Clinical trial of FK 506 immunosuppression in adult cardiac transplantation

The new immunosuppressive agent FK 506 was used as primary immunotherapy in conjunction with low-dose steroids and azathioprine in 72 patients subsequent to orthotopic cardiac transplantation. Overall patient survival at a mean follow-up of 360 days was 92%. The number of episodes of cardiac rejection (grade 3A or greater) within 90 days of transplantation was 0.95 per patient. The actuarial freedom from rejection at 90 days was 41%. Achievement of this level of immunosuppression is comparable with that of cyclosporine-based triple-drug therapy with OKT3 immunoprophylaxis. Thirty percent of patients were tapered off all steroids, and the average steroid dose in the group who received steroids was 8.6 mg of prednisone per day. The incidence of infection reflected the diminished necessity for steroids: seven major infections (10%) and 11 minor infections (16%). Renal dysfunction occurred during the perioperative period in most patients in this trial. However, the incidence of hypertension was 54% compared with 70% during the cyclosporine era. Ten adults underwent successful rescue therapy with FK 506 after cardiac rejection refractory to conventional immunotherapy. Side effects of FK 506 were notably few, and the results of the trial are encouraging for the future of the cardiac transplant recipient. © 1992

Connection between igneous activity and extension in the central Mojave metamorphic core complex, California

This is the published version. Copyright 1976 American Geophysical Union. All Rights Reserved.The development of metamorphic core complexes and associated low-angle detachment faults commonly is intimately associated with synextensional igneous activity. In most areas studied to date, the relation of magmatism to extension is obscured by imprecise dating and by the overprint of later tectonic events. We present data from the early Miocene central Mojave metamorphic core complex (CMMCC) which indicate that extension was accompanied by igneous activity, as reflected by prekinematic, synkinematic, and postkinematic plutons and coeval volcanic rocks deposited in the associated extensional basins. The principal intrusion is an early Miocene granite pluton exposed in outcrops across an area greater than 400 km2. Dikes adjacent to the pluton are common in the Mitchel Range, at The Buttes, and at Fremont Peak. The overall orientation of the pluton and associated dikes is west-northwest, roughly perpendicular to the extension direction. Results of U-Pb analyses on zircon from two pluton and two dike samples yield ages of 20 to 23 Ma. Two other dike samples yield inconclusive results. Synextensional basins formed by detachment faulting during the core complex development. Rocks in these basins compose the Jackhammer and Pickhandle formations and filled an elongate, NW trending trough more than 50 km long. The 40Ar/39Ar ages for tuff beds are as old as 23.8±0.3 Ma near the base of the lower Pickhandle Formation and as young as 21.3±0.5 Ma in the uppermost lower Pickhandle. Hence volcanism and plutonism are coeval. The diversity of intrusive relations relative to the timing and development of the mylonitic fabric in the CMMCC precludes any simple cause-and-effect relationship between magmatism and extensional deformation. Rather, magmatism and extension may have been localized at a releasing bend in a transfer-fault system which links extension in the CMMCC with extension in the Colorado River area to the east

A decade (1982 to 1992) of pediatric cardiac transplantation and the impact of FK 506 immunosuppression

The decade from 1982 through 1992 witnessed tremendous growth in pediatric cardiac transplantation. At Children's Hospital of Pittsburgh 66 cardiac transplants were performed during this period (age range 7 hours to 18 years). The cause of cardiomyopathy was congenital (n = 30), cardiomyopathy (n = 29), myocarditis (n = 2), doxorubicin toxicity (n = 2), ischemic (n = 1), valvular (n = 1), and cardiac angiosarcoma (n = 1). Nine children (14 %) required mechanical circulatory support before transplantation: extracorporeal membrane oxygenation (n = 8) and Novacor left ventricular assist system (n = 1) (Baxter Healthcare Corp., Novacor Div., Oakland, Calif.). The mean follow-up time was 2 years (range 4 months to 8 years). The overall survival in the group was 67 %. In children with congenital heart disease (>6 months of age) the perioperative (30 day) mortality was 66 % before mid-1988 (n = 10) and 0 % since mid-1988 (n = 11). The late mortality (>30 days) in children with cardiomyopathy transplanted prior to mid-1988 was 66 % (n = 14) and 7 % since mid-1988 (n = 15). Since mid-1988 1- and 3-year survival was 82 % in children with congenital heart disease and 90 % in children with cardiomyopathy. Twenty-six children have had FK 506 as their primary immunosuppressive therapy since November 1989. Survival in this group was 82 % at 1 and 3 years. The actuarial freedom from grade 3A rejection in the FK group was 60 % at 3 and 6 months after transplantation versus 20 % and 12 %, respectively, in the 15 children operated on before the advent of FK 506, who were treated with cyclosporine-based triple-drug therapy (p < 0.001, Mantel-Cox and Breslow). Twenty of 24 children (83 %) in the FK 506 group are receiving no steroids. The prevalence of posttransplantation hypertension was 4 % in the FK 506 group versus 70 % in the cyclosporine group (p < 0.001, Fisher). Renal toxicity in children treated with FK 506 has been mild. Additionally, eight children have been switched to FK 506 because of refractory rejection and drug toxicity. FK 506 has not produced hirsutism, gingival hyperplasia, or abnormal facial bone growth. The absence of these debilitating side effects, together with the observed immune advantage and steroid-sparing effects of FK 506, hold tremendous promise for the young patient facing cardiac transplantation and a future wedded to immunosuppression

