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Biomedical subjects

C Cameron

Publications and source records attributed to C Cameron.

At least 19 recordsLinked to original sources
PubMed2001

Systemic delivery of an adenoviral vector encoding canine factor VIII results in short-term phenotypic correction, inhibitor development, and biphasic liver toxicity in hemophilia A dogs.

Canine hemophilia A closely mimics the human disease and has been used previously in the development of factor VIII (FVIII) protein replacement products. FVIII-deficient dogs were studied to evaluate an in vivo gene therapy approach using an E1/E2a/E3-deficient adenoviral vector encoding canine FVIII. Results demonstrated a high level of expression of the canine protein and complete phenotypic correction of the coagulation defect in all 4 treated animals. However, FVIII expression was short-term, lasting 5 to 10 days following vector infusion. All 4 dogs displayed a biphasic liver toxicity, a transient drop in platelets, and development of anticanine FVIII antibody. Canine FVIII inhibitor development was transient in 2 of the 4 treated animals. These data demonstrate that systemic delivery of attenuated adenoviral vectors resulted in liver toxicity and hematologic changes. Therefore, the development of further attenuated adenoviral vectors encoding canine FVIII will be required to improve vector safety and reduce the risk of immunologic sequelae, and may allow achievement of sustained phenotypic correction of canine hemophilia A.

Adenoviridae↗
PubMed2001

Long-term care of people below age 65 with severe acquired brain injury: appropriateness of aged care facilities.

OBJECTIVE: To identify the number of people younger than 65 years with acquired brain injury (ABI) living in aged care facilities in Queensland, and to evaluate the appropriateness of this accommodation option. METHODS: A cross-sectional descriptive study of all 493 Commonwealth Department of Health and Aged Care registered aged care facilities in Queensland. Associations between a range of demographic factors, resources, care provision and client needs were examined, from the perspective of service providers. RESULTS: The response rate was 75%. Twenty-six per cent of facilities (n=97) were providing care for 209 people younger than 65 years with ABI. The social, cognitive and rehabilitation aspects of client care were found to be inadequate in facilities where staffing levels, training and funding resources were limited (p< 0.05). Smaller facilities (<60 beds) reported higher levels of family participation in specific aspects of client care (p<0.05). Almost 40% of the facilities indicated they did not adequately meet the specific and complex rehabilitation needs of these clients. Aged care facilities were the least favoured model of care for this client group (8%) compared with the most favoured model of small group homes (46%). CONCLUSIONS: The current use of aged care facilities for housing younger people with high-level care needs resulting from ABI is inappropriate and does not meet client needs.

Adult↗
PubMed2000

A single nucleotide polymorphism at nucleotide -1793 in the von Willebrand factor (VWF) regulatory region is associated with plasma VWF:Ag levels.

von Willebrand Factor (VWF) is a large multimeric glycoprotein involved in the transport and protection of factor VIII and in mediating platelet-subendothelium and platelet-platelet interactions. We have documented the presence of a single nucleotide polymorphism (SNP) at nucleotide (nt) -1793 (G 0.36 or C 0.64) in the VWF 5'-flanking sequence. This polymorphism is in strong linkage disequilibrium with the previously reported SNPs at nts -1234, -1185 and -1051 and, like this other group of polymorphisms, shows a significant association with plasma VWF levels. This association is more marked in subjects who are more than 40 years of age. Further, circumstantial evidence to support a role for the -1793 sequence in regulating VWF expression comes from our demonstration of differential binding of endothelial cell nuclear proteins, including the transcription factor NFkappaB, by this sequence. In summary, the association of the -1793 SNP with plasma VWF levels provides additional evidence for the role of the VWF regulatory region between nts -1793 and -1051 in controlling VWF expression.

Adult↗
PubMed1999

The complete DNA sequence of myxoma virus.

