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1.
J Child Neurol ; 35(13): 901-907, 2020 11.
Article in English | MEDLINE | ID: mdl-32720856

ABSTRACT

Genetically determined leukoencephalopathies comprise a group of rare inherited white matter disorders. The majority are progressive diseases resulting in early death. We performed a cross-sectional pilot study including 55 parents from 36 families to assess the level of stress experienced by parents of patients with genetically determined leukoencephalopathies, aged 1 month to 12 years. Thirty-four mothers and 21 fathers completed the Parenting Stress Index-4th Edition. One demographic questionnaire was completed per family. Detailed clinical data was gathered on all patients. Statistical analysis was performed with total stress percentile score as the primary outcome. Mothers and fathers had significantly higher stress levels compared with the normative sample; 20% of parents had high levels of stress whereas 11% had clinically significant levels of stress. Mothers and fathers had comparable total stress percentile scores. We identified pediatric behavioral difficulties and gross motor function to be factors influencing stress in mothers. Our study is the first to examine parental stress in this population and highlights the need for parental support early in the disease course. In this pilot study, we demonstrated that using the Parenting Stress Index-4th Edition to assess stress levels in parents of patients with genetically determined leukoencephalopathies is feasible, leads to valuable and actionable results, and should be used in larger, prospective studies.


Subject(s)
Leukoencephalopathies/psychology , Parents/psychology , Stress, Psychological/psychology , Adult , Child , Child, Preschool , Cross-Sectional Studies , Female , Humans , Infant , Male , Pilot Projects , Surveys and Questionnaires
2.
Transplantation ; 71(1): 70-8, 2001 Jan 15.
Article in English | MEDLINE | ID: mdl-11211198

ABSTRACT

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.


Subject(s)
Cyclosporine/administration & dosage , Cyclosporine/pharmacokinetics , Heart Transplantation/immunology , Adolescent , Adult , Aged , Chemistry, Pharmaceutical , Emulsions/administration & dosage , Humans , Maximum Tolerated Dose , Middle Aged , Oils/administration & dosage , Therapeutic Equivalency , Time Factors
4.
J Cell Biochem ; 78(2): 278-96, 2000 May.
Article in English | MEDLINE | ID: mdl-10842322

ABSTRACT

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.


Subject(s)
Interleukin-1/pharmacology , Lipopolysaccharides/pharmacology , Promoter Regions, Genetic/drug effects , Receptors, Bradykinin/genetics , Base Sequence , Binding Sites/genetics , Cell Line , DNA/genetics , DNA/metabolism , DNA Footprinting/methods , DNA Primers/genetics , Gene Expression Regulation/drug effects , Humans , Molecular Sequence Data , Polymerase Chain Reaction/methods , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptor, Bradykinin B1 , Transcription Factors/metabolism , Transfection
5.
Prog Transplant ; 10(4): 199-200, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11216175
6.
Transplantation ; 68(5): 663-71, 1999 Sep 15.
Article in English | MEDLINE | ID: mdl-10507486

ABSTRACT

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.


Subject(s)
Cyclosporine/administration & dosage , Heart Transplantation , Immunosuppressive Agents/administration & dosage , Adolescent , Adult , Aged , Cyclosporine/adverse effects , Cyclosporine/therapeutic use , Double-Blind Method , Emulsions , Female , Graft Rejection/physiopathology , Humans , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Oils , Postoperative Complications , Safety , Time Factors , Treatment Outcome
7.
J Transpl Coord ; 9(2): 109-13, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10703392

ABSTRACT

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.


Subject(s)
Heart Transplantation/psychology , Histrionic Personality Disorder/prevention & control , Histrionic Personality Disorder/psychology , Stress, Psychological/prevention & control , Stress, Psychological/psychology , Adaptation, Psychological , Counseling/methods , Female , Heart Transplantation/adverse effects , Heart Transplantation/nursing , Histrionic Personality Disorder/complications , Histrionic Personality Disorder/diagnosis , Humans , Middle Aged , Nurse-Patient Relations , Nursing Staff, Hospital/psychology , Social Support , Stress, Psychological/complications , Stress, Psychological/diagnosis , Treatment Outcome , Workload
8.
J Heart Lung Transplant ; 17(4): 430-6, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9588589

ABSTRACT

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.


