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Biomedical subjects

I Paradis

Publications and source records attributed to I Paradis.

At least 19 recordsLinked to original sources
PubMed2001

Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine--results at 24 months after transplantation.

BACKGROUND: The widespread use of cyclosporine has improved the survival of cardiac transplant patients as a result of reduced morbidity and mortality from rejection and infection. The original oil-based form of cyclosporine demonstrated unpredictable absorption resulting in an increased frequency of acute and chronic rejection in patients with poor bioavailability. The primary end. points of the present, prospective, randomized multicenter, double-blind trial were to compare the efficacy of the micro-emulsion form of cycolsporine (CsA-NL) with the oil-based formulation as determined by cardiac allograft and recipient survival and the incidence and severity of the acute rejection episodes and to determine the safety and tolerability of CsA-NL compared with Sandimmune CsA-(SM) in the study population. The 6-month analysis of the study showed reduced number of CsA-NL patients requiring antilymphocyte antibody therapy for rejection, fewer International Society of Heart and Lung Transplantation grade > or =3A rejections in female patients and fewer infections. Our report represents the final analysis of the results 24 months after transplantation. METHODS: A total of 380 patients undergoing de novo cardiac transplants at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial evaluating the efficacy and safety of CsA-NL versus CsA-SM. Acute allograft rejection was diagnosed by endomyocardial biopsy and graded according to the International Society of Heart and Lung Transplantation nomenclature. Kaplan-Meier analysis and Fisher's exact test were used for comparisons between groups. RESULTS: After 24 months, allograft and recipient survival were identical in both groups. There were fewer CsA-NL patients (6.9%) requiring antilymphocyte antibody therapy for rejection than in the CsA-SM-treated patient group (17.7%, P=0.002). There were fewer discontinuations of study drug for treatment failures in the CsA-NL groups (7; 3.7%) compared with the CsA-SM group (18; 9.4%, P=0.037). The average corticosteroid dose was lower in the CsA-NL group (0.37 mg/kg/day) compared with the CsA-SM group (0.48 mg/kg/day, P=0.034) over the 24-month study period. Overall, there was no difference in blood pressure or creatinine between the two study groups. CONCLUSIONS: The final results of this multi-center, randomized study of two forms of cyclosporine confirmed that there were fewer episodes of rejection requiring antilymphocyte antibodies and fewer study discontinuations for treatment failures in CsA-NL-treated patients compared to those treated with CsA-SM. The use of CsA-NL did not predispose these patients to a higher risk of adverse events.

Adolescent↗
PubMed2000

In vivo protein-DNA interactions at the kinin B(1) receptor gene promoter: no modification on interleukin-1 beta or lipopolysaccharide induction.

The kinin B(1) receptor (B(1)R) gene is strongly upregulated following tissue injury and inflammation. In an attempt to define the regulatory elements that account for the control of B(1)R gene expression, we have conducted in vivo footprinting analysis of the B(1)R gene promoter region in three human cell types: embryonic lung fibroblast cells (IMR-90), embryonic kidney cells (HEK-293), and primary cultures of vascular umbilical smooth muscle cells. Initial in vitro delineation of the B(1)R gene promoter by transient transfection experiments with a reporter gene indicated that a 1.4-kb region, located just upstream of the transcription initiation site, bears all the characteristics of a core promoter with a functional TATA box and additional positive and negative control elements, as some of them could be tissue-specific. In vivo ultraviolet and dimethylsulfate footprinting analyses of the 1.4-kb region revealed no difference between the footprint patterns in the three cell types studied. We found that even in the noninduced state, the B(1)R gene promoter is possibly bound by several sequence-specific DNA binding proteins (GATA-1, PEA3, AP-1, CAAT, Sp1, Pit-1a, Oct-1, CREB). Some other footprints were detected on sequences that do not correspond to any known transcription factor binding site. No additional changes in protein-DNA complexes were observed upon treatment with interleukin-1 beta (IL-1beta) or bacterial lipopolysaccharide, shown previously to induce B(1)R gene expression. These results indicate that complex protein-DNA interactions exist at the B(1)R gene promoter prior to induction by external stimuli even in cells (HEK-293) that do not express a functional B(1)R.

