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Biomedical subjects

M Courtney

Publications and source records attributed to M Courtney.

At least 19 recordsLinked to original sources
PubMed2001

Tacrolimus monotherapy in adult cardiac transplant recipients: intermediate-term results.

BACKGROUND: Tacrolimus (FK506) is a macrolide antibiotic that inhibits T-cell activation and proliferation. To date, all published trials have used tacrolimus and steroids in combination with either azathioprine or mycophenolate mofetil. Previous experience with pediatric cardiac transplant patients at our institution suggested that use of tacrolimus alone provides an adequate level of immunosuppression and that withdrawal of steroids is readily achieved in most recipients. Between January 1, 1996, and July 7, 1999, we performed 77 adult cardiac transplants. Forty-three of these patients received tacrolimus and prednisone as primary immunosuppression, without azathioprine or mycophenolate mofetil. Thirty-two of the 43 patients started on tacrolimus have been weaned off steroids and are maintained on monotherapy. These latter patients form the basis of this report. The mean time for achieving monotherapy was 246 +/- 127 days (range, 106 to 730). Grade > or = 2 rejection occurred at 0.40 episodes per patient in the first 90 days (a combination of Grades 2 and 3A/3B rejections). The freedom from treated rejection (includes all 3A/3B and Grade 2 rejection in the first 90 days) was 69% at 90 days and 52% at 1 year. One patient (of 32) had documented cytomegalovirus infection (gastritis) diagnosed at 8 months post-transplant. We observed 1 case of transplant vasculopathy and 1 case of post-transplant lymphoproliferative disorder during the follow-up period. Our results show that use of tacrolimus alone after steroid weaning provides effective immunosuppression with low incidence of rejection, cytomegalovirus infection, transplant arteriopathy, or post-transplant lymphoproliferative disease.

Adult↗
PubMed2000

Older patients in the acute care setting: rural and metropolitan nurses' knowledge, attitudes and practices.

Many studies reporting nurses' knowledge of and attitudes toward older patients in long-term care settings have used instruments designed for older people. However, nurses' attitudes toward older patients are not as positive as their attitudes toward older people. Few studies investigate acute care nurses' knowledge of and attitudes toward older patients. In order to address these shortcomings, a self-report questionnaire was developed to determine nurses' knowledge of, and attitudes and practices toward, older patients in both rural and metropolitan acute care settings. Rural nurses were more knowledgeable about older patients' activities during hospitalisation, the likelihood of them developing postoperative complications and the improbability of their reporting incontinence. Rural nurses also reported more positive practices regarding pain management and restraint usage. However, metropolitan nurses reported more positive attitudes toward sleeping medications, decision making, discharge planning and the benefits of acute gerontological units, and were more knowledgeable about older patients' bowel changes in the acute care setting.

Acute Disease↗
PubMed2000

Acute-care nurses' attitudes towards older patients: a literature review.

With increases in life expectancy and increasing numbers of older patients utilising the acute setting, attitudes of registered nurses caring for older people may affect the quality of care provided. This paper reviews recent research on positive and negative attitudes of acute-care nurses towards older people. Many negative attitudes reflect ageist streotypes and knowledge deficits that significantly influence registered nurses' practice and older patients' quality of care. In the acute setting, older patients experience reduced independence, limited decision-making opportunities, increased probability of developing complications, little consideration of their ageing-related needs, limited health education and social isolation. Available instruments to measure attitudes towards and knowledge about older people, although reliable and valid, are outdated, country-specific and do not include either a patient-focus or a caring perspective. This paper argues for the development and utilisation of a research instrument that includes both a patient focus and a caring dimension.

Aged↗
PubMed2000

Phase I clinical trial with IL-2-transfected xenogeneic cells administered in subcutaneous metastatic tumours: clinical and immunological findings.