Subject(s)
Employment , Lung Transplantation , Adult , Colorado/epidemiology , Cystic Fibrosis/diagnosis , Cystic Fibrosis/surgery , Disabled Persons/statistics & numerical data , Discriminant Analysis , Employment/statistics & numerical data , Female , Humans , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/surgery , Lung Transplantation/methods , Lung Transplantation/physiology , Lung Transplantation/rehabilitation , Male , Middle Aged , Ontario/epidemiology , Pulmonary Emphysema/diagnosis , Pulmonary Emphysema/surgery , Retirement/statistics & numerical data , Self-Assessment , Unemployment/statistics & numerical data , Vital Capacity/physiology , Walking/physiology
9.
Am J Med Sci ; 315(3): 161-78, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9519929

ABSTRACT

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.


Subject(s)
Bronchiolitis Obliterans/prevention & control , Lung Transplantation/adverse effects , Animals , Bronchiolitis Obliterans/etiology , Bronchiolitis Obliterans/immunology , Bronchiolitis Obliterans/therapy , Disease Models, Animal , Graft Rejection , Humans , Immunosuppression Therapy , Risk Factors
10.
Am J Pathol ; 152(1): 125-33, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9422530

ABSTRACT

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.


Subject(s)
Chemokine CCL2/metabolism , Endometriosis/metabolism , Endometrium/metabolism , Adult , Chemokine CCL2/genetics , Endometriosis/pathology , Endometriosis/physiopathology , Female , Humans , Immunohistochemistry , In Situ Hybridization , Menstrual Cycle/physiology , RNA, Messenger/metabolism , Reference Values
11.
Am J Respir Crit Care Med ; 155(1): 285-90, 1997 Jan.
Article in English | MEDLINE | ID: mdl-9001326

ABSTRACT

To clarify the usefulness of spirometry to assess the function of the lung allograft post-transplant, we retrospectively reviewed 351 sequential spirometry measurements performed by 65 healthy recipients after the 80th postoperative day when the clinical evaluation and fiberoptic bronchoscopy with transbronchial biopsies and bronchoalveolar lavage excluded significant rejection or infection in the allograft. The mean coefficients of variation (CV) and significant values for change (SC) for the FVC, FEV1, and FEF25-75% were calculated according to the type of transplant procedure (heart-lung and double-lung [HL-DL] versus single-lung [SL]), and to the time after transplant when the spirometry measurements were obtained < or = 1 yr versus > 1 yr). The SC for the FVC decreased with time after transplantation for both HL-DL (< or = 1 yr: 17% versus > 1 yr: 7%) and SL recipients (< or = 1 yr: 13% versus > 1 yr: 8%). The higher degree of variability within the first year was primarily due to increasing values especially in the HL-DL recipients. The SC for the FEV1 also decreased over time for HL-DL recipients (< or = 1 yr: 18% versus > 1 yr: 9%) but was similar for SL recipients at both intervals (13%). Our results suggest that decreases of > or = 11% in FVC or 12% in FEV1 in HL-DL recipients and > or = 12% in FVC or 13% in FEV1 for SL recipients indicate a significant decrease in allograft function that may be due to infection or rejection.


Subject(s)
Lung Transplantation , Spirometry , Forced Expiratory Volume , Humans , Maximal Midexpiratory Flow Rate , Retrospective Studies , Time Factors , Vital Capacity
12.
Am J Obstet Gynecol ; 175(6): 1620-5, 1996 Dec.
Article in English | MEDLINE | ID: mdl-8987950

ABSTRACT

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.


Subject(s)
Chemokine CCL2/blood , Endometriosis/blood , Adult , Cell Line , Chemotaxis , Endometriosis/pathology , Enzyme-Linked Immunosorbent Assay , Female , Humans , Monocytes/physiology , Osmolar Concentration , Reference Values
13.
Hum Reprod ; 11(10): 2269-75, 1996 Oct.
Article in English | MEDLINE | ID: mdl-8943541

ABSTRACT

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.