Base Sequence↗
PubMed1999

Safety, tolerability and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil based formulation of cyclosporine--results at six months after transplantation.

BACKGROUND: The introduction of cyclosporine has resulted in significant improvement in the survival of cardiac allograft recipients due to decreased mortality from infection and rejection. The original oil-based cyclosporine formulation exhibits variable and unpredictable bioavailability that correlates with an increased incidence of acute and chronic rejection in those patients in whom this is most pronounced. The primary objectives of this prospective, multicenter, randomized, double-blind study in cardiac transplant patients were: to compare the efficacy of cyclosporine microemulsion (CsA-NL) with oil-based cyclosporine (CsA-SM) as measured by cardiac allograft and recipient survival and the incidence and severity of acute rejection episodes; and to assess the safety and tolerability of CsA-NL compared with CsA-SM in this population. This report represents the analysis of results 6 months after transplantation. METHODS: A total of 380 patients undergoing their first cardiac transplant at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial examining the safety and efficacy of CsA-NL versus CsA-SM. Rejection was diagnosed using endomyocardial biopsy and were graded according to standardized criteria of the International Society of Heart and Lung Transplantation (ISHLT). Clinical parameters were monitored during the study. Survival and freedom from were used for analysis as was Fisher's exact test for comparisons between groups. RESULTS: At 6 months after transplantation, allograft and patient survival were the same for both groups. The frequency of ISHLT grade 3A or greater episodes in the two groups was identical. Fewer CsA-NL patients (5.9%) required antilymphocyte antibody (ATG or OKT-3) therapy for rejection compared with the CsA-SM-treated patients (14.1%, P=0.01). Females with ISHLT rejection grade > or = 3A treated with CsA-NL had a 46% lower incidence of rejection compared with the CsA-SM-treated group (31.3% vs. 57.6%, P=0.032). Fewer infections were seen in the CsA-NL. With the exception of baseline and 1 week posttransplant creatinines which were higher in the CsA-NL group, the overall creatinine was not significantly different between the two groups. CONCLUSIONS: This multicenter, randomized study of cardiac transplant recipients documented less severe rejection (in particular those requiring antibody therapy) and a lower incidence of infection in CsA-NL-treated patients. Results from the female subgroup analysis suggest that the improved bioavailability of CsA-NL might reduce the frequency of rejection episodes in female patients. The use of CsA-NL was not associated with an increased risk of adverse events.

Adolescent↗
PubMed1999

Interventions in a heart transplant recipient with a histrionic personality disorder.

Organ transplantation is a psychosocially demanding process. Patients must undergo a comprehensive evaluation to await a donor organ that may never become available. After transplantation, recipients must deal with the acceptance of a new organ and comply with a medical regimen that includes numerous medications, follow-up exams, and procedures. Emotional well-being is monitored throughout the transplant process. However, despite the best of efforts and thorough pretransplant bio-psycho-social evaluations, it is possible for patients to have significant psychopathology that remains undetected. Following the stress of transplantation, such patients may present with exacerbation of symptomatology, which has the potential to negatively affect compliance and long-term outcome.

Adaptation, Psychological↗
PubMed1998

Bronchiolitis obliterans: pathogenesis, prevention, and management.

Increasing early success-post lung transplant has been tempered by the long-term development of histologic bronchiolitis obliterans (OB) or of the progressive airway obstruction which is called bronchiolitis obliterans syndrome (BOS). Multiple lines of evidence suggest that OB/BOS is due to an injury directed against the epithelial cells in the airways of the donor lung by the immune system of the recipient. Acute rejection is the strongest risk factor for the subsequent development of this process. Efforts to prevent or minimize acute rejection may reduce the prevalence of OB/BOS. Results of treatment with augmented immunosuppression have been disappointing but the treatment of complicating infections in the allograft can be beneficial. Multicenter studies are needed to assess the efficacy of new immunosuppressive agents in preventing or treating OB/BOS.