Myxomatosis in European rabbits is a severely debilitating disease characterized by profound systemic cellular immunosuppression and a high rate of mortality. The causative agent, myxoma virus, is a member of the poxvirus family and prototype of the Leporipoxvirus genus. As a major step toward defining the genetic strategies by which the virus circumvents host antiviral responses, the genomic DNA sequence of myxoma virus, strain Lausanne, was determined. A total of 171 open reading frames were assigned to cover the 161.8-kb genome, including two copies each of the 12 genes that map within the 11.5-kb terminal inverted repeats. Database searches revealed a central core of approximately 120 kb that encodes more than 100 genes that exhibit close relationships to the conserved genes of members of other poxvirus genera. Open reading frames with predicted signal sequences, localization motifs, or homology to known proteins with immunomodulatory or host-range functions were examined more extensively for predicted features such as hydrophobic regions, nucleic acid binding domains, ankyrin repeats, serpin signatures, lectin domains. and structural cysteine spacings. As a result, several novel, potentially immunomodulatory proteins have been identified, including a family with multiple ankyrin-repeat domains, an OX-2 like member of the neural cell adhesion molecule family, a third myxoma serpin, a putative chemokine receptor fragment, two natural killer receptor-like species, and a variety of species with domains closely related to diverse host immune regulatory proteins. Coupled with the genomic sequencing of the related leporipoxvirus Shope fibroma virus, this work affirms the existence of a conserved complement of poxvirus-specific core genes and expands the growing repertoire of virus genes that confer the unique capacity of each poxvirus family member to counter the immune responses of the infected host.

Amino Acid Sequence↗
PubMed1999

In vivo evaluation of an adenoviral vector encoding canine factor VIII: high-level, sustained expression in hemophiliac mice.

Hemophilia A is the most common severe hereditary coagulation disorder and is caused by a deficiency in blood clotting factor VIII (FVIII). Canine hemophilia A represents an excellent large animal model that closely mimicks the human disease. In previous studies, treatment of hemophiliac dogs with an adenoviral vector encoding human FVIII resulted in complete correction of the coagulation defect and high-level FVIII expression [Connelly et al. (1996). Blood 88, 3846]. However, FVIII expression was short term, limited by a strong antibody response directed against the human protein. Human FVIII is highly immunogenic in dogs, whereas the canine protein is significantly less immunogenic. Therefore, sustained phenotypic correction of canine hemophilia A may require the expression of the canine protein. In this work, we have isolated the canine FVIII cDNA and generated an adenoviral vector encoding canine FVIII. We demonstrate expression of canine FVIII in hemophiliac mice at levels 10-fold higher than those of the human protein expressed from an analogous vector. Canine FVIII expression was sustained above human therapeutic levels (50 mU/ml) for at least 1 year in hemophiliac mice.

Adenoviridae↗
PubMed1999

No impact from active dissemination of the Ottawa Ankle Rules: further evidence of the need for local implementation of practice guidelines.

BACKGROUND: Local implementation strategies are often required to promote consistent adherence to clinical guidelines, but they are time consuming and expensive. The authors tested an educational intervention designed to increase use of the Ottawa Ankle Rules, a widely publicized set of clinical guidelines previously shown to reduce the use of radiography for diagnosis of acute ankle injuries. METHODS: The study consisted of a quasi-experimental, before-and-after comparative analysis. Trained experts provided 1-hour educational sessions and supplied resource materials on the Ottawa Ankle Rules to health care professionals from 63 Ontario hospitals. Participants were asked to evaluate the intervention. The authors then compared, for periods before and after the educational sessions, the use of ankle radiography for adults with acute ankle injury in 10 hospitals that received the educational intervention and reported no (n = 5) or some (n = 5) prior use of the rules and in 5 control hospitals, which declined the educational intervention because they were already implementing the rules. RESULTS: Although participants gave highly positive appraisals of the Ottawa Ankle Rules and the educational sessions, there was no reduction in the use of ankle radiography for the 10 hospitals that received the educational sessions (73% before and 78% after the intervention, p = 0.11). In contrast, use of radiography decreased significantly, from 75% to 65%, in the 5 control hospitals (p = 0.022). INTERPRETATION: Even when a dissemination strategy is well received and involves a widely accepted clinical guideline, the impact on behaviour in clinical practice may be small. In addition to broad dissemination, an active local implementation strategy is necessary to encourage physicians to adopt clinical guidelines.

Acute Disease↗
PubMed1999

Treponema pallidum major sheath protein homologue Tpr K is a target of opsonic antibody and the protective immune response.

