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Biomedical subjects

D S Ko

Publications and source records attributed to D S Ko.

13 recordsLinked to original sources
PubMed2000

Association of natural killer cell depletion with induction of mixed chimerism and allograft tolerance in non-human primates.

BACKGROUND: Nonmyeloablative T cell depletion followed by donor bone marrow infusion has proved to be an effective approach to induction of mixed chimerism and tolerance of organ allografts in non-human primates. To help define the mechanisms involved we have compared T cell depletion with ATG versus anti-CD2 monoclonal antibody with respect to establishment of mixed chimerism and induction of tolerance. METHOD: Both nonmyeloablative regimens included low dose total body irradiation (1.5 Gy x 2), thymic irradiation (7 Gy), splenectomy and kidney plus donor bone marrow transplantation, followed by a 4-week posttransplant course of cyclosporine. In addition, the ATG group (13 recipients) received antithymocyte globulin, although the LOCD2b group (10 recipients) were treated with an anti-CD2 monoclonal antibody (LOCD2b). RESULTS: In the ATG group, 11 of 13 monkeys developed multilineage chimerism and 9 survived for more than 100 days without kidney allograft rejection. In contrast, 0/10 monkeys in the LOCD2b group developed chimerism, 5 died of infection and 5 suffered progressive rejection; only 1 recipient survived beyond 100 days. Sequential monitoring of peripheral blood mononuclear cells revealed greater T cell (CD3+) depletion in the LOCD2b-treated animals compared to those receiving ATG. However, NK cells (CD16+CD8+) were significantly more depleted in the ATG group and NK function remained abrogated longer after ATG than LOCD2b treatment (3 weeks vs. <5 days). CONCLUSION: Despite excellent T cell depletion by LoCD2b, ATG was more effective in inducing chimerism and tolerance. This difference correlated with anti-NK activity of the two reagents. These data suggest that NK cells may also resist engraftment of allogeneic bone marrow cells in this model.

Animals↗
PubMed1999

Long-term outcome and alloantibody production in a non-myeloablative regimen for induction of renal allograft tolerance.

BACKGROUND: Multilineage chimerism and long-term acceptance of renal allografts has been produced in non-human primates conditioned with a nonmyeloablative regimen. Our study was undertaken to evaluate the immunological and pathological status of long-term survivors and to define the role of splenectomy and of the primarily vascularized kidney in the regimen. METHOD: Monkeys were treated with the basic regimen, including: total body irradiation, thymic irradiation, antithymocyte globulin, donor bone marrow transplantation, and a 4-week course of cyclosporine after which no further immunosuppression was given. They were divided into four groups according to the timing of kidney transplantation (KTx) and splenectomy as follows; group A (n=13): KTx and splenectomy on the day of donor bone marrow transplantation (day 0); group B (n=3): KTx on day 0 without splenectomy; group C (n=7): splenectomy on day 0 but delayed KTx until 3 to 16 weeks post-donor bone marrow transplantation; group D (n=3): both splenectomy and KTx delayed until day 120 post-donor bone marrow transplantation. RESULTS: In group A, 11 of 13 monkeys developed chimerism and 9 monkeys achieved long-term survival of 4 to 70 months without evidence of chronic vascular rejection. Alloantibodies were detected in only one long-term survivor. In contrast, all three monkeys in group B developed alloantibodies and rejected their allografts. In group C, long-term survival without alloantibody production was observed in two of three monkeys that had developed chimerism. In group D, all three recipients were sensitized and rejected the kidney allografts rapidly after transplantation. CONCLUSIONS: 1) Production of anti-donor antibody was prevented in most recipients that developed mixed chimerism in the regimens with splenectomy at the time of donor bone marrow transplantation. 2) If splenectomy is not included in the initial conditioning regimen, induction of B cell tolerance is less likely and the result is late onset of alloantibody production and allograft rejection. 3) Immediate transplantation of the kidney at the time of recipient conditioning is not essential for induction of donor specific hyporesponsiveness by bone marrow transplantation.

Animals↗
PubMed1999

The clinical usefulness of the renal allograft biopsy in the cyclosporine era: a prospective study.