Animals↗
PubMed1998

Increased expression of monocyte chemotactic protein-1 in the endometrium of women with endometriosis.

The pathogenesis of endometriosis, a disease widely believed to arise from an aberrant growth of endometrial tissue outside the uterus, is still unclear. We have previously observed that cytokine-stimulated endometrial cells of women with endometriosis secrete in vitro increased amounts of monocyte chemotactic protein-1 (MCP-1). This factor may be important in the recruitment and activation of peritoneal macrophages observed in endometriosis patients. The present study reports that, in the presence of the disease, such an up-regulation of MCP-1 expression arises in vivo and can be encountered in situ in the intrauterine endometrium. In women with endometriosis, MCP-1 expression was elevated in endometrial glands, both at the level of the protein (immunohistochemistry) and the mRNA (in situ hybridization). This was observed throughout the menstrual cycle and varied according to the stage of the disease. These findings strongly argue in favor of the presence of pathophysiological changes in the eutopic endometrium of patients with endometriosis and make plausible MCP-1 as a key effector cell mediator involved in the pathogenesis of the disease.

Adult↗
PubMed1998

Return to work after lung transplantation.

The social rehabilitation of lung transplant recipients becomes increasingly important as the results of lung transplantation improve. Although return-to-work (RTW) rates have been published for recipients of other organ transplants, no such data are available after lung transplantation. The purpose of this study was to determine what factors influence RTW after lung transplantation. Of 99 lung transplant recipients (43 single, 56 bilateral) surveyed from Denver, Colorado, (n = 49) and Toronto, Ontario, Canada (n = 50), 22% (n = 22) were employed, 38% (n = 38) were unemployed but medically able to work, 29% (n = 29) were medically disabled, and 10% (n = 10) had retired. The RTW rate for those medically able to work was 37% (22/60), and it was identical at each center (n = 11). Only Canadian lung transplant recipients (36%, 4/11) secured new jobs, whereas all Colorado lung transplant recipients returned to their previous employment (100%, 11/11). A stepwise discriminant analysis revealed that (1) pretransplantation employment, (2) a diagnosis of emphysema, cystic fibrosis, or primary pulmonary hypertension, (3) a self-report of being physically able to work, (4) greater functional improvement as measured by post-lung transplantation percent predicted forced vital capacity, and (5) post-lung transplantation 6-minute walk > 550 m positively influenced RTW. This analysis accurately profiled 82% of the employed and 76% of the unemployed recipients for an overall effectiveness of 79%. The findings of this study are that (1) a 37% employment rate for those physically able was comparable to other types of organ transplant recipients, (2) employment was not determined by the type of lung transplantation procedure (single or bilateral), and (3) social factors remain employment barriers for some recipients, but their absence did not guarantee a better employment rate.

Adult↗
PubMed1996

Increased monocyte chemotactic protein-1 level and activity in the peripheral blood of women with endometriosis. Le Groupe d'Investigation en Gynécologie.

OBJECTIVE: Our purpose was to evaluate monocyte chemotactic protein-1 in the peripheral blood of women with and without endometriosis. STUDY DESIGN: Fifty-seven patients with endometriosis at laparoscopy done for infertility and pelvic pain were compared with 44 fertile women with no evidence of endometriosis at tubal ligation by laparoscopy. Monocyte chemotactic protein-1 concentration in the plasma was determined by enzyme-linked immunosorbent assay and its biologic activity was evaluated by measuring monocyte chemotaxis with use of a human histiocytic cell line (U937). RESULTS: Monocyte chemotactic protein-1 concentrations (median and range of values) found in the plasma were higher in patients with endometriosis (163, 0 to 788 pg/ml) than in normal controls (0, 0 to 355 pg/ml). This elevation was significant only in the minimal stage of endometriosis (revised American Fertility Society stage I). However, increased chemotactic activity (mean number of migrating cells/mm2 +/- SEM) was found in the stages I (1240 +/- 141), II (519 +/- 30), and III-IV (523 +/- 23) of the disease compared with normal controls (205 +/- 20). A total of 35% to 44% of this activity was inhibited in the presence of an antibody specific to monocyte chemotactic protein-1. CONCLUSION: Endometriosis is associated with increased level and activity of monocyte chemotactic protein-1 in the peripheral blood. The elevation and activation of this cytokine could play a relevant role in the immunoinflammatory process associated with the disease.

