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Biomedical subjects

D J Norman

Publications and source records attributed to D J Norman.

At least 19 recordsLinked to original sources
PubMed1998

Efficacy and safety of low molecular weight heparin in renal transplantation.

BACKGROUND: Deep venous thrombosis (DVT) is a common problem with potentially devastating results in patients undergoing major surgical procedures. Certain renal transplant recipients are particularly at risk for allograft loss as a consequence of renal vein and artery thrombosis. Over the past few years, low molecular weight heparin has been well established as an accepted modality of treatment and prophylaxis of DVT. The efficacy and safety of low molecular weight heparin in the prophylaxis of DVT following renal transplantation in adults has not previously been reported. METHODS: Dalteparin was administered to 120 adult renal transplant recipients postoperatively at the Oregon Health Sciences University. RESULTS: No patient developed allograft arterial or venous thrombosis. One patient developed subclavian vein thrombosis. No bleeding complications were encountered, and side effects were very minimal. CONCLUSION: Prophylaxis with dalteparin is an effective and safe modality for the prevention of thrombosis in adult patients undergoing renal transplantation.

Adolescent↗
PubMed1998

Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation.

BACKGROUND: Thymoglobulin, a rabbit anti-human thymocyte globulin, was compared with Atgam, a horse anti-human thymocyte globulin for the treatment of acute rejection after renal transplantation. METHODS: A multicenter, double-blind, randomized trial with enrollment stratification based on standardized histology (Banff grading) was conducted. Subjects received 7-14 days of Thymoglobulin (1.5 mg/kg/ day) or Atgam (15 mg/kg/day). The primary end point was rejection reversal (return of serum creatinine level to or below the day 0 baseline value). RESULTS: A total of 163 patients were enrolled at 25 transplant centers in the United States. No differences in demographics or transplant characteristics were noted. Intent-to-treat analysis demonstrated that Thymoglobulin had a higher rejection reversal rate than Atgam (88% versus 76%, P=0.027, primary end point). Day 30 graft survival rates (Thymoglobulin 94% and Atgam 90%, P=0.17), day 30 serum creatinine levels as a percentage of baseline (Thymoglobulin 72% and Atgam 80%; P=0.43), and improvement in posttreatment biopsy results (Thymoglobulin 65% and Atgam 50%; P=0.15) were not statistically different. T-cell depletion was maintained more effectively with Thymoglobulin than Atgam both at the end of therapy (P=0.001) and at day 30 (P=0.016). Recurrent rejection, at 90 days after therapy, occurred less frequently with Thymoglobulin (17%) versus Atgam (36%) (P=0.011). A similar incidence of adverse events, post-therapy infections, and 1-year patient and graft survival rates were observed with both treatments. CONCLUSIONS: Thymoglobulin was found to be superior to Atgam in reversing acute rejection and preventing recurrent rejection after therapy in renal transplant recipients.

Acute Disease↗
PubMed1998

Squamous and basal cell carcinoma in heart transplant recipients.

BACKGROUND: Cutaneous malignancies are frequent in organ transplant recipients. We retrospectively reviewed a large series of heart transplant recipients and report on the prevalence and risk factors for development of cutaneous squamous and basal cell carcinoma. METHODS: Between Dec. 4, 1985, and Dec. 27, 1996, 299 heart transplantations were performed at the Oregon Health Sciences University. Heart transplant recipients with more than 6 months survival or follow-up were investigated for squamous and basal cell carcinoma (n = 248). RESULTS: Forty-one patients (17%) were found to have 192 squamous or basal cell carcinomas. Squamous cell carcinoma was the predominate skin malignancy, constituting 172 (90%) of the lesions. The mean number of skin malignancies per patient was 4.7 +/- 0.81 (range 125). Patients with development of a skin malignancy were 8 years older on average, with a male-to-female ratio of 19.5:1. The predominant skin type and eye color were fair (59%) and blue (59%), respectively. Cumulative risk, based on actuarial survival analysis for development of a squamous or basal cell carcinoma at 1 year, was 3% and increased to 21% and 35% at 5 and 10 years, respectively. In addition, cumulative risk increased in patients who received treatment with OKT3. CONCLUSION: Cumulative risk of development of a skin malignancy increased with time and use of OKT3. Additional patient risk factors included older age, male sex, fair skin, and blue eyes.