BACKGROUND: The renal allograft biopsy is generally accepted as the gold standard for clarifying the cause of renal dysfunction. However, the clinical usefulness of this procedure has rarely been studied prospectively, nor have most studies included follow-up of patients to delineate the influence of the biopsy on clinical outcome. In this study, we evaluated prospectively the clinical usefulness of the allograft biopsy in renal transplant recipients receiving cyclosporine (CyA). METHODS: During a 21-month period, 82 biopsies were performed. In 54 instances (47 patients), we outlined a presumed diagnosis and tentative treatment plan before the procedure. After the biopsy, a definitive diagnosis was made and an appropriate patient management approach was instituted. We analyzed the incidence of change in patient management that resulted from histological findings. All patients were followed to monitor their response to treatment and allograft survival. In cases of biopsy-proven acute cellular rejection (ACR) or cyclosporine (CyA) toxicity, clinical and laboratory data from the day of the biopsy were reviewed to determine their diagnostic value. RESULTS: One biopsy specimen was inadequate for definitive interpretation. The biopsy findings resulted in a change in patient management in 22 (41.5%) of the remaining 53 cases (change group). The incidence of altered patient management was 38.7% in biopsy specimens taken in the first month, 55.6% between 1 and 12 months, and 38.5% after 1 year posttransplantation. A change in management was required in 2 of 2 patients with chronic allograft dysfunction, in 44.4% of the 45 patients with acute allograft dysfunction, and in none of the patients with delayed graft function (n=6). Within the first week of treatment 19 of 22 (86.4%) in the change group and 25 of 31 (80.6%) in the no change group had a positive response to therapy. The 1-year allograft survival rate was also similar between the two groups. None of the clinical and laboratory data was useful in distinguishing ACR from CyA toxicity. CONCLUSIONS: Renal allograft biopsy findings alter patient management recommendations in approximately 40% of patients in whom a presumptive diagnosis had been made on the basis of clinical and laboratory findings. Patients who had a change in patient management because of biopsy findings demonstrated a response to therapy and allograft survival similar to those of patients who had no alteration in management plan after the biopsy.

Adult↗
PubMed1998

Effective treatment of lymphedema of the extremities.

OBJECTIVE: To define the immediate and long-term volumetric reduction following complete decongestive physiotherapy (CDP) for lymphedema. DESIGN: Prospective study of consecutively treated patients. SETTING: Freestanding outpatient referral centers. PATIENTS: Two hundred ninety-nine patients referred for evaluation of lymphedema of the upper (2% primary, 98% secondary) or lower (61.3% primary, 38.7% secondary) extremities were treated with CDP for an average duration of 15.7 days. Lymphedema reduction was measured following completion of treatment and at 6- and 12-month follow-up visits. INTERVENTION: Complete decongestive physiotherapy is a 2-phase noninvasive therapeutic regimen. The first phase consists of manual lymphatic massage, multilayered inelastic compression bandaging, remedial exercises, and meticulous skin care. Phase 2 focuses on self-care by means of daytime elastic sleeve or stocking compression, nocturnal wrapping, and continued exercises. MAIN OUTCOME MEASURES: Average limb volumes in milliliters were calculated prior to treatment, at the end of phase 1, and at 6- to 12-month intervals during phase 2 to assess percent volume reduction. RESULTS: Lymphedema reduction averaged 59.1% after upper-extremity CDP and 67.7% after lower-extremity treatment. With an average follow-up of 9 months, this improvement was maintained in compliant patients (86%) at 90% of the initial reduction for upper extremities and lower extremities. Noncompliant patients lost a part (33%) of their initial reduction. The incidence of infections decreased from 1.10 infections per patient per year to 0.65 infections per patient per year after a complete course of CDP. CONCLUSIONS: Complete decongestive physiotherapy is a highly effective treatment for both primary and secondary lymphedema. The initial reductions in volume achieved are maintained in the majority of the treated patients. These patients typically report a significant recovery from their previous cosmetic and functional impairments, and also from the psychosocial limitations they experienced from a physical stigma they felt was often trivialized by the medical and payor communities.

Bandages↗
PubMed1998

An evaluation of quality of life in patients with continent urinary diversions after cystectomy.

OBJECTIVE: To determine the long-term results and assess the quality of life in patients with continent urinary diversions after cystectomy. PATIENTS AND METHODS: Eighty-six consecutive patients who received a continent urinary diversion from 1988 to 1994 at the Vancouver Hospital and Health Sciences Center were evaluated. The evaluation comprised a review of their hospital charts and clinic visits at 3 months and then yearly. Quality of life issues were assessed using a postal questionnaire pertaining to the patient's urinary symptoms. activity level and overall well-being while living with a continent urinary diversion. Two separate questionnaires were sent, addressing heterotopic or orthotopic diversions. RESULTS: There was an acceptable rate of complications, with stone formation and urinary tract infection as the most common morbidities. Continence was rated as good in most patients, with no patient reporting complete incontinence. Undesirable urinary symptoms occurred less often than 20% of the time in most patients. Although there was a significant effect on sex life, the overall quality of life appeared to be very good, as 70% of the patients had no limitations to their activities. CONCLUSIONS: The techniques currently evolved for urinary diversion produce good long-term results and quality of life. These diversions should be considered in a well selected patient population.

