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Biomedical subjects

S M Pham

Publications and source records attributed to S M Pham.

At least 19 recordsLinked to original sources
PubMed2003

Effects of oestrogen deficiency on rat mandibular and tibial microarchitecture.

OBJECTIVES: To investigate the effects of oestrogen deficiency on the microarchitecture of trabecular bone in the mandible and the tibia and to test whether they are correlated. METHODS: Twenty-four age-matched Lewis-Brown-Norway female rats underwent surgical intervention either to remove ovaries (ovariectomy, n=12) or to create a complementary control group (sham-operated, n=12). Sixteen weeks later, the animals were sacrificed and the left side of the mandibles and the tibias were scanned with high resolution micro-CT (15 micro m). Multiple morphological measures including the ratio of bone volume/tissue volume, trabecular thickness, trabecular separation and structure model index were obtained from the experimental and control groups. RESULTS: Ovariectomy significantly decreased the ratio of bone volume/soft tissue volume and trabecular thickness, whilst significantly increasing trabecular separation and structure model index in the mandible (P<0.005) and the tibia (P<0.005). There were significant positive correlations between the mandible and the tibia for trabecular separation (r=0.68, P<0.01) and structure model index (r=0.60, P<0.01). CONCLUSIONS: Oestrogen deficiency results in microarchitectural alterations of trabecular bone in both the mandible and the tibia within 16 weeks. The size of marrow spaces and the shape of trabeculae in the mandible correlate with osteoporotic changes in the long bone.

Animals↗
PubMed2001

A new fluorescent chemosensor for copper ions based on tripeptide glycyl-histidyl-lysine (GHK).

[structure: see text]. A new fluorescent chemosensor for Cu2+ ions was synthesized by modifying the tripeptide glycyl-histidyl-lysine (GHK) with 9-carbonylanthracene via the standard Fmoc solid-phase peptide synthesis method. While significant fluorescence quenching was observed from the molecule upon binding with Cu2+, addition of Fe2+, Co2+, Ni2+, and Zn2+ to the peptide solution caused a minimum fluorescence emission spectral change, indicating a high specificity of this chemosensor for Cu2+ ions. Effects of pH were also investigated.

Anthracenes↗
PubMed2001

Highly diastereoselective aldol additions of a chiral ethyl ketone enolate under Lewis base catalysis.

[reaction: see text] The aldol addition of a chiral ethyl ketone enolate bearing an oxygen substituent (OTBS) at the alpha-position proceeds with high internal and relative diastereoselectivities with various achiral aldehydes in good yields. The profound influence of the resident stereogenic center allows for the use of an achiral catalyst, such as HMPA, with minor attenuation in internal stereoselectivity.

Journal Article↗
PubMed2001

Long-term survival of rat cardiac allografts by intrathymic plus portal venous injections of donor bone marrow cells and short-term tacrolimus immunosuppression.

Intrathymic (IT) or portal venous (PV) injection of donor antigens has been shown to prolong organ acceptance in low responder rat strain combinations. We determined whether a combination of these strategies would prolong cardiac allograft survival in high responder combinations. Wistar Furth rats received 1 x 10(8) ACI rat bone marrow cells (BMCs) via IT, intravenous (IV), PV, IV + PV, IT + IV or IT + PV route at the time of ACI cardiac transplantation. Without tacrolimus (FK), all grafts were acutely rejected. With FK immunosuppression (1.5 mg/kg per day, I. M., days 0-4), single BMC injection did not increase graft survival beyond 93 days, whereas 70% of grafts survived indefinitely ( > 150 days) when IT and PV BMCs were combined. Animals receiving IT and PV BMCs also had less allograft vasculopathy. Thus, IT and PV injections of donor BMCs under a brief course of FK synergistically improve cardiac allograft survival.

Animals↗
PubMed2001

A multicenter, randomized, controlled trial of Celsior for flush and hypothermic storage of cardiac allografts.

BACKGROUND: A multicenter, randomized, controlled, open-label trial was conducted to evaluate the safety and efficacy of Celsior when used for flush and hypothermic storage of donor hearts before transplantation. METHODS: Heart transplant recipients were randomized to one of two treatment groups in which donor hearts were flushed and stored in either Celsior or conventional preservation solution(s) (control). Study subjects were followed for 30 days after transplantation. RESULTS: A total of 131 heart transplant recipients were enrolled (Celsior, n = 64; control, n = 67). The treatment groups were evenly distributed in donor and recipient base line characteristics. Graft loss rate was lower in the Celsior group on day 7 (3% versus 9%) and on day 30 (6% versus 13%), but the difference was not statistically significant based on 95% confidence interval analysis. No significant difference was measured between the Celsior and control groups in 7-day patient survival (97% versus 94%) and the proportion of patients with one or more adverse events (Celsior, 88%; control 87%) or serious adverse events (Celsior, 38%; control, 46%). Significantly fewer patients in the Celsior group developed at least one cardiac-related serious adverse event (13% versus 25%). CONCLUSIONS: Celsior was demonstrated to be as safe and effective as conventional solutions for flush and cold storage of cardiac allografts before transplantation.