Actuarial Analysis↗
PubMed1997

Cardiac risk stratification in renal transplantation using a form of artificial intelligence.

The purpose of this study was to determine if an expert network, a form of artificial intelligence, could effectively stratify cardiac risk in candidates for renal transplant. Input into the expert network consisted of clinical risk factors and thallium-201 stress test data. Clinical risk factor screening alone identified 95 of 189 patients as high risk. These 95 patients underwent thallium-201 stress testing, and 53 had either reversible or fixed defects. The other 42 patients were classified as low risk. This algorithm made up the "expert system," and during the 4-year follow-up period had a sensitivity of 82%, specificity of 77%, and accuracy of 78%. An artificial neural network was added to the expert system, creating an expert network. Input into the neural network consisted of both clinical variables and thallium-201 stress test data. There were 5 hidden nodes and the output (end point) was cardiac death. The expert network increased the specificity of the expert system alone from 77% to 90% (p < 0.001), the accuracy from 78% to 89% (p < 0.005), and maintained the overall sensitivity at 88%. An expert network based on clinical risk factor screening and thallium-201 stress testing had an accuracy of 89% in predicting the 4-year cardiac mortality among 189 renal transplant candidates.

Adult↗
PubMed1997

Interleukin-12 p40 m-RNA expression in human kidney allograft biopsies.

Interleukin-12 (IL-12) is a heterodimeric cytokine implicated in the early differentiation of naive T-lymphocytes into the Th1 subset. IL-12 is important for induction of the cellular immune response against viruses, intracellular parasites and neoplasms. Its role in alloresponsiveness has not been fully elucidated. Preliminary data in the literature point toward the prevalence of Th1 lymphocytes in processes of allograft rejection. In attempt to further investigate the expression of this cytokine during episodes of cellular rejection of renal allografts, we searched for IL-12 message in human kidney allograft biopsies using the reverse transcriptase-polymerase chain reaction technique. Twenty-three allograft core biopsies from 19 patients were obtained percutaneously for clinical indications in 18 cases, and as part of an investigational protocol in five cases. A portion of the tissue was used for RNA extraction using the guanidium-thiocyanide phenol-chloroform method. Histology was performed on the remaining core material. Ten mg of total RNA were used for reverse transcription. PCR of the c-DNAs was done for 40 cycles using primers for the p40 subunit of IL-12 and GAPDH which was used as a control. PCR products were photographed after electrophoresis, transferred to a nylon membrane and hybridized with a radiolabelled cloned human IL-12 p40 1 kb c-DNA fragment. Autoradiographies were developed after 20-min exposure. All samples were run in triplicate. IL-12 p40 m-RNA was expressed in all 17 biopsies showing acute cellular rejection as well as in all three biopsies showing focal interstitial fibrosis. No message was found in the presence of normal allograft histology. This is the first in vivo report of IL-12 p40 subunit m-RNA expression during renal allograft rejection in humans. The role of this Th1 cytokine in the alloresponse deserves further investigation.

Adult↗
PubMed1996

Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism.

The gene apparently responsible for a heritable form of murine pituitary-dependent dwarfism (Ames dwarf, df) has been positionally cloned, identifying a novel, tissue-specific, paired-like homeodomain transcription factor, termed Prophet of Pit-1 (Prop-1). The df phenotype results from an apparent failure of initial determination of the Pit-1 lineage required for production of growth hormone, prolactin or thyroid-stimulating hormone, resulting in dysmorphogenesis and failure to activate Pit-1 gene expression. These results imply that a cascade of tissue-specific regulators is responsible for the determination and differentiation of specific cell lineages in pituitary organogenesis.

Alleles↗
PubMed1996

Identification of high- and low-risk second kidney grafts.