Various studies have emphasized an immunodepression state observed at the tumour site. To reverse this defect and based upon animal studies, we initiated a phase I clinical trial of gene therapy in which various doses of xenogeneic monkey fibroblasts (Vero cells) genetically engineered to produce human IL-2 were administered intratumorally in 8 patients with metastatic solid tumours. No severe adverse effect was observed in the 8 patients analysed during this clinical trial even in the highest dose (5 yen 107 cells) group. This absence of toxicity seems to be associated with rapid elimination of Vero-IL-2 cells from the organism. Indeed, exogenous IL-2 mRNA could no longer be detected in the peripheral whole blood 48 hours after Vero-IL-2 cell administration. In addition, we did not find any expression of exogenous IL-2 mRNA in post-therapeutic lesions removed 29 days after the start of therapy. A major finding of this trial concerns the two histological responses of two treated subcutaneous nodules not associated with an apparent clinical response. The relationship between local treatment and tumour regression was supported by replacement of tumour cells by inflammatory cells in regressing lesions and marked induction of T and natural killer cell derived cytokines (IL-2, IL-4, IFNg ...) in post-therapeutic lesions analysed 28 days after the start of Vero-IL-2 administration. Gene therapy using xenogeneic cells as vehicle may therefore present certain advantages over other vectors, such as its complete absence of toxicity. Furthermore, the in vivo biological effect of immunostimulatory genes, i.e IL-2-, may be potentiated by the xenogeneic rejection reaction.

Adenocarcinoma↗
PubMed2000

Australian Aboriginal trainee health service management program: a new initiative.

This paper explores the development, implementation and evaluation of the Australian Aboriginal trainee health service management program in New South Wales. In 1997, the two-year pilot program commenced with ten trainees. The program consisted of a combination of work-based placements, formal university education and Australian College of Health Service Executives (ACHSE) professional development sessions. The program has allowed trainees to gain professional skills and knowledge and broader work experience, in order to increase their employment opportunities throughout the Australian health care system.

Clinical Competence↗
PubMed1999

Gene therapy with cytokine-transfected xenogenic cells (Vero-IL-2) in patients with metastatic solid tumors: mechanism(s) of elimination of the transgene-carrying cells.

Eleven patients with advanced cancer were treated in a clinical gene therapy trial by repeated intra- tumoral injections with different doses of xenogenic fibroblasts secreting high amounts of human interleukin-2 (Vero-IL2). Treatments in a total of 14 courses were well tolerated and resulted in clinical responses and measurable biological effects. Together with increases in serum interleukin-2 (IL-2), modifications of the V-beta T cell receptor repertoire and induction of intratumoral T-cell infiltration were observed. When the intratumoral expression of endogenous cytokine genes and the persistence of the IL-2 transgene at the application site and in peripheral blood were investigated, rapid disappearance of the transgene at the application site appeared to be the most prominent biological effect. Tests detecting a single Vero-IL2 cell against a background of 10(5) non-transfected cells were not able to demonstrate significant expression of exogenous IL-2 (i.e. the transgene or transgene-carrying cells) in tumor biopsies or blood at different times. Therefore, further studies were performed to evaluate the mechanism(s) involved in the rapid disappearance of xenogenic carrier cells in more detail. We show here that significant in vitro cytotoxicity against transgene-carrying Vero cells can be observed in peripheral blood of all the patients before treatment as well as in healthy controls. "Cold" target inhibition shows that significant killing of Vero-IL2 cells is mediated by natural killer (NK) cells. This was confirmed by showing that established CD3(-)/CD16(+)/CD56(+) peripheral blood NK cell clones kill both K562 and Vero-IL2 target cells. The failure of other mechanisms (complement, antibody-dependent cell cytotoxicity or cytotoxic T lymphocytes) to destroy xenogenic, histoincompatible Vero cells in vitro suggests that NK cells also might be responsible for the killing of Vero-IL2 in vivo and for the failure to detect the transgene at the application site. These results might also be of importance for some aspects of the current discussion of xenotransplantation.

Adult↗
PubMed1999

Using self-efficacy to increase physical activity in patients with heart failure.

