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Biomedical subjects

S M Pham

Publications and source records attributed to S M Pham.

At least 37 records · Page 2Linked to original sources
PubMed1999

Simultaneous donor bone marrow and cardiac transplantation: can tolerance be induced with the development of chimerism?

Mixed bone marrow chimerism (mixed chimerism) is defined by the coexistence of two genetically different bone marrow stem cells in an individual. The chimeric immune system recognizes donor antigen as self, yet is capable of mounting a normal response to third-party antigens. In animal models, mixed chimerism confers donor-specific tolerance for solid-organ and cellular grafts: tissue from the bone marrow donor is permanently accepted by mixed chimeras in the absence of conventional immunosuppressive agents. Clinical application of mixed chimerism to induce transplantation tolerance requires novel approaches to safely and reliably achieve engraftment of donor bone marrow in transplant recipients. Recent advances offer potential solutions to these obstacles and suggest that the application of mixed chimerism to induce tolerance to transplanted organs may soon be a clinical reality.

Animals↗
PubMed1999

Mixed hematopoietic chimerism induces donor-specific tolerance for lung allografts in rodents.

Mixed hematopoietic chimerism is a state in which bone marrow hematopoietic stem cells from two genetically different animals coexist. We investigated whether mixed hematopoietic chimerism, resulting from the transplantation of host and donor bone marrow into a lethally irradiated rat, would confer donor-specific tolerance to lung allografts. Recipient rats (Fisher or or Wistar Furth [WF]) were irradiated (1,100 cGy) and reconstituted with a mixture of T-cell-depleted syngeneic plus allogeneic bone marrow. After mixed chimerism was documented by the presence of donor- and host-derived cells in the peripheral blood 4 wk after bone marrow reconstitution, mixed chimeras underwent orthotopic left lung transplantation with donor-specific and third-party lung allografts. No immunosuppressive agents were administered after lung transplantation. All donor-specific lung allografts were accepted by mixed chimeras (n = 40), while all third-party grafts (n = 7) were rejected within 10 d, a time course similar to that for grafts transplanted into naive recipients (n = 14). Radiation control recipients (n = 7) who did not develop mixed chimerism because the donor bone marrow had failed to engraft, also rejected donor-specific grafts within 10 d. We conclude that mixed hematopoietic chimerism induces donor-specific transplantation tolerance to lung allografts.

Animals↗
PubMed1998

Tacrolimus-based partial conditioning produces stable mixed lymphohematopoietic chimerism and tolerance for cardiac allografts.

BACKGROUND: Thoracic organ transplantation remains limited by the reciprocal problems of rejection and the toxicities of nonspecific immunosuppression. Mixed bone marrow chimerism reliably produces donor-specific transplantation tolerance without immunosuppressive drugs. We have previously described a nonmyeloablative conditioning regimen based on recipient treatment with antilymphocyte serum, tacrolimus, and low-dose total-body irradiation that yields long-term multilineage allogeneic bone marrow chimerism in the rat. We have now investigated whether mixed bone marrow chimerism that arises from this partial conditioning strategy produces permanent acceptance of donor-specific cardiac allografts. METHODS AND RESULTS: Mixed allogeneic chimeras (ACI-->WF) were prepared by treating Wistar Furth recipients with a single dose of antilymphocyte serum 5 days before bone marrow transplantation and tacrolimus 1 mg/kg/d from days -1 to 10. Five hundred cGy total-body irradiation was administered immediately before infusion of 1 x 10(8) donor (ACI) T-cell depleted marrow cells. All recipients were chimeric, with a mean level of donor chimerism = 26.3 +/- 3.5%. Chimeras underwent heterotopic cardiac transplantation 4 weeks after bone marrow transplantation. All donor-specific (ACI) grafts were permanently accepted (follow-up, 230 to 360 days). Third-party grafts were rapidly rejected. Histology of long-surviving donor-specific grafts was without evidence of acute or chronic rejection. Second-set donor-specific skin grafts transplanted to chimeras 135 days after heart transplantation showed long-term survival (> 130 days), whereas third-party skin grafts were rapidly rejected. Mixed lymphocyte reaction demonstrated in vitro donor-specific hyporeactivity. CONCLUSIONS: A tacrolimus-based nonmyeloablative recipient conditioning regimen produces mixed bone marrow chimerism and donor-specific tolerance to cardiac allografts in the rat.

Animals↗
PubMed1998

Traumatic aortic rupture: diagnosis and management.