Adult↗
PubMed1998

Demonstration of multilineage chimerism in a nonhuman primate concordant xenograft model.

Prior studies from our laboratory have demonstrated that a nonmyeloablative conditioning regimen can induce transient mixed chimerism and renal allograft tolerance between MHC disparate cynomolgus monkeys. We have also shown that this preparative regimen can be extended to a concordant baboon to cynomolgus xenograft model by adding, to the post transplant protocol, therapy designed to prevent antibody production. Here we examine the use of brequinar (BQR) for this purpose and the efficacy of two new reagents developed to demonstrate the establishment of chimerism in the xenograft recipients. The cynomolgus recipients were conditioned with WBI (300 cGy), TI (700 cGy), ATG, cyclosporine, and brequinar sodium. To detect engraftment of the donor marrow, we prepared a polyclonal cynomolgus anti-baboon antibody (CABA) and a monoclonal antibody (215.1), which distinguish baboon and cynomolgus lymphocytes and granulocytes. We employed flow cytometry analysis to detect multilineage chimerism in the xenograft recipients. Five of the six recipients monitored using our new reagents (CABA and 215.1) developed detectable chimerism and only one of these animals lost its kidney to rejection. However, other complications have not permitted assessment of long-term outcome. The features of the multilineage chimerism included the detection of donor granulocytes (1.8-77.4%) and lymphocytes (2.4-22.2%) for 9 to 37 days. Our new reagents permit the detection of multilineage mixed chimerism, which may be a predictor of xenograft tolerance. We also conclude that brequinar may be effective in preventing antibody formation, but because of its toxicity, it is probably not the drug of choice for extension of the mixed chimerism protocol to concordant xenografts.

Animals↗
PubMed1997

Multiple-transducer scheme for scanning tomographic acoustic microscopy using transverse waves.

We propose a new type of multiple-transducer scheme with functions of multiple-angle and multiple-frequency tomography for scanning tomographic acoustic microscopy (STAM) using transverse waves. We review the data acquisition system and mode conversion of the acoustic waves for STAM and the multiple-angle and multiple-frequency tomography. Our multiple-transducer scheme has three insonification angles and three resonance frequencies in order to operate, in the transverse wave mode, multiple-angle and multiple frequency tomography for STAM. In order to evaluate the performance of our transducer scheme, we have simulated tomographic reconstruction with a back-and-forth propagation algorithm. Simulation results show that our multiple-transducer scheme is capable of obtaining good resolution with transverse wave mode and multiple-frequency tomography. We also show that our multiple-transducer scheme is an efficient rotation tool for a number of projections.

Microscopy↗
PubMed1995

Quantitative PCR for the measurement of circulating proviral load in HIV-infected individuals.

BACKGROUND: PCR has been applied extensively as a tool for the detection of HIV. We have previously developed a semi-quantitative microtiter plate assay for the specific detection of HIV PCR products. OBJECTIVE: To develop and evaluate a novel quantitative assay for the measurement of circulating proviral load in HIV-infected individuals. STUDY DESIGN: We evaluated 70 consecutive, unselected HIV-infected patients, divided into 3 groups, according to their CD4 cell count: greater than 500 cells/microl (10 subjects); 200-500 cells/microl (31 subjects); less than 200 cells/microl (29 subjects). Peripheral blood mononuclear cell lysates were amplified, and a portion of the product was added to streptavidin-coated wells with a biotinylated capture probe and a horseradish peroxidase-linked reporter probe, complementary to separate regions of the amplified product. Following incubation, readings were taken with an automated plate reader. Products were quantitated by interpolation into a standard curve of serial dilutions of an HIV-containing plasmid, included in each assay. RESULTS: HIV sequences were detected in all 70 clinical samples. Within each patient category, a wide range of proviral loads were observed. However, proviral load/10(6) CD4 cells was associated with disease progression when the patient groups were considered (up to 9.6% infected cells in subjects with CD4 cell counts below 200/microl). CONCLUSIONS: This quantitative PCR assay will allow the measurement of proviral load in clinical samples. It may be useful in the managment of HIV-infected individuals and the evaluation of the efficacy of antiretroviral therapy.