Adult↗
PubMed2001

A clinically relevant CTLA4-Ig-based regimen induces chimerism and tolerance to heart grafts.

BACKGROUND: We determined whether a nontoxic CTLA4-Ig-based conditioning regimen effected mixed chimerism and donor-specific tolerance when heart and bone marrow were transplanted simultaneously. METHODS: Fully mismatched rat strain combinations were used. Recipients received total-body irradiation (300 centigrays), bone marrow (10(8) cells), and cardiac transplants from the donor on day 0. Subsequently, recipient animals received CTLA4-Ig (2 mg/kg, every other day, x 5 doses), tacrolimus (1 mg/kg/day; days 0 to 9), and one dose (10 mg) of antilymphocyte serum on day 10. RESULTS: All bone marrow recipients (n = 7) developed mixed chimerism (mean = 25% +/- 9% at 1 year) and accepted cardiac allografts permanently (> 375 +/- 32 days). Recipients that received conditioning regimen but no bone marrow (n = 5) rejected donor hearts within 51 +/- 13 days (p < 0.01). Recipients that accepted heart grafts also permanently accepted (> 180 days) donor-specific skin grafts, but rapidly rejected (< 10 days) third-party skin grafts. CONCLUSIONS: A nontoxic CTLA4-Ig-based conditioning regimen effects mixed chimerism and donor-specific tolerance when heart and bone marrow are transplanted simultaneously. This regimen may have clinical application.

Abatacept↗
PubMed2001

Combined host-conditioning with CTLA4-Ig, tacrolimus, anti-lymphocyte serum, and low-dose radiation leads to stable mixed hematopoietic chimerism.

The toxic dose of irradiation required to achieve stable mixed hematopoietic chimerism is the major limitation to its clinical application in transplantation and other nonmalignant conditions such as hemoglobinopathies. This study examines the additive effect of costimulatory blockage, to our previously described tacrolimus-based conditioning regimen, in further reducing the dose of total-body irradiation to achieve stable mixed chimerism in rats. Fully mismatched, 4- to 6-week-old ACI and Wistar Furth rats were used as donors and recipients, respectively. Recipients were administered CTLA4-Ig 2mg/kg/day (alternate days) in combination with tacrolimus 1 mg/kg/day (daily) from day 0 through day +10, anti-lymphocyte serum 10 mg at day +10 (single dose), and total-body irradiation ranging from 100-600 cGy, prior to bone marrow transplantation (day 0) with 100 x 10(6) of T-cell-depleted bone marrow cells. Levels of donor chimerism were determined over a period of 12 months. The short course of CTLA4-Ig, tacrolimus, and ALS led to dramatic engraftments at reduced doses of irradiation: 100% (5/5) and 93% (13/14) of the animals developed mixed chimerism at 400 cGy and 300 cGy, respectively. At 300 cGy, recipients exhibited durable, multilineage mixed chimerism at 365 days with donor cells ranging from 19-42% (mean 23.4%) with no evidence of graft-vs-host disease. These mixed chimeras exhibited in vitro (mixed lymphocyte reaction) and in vivo (skin grafts) donor-specific tolerance. This study suggests that addition of costimulatory blockade to a tacrolimus-based conditioning regimen reduces the dose of irradiation required to achieve stable multilineage chimerism in rats.

Abatacept↗
PubMed2000

FK409, a spontaneous nitric oxide releaser, attenuates allograft vasculopathy in a rat aortic transplant model.