BACKGROUND: Traumatic aortic rupture is a relatively uncommon lesion that presents the cardiothoracic surgeon with unique challenges in diagnosis and management. To address controversial aspects of this disease, we reviewed our experience. METHODS: The study was performed by retrospective chart review. RESULTS: Forty-two patients with traumatic thoracic aortic ruptures were managed between January 1988 and June 1997. Nine arrived without vital signs and died in the emergency department. Admission chest radiographs were normal in 3 patients (12%) and caused significant delays in diagnosis. Four of 30 patients admitted with vital signs had rupture before thoracotomy and died. Twenty-six underwent aortic repair. In 1 patient repair was performed with simple aortic cross-clamping, whereas a second was managed with a Gott shunt. The remaining 24 patients had repair with partial left heart bypass. In 1 patient hypothermic circulatory arrest was required. Two patients (7.7%) died. There were no cases of new postoperative paraplegia in the bypass group. There was no morbidity directly attributable to the administration of heparin for cardiopulmonary bypass. CONCLUSIONS: In a discrete group of patients with traumatic rupture of the aorta, the rupture will become complete during the first few hours of hospital admission; aggressive medical treatment with beta-blockade and vasodilators in the interval before the operation is an essential aspect of management. Active distal circulatory support with partial left-heart bypass provides the optimal means of preventing spinal cord ischemia during repair of acute traumatic aortic rupture.

Adult↗
PubMed1998

Single- versus double-lung transplantation for pulmonary hypertension.

OBJECTIVES: Uncertainty persists as to the best lung transplant operation for patients with pulmonary hypertension. To quantify short- and long-term outcomes after single- and double-lung transplantation for pulmonary hypertension, we reviewed our clinical experience. METHODS: A retrospective review of 58 lung transplants at a single institution between 1989 and 1996 was performed. Recipients had primary (n = 19) or secondary (n = 39) pulmonary hypertension. RESULTS: Thirty-seven double- and 21 single-lung transplants were performed. The groups were well matched with regard to preoperative characteristics. Cardiopulmonary bypass time was longer (151 vs 250 minutes) in the double-lung group. Excluding 10 patients surviving less than 30 days (6 double- and 4 single-lung transplants), median duration of intubation (7.5 vs 10 days), length of stay in the intensive care unit (10 vs 16 days), and hospital stay (32 vs 52 days) were not significantly different for the single- and double-lung groups, respectively. Actuarial survival was nearly identical, with 81% and 84% 1-month survivals for the single- and double-lung groups, and identical 1-year (67%) and 4-year (57%) survivals for both groups. Late functional status was similar for recipients of single- and double-lung grafts. During the period of this study, 58 patients with pulmonary hypertension died on our center's waiting list before coming to transplantation. CONCLUSIONS: These data suggest that lung transplant recipients with pulmonary hypertension have similar outcomes after single- or double-lung transplantation. These results support cautious preferential application of single-lung transplantation for pulmonary hypertension.

Actuarial Analysis↗
PubMed1998

Cardiopulmonary bypass is associated with early allograft dysfunction but not death after double-lung transplantation.

OBJECTIVES: To assess the effect of cardiopulmonary bypass on allograft function and recipient survival in double-lung transplantation. METHODS: Retrospective review of 94 double-lung transplantations. RESULTS: Cardiopulmonary bypass was used in 37 patients (CPB); 57 transplantations were accomplished without bypass (no-CPB). Bypass was routinely used for patients with pulmonary hypertension (n = 27) and for two recipients undergoing en bloc transplantation. Cardiopulmonary bypass was required in eight (12.3%) of the remaining 65 patients. Mean ischemic time was longer in the CPB group (346 vs 315 minutes, p = 0.04). The CPB group required more perioperative blood (11.4 vs 6.0 units, p = 0.01). Allograft function, assessed by the arterial/alveolar oxygen tension ratio, was better in the no-CPB group at 12 and 24 hours after operation (0.54 vs 0.39 at 12 hours, p = 0.002; and 0.63 vs 0.38 at 24 hours, p = 0.001). The CPB group had more severe pulmonary infiltrates at both 1 and 24 hours (p = 0.005). Diffuse alveolar damage was more common in the CPB group (69% vs 35%, p = 0.002). Median duration of intubation was longer in the CPB group (10 days) than in the no-CPB group (2 days, p = 0.002). The 30-day mortality rate (13.5% vs 7.0% in the CPB and no-CPB groups) and 1-year survival (65% vs 67%, CPB and no-CPB) were not significantly different. CONCLUSIONS: In the absence of pulmonary hypertension, cardiopulmonary bypass is only occasionally necessary in double-lung transplantation. Bypass is associated with substantial early allograft dysfunction after transplantation.