Increasing self-efficacy is not a state that develops quickly. It is unrealistic to expect that the factors contributing to illness and disability will be modified easily. The home care nurse can positively influence self-efficacy expectations in the heart failure population by creating a supportive environment to perform physical activities (performance mastery), assisting with encouragement and support (verbal persuasion), providing anticipatory guidance and sharing how others perform (vicarious experience), and providing a realistic assessment of a person's abilities (physiologic state). By enhancing self-efficacy, the home care nurse can increase physical activity levels in this population, leading to decreased symptomatology and improved quality of life.

Activities of Daily Living↗
PubMed1998

Usefulness of tacrolimus versus cyclosporine after pediatric heart transplantation.

This study compared the early clinical course of 9 pediatric heart transplantation recipients treated with cyclosporine A-based immunosuppression with 10 similarly aged recipients treated with tacrolimus-based therapy. One-year follow-up after transplantation revealed that tacrolimus-treated children had similar left ventricular function, experienced fewer episodes of severe rejection, were more rapidly weaned from corticosteroids, and had relatively few side effects from immunosuppression compared with cyclosporine A-treated children.

Adolescent↗
PubMed1998

Gene therapy with cytokine-transfected xenogeneic cells in metastatic tumors.

On the basis of compelling preclinical data in cats and dogs we initiated a clinical gene therapy study in nine patients with advanced solid tumors using xenogeneic fibroblasts secreting human IL-2 (Vero-IL-2 cells). Cohorts of three successive patients with tumors accessible to CT- or ultrasound-guided injection were treated repeatedly with 5 x 10(5), 5 x 10(6), or 5 x 10(7) Vero-IL-2 cells. Endpoints of the study were feasibility, toxicity, and clinical and biological effects of this novel approach to immunotherapy of cancer. Histopathological, immunological and molecular analyses were performed on biopsy specimens of tumors and blood samples from before, during and after treatment. Low levels of serum antibodies to Vero cells developed in 2/9 patients. Analysis of tumor biopsies showed increased expression of CD3 mRNA and enhanced tumor infiltration with varying lymphocyte subpopulations after treatment. In addition, monoclonal alterations of the TCR repertoire of blood and tumor lymphocytes were observed. Treatment was well tolerated and toxicity consisted of transient fever in one patient and short-lived, mild itching and erythema in two others. One patient with soft tissue sarcoma showed a more than 90% and more than 50% reduction of the volume of two distant, non-injected metastases, respectively, lasting for 22+ months. Four other patients showed stabilization of their disease for three to nine months, among whom was a patient with melanoma who developed marked vitiligo. We conclude that repeated injection of up to 5 x 10(7) Vero-IL-2 cells was safe and showed biological and clinical activity in heavily pretreated patients with advanced solid tumors. Further evaluation of intratumoral application of Vero-IL-2 seems warranted.

Adult↗
PubMed1998

Recombinant antitrypsin Pittsburgh undergoes proteolytic cleavage during E. coli sepsis and fails to prevent the associated coagulopathy in a primate model.

During severe sepsis there is dramatic activation of both contact proteases and the coagulation pathway. These processes contribute to the development of shock and disseminated intravascular coagulation (DIC) respectively. The Pittsburgh mutant of antitrypsin (358Met-Arg) is a novel protease inhibitor with activity against both thrombin and the contact proteases and should therefore prove beneficial as a therapeutic agent in the management of septic shock. This hypothesis was supported by an earlier study in a pig model where recombinant antitrypsin Pittsburgh (rAT Pittsburgh) at a concentration of 1 microM alleviated some of the features of shock, but did not improve survival. In order to reduce the lethal effects of E. coli sepsis we postulated that a higher concentration of antitrypsin Pittsburgh would be necessary. To test this hypothesis we used rAT Pittsburgh in a primate model. This was chosen in preference to another species as E. coli sepsis in the primate has been well characterised and closely resembles the changes seen in man. Surprisingly this treatment did not alleviate the features of shock and unexpectedly appeared to exacerbate the associated coagulopathy. We propose two possible mechanisms for this unforeseen outcome. The first results from the broad spectrum of activity of antitrypsin Pittsburgh. As well as inhibiting thrombin and the contact proteases, the Pittsburgh mutant also inhibits activated protein C. Inhibition of the protein C system is known to exacerbate septic shock. Secondly, a significant quantity of inactive antitrypsin Pittsburgh, cleaved at the reactive centre, was detected in the plasma of the treated animals. Proteolytically altered serpins, including antitrypsin. have been shown to enhance the inflammatory process. Therefore the accumulation of cleaved rAT Pittsburgh might be expected to exacerbate septic shock.