The purpose of this study was to identify recipients who are at low or high risk of early cadaveric regraft failure by segregating results of the flow cytometric crossmatch (FCXM) test with previous graft survival time (PGST). Early immunologic kidney regraft failure was analyzed in 103 multicenter recipients by cross-stratifying FCXM negative/positive status with < or =3- and >3-month PGST. T cell and B cell cytotoxicity crossmatches were negative. All were tested retrospectively in the T cell FCXM and 60 of the 103 were also tested in the B cell FCXM. A positive T and B cell FCXM was defined as a mean channel shift of > or = 9 (256 channel log scale) or > or = 40 (1024 channel log scale) for pretransplant crossmatch serum above negative control serum. Recipients received triple immunosuppression therapy and limited-use antilymphocyte induction therapy. Early cadaveric regraft losses were biopsied. Comparably good rates of second kidney graft survival at 3 years were found among three ow risk subsets: 78% for 18 FCXM-positive patients with PGST >3 months, 78% for 49 FCXM-negative patients with PGST >3 months, and 84% for 19 FCXM-negative patients with PGST < or =3 months. in contrast, 53% 3-month and 44% 3-year regraft survival rates occurred in 17 high-risk FCXM-positive recipients with a PGST < or =3 months. The odds ratio for increased relative risk of early second graft loss was 4.5 (confidence interval: 1.32-1.67) for the high-risk versus low-risk subsets (P = 0.009). Within the high-risk subset, 56% (5 of 9) of those who were FCXM T negative B positive experienced early regraft loss. A positive B cell FCXM has an adverse clinical impact only for high-risk regraft recipients. Pretransplant panel reactive antibody levels, pregnancy, number of blood transfusions between grafts, repeat donor HLA mismatches, and regraft recipient HLA mismatches did not correlate with early regraft loss. We conclude that kidney regraft survival rates in low-risk recipients (PGST >3 months/FCXM negative or positive [T and/or B cell] and PGST < or = 3 months/FCXM negative) approach primary graft survival rates and justify retransplantation, but the rate in high-risk regraft candidates (PGST < or =3 months/FCXM positive T and/or B cell) suggests that retransplantation should be performed only with a negative FCXM.

Female↗
PubMed1996

Cadaver kidney transplantation in patients more than 65 years old.

Elderly patients with end-stage renal disease often remain on dialytic therapy because they are at increased risk for mortality and morbidity. We placed 24 cadaver kidney transplants into 24 patients aged 65-74 years between September 1, 1985, and August 31, 1995. Rates of patient and graft survival were compared with those of 404 concurrent first cadaver-kidney transplant recipients between the ages of 20 and 44 years. The 5-year rates of patient and graft survival were not significantly different (86% versus 92% and 77% versus 63%, respectively; study group presented first). Primary cadaver kidney transplantation can be successfully performed in patients older than 65 years when a selection algorithm is applied to exclude active infection, active malignancy, unsuitable anatomy for technical success, high probability of operative mortality, and noncompliance. Pelvic arteriosclerosis and lower urinary tract abnormalities can cause intraoperative technical problems.

Adult↗
PubMed1996

OKT3 prophylaxis in renal grafts with prolonged cold ischemia times: association with improvement in long-term survival.

The data on patients participating in two randomized, prospective studies with similar immunosuppressive regimens were updated and combined to evaluate the long-term effects of OKT3 according to cold ischemia time (< or = or > 24 hr). Among 159 patients in the OKT3 and 153 in the cyclosporine A (CsA) group, 8 and 12 deaths occurred, respectively (P = NS). In patients with cold ischemia > 24 hours, OKT3 prophylaxis resulted in a lower mean number of rejection episodes per patient than did CsA prophylaxis within one year (mean +/- SEM: 0.87 +/- 0.11 vs. 1.35 +/- 0.14, respectively; P = 0.008) and within five years (1.07 +/- 0.12 vs. 1.49 +/- 0.15, respectively; P = 0.032). In contrast, rejection incidences in patients with cold ischemia < or = 24 hours was not significantly different in the two groups. In all study patients, there was a trend towards higher graft survival rates in the OKT3 group versus the CsA group (at 5 years, 73% vs. 66%, respectively; P = 0.182). Among recipients of kidneys with cold ischemia times > 24 hours, OKT3 patients had significantly higher graft survival than CsA patients at two years (84% vs. 64%, respectively) and at five years (71% vs. 56%, respectively; P = 0.045). Significant differences were not observed in recipients of kidneys with cold ischemia times < or = 24 hours. In conclusion, patients receiving renal grafts with long cold ischemia times strongly benefit from OKT3 prophylaxis.