Subject(s)
Cytokines/pharmacology , Danazol/pharmacology , Endometriosis/metabolism , Estradiol/pharmacology , Estrogen Antagonists/pharmacology , Gonadal Steroid Hormones/pharmacology , Inflammation Mediators/pharmacology , Interleukin-6/metabolism , Progesterone/pharmacology , Adult , Cells, Cultured , Endometriosis/pathology , Female , Hormone Antagonists/pharmacology , Humans , Interleukin-1/pharmacology , Mifepristone/pharmacology , Tumor Necrosis Factor-alpha/pharmacology
14.
Am J Respir Crit Care Med ; 153(4 Pt 1): 1451-5, 1996 Apr.
Article in English | MEDLINE | ID: mdl-8616581

ABSTRACT

This study evaluated aerosolized cyclosporine as rescue therapy for lung transplant recipients with unremitting chronic rejection. Nine patients with histologic active obliterative bronchiolitis and progressively worsening airway obstruction refractory to conventional immune suppression received aerosolized cyclosporine. Improvement in rejection histology was seen in seven of nine patients. We compared the changes in the FVC and FEV1 over time using linear regression analysis in these seven histologic responders and nine historical control patients. During the pretreatment period for both the experimental and control groups, the FVC and FEV1 declined at comparable rates. After aerosolized cyclosporine there was stabilization of pulmonary function, whereas in the controls there was continued decline. Cyclosporine blood levels were less than 50 ng/ml 24 h after an aerosolized dose of 300 mg in five patients receiving oral tacrolimus. Nephrotoxicity, hepatotoxicity, and a greater than expected rate of infection was not observed. This study suggests that aerosolized cyclosporine is safe and may be effective therapy for refractory chronic rejection in lung transplant recipients.


Subject(s)
Cyclosporine/therapeutic use , Graft Rejection/drug therapy , Immunosuppressive Agents/therapeutic use , Lung Transplantation/immunology , Adult , Aerosols , Bronchiolitis Obliterans/drug therapy , Chronic Disease , Cyclosporine/administration & dosage , Female , Humans , Immunosuppressive Agents/administration & dosage , Male , Respiratory Function Tests
15.
Am J Respir Crit Care Med ; 152(6 Pt 1): 2037-43, 1995 Dec.
Article in English | MEDLINE | ID: mdl-8520773

ABSTRACT

Medical and surgical advances have made lung transplantation a feasible therapy for end-stage lung disease. Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBBx) is an accepted technique for detecting clinically evident rejection and infection in the allograft of symptomatic recipients. The role of TBBx and BAL in managing asymptomatic recipients is less defined. We retrospectively examined the role of bronchoscopy with TBBx and BAL in 1124 bronchoscopy procedures that were performed on 161 lung transplant recipients between January 1, 1988, and December 31, 1993. Bronchoscopy was performed when there was a change in the recipient's clinical condition, to assess the response of the allograft to a prior therapy, and under a surveillance protocol for detecting asymptomatic rejection or infection. Surveillance bronchoscopy was performed according to the following schedule: 10-14 days after transplantation, every 3 mo during the first year, every 4 mo during the second year, and at 6-mo intervals thereafter. Surveillance bronchoscopies were defined as procedures where the physician felt that there was no infection or rejection in the allograft on the basis of a standardized clinical evaluation, which excluded the results of the TBBx and BAL. We compared the clinical impression recorded by the physician on the day of the procedure with the final diagnosis determined after the results of the TBBx and BAL were known. We found unsuspected rejection and/or infection that required therapy in 25% (90/355) of all surveillance bronchoscopy procedures. Most episodes (61/90, 68%) of unsuspected rejection and/or infection occurred in the first 6 mo after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Bronchi/pathology , Bronchoalveolar Lavage Fluid , Bronchoscopy , Lung Transplantation , Postoperative Complications/diagnosis , Graft Rejection/diagnosis , Heart-Lung Transplantation , Humans , Infections/diagnosis , Infections/etiology , Lung Transplantation/adverse effects
16.
Ann Thorac Surg ; 60(3): 580-4; discussion 584-5, 1995 Sep.
Article in English | MEDLINE | ID: mdl-7545889