Although systemic administration of NO donors has been shown to attenuate the development of neointimal hyperplasia in the balloon injury model, this strategy has not been tested in a model of allograft vasculopathy. In this study, we investigated the effect of FK409, a spontaneous NO releaser, on the development of allograft vasculopathy, using a rat aortic transplant model. Thoracic aortas from ACI rats were transplanted heterotopically into the abdominal aorta of Wistar-Furth rats. Postoperatively, recipients received FK409 orally every 8 hours from the day of transplantation to the time of euthanization. Morphometric and immunohistochemical analyses were performed on the aortic grafts 8 weeks after transplantation. Control allografts showed severe neointimal hyperplasia, which consists mainly of alpha-actin-containing vascular smooth muscle cells. The FK409-treated allografts showed a dose-dependent reduction (statistically significant compared with the control) in the neointimal thickness as the dose increased from 1 to 10 mg/kg (thrice per day). However, there was no significant difference in the neointimal thickness between groups treated with 10 and with 20 mg/kg. FK409 treatment (10 mg/kg) caused a significant decrease in DNA synthesis (5-bromo-2-deoxyuridine [BrdU] uptake), an increase in DNA fragmentation (terminal deoxynucleotidyltransferase-mediated uridine nick-end labeling [TUNEL]), and upregulation of Fas expression, in the neointimal vascular smooth muscle cells. These data suggest that FK409 attenuates the allograft vasculopathy in a rat aortic transplant model.

Animals↗
PubMed2000

Cardiac transplantation in survivors of lymphoma: a multi-institutional survey.

BACKGROUND: Cardiac transplantation has been successfully performed in patients with a history of presumably cured Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). Though the risk of recurrence is a major concern, the long-term influence of prior cancer and cancer therapy on posttransplant outcome has not been previously investigated. METHODS: Questionnaires were sent to 130 cardiac transplant centers in the United States registered with the United Network for Organ Sharing. Data collected included patient demographics; type, stage, and timing of HD/NHL; treatment for HD/NHL; posttransplant immunosuppressive regimen, rejection history, and outcomes; and Epstein-Barr virus status. RESULTS: Thirty-four cardiac transplant recipients with a previous history of HD (n=16) or NHL (n=18) were identified. HD patients averaged 41+/-15 years of age, with a mean disease-free interval of 15+/-9 years at the time of transplantation. NHL patients averaged 42+/-17 years of age with a mean disease-free interval of 10+/-9 years at the time of transplantation. The mean follow-up for the entire group was 50 months (range, 2 days to 136 months), and mean follow-up for the survivors was 67 months (range, 23-136 months). The 1-, 3-, 5-, 7-, and 10-year actuarial survival estimates for the entire group are 77%, 64%, 64%, 64%, and 50%, respectively. Actuarial survival was lower in HD patients (P=0.04) and in patients who had previously undergone splenectomy (P=0.008). Cox regression analysis identified only prior splenectomy (P=0.02) as an independent risk factor for mortality after cardiac transplantation with an adjusted relative risk of 6.2 (1.7-21.9, 95% confidence intervals). CONCLUSIONS: Although the numbers are small, these data strongly suggest that there is an increased mortality risk for cardiac transplant recipients with prior HD who have undergone splenectomy.

Actuarial Analysis↗
PubMed2000

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 10(8) 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.

Adult↗
PubMed2000

A clinical trial combining donor bone marrow infusion and heart transplantation: intermediate-term results.

BACKGROUND: Donor chimerism (the presence of donor cells of bone marrow origin) is present for years after transplantation in recipients of solid organs. In lung recipients, chimerism is associated with a lower incidence of chronic rejection. To augment donor chimerism with the aim to enhance graft acceptance and to reduce immunosuppression, we initiated a trial combining infusion of donor bone marrow with heart transplantation. Reported herein are the intermediate-term results of this ongoing trial. METHODS: Between September 1993 and August 1998, 28 patients received concurrent heart transplantation and infusion of donor bone marrow at 3.0 x 10(8) cells/kg (study group). Twenty-four contemporaneous heart recipients who did not receive bone marrow served as controls. All patients received an immunosuppressive regimen consisting of tacrolimus and steroids. RESULTS: Patient survival was similar between the study and control groups (86% and 87% at 3 years, respectively). However, the proportion of patients free from grade 3A rejection was higher in the study group (64% at 6 months) than in the control group (40%; P =.03). The prevalence of coronary artery disease was similar between the two groups (freedom from disease at 3 years was 78% in study patients and 69% in controls). Similar proportions of study (18%) and control (15%) patients exhibited in vitro evidence of donor-specific hyporesponsiveness. CONCLUSIONS: The infusion of donor bone marrow reduces the rate of acute rejection in heart recipients. Donor bone marrow may play an important role in strategies aiming to enhance the graft acceptance.

Acute Disease↗
PubMed1999

A partial conditioning approach to achieve mixed chimerism in the rat: depletion of host natural killer cells significantly reduces the amount of total body irradiation required for engraftment.