The surface of iron molybdate catalysts used for the selective oxidation of methanol

The oxidation of methanol to formaldehyde is a major chemical process carried out catalytically and iron molybdate is one of the major catalysts for this process. In this paper we explore the nature of the active and selective surfaces of iron molybdate catalysts and show that the effective catalysts comprise molybdenum rich surfaces. We conclude that it is therefore important to maximise the surface area of these active catalysts and to this end we have studied catalysts made using a new physical grinding method with oxalic acid. For super-stoichiometric materials (Fe:Mo = 1:2.2) the reaction data show that physical mixing produces effective catalysts, possibly offering an improvement over the conventional co-precipitation method

Perioperative donor bone marrow infusion augments chimerism in heart and lung transplant recipients

Background.: We and others have demonstrated that a low level of donor cell chimerism was present for years after transplantation in tissues and peripheral blood of heart and lung recipients; it was associated, in the latter, with a lower incidence of chronic rejection. To augment this phenomenon, we initiated a trial combining simultaneous infusion of donor bone marrow with heart or lung allotransplantation. Methods.: Between September 1993 and January 1995, 15 nonconditioned patients received either heart (n = 10) or lung (n = 5) allografts concurrently with an infusion of unmodified donor bone marrow (3.0 × 108 cells/kg), and were maintained on an immunosuppressive regimen consisting of tacrolimus and steroids. Results.: There was no complication associated with the infusion of donor bone marrow. Chimerism was detectable in 73% of bone marrow-augmented patients up to the last sample tested. Of the 5 control recipients who did not receive bone marrow infusion, only 1 had detectable chimerism by flow on postoperative day 15, which dwindled to an undetectable level by postoperative day 36. None of the patients had evidence of donor-specific immune modulation by mixed lymphocyte reaction. Conclusions.: The combined infusion of donor bone marrow and heart or lung transplantation, without preconditioning of the recipient, is safe and is associated with an augmentation of donor cell chimerism. © 1995 The Society of Thoracic Surgeons

Connection between igneous activity and extension in the central Mojave metamorphic core complex, California

The development of metamorphic core complexes and associated low-angle detachment faults commonly is intimately associated with synextensional igneous activity. In most areas studied to date, the relation of magmatism to extension is obscured by imprecise dating and by the overprint of later tectonic events. We present data from the early Miocene central Mojave metamorphic core complex (CMMCC) which indicate that extension was accompanied by igneous activity, as reflected by prekinematic, synkinematic, and postkinematic plutons and coeval volcanic rocks deposited in the associated extensional basins. The principal intrusion is an early Miocene granite pluton exposed in outcrops across an area greater than 400 km2. Dikes adjacent to the pluton are common in the Mitchel Range, at The Buttes, and at Fremont Peak. The overall orientation of the pluton and associated dikes is west-northwest, roughly perpendicular to the extension direction. Results of U-Pb analyses on zircon from two pluton and two dike samples yield ages of 20 to 23 Ma. Two other dike samples yield inconclusive results. Synextensional basins formed by detachment faulting during the core complex development. Rocks in these basins compose the Jackhammer and Pickhandle formations and filled an elongate, NW trending trough more than 50 km long. The 40Ar/39Ar ages for tuff beds are as old as 23.8±0.3 Ma near the base of the lower Pickhandle Formation and as young as 21.3±0.5 Ma in the uppermost lower Pickhandle. Hence volcanism and plutonism are coeval. The diversity of intrusive relations relative to the timing and development of the mylonitic fabric in the CMMCC precludes any simple cause-and-effect relationship between magmatism and extensional deformation. Rather, magmatism and extension may have been localized at a releasing bend in a transfer-fault system which links extension in the CMMCC with extension in the Colorado River area to the east