Animals↗
PubMed1998

The effects of HLA mismatching and immunosuppressive therapy on early rejection outcome in pediatric heart transplant recipients.

BACKGROUND: Although HLA-DR antigen mismatching between heart transplant recipients and donors has been associated with increased early allograft rejection in adult patients treated with cyclosporine, little information exists in the pediatric age group. In this study we examined retrospectively the effects of HLA mismatching and immunosuppression choice, cyclosporine versus tacrolimus on early rejection outcome in pediatric heart transplant recipients. METHODS: Between 1992 and 1997, 38 patients (ages 10 days to 18 years) underwent 40 heart transplantations. All recipients were typed prospectively and donors retrospectively by use of serologic microcytotoxicity testing for HLA-A and HLA-B antigens and by a polymerase chain reaction technique for HLA-DR antigens. All heart transplant recipients received induction immunosuppression with methylprednisolone and maintenance prednisone, and 38 received OKT3. The first 25 heart transplant recipients received cyclosporine and azathioprine, and the last 15 were given tacrolimus. Clinical courses, HLA mismatching, and biopsy results for the first year after heart transplantation were reviewed and compared between treatment groups. RESULTS: Mean age, donor/recipient weight ratios, and biopsies/patient were similar between treatment groups. Five deaths occurred among cyclosporine-treated patients and none among tacrolimus-treated patients during the study period. HLA mismatching was similar between groups, with 94% of patients having 1 or 2 HLA-A mismatches and 96% having 1 or 2 HLA-B and -DR mismatches. Both International Society for Heart and Lung Transplantation grade 2 and grade 3 or 4 rejections were significantly increased in biopsies from cyclosporine-treated patients (P < .05). Significantly increased grade 3 or 4 rejection was present in patients treated with cyclosporine who had two DR mismatches versus those with one DR mismatch (3.0+/-1.6 vs 1.4+/-0.8; P < .05); no statistical significance between patients treated with tacrolimus with 1 vs 2 DR mismatches was noted. Patients treated with tacrolimus who had 2 DR mismatches had fewer grade 3 or 4 rejection episodes/patient than either patients treated with cyclosporine who had one DR mismatch (0.6+/-0.4 vs 1.4+/-0.8, P = .03) or those treated with cyclosporine who had two DR mismatches (0.6+/-0.4 vs 3.0+/-1.6, P = .01). Grade 3 or 4 rejection episodes/patient were not affected by HLA-A or B mismatching, and grade 2 rejection was not affected by mismatching at any of the loci. CONCLUSION: Although mismatching of HLA-A and -B antigens did not affect frequency of early cellular rejection, the presence of 2 HLA-DR loci mismatches increased the risk of high-grade rejection in pediatric heart transplant recipients treated with cyclosporine. The potent effects of tacrolimus-based immunosuppression mitigated the impact of HLA-DR mismatching, because patients treated with tacrolimus who had 2 DR mismatches had less rejection than even patients treated with cyclosporine who had one DR mismatch and seemed to be at no greater risk for rejection than patients treated with tacrolimus who had 1 DR mismatch.

Adolescent↗
PubMed1997

Phase I trial of recombinant adenovirus gene transfer in lung cancer. Longitudinal study of the immune responses to transgene and viral products.