We have identified a family of genes that code for targets for opsonic antibody and protective immunity in T. pallidum subspecies pallidum using two different approaches, subtraction hybridization and differential immunologic screening of a T. pallidum genomic library. Both approaches led to the identification of a polymorphic multicopy gene family with predicted amino acid homology to the major sheath protein of Treponema denticola. One of the members of this gene family, tpr K, codes for a protein that is predicted to have a cleavable signal peptide and be located in the outer membrane of the bacterium. Reverse transcription polymerase chain reaction analysis of T. pallidum reveals that Tpr K is preferentially transcribed in the Nichols strain of T. pallidum. Antibodies directed to purified recombinant variable domain of Tpr K can opsonize T. pallidum, Nichols strain, for phagocytosis, supporting the hypothesis that this portion of the protein is exposed at the surface of the treponeme. Immunization of rabbits with the purified recombinant variable domain of Tpr K provides significant protection against infection with the Nichols strain of T. pallidum. This gene family is hypothesized to be central to pathogenesis and immunity during syphilis infection.

Amino Acid Sequence↗
PubMed1999

Immunological effects of interleukin 12 administered by bolus intravenous injection to patients with cancer.

The immunological effects of recombinant human interleukin 12 (rhIL-12) administration were examined during the conduct of a Phase I clinical trial. Forty patients with advanced cancer received bolus i.v. injections of rhIL-12 in doses ranging between 3 and 1000 ng/kg. Dose-dependent increases in serum IFN-gamma levels were seen during rhIL-12 therapy. Significant lymphopenia was observed 24 h after single i.v. injections of rhIL-12 at each dose level. The degree of lymphopenia was dose dependent, and a plateau effect was seen with rhIL-12 doses of 100 ng/kg and higher. Lymphocyte counts reached nadir levels at approximately 10 h after rhIL-12 injection and returned to baseline within 14 days postinjection. Rebound lymphocytosis, as seen after interleukin 2 therapy, was not observed after recovery from rhIL-12-induced lymphopenia. rhIL-12-induced lymphopenia involved all major lymphocyte subsets, although natural killer (NK) cell numbers were the most profoundly affected, and CD4 T-cell numbers were the least affected. CD2, LFA-1, and CD56 were transiently up-regulated on the surface of NK cells exposed to rhIL-12 in vivo. Peripheral blood mononuclear cells obtained from cancer patients before rhIL-12 therapy exhibited defective NK cell cytotoxicity and T-cell-proliferative responses. Peripheral blood mononuclear cells obtained after lymphocyte recovery following the administration of a single 500 ng/kg dose of rhIL-12 displayed augmented NK cell cytolytic activity in four of four patients tested and enhanced T-cell proliferation in three of four patients tested. These studies confirm that doses of rhIL-12 resulting in significant immunological activity can be administered with acceptable toxicity to cancer patients. Furthermore, rhIL-12 therapy can reverse defects in NK cell and T-cell function that are associated with advanced cancer in humans.

Antineoplastic Agents↗
PubMed1998

One-on-one peer support and quality of life for breast cancer patients.

The Canadian Cancer Society's Reach to Recovery program provides one-on-one support for breast cancer patients that is delivered by breast cancer survivors. Professionally-led social support programs have generally been found to influence positively the quality of life of cancer patients. However, there is a lack of evidence on the benefits of one-on-one peer support programs. An evaluation of the Reach to Recovery program was completed in 1995 to determine if cancer patients who received the program were satisfied with the program and to determine if participation in Reach to Recovery affected the quality of life of program participants compared to patients who did not receive the program. We found that Reach to Recovery program participants were generally satisfied with the program they received and that the program has incremental benefits to the quality of life of patients with breast cancer. Peer-led, volunteer breast cancer support programs can be effective in enhancing the quality of life of breast cancer patients.

Adult↗
PubMed1998

Androgen effects on factor IX expression: in-vitro and in-vivo studies in mice.