Adult↗
PubMed1996

When perfectly HLA-matched kidneys are refused for transplant: implications for a national cooperative sharing system.

BACKGROUND: The transplant community attempts to maximize overall renal graft survival rates through nationwide sharing of perfectly-matched cadaveric kidneys. Although the number of such transplants is determined annually, the number available but not transplanted has never been assessed. There has also been no verification of the widespread claim that kidneys transplanted as paybacks for perfect matches are inferior. STUDY DESIGN: From records of the United Network for Organ Sharing, a complete accounting of six-antigen-matched kidney disposition was obtained, including a frequency distribution of reasons for refusal given when kidneys were refused for matched patients. Actuarial graft survival (GS) rates for matched, payback, and other cadaveric renal transplants were determined. RESULTS: Of the six-antigen-matched kidneys available, 97 percent were transplanted; 71 percent of those were accepted for matched patients. The two-year GS rate for matched patients was 84 percent, significantly higher than that for kidneys available for matched patients but transplanted into other patients (71.3 percent) and that for all other cadaveric kidneys (75.5 percent). Most reasons for refusal were related to donor quality. Kidneys refused for such reasons showed a 67.7 percent two-year GS rate in nonmatched patients and the highest rates of acute and chronic rejection and primary failure. The two-year GS rate for kidneys accepted as paybacks for matched kidneys (75.7 percent) was equivalent to that for all non-matched cadaveric kidneys (75.5 percent). CONCLUSIONS: If all normal-quality grafts refused for perfectly matched patients during 1990 through 1992 had been accepted for those patients, the number of transplants with typically superior survival rates could have increased by 25 percent, from 1,365 to 1,704. The payback requirement of the United Network for Organ Sharing does not seem to reduce the overall benefits of sharing perfectly matched kidneys nationwide.

Cadaver↗
PubMed1996

Thirty-seven years of renal transplantation in Oregon.

What we accomplish today as a matter of routine was only imagined by a few 4 decades ago. The journey from that first successful kidney transplant in the 1950s to the multidisciplinary, multiorgan transplant program of today has been a fascinating one. Although we attribute our current results to careful recipient selection and preparation, improvements in organ procurement and preservation, refinement of surgical techniques, improvement in histocompatibility techniques and organ sharing, improvements in immunosuppression and infection control, and careful monitoring of recipients, we and our patients have benefited from significant contributions from our colleagues in government and the law. The 4 that come to mind are the provision of near-universal insurance coverage for end stage renal disease patients in 1972 under the Medicare program, the passage of brain death laws in the mid 1970s, the passage of the National Transplant Act in 1984, and the passage of the Oregon required request law in 1985.

Brain Death↗
PubMed1995

Reduced human IgG anti-ATGAM antibody formation in renal transplant recipients receiving mycophenolate mofetil.

Exposure to the equine-derived polyclonal antithymocyte preparation, ATGAM, frequently elicits human anti-ATGAM antibody formation. The influence of concomitant immunosuppressants on this antiantibody response has not been established. We therefore evaluated IgG antibody formation to ATGAM in 47 patients receiving ATGAM as part of a prospective, randomized, double-blinded study of mycophenolate mofetil versus azathioprine for maintenance immunosuppression after primary cadaveric renal transplantation. All patients received ATGAM for induction of immunosuppression plus methylprednisolone, prednisone, and cyclosporine. In addition, patients were randomized to receive maintenance immunosuppression consisting of either azathioprine (AZA) 1-2 mg/kg/day, mycophenolate mofetil 2 gm/day (MMF2), or mycophenolate mofetil 3 gm/day (MMF3). Patient sequential sera were independently tested for IgG anti-ATGAM antibody by 2 laboratories, which were blinded to treatment arm assignments, using enzyme-linked immunosorbent assays. Both laboratories found significantly greater anti-ATGAM antibody formation in group AZA compared with groups MMF2 and MMF3: laboratory 1 reported sensitization rates in the 3 groups of 94% (AZA), 50% (MMF2) (P < 0.02 vs. AZA), and 60% (MMF3) (P < 0.05 vs. AZA); and laboratory 2 reported rates of 67% (AZA), 17% (MMF2) (P < 0.02 vs. AZA), and 10% (MMF3) (P < 0.02 vs. AZA). In addition, fewer patients formed high titer antibody in the MMF arms compared to the AZA arm: 56% (AZA), 0% (MMF2) (P < 0.02 vs. AZA), and 20% (MMF3) (P < 0.02 vs. AZA) of patients for laboratory 1; and 20% (AZA), 0% (MMF2) (P < 0.05 vs. AZA), and 0% (MMF3) (P < 0.05 vs. AZA) of patients for laboratory 2. Differences in test results between the 2 laboratories were explained by differences in the sensitivity of their respective immunoassays and in the criteria used for assigning a positive result to test specimens. In this protocol, MMF at 2-3 gm/day was associated with a reduced incidence and titer of IgG anti-ATGAM antibody formation compared with standard azathioprine dosing. Although MMF previously has been reported to inhibit T cell responses that mediate acute cellular rejection, this is the first demonstration that MMF significantly inhibits human B cell responses to antigen in vivo.