ABSTRACT

BACKGROUND: A prospective clinical trial was undertaken to compare the efficacy of tacrolimus (FK 506) versus cyclosporine as the primary immunosuppressive agent after lung transplantation. METHODS: Between October 1991 and May 1994, 133 single-lung and bilateral-lung recipients were randomized to receive either cyclosporine (n = 67) or tacrolimus (n = 66). The two groups were similar in age, sex, and underlying disease. RESULTS: One-year and 2-year survival rates were similar in the two groups, although the trend was toward increased survival with tacrolimus. Acute rejection episodes per 100 patient-days were fewer (p = 0.07) in the tacrolimus group (0.85) than in the cyclosporine group (1.09). Obliterative bronchiolitis developed in significantly fewer patients in the tacrolimus group (21.7%) compared with the cyclosporine group (38%) (p = 0.025), and there was greater freedom from obliterative bronchiolitis over time for patients receiving tacrolimus (p < 0.03). Significantly more cyclosporine-treated patients (n = 13) required crossover to tacrolimus than tacrolimus-treated patients to cyclosporine (n = 2) (p = 0.02). The switch to tacrolimus controlled persistent acute rejection in 6 of 9 patients. The overall incidence of infections was similar in the two groups, although bacterial infections were more common with cyclosporine (p = 0.0375), whereas the risk of fungal infection was higher with tacrolimus (p < 0.05). CONCLUSIONS: This trial demonstrates the advantage of tacrolimus in reducing the risk of obliterative bronchiolitis, the most important cause of long-term morbidity and mortality after lung transplantation.


Subject(s)
Cyclosporine/therapeutic use , Immunosuppressive Agents/therapeutic use , Lung Transplantation , Tacrolimus/therapeutic use , Acute Disease , Adult , Bronchiolitis Obliterans/chemically induced , Bronchiolitis Obliterans/prevention & control , Cross-Over Studies , Cyclosporine/adverse effects , Female , Follow-Up Studies , Fungemia/etiology , Graft Rejection/prevention & control , Humans , Incidence , Lung Transplantation/adverse effects , Male , Middle Aged , Pneumonia, Bacterial/etiology , Prospective Studies , Risk Factors , Survival Rate , Tacrolimus/adverse effects
17.
Surgery ; 118(2): 385-91, 1995 Aug.
Article in English | MEDLINE | ID: mdl-7638755

ABSTRACT

BACKGROUND: Refractory rejection is a major cause of morbidity and death among lung transplant recipients. Traditional rescue therapies have proved only modestly successful. We recently demonstrated the safety of inhaled cyclosporine for patients with end-stage chronic rejection; this trial was extended to patients with refractory acute rejection. The present study was to determine whether effective inhaled cyclosporine therapy was correlated with suppression of cytokine gene expression. METHODS: Twelve lung transplant recipients were studied. Maintenance therapy, cyclosporine or FK 506, azathioprine, and prednisone, was continued, and inhaled cyclosporine at a dose of 300 mg/day was added. Pulmonary function testing and histologic characteristics from transbronchial biopsy specimens were used to assess efficacy of therapy. Bronchoalveolar lavage (BAL) and peripheral blood cells were analyzed for the presence of messenger RNA by using 32P-labeled primers of cytokines interleukin-2 (IL-2), IL-6, IL-10, and interferon-gamma (gamma) via reverse transcriptase-polymerase chain reaction. RESULTS: Nine of 12 patients (five with acute rejection, four with chronic rejection) exhibited histologic resolution of rejection within 3 months of inhaled cyclosporine therapy. Pulmonary function (forced expiratory volume in 1 second) improved from pretherapy levels in the patients with acute rejection (p < 0.05). All of the nine histologic responders exhibited 4- to 150-fold decreases (p < 0.05) in IL-6 and interferon-gamma messenger RNA levels in the BAL, whereas the three patients who failed exhibited persistent or increased cytokine profiles. IL-2 and IL-10 in BAL and peripheral blood lymphocyte cytokines were not informative. CONCLUSIONS: These results indicate that inhaled cyclosporine is effective therapy for refractory pulmonary rejection and that its mechanism of action is associated with suppression of proinflammatory cytokines IL-6 and interferon-gamma within the allograft.


Subject(s)
Cyclosporine/therapeutic use , Cytokines/genetics , Gene Expression , Graft Rejection/drug therapy , Lung Transplantation , Lung/physiopathology , Administration, Inhalation , Adult , Blood Cells/metabolism , Bronchoalveolar Lavage Fluid/chemistry , Cytokines/metabolism , Female , Graft Rejection/pathology , Graft Rejection/physiopathology , Humans , Lung/pathology , Lymphocytes/metabolism , Male , Middle Aged
18.
J Thorac Cardiovasc Surg ; 110(1): 4-13; discussion 13-4, 1995 Jul.
Article in English | MEDLINE | ID: mdl-7609567