Adult↗
PubMed1996

Secretion of interleukin-6 by human endometriotic cells and regulation by proinflammatory cytokines and sex steroids.

Endometriosis is generally associated with an immunoinflammatory process that takes place in the peritoneal cavity of patients. Interleukin (IL)-6, a multifunctional cytokine involved in numerous immunological and proliferative processes, has been found at high concentrations in the peritoneal fluid of endometriosis patients. The purpose of this study was to investigate the ability of endometriotic cells to produce IL-y and to assess the regulation of its secretion by proinflammatory cytokines and sex steroids. Cultures of human endometriotic cells were exposed to different concentrations of cytokines and sex steroid hormones for varying periods of time. IL-6 secretion was measured using an enzyme-linked immunosorbent assay. Endometriotic cells spontaneously released IL-6 in culture. IL-1 beta and tumour necrosis factor (TNF)-alpha (0.1-100.0 ng/ ml) potentiated IL-y secretion in a time- and dose-dependent manner. Interferon-gamma (0.4-400 ng/ml) induced a dose-related increase in IL-6 secretion and showed a synergistic effect on that secretion in combination with TNF-alpha (10 ng/ ml). Either spontaneous or cytokine-induced IL-6 secretion was inhibited by progesterone (10(-8)-10(-5) M) and danazol (10(-6) M), whereas oestradiol (10(-8)-10(-5) M) had a limited inhibitory effect. The antiprogestin RU486 (10(-8)-10(-4) M) antagonized the inhibitory effects of progesterone and danazol, but showed agonist action when used alone. These findings indicate that endometriotic tissue may actively contribute to the biological changes observed in the peritoneal fluid of endometriosis patients. They also provide new insights into the mechanisms of action of progesterone and those of danazol and RU486 used in the treatment of endometriosis.

Adult↗
PubMed1994

Mixed allogeneic chimerism in lung allograft recipients.

Microchimerism in lung allograft recipients was studied in the autopsies of nine female recipients of male lung grafts who had survived for more than 1 month after transplantation. Using a Y chromosome-specific probe tissues were studied for the presence of donor cells that had migrated beyond the graft itself. They were quantitated by cell counting to give absolute numbers of cells per organ volume. While donor cells were disseminated throughout the body, their numbers were small. These absolute numbers should be studied in a larger group of recipients to determine if they correlate with prognosis and the development of bronchiolitis obliterans.

Adult↗
PubMed1993

A decade of lung transplantation.