Adolescent↗
PubMed1998

Aerosol cyclosporine prevents acute allograft rejection in experimental lung transplantation.

BACKGROUND: The incidence of acute rejection and the morbidity of systemic cyclosporine (INN: cyclosporine) after lung transplantation is significant. Experimental evidence suggests that the allograft locally modulates the immune mechanisms of acute rejection. The purpose of this study was to determine whether aerosolized cyclosporine would prevent acute cellular rejection, achieve effective graft concentrations with low systemic drug delivery, and locally affect production of the inflammatory cytokines involved in acute rejection. METHODS: Unilateral orthotopic left lung transplantation was performed in 64 rats (ACI to Lewis), which were divided into eight groups (each group, n = 8): group A, no treatment; groups B to D, aerosol cyclosporine 1 to 3 mg/kg per day, respectively; group E to H, systemic cyclosporine 2, 5, 10, and 15 mg/kg per day, respectively. After the animals were killed on postoperative day 2, 4, or 6, the transplanted lung, native lung, spleen, and blood were collected. Histologic studies, high-pressure liquid chromatography for trough cyclosporine concentrations, and reverse-transcriptase polymerase chain reaction for cytokine gene expression were performed. RESULTS: Untreated animals showed grade 4 rejection by postoperative day 6. Aerosol cyclosporine prevented acute rejection in a dose-dependent fashion, with group D animals (3 mg/kg per day) showing minimal grade 1 changes. Among animals receiving systemic cyclosporine, only group H (15 mg/kg per day) controlled (grade 1) rejection. However, aerosol cyclosporine, at an 80% lower dose, achieved significantly lower concentrations of cyclosporine in the graft (12,349 vs 28,714 ng/mg, p = 0.002004) and blood (725 vs 3306 ng/ml, p = 0.000378). Group F (systemic 5 mg/kg per day) had higher cyclosporine concentrations in the blood than group D (p = 0.004572) and similar tissue concentrations (p = 0.115180), yet had grade 2 rejection. Reverse-transcriptase polymerase chain reaction demonstrated equivalent suppression of inducible nitric oxide synthase but a 20- to 25-fold higher expression of interleukin-6, interleukin-10, and interferon-gamma in group D versus group H recipient allografts. CONCLUSION: Local delivery of cyclosporine by aerosol inhalation dose-dependently prevented acute pulmonary allograft rejection. Effective graft levels and low systemic drug delivery required significantly lower doses than systemic therapy alone. The gene expression of proinflammatory cytokines involved in allograft rejection was suppressed by aerosol cyclosporine therapy.

Administration, Inhalation↗
PubMed1998

A partial conditioning strategy for achieving mixed chimerism in the rat: tacrolimus and anti-lymphocyte serum substantially reduce the minimum radiation dose for engraftment.

Development of partial conditioning strategies to achieve reliable engraftment of allogeneic bone marrow with minimum recipient morbidity could extend the therapeutic application of bone marrow transplantation (BMT) to enzyme deficiency states, hemoglobinopathies, autoimmune diseases, and the induction of tolerance for solid organ and cellular allografts. In this study we describe a nonmyeloablative rat BMT model and examine the effect of clinically available immunosuppressants on the minimum amount of total body irradiation (TBI) required for allogeneic engraftment. Donor ACI marrow was depleted of T cells using immunomagnetic beads and transplanted to major histocompatibility complex- and minor antigen-mismatched Wistar Furth (WF) rats (ACI --> WF) conditioned with varying doses of TBI. Recipients conditioned with TBI alone required myeloablation with 1000 cGy for reliable allogeneic marrow engraftment. Administration to WF recipients of a single dose of anti-lymphocyte serum (ALS) 5 days prior to BMT together with a limited course of tacrolimus (1 mg/kg/day) resulted in engraftment of ACI bone marrow at only 500 cGy TBI. ACI --> WF recipients were stable mixed chimeras (mean donor chimerism 49% at 330 days post-BMT). Chimerism was multilineage. All recipient animals were free of graft-versus-host disease. These results suggest that a nonmyeloablative conditioning strategy based on low-dose TBI and a limited course of tacrolimus plus ALS can produce long-term mixed multilineage chimerism.

Animals↗
PubMed1998

Mixed allogeneic chimerism prevents obstructive airway disease in a rat heterotopic tracheal transplant model.