Adult↗
PubMed1995

The OKT3 Antibody Response Study: a multicentre study of human anti-mouse antibody (HAMA) production following OKT3 use in solid organ transplantation.

Human anti-murine antibody titres following patient exposure to the monoclonal antibody Orthoclone OKT3 (muromonab-CD3) are determined by laboratories using diverse analytical methods which are not standardized and whose concordance is not established. A multicentre study group therefore compared testing for IgG anti-OKT3 antibody among seven laboratories. A set of 270 sera was obtained from 30 heart, 30 kidney and 30 liver transplant recipients with no previous exposure to OKT3 who were receiving OKT3 for induction immunosuppression. Sera were collected from each patient prior to and at 24 +/- 2 days and 31 +/- 2 days following initial OKT3 exposure. Identical aliquots of all 270 sera were tested for IgG anti-OKT3 antibody by each laboratory. In addition, the limit of detection of each laboratory's method was estimated by titration of an affinity-purified IgG anti-OKT3 reference material of known concentration. Anti-OKT3 antibody formation differed greatly among the three organ groups. Cardiac patients demonstrated the least sensitization and almost exclusively lower titres, while kidney recipients had more frequent and higher titre antibody formation. Liver recipients yielded the highest sensitization rate and the most frequent high titre sera. Importantly, the seven laboratories differed widely in the number of pretreatment sera reported as positive (ranging from 0% to 41% among laboratories), the number of post-OKT3 sera reported as positive (17-63%), the number of post-OKT3 samples with titre > or = 1000 (2-31%), and the number of patients sensitized 19-69%). Concordance among laboratories was highly variable, with interlaboratory agreement ranging from 38% to 83% on the sample titres assigned to 180 post-OKT3 sera. Many of the discordant results were consistent with differences in the limit of detection of the analytical methods, which ranged from 0.19 microgram/ml to > or = 15 micrograms/ml, a nearly 100-fold difference among laboratories. This study demonstrated the presence of both good concordance and significant discordance among laboratories in determining human anti-mouse antibody titres, and demonstrated that common titre categories (100, 1000, 10,000) were not equivalent among laboratories. The level of concordance among methods should be considered when comparing anti-OKT3 antibody results from different centres and their correlation with clinical events. Universal comparative testing, patterned after proficiency testing programmes, is needed to assess differences among laboratories and to bring uniformity and a sound interpretative basis to this field of testing.

Adult↗
PubMed1995

Mechanisms of action and overview of OKT3.