BACKGROUND: Mixed allogeneic bone marrow chimerism induces tolerance to solid organ grafts. Although we previously reported that partially ablative conditioning with 700 cGy of total body irradiation (TBI) is sufficient to allow for bone marrow engraftment in mice, we determined that a minimum of 1000 cGy was required in the rat. Because T cells and NK cells are critical in bone marrow graft rejection, our purpose was to examine whether targeting of radioresistant NK cells and/or T cells in the recipient hematopoietic microenvironment would reduce the TBI dose required for engraftment of allogeneic rat bone marrow. METHODS: Wistar Furth rats received either anti-NK3.2.3 monoclonal antibodies on days -3 and -2, anti-lymphocyte serum on day -5, a combination of both or no pretreatment. TBI was performed on day 0 and rats were reconstituted with 100x10(6) T cell-depleted bone marrow cells from ACI donors. RESULTS: Engraftment of T cell-depleted rat bone marrow was readily achieved in animals conditioned with 1000 cGy TBI alone (12/12) and the level of donor chimerism averaged 89%. At 900 cGy TBI alone only one of eight recipients engrafted. In striking contrast, 11 of 12 animals pretreated with anti-NK monoclonal antibodies and irradiated with 900 cGy showed donor chimerism at a mean level of 41%. No further enhancement of bone marrow engraftment could be achieved when recipients were pretreated with antilymphocyte serum alone or antilymphocyte serum plus anti-NK monoclonal antibodies. Mixed allogeneic chimeras exhibited stable multilineage chimerism and donor-specific tolerance to subsequent cardiac allografts. CONCLUSION: Specific targeting of radioresistant host NK cells allows for a significant reduction of the TBI dose required for allogeneic bone marrow engraftment.

Animals↗
PubMed1999

Effect of ischemic time on survival in clinical lung transplantation.

BACKGROUND: While there is convincing evidence that prolonged ischemic times correlate with reduced long-term survival in heart transplantation, the effect of ischemic time on outcome in clinical lung transplantation remains controversial. To assess the effect of ischemic time on outcomes in lung transplantation, we reviewed our experience. METHODS: The study was performed by retrospective chart review. RESULTS: First-time lung transplantation was performed on 392 patients between 1988 and 1998. All grafts were flushed with cold crystalloid preservation solution and stored on ice. Ischemic time data were available for 352 of 392 (90%) patients. Ischemic times were grouped as follows: 0 to 4 hours (n = 91), 4 to 6 hours (n = 201), more than 6 hours (n = 60). Ischemic time did not correlate with survival: 3-year actuarial survival = 56% (0 to 4 hours), 58% (4 to 6 hours), 68% (> 6 hours), p = 0.58. There was no significant difference in the incidence of biopsy-proven diffuse alveolar damage in the first 30 days after transplantation (31%, 32%, 38%), episodes of acute rejection in the first 100 days after transplantation (1.9, 1.8, 1.7), duration of intubation (median 3, 4, 3 days), or incidence of obliterative bronchiolitis (23%, 28%, 26%) between the three groups (0 to 4 hours, 4 to 6 hours, > 6 hours, respectively). A diagnosis of diffuse alveolar damage was associated with a significantly worse outcome (1-year survival = 82% versus 54%, p < 0.0001). CONCLUSIONS: In contrast to heart transplantation, pulmonary allograft ischemic time up to 9 hours does not appear to have a significant impact on early graft function or survival. The presence of diffuse alveolar damage on biopsy early after transplantation does not correlate with prolonged ischemic time, but is associated with substantially reduced posttransplantation survival.

Adolescent↗
PubMed1999

T-cell depletion of allogeneic bone marrow using anti-alphabetaTCR monoclonal antibody: prevention of graft-versus-host disease without affecting engraftment potential in rats.