BACKGROUND: Mixed bone marrow chimerism reliably produces donor-specific transplantation tolerance for a variety of solid organ and cellular grafts. We used a rat heterotopic tracheal transplant model for chronic rejection to investigate whether mixed chimerism could successfully prevent obstructive airway disease. METHODS: Mixed allogeneic chimeras were prepared by reconstituting lethally irradiated Wistar-Furth (WF) recipients with a mixture of 5 x 10(6) T-cell-depleted syngeneic (WF) and 100 x 10(6) T-cell-depleted allogeneic (ACI) bone marrow cells (ACI + WF --> WF). Mixed chimerism was present in all animals 28 days after bone marrow transplantation. Donor-specific, syngeneic, or major histocompatibility complex (MHC)-disparate allogeneic tracheas were implanted in recipient's omentum and removed for histologic analysis 30 to 150 days after transplantation. RESULTS: At 30 days after implantation, median luminal obstruction grades (0=none, 4=complete) of syngeneic and allogeneic tracheas were 0 and 4, respectively. Donor-specific (ACI) tracheas implanted in chimeric (ACI + WF --> WF) recipients were remarkably free of obstruction (median luminal obstruction grade=0 at 150 days) and had excellent preservation of respiratory epithelium. Third-party F344 tracheas implanted in chimeric recipients developed progressive luminal obstruction (grade 2 at 30 days, grade 3 at 90 days). CONCLUSIONS: Mixed allogeneic chimerism induces donor-specific tolerance and prevents development of the characteristic fibroproliferative obstructive lesion of bronchiolitis obliterans in a rat heterotopic tracheal transplant model. Excellent preservation of tracheal structure and morphology was achieved across major and minor histocompatibility barriers.

Airway Obstruction↗
PubMed1997

Inducible nitric oxide synthase suppresses the development of allograft arteriosclerosis.

In cardiac transplantation, chronic rejection takes the form of an occlusive vasculopathy. The mechanism underlying this disorder remains unclear. The purpose of this study was to investigate the role nitric oxide (NO) may play in the development of allograft arteriosclerosis. Rat aortic allografts from ACI donors to Wistar Furth recipients with a strong genetic disparity in both major and minor histocompatibility antigens were used for transplantation. Allografts collected at 28 d were found to have significant increases in both inducible NO synthase (iNOS) mRNA and protein as well as in intimal thickness when compared with isografts. Inhibiting NO production with an iNOS inhibitor increased the intimal thickening by 57.2%, indicating that NO suppresses the development of allograft arteriosclerosis. Next, we evaluated the effect of cyclosporine (CsA) on iNOS expression and allograft arteriosclerosis. CsA (10 mg/kg/d) suppressed the expression of iNOS in response to balloon-induced aortic injury. Similarly, CsA inhibited iNOS expression in the aortic allografts, associated with a 65% increase in intimal thickening. Finally, we investigated the effect of adenoviral-mediated iNOS gene transfer on allograft arteriosclerosis. Transduction with iNOS using an adenoviral vector suppressed completely the development of allograft arteriosclerosis in both untreated recipients and recipients treated with CsA. These results suggest that the early immune-mediated upregulation in iNOS expression partially protects aortic allografts from the development of allograft arteriosclerosis, and that iNOS gene transfer strategies may prove useful in preventing the development of this otherwise untreatable disease process.

Animals↗
PubMed1997

Right ventricular performance and left ventricular assist device filling.

BACKGROUND: Right ventricular (RV) function is believed to be an important determinant of left ventricular assist device (LVAD) filling. This study was designed to demonstrate this relation in patients. METHODS: To demonstrate the interaction between RV ejection and LVAD filling, 10 patients (mean age, 49 +/- 13 years) supported with an LVAD were studied. Right ventricular pressure-area loops from cross-sectional area using transesophageal echocardiographic automated border detection and high-fidelity RV pressure were recorded simultaneously with LVAD volume during intraoperative inferior vena cava occlusion. Beat-by-beat RV ejection phase indices were calculated: stroke area, peak ejection rate, and stroke work. The LVAD filling rate was calculated as the first derivative of the volume, and the peak filling rate and the mean filling rate during RV systole were determined for each cardiac cycle. RESULTS: Right ventricular stroke area, peak ejection rate, and stroke work were closely correlated with LVAD peak filling rate (r = 0.87 +/- 0.09, r = 0.83 +/- 0.09, and r = 0.85 +/- 0.10, respectively). Also, baseline LVAD mean filling rate correlated with RV stroke work (r = 0.77) and LVAD peak filling rate with RV peak ejection rate for the group (r = 0.75). CONCLUSIONS: These correlations demonstrate predictable associations of RV ejection with LVAD filling.