OKT3 is a murine monoclonal antibody of the immunoglobulin IgG2a isotype. The target of OKT3, CD3, is a 17-20 kilodalton (kD) molecule that is part of a multimolecular complex found only on mature T cells and medullary thymocytes. This complex is uniquely situated next to the T-cell receptor for antigen. An interaction between T cells, OKT3, and monocytes causes T-cell activation (mitogenesis) in vitro. Because of the unique association between the antigen receptor and CD3, antibodies that react with CD3 block T-cell receptor function and vice versa. Thus, OKT3 blocks both the generation and function of cytotoxic T cells. After an initial dose of OKT3, T cells virtually disappear from the circulation within minutes to hours. During treatment with OKT3, T cells bearing the usual array of surface molecules (CD2, CD4, CD8) reappear in the peripheral blood circulation but these cells are devoid of the OKT3 target molecule, CD3. Within 48 hours of discontinuing OKT3, the normal array of surface molecules including CD3 is found again on all T cells. The selective removal of CD3 by internalization is thought to be the key mechanism of action of OKT3. Comodulation of the antigen receptor with CD3 explains the immunoblocking action of OKT3 in vivo. Experience with a second or third treatment with OKT3 indicates that OKT3 is ineffective clinically if the CD3 target molecule is not modulated. OKT3 has been found to be effective for induction of immunosuppression and for treating initial and steroid-resistant rejections.

Animals↗
PubMed1995

Generation of a high-resolution genetic map and a YAC contig of the Lurcher locus on mouse chromosome 6.

Lurcher (Lc) is a semidominant mouse mutant that displays progressive neurodegeneration during perinatal development. This genetic lesion results in apoptotic neuronal death in a dosage dependent and cell autonomous manner in specific neurons during their terminal differentiation. To understand the molecular basis of the Lc mutation, we have adopted a positional cloning approach based on its location on mouse chromosome 6. To define the Lc locus, we have extended our previous analysis of an intersubspecific backcross between Mus m. castaneus and B6CBACa-Aw-j/A-Lc consisting of 504 animals (Norman et al. 1991). In addition, 580 animals of a generic backcross between Mus spretus and C57BL/6 (The European Collaborative Interspecific Backcross) were utilized for the fine genetic mapping of the Lc locus. Using three RFLP markers and nine microsatellite markers in the vicinity of the Lc locus, we determined the order and relative genetic distances of these markers at a resolution of 0.1 cM. The Lc mutation was mapped between two flanking markers, D6Mit121 and D6Mit175, separated by a genetic distance of 0.5 cM. We then initiated the cloning of the genomic region surrounding these two markers by screening a YAC library and characterizing YAC end sequences for further screening. This effort has resulted in the construction of a YAC contig consisting of 14 YACs and spanning a 3-Mb region. Markers isolated from these YACs were used to further define the Lc locus, resulting in a physical map that places the Lc gene within an estimated 300-kb interval. This set of YACs and markers will serve as DNA sources for the identification of the Lc gene.

Animals↗
PubMed1995

The lurcher gene induces apoptotic death in cerebellar Purkinje cells.

In the neurologically mutant mouse strain lurcher (Lc), heterozygous animals display cell autonomous degeneration of cerebellar Purkinje cells beginning in the second postnatal week. During the course of our studies to identify the genetic lesion responsible for this disease (Norman et al., 1991), we have formulated an hypothesis suggesting that in Lc Purkinje cells homeostasis is sufficiently perturbed to lead to the activation of programmed cell death, thus resulting in neuronal loss and the consequent neurologic disease (Heintz, 1993). To address this possibility, we have examined the properties of Lc Purkinje cells as they die during the second postnatal week. Our light and electron microscopic studies demonstrate that dying Lc Purkinje cells exhibit the characteristic morphologic features of apoptosis, including nuclear condensation, axon beading and membrane blebbing. Using an in situ end-labeling method, we have also detected nicked nuclear DNA in these cells. Furthermore, we have examined the expression of the sulfated glycoprotein 2 (SGP2), whose mRNA is induced in both T-cells and prostate epithelial cells undergoing apoptotic death. We show by in situ hybridization that SGP2 is not expressed at detectable levels in normal Purkinje cells, but that its mRNA is present in Lc Purkinje cells prior to their death. Also expression of the Kv3.3b potassium channel, which marks the terminal phase of Purkinje cell differentiation, is evident in Lc Purkinje cells prior to their death. These data demonstrate that the Lc mutation induces apoptosis in cerebellar Purkinje cells following their maturation in postnatal cerebellum. Isolation of the Lc mutation and further analysis of its action in eliciting apoptosis can provide an important opportunity for understanding the etiology of neurodegenerative disease.

Animals↗