Animal studies indicate that the use of replication-deficient adenovirus for human gene therapy is limited by host antivector immune responses that result in transient recombinant protein expression and blocking of gene transfer when rechallenged. Therefore, we have examined immune responses to an adenoviral vector and to the beta-galactosidase protein in four patients with lung cancer given a single intratumor injection of 10(9) plaque-forming units of recombinant adenovirus. The beta-galactosidase protein was expressed in day-8 tumor biopsies from all patients at variable levels. Recombinant virus DNA was detected by PCR in day-30 and day-60 tumor biopsies from all patients except patient 1. A high level of neutralizing antiadenovirus antibodies was detected in patient 1 before Ad-beta-gal injection whereas it was low (patient 3) or undetectable in the other two patients. All patients developed potent CD4 type 1 helper T cell (Th1) responses to adenoviral particles which increased gradually over time after injection. Antiadenovirus cytotoxic T lymphocyte responses were consistently boosted in the two patients examined (patients 3 and 4). Sustained production of anti-beta-galactosidase IgG was observed in all patients except patient 1. Consistent with anti-beta-gal antibody production, all patients except patient 1 developed intense, dose-dependent Th1 responses to soluble beta-galactosidase which increased over time. Strong beta-galactosidase-specific cytotoxic T lymphocyte responses were detected in patients 2, 3, and 4. Our results clearly show that despite the intensity of antiadenovirus responses, transgene protein expression was sufficient to induce strong and prolonged immunity in three patients. Recombinant adenovirus injected directly into the tumor is a highly efficient vector for immunizing patients against the transgene protein.

Adenoviridae↗
PubMed1997

Aerosol administration of a recombinant adenovirus expressing CFTR to cystic fibrosis patients: a phase I clinical trial.

Ad CFTR, a replication-deficient adenovirus expressing the human cystic fibrosis transmembrane conductance regulator (CFTR), was administered by aerosolization in a single escalating dose to three pairs (cohorts) of cystic fibrosis (CF) patients. Buffer only was administered to the nose and lungs 9-14 days before nasal instillation of virus followed the day after by aerosolization of Ad CFTR to the lung. Nasal doses (defined in terms of viral plaque forming units, pfu) were 10(5), 10(7), and 4 x 10(8), whereas aerosolized doses were 10(7), 10(8), 5.4 x 10(8) for each cohort, respectively. No acute toxic effects were observed in the first 4 weeks after virus treatment. Shedding of infectious Ad CFTR was never detected, whereas detection of vector DNA sequences and CFTR expression demonstrated DNA transfer to the nose and airways of patients. No significant deviations in immunological and inflammatory parameters were observed in serum and in bronchoalveolar lavage (BAL). Importantly, for all patients, the serum anti-adenovirus antibody levels did not change significantly from baseline and no antibodies against adenovirus were found in BAL.

Adenoviridae↗
PubMed1997

The embryo versus endometrium controversy revisited as it relates to predicting pregnancy outcome in in-vitro fertilization-embryo transfer cycles.

To evaluate embryonic and endometrial factors for their value in predicting pregnancy outcome in in-vitro fertilization (IVF) and embryo transfer, a retrospective data collection and prospective uterine artery colour Doppler imaging study was performed in a university-based IVF-embryo transfer programme setting. A total of 210 patients were included and grouped as follows: (I) IVF with controlled ovarian stimulation (214 cycles); (II) frozen-thaw cycle of autologous embryos (30 cycles); (III) oocyte donation, no cryopreservation (12 cycles); (IV) frozen-thaw cycle with embryos from donated oocytes (10 cycles). Embryo quality was significantly better in pregnant than non-pregnant cycles (group I, P = 0.0104; groups II-IV, P = 0.0418). The endometrial echo was significantly thicker in pregnant versus non-pregnant patients in group I (P = 0.0059), but not in groups II-IV (P = 0.741). Past uterine surgery or abnormalities had no effect on pregnancy outcome. There were no significant differences in mean uterine artery resistance index or peak systolic velocity in pregnant versus non-pregnant patients in groups II-IV. Thus, embryo quality is the most reliable predictor of pregnancy outcome. Endometrial measurements were significantly thicker in subsequently pregnant patients only in group I, where the endometrium reflects the hormonal environment. Doppler parameters were not useful in predicting pregnancy outcome.