Heart Failure↗
PubMed1997

Cardiac operations in solid-organ transplant recipients.

BACKGROUND: The success of solid organ transplantation has resulted in an increasing pool of patients that subsequently require cardiac surgical procedures, yet the perioperative management of these patients is not well documented. We report a single institutional experience with the management techniques used and the outcomes of the cardiac surgical procedures performed in solid organ transplant recipients with functioning allografts. METHODS: Sixty-four patients underwent 66 cardiac procedures broken down as follows: coronary artery bypass grafting, 30; single or combined valve replacement-repair, 24; combined coronary artery bypass grafting and valve repair, 3; aortic repair, 4; pericardiectomy, 3; transmyocardial laser revascularization, 1; and native cardiectomy, 1. Patients consisted of 40 kidney, 16 liver, 5 heart, 2 lung, and 1 liver and kidney transplant recipients. The mean interval from the time of transplantation to the cardiac operation was 53 months (range, 1 day to 220 months). Forty-six male and 18 female patients in New York Heart Association functional class III or IV had a mean age of 53 years (range, 19 to 77 years); 50% (32/64) were diabetic, and 97% (62/64) were hypertensive. Immunosuppressive therapy, cardiopulmonary bypass, and medical management were similar in all patients. RESULTS: There were two (3%) perioperative deaths, one of which was caused by an arrhythmia-induced cardiac arrest, and there were seven (11%) late deaths from non-cardiac-related causes. Major complications included 12 infections (19%), ten mediastinal reexplorations for the control of bleeding (16%), and nine others (15%). Sixteen of the 64 (25%) transplant recipients had chronic renal failure (serum creatinine levels, > 3 mg/dL), including 13 of 40 (33%) kidney transplant patients. Acute renal failure developed postoperatively in 7 (54%) of these 13 patients; the grafts failed permanently in 3 (23%). Three patients (5%), 2 kidney transplant recipients and 1 lung transplant recipient, experienced transient acute rejection. Fifty of the 55 surviving patients are alive and well (New York Heart Association functional class I or II) without recurrent cardiac disease at a mean follow-up period of 22 months. CONCLUSIONS: Although the short-term morbidity was significant, the low mortality and low incidence of permanent graft dysfunction indicate that solid organ transplant recipients can safely and effectively undergo subsequent cardiac surgical procedures.

Adult↗
PubMed1997

Left atrial myxoma with embolization presenting as an acute infrarenal aortic occlusion.

We present the case of a 42-year-old woman who had acute total infrarenal aortic occlusion resulting from embolic implantation from a left atrial myxoma. We propose that the small aortic aneurysm that was discovered and repaired in this case may be a direct result of invasion and destruction of the aortic elastic laminae by implanted myxomatous tissue originating in the primary atrial tumor. This behavior has been noted in small vessels of the cerebrum and upper extremities with this lesion, but no prior reports of this occurrence in the aorta has been noted after extensive review of the literature.

Acute Disease↗
PubMed1997

Influence of panel-reactive antibody on survival and rejection after lung transplantation.

BACKGROUND: Panel-reactive antibody (PRA) is commonly used before thoracic organ transplantation to estimate a potential recipient's degree of humoral sensitization. METHODS: To assess the influence of an elevated PRA on survival and the incidence of rejection in pulmonary transplantation, the records of 247 patients that underwent single or double lung transplantation were reviewed. RESULTS: Twenty-one of 247 patients (8.5%) had PRA values greater than 10%. Survival of this population was not significantly different from that of patients with low PRA levels: 74% (low PRA) vs 65% (elevated PRA) at 1 year and 58% in both groups at 3 years. The acute rejection rates (episodes/first 100 days) for the elevated and low PRA groups were 2.1 and 1.9, respectively (p = NS). Obliterative bronchiolitis developed in 38.9% of the high and 31.2% of the low PRA groups (p = NS). Six of 247 patients had a retrospective positive lymphocytotoxic cross-match result; three had PRA values greater than 10%. Patients with a positive cross-match result experienced similar survival and incidence of rejection as the remainder of the population. Among 957 patients evaluated for lung transplantation, 16 (1.7%) had a PRA (with dithiothreitol) greater than 15%. All had a history of pregnancy, blood transfusion, connective tissue disease, or previous transplantation. CONCLUSIONS: Humoral sensitization is uncommon in the lung transplantation population. A modestly elevated PRA does not predict survival or the development of acute rejection or bronchiolitis obliterans. PRA testing before lung transplantation should be reserved for those patients with specific risk factors for humoral sensitization.

Adolescent↗