Bone marrow chimerism may solve two major limitations in the transplantation of solid organs and cellular grafts: (1) the requirement for life-long immunosuppressive therapy, and (2) acute and chronic rejection. When untreated bone marrow is transplanted into major histocompatibility complex (MHC)-disparate rats, lethal graft-vs-host disease (GVHD) occurs in the majority of recipients. T-cell depletion using anti-CD3 and anti-CD5 monoclonal antibody (mAb) to avoid GVHD led to an increased occurrence of failure of engraftment. We previously identified a cellular population in mouse bone marrow that facilitates engraftment of highly purified hematopoietic stem cells (HSC) across complete MHC barriers. In light of the fact that facilitating cells have a CD8+/CD3+/TCR- phenotype and mostly coexpress CD5, we evaluated in this study whether T-cell depletion of rat bone marrow using anti-alphabetaTCR mAb would retain engraftment potential yet avoid GVHD. T-cell depletion of bone marrow was performed using anti-alphabetaTCR mAb and immunomagnetic beads. Recipients were conditioned with 1100 or 1000 cGy of total body irradiation and reconstituted with 100 x 10(6) T-cell depleted (TCD) MHC- and minor antigen-disparate bone marrow cells. Animals were monitored clinically and histologically for GVHD. Chimerism was assessed by flow cytometry. Immunomagnetic bead depletion resulted in a reduction of T cells from 1.92%+/-0.21% to 0.10%+/-0.04% of total bone marrow. T-cell depletion did not remove facilitating cells (CD8+/alphabetaTCR-/gammadeltaTCR-/NK3.2.3-) from bone marrow. Further, the engraftment potential of TCD bone marrow was not affected, as 100% of animals engrafted and high levels of donor chimerism were detectable. Animals reconstituted with TCD bone marrow showed no clinical evidence of GVHD and histology revealed none to minimal changes, whereas recipients transplanted with untreated bone marrow succumbed to severe lethal GVHD. T-cell depletion using antialphabetaTCR mAb and immunomagnetic beads selectively removes T cells from the bone marrow graft while sparing facilitating cells that are required for engraftment of allogeneic bone marrow across MHC barriers. Moreover, the cells required for engraftment of HSC do not produce GVHD.

Animals↗
PubMed1999

Mixed hematopoietic chimerism prevents allograft vasculopathy.

BACKGROUND: Mixed hematopoietic chimerism has been shown to induce long-term acceptance of transplant organs. We determined whether mixed chimerism prevented allograft vasculopathy, using the rat aortic allograft model. METHODS: Mixed chimeras were prepared by reconstituting lethally irradiated (1100 cGy) WF rats with a mixture of T-cell depleted (TCD) syngeneic (WF) plus TCD allogeneic (ACI) bone marrow. Donor-specific (ACI) or third-party (F344) aortic grafts were transplanted into mixed chimeric animals 1 to 2 months after bone marrow reconstitution. No immunosuppressive drugs were administered. At 30 days postoperatively, aortic allografts were harvested for histology and measurement of cytokine mRNA by semiquantitative RT-PCR. Some aortic grafts were harvested at 90 and 180 days after transplantation for histological analysis. The degree of intimal hyperplasia and cytokine gene expression were compared among 4 groups: I (syngeneic; ACI donors to ACI recipients), II (allografts; ACI to WF), III (donor specific; ACI donor to chimeras) and IV (third-party; F344 to chimeras). RESULTS: There was no difference in the degree of intimal hyperplasia (IH) between groups I and III. Groups II and IV had significantly more IH than group I. Compared to group I, levels of mRNA for IFN-y, IL-2, IL-10 and iNOS in groups II and IV were higher, while there was no difference in mRNA levels between group I and III. CONCLUSIONS: These data suggest that mixed chimerism prevents allograft vasculopathy. Mixed chimerism holds great promise in clinical transplantation as a means to prevent allograft vasculopathy.

Animals↗
PubMed1999

Native heart complications after heterotopic heart transplantation: insight into the potential risk of left ventricular assist device.

BACKGROUND: In heterotopic heart transplantation, the donor heart is connected parallel to the recipient's diseased heart. Recipients continue to have risks, such as arrhythmia, thromboembolism, valvular heart disease, and ischemic heart disease which can develop in the native heart. It may serve as a clinical model to study long-term pathophysiologic processes in the native heart of patients with a left ventricular assist device. METHOD: We analyzed the prevalence of long-term complications related to the native heart in the heterotopic heart transplant and attempted to gain insight into the potential risk to a native heart after receiving a left ventricular assist device. RESULTS: Between December 1984 and December 1994, 16 patients (13 men, 3 women, ranging in age from 37 to 60 years) underwent heterotopic heart transplant at the University of Pittsburgh. The 1- and 5-year survival rate after the transplant was 81% and 44%, respectively. Actuarial freedom from complications related to the native heart after 1 year and 4 years was ventricular arrhythmia: 85%, 75%; ischemic disease: 85%, 64%; valvular disease: 100%, 88%; and thromboembolism: 85%, 58%. Of these complications, thromboembolism was not considered in determining actuarial freedom from complications because thromboembolism should be regarded as a device-related complication rather than as a native-heart-related complication for left ventricular assist device recipients. Consequently, actuarial freedom from all complications excluding thromboembolism was 70% after 1 year and 50% after 4 years. In addition, the hazard function curve remains constant up to 80 months after the operation without significant differences among the yearly ratios. CONCLUSIONS: This analysis suggests that cautious observation of the native heart's long-term performance is necessary for the left ventricular assist device recipient.

Adult↗