A role for steroid hormones has been proposed for the post-pubertal factor IX increment of approximately 25% seen in both normal males and females, as well as in the post-pubertal phenotypic recovery seen in haemophilia B Leyden. We have evaluated androgen receptor binding to the factor IX promoter and have assessed transcriptional activation of the factor IX gene in hepatocytes through transient transfection studies and through expression of factor IX in a murine model of androgen insensitivity. Whereas transfection of the androgen receptor alone did not activate expression from the factor IX promoter, co-transfection with the CCAAT enhancer binding protein resulted in a synergistic 17-fold enhancement of transcriptional activity. Using liver nuclear extracts and recombinant androgen receptor protein we have confirmed binding of this protein to the factor IX proximal promoter and disruption of binding with a mutation at nucleotide -26. Finally, studies in normal and testicular feminized male mice showed different developmental patterns of factor IX expression. In normal mice, expression recapitulates that seen in humans, with early post-natal levels being approximately 50% of the adult values and with a post-pubertal increment of approximately 25%. In contrast, testicular feminized animals did not show a significant post-pubertal increment of factor IX. These studies provide further support for the role of androgen receptor binding to the factor IX promoter in regulating the developmental expression of factor IX.

Animals↗
PubMed1998

The canine factor VIII cDNA and 5' flanking sequence.

Factor VIII is a trace plasma glycoprotein involved as a cofactor in the activation of factor X by factor IXa. Inherited deficiency of factor VIII results in the X-linked bleeding disorder hemophilia A which has been documented in humans, horses, sheep and dogs. In this report, the putative proximal promoter, 5' untranslated region, complete coding sequence and 3' untranslated region of the canine factor VIII gene have been characterized. When compared to the human gene, the 5' flanking region shows conservation of transcription factor binding sites in the 5' untranslated region. Alignment of the amino acid sequence with that of the previously reported human, mouse and pig proteins demonstrates sequence identity of between 77 and 92% for the A1, A2, A3, C1 and C2 domains but an identity of only between 44 and 62% for the central B domain. The three thrombin cleavage sites are conserved in the canine sequence as are the protein C cleavage sites and the von Willebrand factor binding region. In addition, all six tyrosine residues that are known to undergo sulfation in the human protein are conserved in the dog. The 3' untranslated region of the canine gene extends 1.5 kilobases. The initial 700 basepairs of this sequence are highly GC rich and the sequence terminates with 2 alternative potential polyadenylation sites. The knowledge of this sequence, in combination with a well described canine model of hemophilia A, provides the necessary starting point for studies addressing the long-term evaluation of factor VIII gene therapy using a homologous transgene.

Amino Acid Sequence↗
PubMed1997

Promotion of regeneration and axon growth following injury in an invertebrate nervous system by the use of three-dimensional collagen gels.

We describe the application of three-dimensional collagen matrices to the study of nerve cord repair in the leech. Our experiments show that ganglia and connectives of the leech ventral nerve cord can be maintained for up to four weeks embedded in 3D gels constructed from mammalian type I collagen. Severed nerve cords embedded in the collagen gel reliably repaired within a few days of culture. The gel was penetrable by cells emigrating from the cut ends of nerves and connectives, and we consistently saw regenerative outgrowth of severed peripheral and central axons into the gel matrix. Thus, 3D gels provide an in vitro system in which we can reliably obtain repair of severed nerve cords in the dish, and visualize cell behaviour underlying regenerative growth at the damage site: and which offers the possibility of manipulating the regenerating cells and their extracellular environment in various ways at stages during repair. Using this system it should be possible to test the effect on the repair process of altering expression of selected genes in identified nerve cells.

Animals↗
PubMed1997

Perspectives on Reach to Recovery and CanSurmount: informing the evaluation model.

The Canadian Cancer Society requested that the Centre for Behavioural Research and Program Evaluation of the National Cancer Institute of Canada evaluate Reach to Recovery and CanSurmount, 1-on-1 peer-support programs that provide information and support to individuals with cancer and their families. Key informant interviews (with program participants and volunteer visitors) were conducted to gather qualitative data and to help us develop a framework and tools to evaluate these programs. We found that 1) there are program objectives from the perspective of volunteers and participants in addition to those outlined in the program materials; 2) there are variations in how the programs are delivered and how patients or family members are recruited into the program; and 3) there is evidence that Reach to Recovery and CanSurmount volunteers are in a unique position to deliver the programs, either because they have personally experienced cancer or have family members who have had cancer. We describe the key informant exercise developed for this evaluation project and present the results of preliminary data-gathering activities.

Breast Neoplasms↗