Obliterative bronchiolitis after lung and heart-lung transplantation An analysis of risk factors and management

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

Novel cobalt zinc oxide Fischer-Tropsch catalysts synthesised using supercritical anti-solvent precipitation

Cobalt zinc oxide catalysts have been prepared by anti-solvent precipitation in supercritical CO2 and investigated for CO hydrogenation. Here we show how the textural and catalytic properties of the catalyst can be tailored by the addition of water to the initial solution of cobalt and zinc acetates in methanol. Characterization of the catalysts by powder X-ray diffraction, infra-red and Raman spectroscopy showed that in the absence of water a high surface area mixed acetate was produced which upon calcination formed wurtzite type Zn1−xCoxO and spinel type ZnxCo3−xO4. The addition of 5 vol.% water resulted in a phase separated Co3O4/ZnO catalyst and enhanced active cobalt surface area as a result of disruption of the solvent/CO2 phase equilibrium during precipitation

Pediatric lung transplantation: The years 1985 to 1992 and the clinical trial of FK 506

The application of lung transplantation to the pediatric population was a natural extension of the success realized in our adult transplantation program, which began in 1982. Twenty pediatric patients (age range 3 to 18 years) have had heart-lung (n = 11), double lung (n = 8), and single lung (n = 1) transplantation procedures. The causes of end-stage lung disease were primary pulmonary hypertension (n = 7), congenital heart disease (n = 5), cystic fibrosis (n = 4), pulmonary arteriovenous malformation (n = 2), graft- versus-host disease (n = 1), and desquamative interstitial pneumonitis (n = 1). Four (20%) patients had thoracic surgical procedures before the transplantation operation. The survival was 80% at a mean follow-up of 2 years. Immunosuppressive drugs included cyclosporine (n = 9) or FK 506 (n = 11) based therapy with azathioprine and steroids. Children were followed up by means of spirometry, transbronchial biopsy, and primed lymphocyte testing of bronchoalveolar lavage fluid. The mean number of treated episodes of rejection was 1.4 at 30 days, 0.5 at 30 to 90 days, and 1.4 at more than 90 days, and the first treated rejection episode occurred on average 28 days after the operation. Obliterative bronchiolitis developed in four (25%) of 16 patients surviving more than 100 days. Results of pulmonary function tests have remained good in almost all recipients. The greatest infectious risk was that of cytomegalovirus: one death and one case of pneumonia. Posttransplantation lymphoproliferative disease was diagnosed in two (12.5%) patients; both recovered. The most common complications were hypertension (25%) and postoperative bleeding (15%). Early results indicate that lung transplantation is a most promising therapy for children with severe vascular and parenchymal lung disease

Effects of donor bone marrow infusion in clinical lung transplantation

Background. We have demonstrated that donor cell chimerism is associated with a lower incidence of obliterative bronchiolitis (OB) in lung recipients, and that donor chimerism is augmented by the infusion of donor bone marrow (BM). We herein report the intermediate results of a trial combining the infusion of donor BM and lung transplantation. Methods. Clinical and in vitro data of 26 lung recipients receiving concurrent infusion of donor bone marrow (3.0 to 6.0 x 108 cells/kg) were compared with those of 13 patients receiving lung transplant alone. Results. Patient survival and freedom from acute rejection were similar between groups. Of the patients whose graft survived greater than 4 months, 5% (1 of 22) of BM and 33% (4 of 12) of control patients, developed histologic evidence of OB (p = 0.04). A higher proportion (but not statistically significant) of BM recipients (7 of 10, 70%) exhibited donor-specific hyporeactivity by mixed lymphocyte reaction assays as compared with the controls (2 of 7, 28%). Conclusions. Infusion of donor BM at the time of lung transplantation is safe, and is associated with recipients' immune modulation and a lower rate of obliterative bronchiolitis. (C) 2000 by The Society of Thoracic Surgeons