

Anti-HIV Agents↗
PubMed1998

Capacity to choose place of residence: autonomy vs beneficence?

Health care workers often perceive a conflict between autonomy and beneficence when dealing with clients living at risk in the community. Respect for personal freedom and the desire to help and protect vulnerable people frequently appear to demand opposite interventions. The assessment of decision-making capacity is a vital part of any process that deals with these complicated situations and can resolve some of the apparent conflict. Standardized assessment tools which are flexible enough to deal with the complexities of capacity assessment are needed. Health care workers aim to maximize the safety of people incapable of making decisions while protecting the freedom and autonomy of the capable. Some limits to autonomy must be accepted, especially where others' interests are threatened.

Aged↗
PubMed1997

Bioethics for clinicians: 9. Involving children in medical decisions.

Medical decisions involving children raise particular ethical issues for physicians and other members of the health care team. Although parents and physicians have traditionally made most medical decisions on behalf of children, the developing autonomy of children is increasingly being recognized in medical decision-making. This poses a challenge for physicians, who must work with the child's family and with other health care practitioners to determine the child's role in decision-making. A family-centred approach respects the complex nature of parent-child relationships, the dependence and vulnerability of the child and the child's developing capacity for decision-making.

Adolescent↗
PubMed1997

Neoplastic transformation of the endocervix associated with downregulation of lactoferrin expression.

The incidence of cervical adenocarcinomas in young women over the last two decades has increased. Even with increasing knowledge of the role of human papillomavirus in the etiology of adenocarcinoma of the cervix, there is a paucity of data concerning the genetic and epigenetic factors that contribute to the histologic features and biologic behaviors of these tumors. Lactoferrin is a basic glycoprotein found in human milk, secondary granules of neutrophils, and many body secretions, and it has been associated with carcinogenesis of the endometrium, breast, and lymphoid systems. In this study, we examined the expression of lactoferrin in normal human endocervical epithelium and in cervical adenocarcinomas in relation to proliferative index, steroid receptor status, p53 protein expression, and apoptosis. Immunohistochemical and in situ studies demonstrated that lactoferrin protein and mRNA were strikingly downregulated upon neoplastic transformation of the endocervix as early as in adenocarcinoma in situ when compared with the prominent expression exhibited by the normal cervical epithelium. Furthermore, neoplastic transformation of endocervical epithelial cells was accompanied by a pronounced stimulation of proliferation and a substantial reduction in the expression of the estrogen and progesterone receptors and p53 but little or no change in the number of apoptotic cells. In conclusion, we identified lactoferrin as a novel cancer-specific marker of endocervical adenocarcinomas that may be useful in the early detection of the disease, prediction of prognosis, and the development of new therapeutic modalities.

Adenocarcinoma↗
PubMed1997

Lens clarity after lens-sparing vitrectomy in a pediatric population.

PURPOSE: The purpose of the study is to assess lens clarity after pediatric lens-sparing vitrectomy. METHODS: The study offers a retrospective analysis of 85 eyes of 77 pediatric patients who underwent lens-sparing vitrectomy for tractional retinal detachment or opaque media, and who were observed for 10 to 55 months. RESULTS: A total of 57 eyes maintained clear lenses at last follow-up examination. Cataract was found in 13 (15%) of the 85 eyes. Fifteen eyes (18%) had undergone lens removal as part of reoperation for progressive ocular disease. CONCLUSION: Sixty-seven percent of pediatric lenses remained clear after lens-sparing vitrectomy.

Cataract↗