OBJECTIVE: The experience accrued at the University of Pittsburgh between March 1982 and December 1992 in the various forms of lung transplantation, including heart-lung, double lung, and single lung, is discussed. SUMMARY BACKGROUND DATA: Heart-lung (n = 97) was the most commonly performed operation followed by double lung (n = 80) and single lung (n = 68). Major indications included primary pulmonary hypertension (n = 76), obstructive lung disease (n = 57), Eisenmenger's syndrome (n = 42), cystic fibrosis (n = 32), and retransplantation (n = 13). Since May 1991, 115 procedures have been performed and heart-lung transplantation has decreased from 61% to 15% of the cases with a corresponding doubling in double lung from 24% to 43% and single lung from 15% to 42%. RESULTS: The 1-, 2-, and 5-year survival rates in all 232 recipients were 61%, 55%, and 44%, respectively. The actuarial survival rate was significantly better for those 107 recent recipients compared to the 125 early recipients (70% vs. 61%). Overall, the 63 single (70%) and 74 double (65%) lung procedures were more successful than heart-lung transplantation (53%). Recently, however, lung transplantation has been associated with an improvement in the survival rate from 48% to 72%. The survival rate has also improved from 53% to 77% for single lung transplant recipients. The causes of death in 106 recipients included infection (n = 40), early allograft dysfunction (n = 23), obliterative bronchiolitis (n = 13), and inoperative bleeding (n = 10). Poor outcomes also included technical problems (n = 6), lymphoma (n = 4), acute rejection (n = 3), diaphragmatic paralysis (n = 2), multisystem organ failure (n = 2), stroke (n = 2), liver failure (n = 1), and airway dehiscence (n = 1). CONCLUSIONS: The long-term outlook for lung transplant recipients has improved. There appears to be significant conservation of organs with single lung and double lung transplantation, finding greater acceptance for diseases once exclusively treated by heart-lung transplantation alone. The improved long-term outlook will be dependent upon better treatment for chronic rejection of the airways that histologically is defined by obliterative bronchiolitis.

Adolescent↗
PubMed1993

Airway obstruction and bronchiolitis obliterans after lung transplantation.

Bronchiolitis obliterans, defined histologically or clinically, is the most significant long-term cause of morbidity and mortality after lung transplantation. It shares many pathogenetic features with chronic allograft dysfunction that can occur in bone marrow, liver, heart, and kidney recipients. Lessons learned in the prevention and management of this disorder in lung recipients therefore should have application to the analogous process that develops in other organ allograft recipients. Because the lung is exposed to the external environment, it can be sampled repeatedly by techniques like bronchoalveolar lavage and transbronchial lung biopsy with little or no long-term adverse consequence to the allograft. Excellent pulmonary function tests also are available with which to assess the functional capacity of the allograft and to correlate with the results from immunologic testing. For these reasons, this disorder in lung recipients could serve as a model to determine the pathogenesis and treatment of the analogous disorder that may develop in other major organ recipients. Because this disorder most likely is immunologic in origin, advances in transplant immunology that create tolerance between the donor and recipient as well as efforts to prevent CMV infection and airway ischemic injury likely will be effective preventive measures. Although augmented immunosuppression appears to be of some benefit in treating bronchiolitis obliterans, it is far from optimal and new or better use of current immunosuppressive medications is warranted. Because the number of recipients at any one center is too few to critically assess the efficacy and safety of different immunosuppressive regimens, it is likely that collaboration between transplant centers will be necessary for success to be achieved.

Adrenal Cortex Hormones↗
PubMed1992

Acute rejection of lung allografts with various immunosuppressive protocols.

Between February 1990 and December 1991, 69 patients who survived for a minimum of 5 days after single-lung (27), double-lung (32), or heart-lung transplantation (10) were studied to learn the incidence and severity of acute rejection and the possible effects of various immunosuppressive protocols on this rejection. Acute rejection was less common (2.1 versus 3.1 episodes/patient) after transplantation in those 30 candidates who received rabbit antithymocyte globulin for the first 5 postoperative days versus the 28 who were maintained on cyclosporine, azathioprine, and prednisone alone (p < 0.05), but no patient escaped at least one episode. Patients given cyclosporine received more 3-day courses of methylprednisolone (p < 0.02) than those given rabbit antithymocyte globulin (2.5 versus 1.7 courses). Although no disadvantage in terms of infectious morbidity was noted in the rabbit antithymocyte globulin group, no obvious intermediate advantage was noted in survival (85% at 12 months) or grade of rejection or airway flows. The most common histopathologic grades were mild (A2) and moderate (A3); the average grade was A2.3. FK 506 was tested in 11 patients, and early results are promising relative to low early and likely fewer late episodes of rejection. No differences were noted in the likelihood of rejection for any procedures.

Acute Disease↗