Journal Article↗
PubMed1995

The correlation of multichannel urodynamic pressure-flow studies and American Urological Association symptom index in the evaluation of benign prostatic hyperplasia.

PURPOSE: We correlated multichannel pressure-flow urodynamics and the American Urological Association (AUA) symptom index in the evaluation of benign prostatic hyperplasia. MATERIALS AND METHODS: We evaluated 121 consecutive, symptomatic patients older than 55 years with the AUA symptom score and multichannel pressure-flow urodynamic studies. Testing was performed during a single session and the data obtained from 103 patients were plotted on the Schäfer nomogram for assessment of outflow obstruction. Linear regression statistical analysis was used to determine correlations. RESULTS: There was no significant correlation between uroflowmetry and Schäfer curves (r = 0.173 to 0.326), uroflowmetry and AUA symptom scores (r = 0.134 to 0.153) and, most importantly, AUA symptom scores and Schäfer curves (r = 0.025 to 0.137). CONCLUSIONS: We conclude that these modalities measure independent variables, and should not be linked in the evaluation and treatment decision of the patient with prostatism.

Aged↗
PubMed1995

Venovenous bypass in renal cell carcinoma with caval tumor thrombus.

We describe two patients with a T3bN2M0 renal cell carcinoma with caval extension to the hepatic veins in which we successfully utilized extracorporeal femoralaxillary venovenous bypass for tumor thrombus resection. The inherent advantage of this modified venovenous bypass are discussed with a current review of the literature.

Journal Article↗
PubMed1989

Influence of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice.

The effects of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice have been investigated using a versatile procedure for encapsulating doxorubicin inside liposomes. In this procedure, vesicles exhibiting transmembrane pH gradients (acidic inside) were employed to achieve drug trapping efficiencies in excess of 98%. Drug-to-lipid ratios as high as 0.3:1 (wt:wt) could be obtained in a manner that is relatively independent of lipid composition and vesicle size. Egg phosphatidylcholine (EPC)/cholesterol (55:45; mol/mol) vesicles sized through filters with a 200-nm pore size and loaded employing transmembrane pH gradients to achieve a doxorubicin-to-lipid ratio of 0.3:1 (wt/wt) increased the LD50 of free drug by approximately twofold. Removing cholesterol or decreasing the drug-to-lipid ratio in EPC/cholesterol preparations led to significant decreases in the LD50 of liposomal doxorubicin whereas, the LD50 increased 4- to 6-fold when distearoylphosphatidylcholine was substituted for EPC. The results suggest that the stability of liposomally entrapped doxorubicin in the circulation is an important factor in the toxicity of this drug in liposomal form. In contrast, the antitumor activity of liposomal doxorubicin is not influenced dramatically by alterations in lipid composition. Liposomal doxorubicin preparations of EPC, EPC/cholesterol (55:45; mol:mol), EPC/egg phosphatidylglycerol (EPG)/cholesterol (27.5:27.5:45; mol:mol), and distearoylphosphatidylcholine/cholesterol (55:45; mol:mol) all demonstrated similar efficacy to that of free drug when given at doses of 20 mg/kg and below. Higher dose levels of the less toxic formulations could be administered, leading to enhanced increases in life span (ILS) values. Variations in vesicle size, however, strongly influenced the antitumor activity of liposomal doxorubicin. At a dose of 20 mg/kg, large EPC/cholesterol systems are significantly less effective than free drug (with ILS values of 65% and 145%, respectively). In contrast, small systems sized through filters with a 100-nm pore size are more effective than free drug, resulting in an ILS of 375% and a 30% long term (greater than 60 days) survival rate when administered at a dose of 20 mg/kg. Similar size-dependent effects are observed for distearoylphosphatidylcholine/cholesterol systems.

Animals↗
PubMed1986

Toward an in vitro system for picornavirus assembly: purification of mengovirus 14S capsid precursor particles.

Mengovirus 14S subviral protein particles generated in infected L cells and in a cell-free translation system primed with mengovirus RNA were purified by sucrose gradient centrifugation and immunoaffinity chromatography. The preparations from both sources contained essentially pure proteins epsilon, alpha, and gamma, as was demonstrated in terms of virus-specific proteins (by autoradiography) and total protein content (by silver staining of sodium dodecyl sulfate-polyacrylamide electrophoresis gels). These purified proteins sedimented as discrete particles at the 14S position when recentrifuged in sucrose gradients. Although their assembly properties have not yet been studied in detail, preliminary results indicate that during incubation with virion RNA the 14S particles purified from infected cells can form a structure cosedimenting with mature mengovirus.

Animals↗