ABSTRACT

With a prevalence of 34% (55/162 at-risk recipients) and a mortality of 25% (14/55 affected recipients), obliterative bronchiolitis is the most significant long-term complication after pulmonary transplantation. Because of its importance, we examined donor-recipient characteristics and antecedent clinical events to identify factors associated with development of obliterative bronchiolitis, which might be eliminated or modified to decrease its prevalence. We also compared treatment outcome between recipients whose diagnosis was made early by surveillance transbronchial lung biopsy before symptoms or decline in pulmonary function were present versus recipients whose diagnosis was made later when symptoms or declines in pulmonary function were present. Postoperative airway ischemia, an episode of moderate or severe acute rejection (grade III/IV), three or more episodes of histologic grade II (or greater) acute rejection, and cytomegalovirus disease were risk factors for development of obliterative bronchiolitis. Recipients with obliterative bronchiolitis detected in the preclinical stage were significantly more likely to be in remission than recipients who had clinical disease at the time of diagnosis: 81% (13/15) versus 33% (13/40); p < 0.05). These results indicate that acute rejection is the most significant risk factor for development of obliterative bronchiolitis and that obliterative bronchiolitis responds to treatment with augmented immunosuppression when it is detected early by surveillance transbronchial biopsy.


Subject(s)
Bronchiolitis Obliterans/etiology , Heart-Lung Transplantation , Lung Transplantation , Postoperative Complications/etiology , Adolescent , Adult , Bronchiolitis Obliterans/diagnosis , Bronchiolitis Obliterans/epidemiology , Child , Child, Preschool , Female , Follow-Up Studies , Graft Rejection/complications , HLA Antigens/analysis , Humans , Immunosuppression Therapy , Infant , Lung Diseases/complications , Lung Diseases/surgery , Male , Middle Aged , Multivariate Analysis , Postoperative Complications/diagnosis , Postoperative Complications/epidemiology , Prevalence , Risk Factors , Survival Analysis , Treatment Outcome
19.
J Heart Lung Transplant ; 14(4): 692-8, 1995.
Article in English | MEDLINE | ID: mdl-7578177

ABSTRACT

BACKGROUND AND METHODS: To determine the long-term functional outcome for single versus bilateral lung transplant for nonseptic obstructive lung disease, we compared the results from 39 single and nine bilateral lung transplant procedures. The nine bilateral lung transplants included three en bloc double lung and six bilateral sequential lung transplants. RESULTS: Early deaths within 30 days of transplantation occurred in two of nine (22%) bilateral and 4 of 39 (10%) single lung transplants (p = Not significant). Compared with pretransplant values, pulmonary function as assessed by the spirometric indexes of the percent predicted forced vital capacity, forced expiratory volume in one second, forced expiratory volume in one second/forced vital capacity, and forced expiratory flow at 25% and 75% of forced vital capacity improved significantly up to at least 12 months after transplantation for both single and bilateral lung transplant recipients. The degree of pulmonary function improvement was better in single as compared with bilateral lung recipients. By 6 months after transplantation, all but one single and all bilateral lung recipients were in New York Heart Association class I or II (p = Not significant). One-year survival was significantly better after single (77%) compared with after bilateral lung transplantation (35%) (p < 0.05). CONCLUSIONS: These results suggest that single lung transplantation is the procedure of choice for patients with nonseptic obstructive lung disease.


Subject(s)
Lung Diseases, Obstructive/surgery , Lung Transplantation/methods , Lung Volume Measurements , Postoperative Complications/physiopathology , Spirometry , Adolescent , Adult , Aged , Child , Female , Follow-Up Studies , Humans , Lung/physiopathology , Lung Diseases, Obstructive/diagnosis , Lung Diseases, Obstructive/mortality , Lung Diseases, Obstructive/physiopathology , Lung Transplantation/mortality , Lung Transplantation/physiology , Male , Middle Aged , Postoperative Complications/diagnosis , Postoperative Complications/mortality , Treatment Outcome , Ventilation-Perfusion Ratio/physiology
20.
Ann Thorac Surg ; 59(6): 1581-3, 1995 Jun.
Article in English | MEDLINE | ID: mdl-7771852

ABSTRACT

We present a case of bridging to lung transplantation by means of laser ablation of emphysematous bullae in a lung transplant candidate. The patient underwent successful left single-lung transplantation 17 months after lung reduction. He is now well 3 months after transplantation.


Subject(s)
Lung Transplantation , Pneumonectomy/methods , Pulmonary Emphysema/surgery , Humans , Laser Therapy , Male , Middle Aged , Pulmonary Emphysema/diagnostic imaging , Radiography , Thoracoscopy , Video Recording , Waiting Lists
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