Arteries↗
PubMed1996

Phase I study of a recombinant adenovirus-mediated gene transfer in lung cancer patients.

BACKGROUND: Despite vigorous efforts at curbing tobacco consumption and aggressive combined-modality treatment programs, both the incidence of and the mortality from lung cancer have remained virtually unchanged in the last 10 years. More effective innovative therapies are clearly needed. The direct transfer into tumor cells of tumor suppressor genes or toxic gene products that specifically promote tumor cell death and spare nonmalignant cells is a potentially novel anticancer treatment approach that should be investigated. PURPOSE: On the basis of compelling preclinical data, we initiated a phase I study involving six patients with inoperable lung cancer and an endobronchial lesion accessible by bronchoscopy. Our purpose was to evaluate the feasibility, tolerance, and clinical, biologic, and immunologic effects of the intratumoral administration of a recombinant, replication-deficient adenovirus (rAd.RSV beta-gal), using the Rous sarcoma virus promoter to drive transcription of the Escherichia coli lacZ marker gene that encodes for the bacterial enzyme beta-galactosidase (beta-gal). METHODS: From June 1994 through April 1995, six patients (five males and one female) were enrolled in the trial. A single dose of recombinant virus suspension containing 10(7) or 10(8) plaque-forming units (PFU) was injected intratumorally into two successive cohorts of three patients. Eligible patients received concomitant chemotherapy. Patients were kept under isolation conditions from 3 days before the injection was given until virus excretion was undetectable. Biopsy specimens of the tumor and surrounding mucosa were collected on the 8th day and at 1, 2, and 3 months after injection. They were analyzed by cell culture, polymerase chain reaction (PCR), and beta-gal expression for the presence of recombinant adenovirus. So that the risk of virus recombination or complementation could be minimized, wildtype adenovirus carriers among the hospital staff (identified by PCR) were excluded from contact with patients who were potentially excreting recombinant virus. RESULTS: beta-gal was expressed in tumor biopsy specimens of three patients (one who received the 10(7) PFU dose level and two who received 10(8)). Bronchoalveolar lavage specimens collected immediately after injection were positive for recombinant adenovirus when analyzed in culture and by PCR. All biologic fluids were negative for recombinant virus as judged by PCR after day 12, with the exception of bronchoalveolar lavage specimens (positive PCR up to 90 days in two of three patients treated with 10(8) PFU). The blood samples obtained from the three patients treated with 10(8) PFU showed positive PCR results immediately after virus injection. Patients were kept in isolation for a median of 17 days. The most common toxic effects were moderate bleeding (occurring in two patients) during bronchoscopy and fever (seen in four patients). Endoscopic and clinically objective antitumor responses were seen in four patients, including one patient who showed a complete response by pathologic evaluation. The median survival for the patients was 12.5 months (range, 3-16+ months). Throughout the study, hospital staff remained negative for recombinant adenovirus infection. CONCLUSIONS: This ongoing phase I study has demonstrated that a recombinant adenovirus-mediated marker gene, such as rAd.RSV beta-gal, can be safely introduced into humans and that the gene product is expressed by lung tumor cells of the host.

Adenoviridae↗
PubMed1996

Maxillary and cranial base changes during treatment with functional appliances.

The purpose of this prospective study was to investigate the maxillary and the cranial base changes after treatment with the Harvold activator and the Fränkel function regulator appliances. Forty-two children, who are 10 to 13 years old, with Class II, Division 1 malocclusions were matched in triads according to age and sex and randomly assigned to either the control, Harvold activator, or Fränkel function regulator group. Lateral cephalometric radiographs were taken at the start of the study and 18 months later. Both appliances reduced the overjet by tipping the maxillary incisors palatally and, as a consequence, the length of the maxillary arch was reduced. The appliances had no effect on either the horizontal or vertical position of the maxillary molars. Small, but statistically significant, changes in the cranial base angle in the Fränkel function regulator group were attributed to relatively large changes at basion in several children, influencing the results because of the small size of the sample. The appliances had no effect on the position of the maxilla.

Activator Appliances↗