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Biomedical subjects

D K Cooper

Publications and source records attributed to D K Cooper.

At least 91 records · Page 5Linked to original sources
PubMed1998

Personal social networks and HIV status among women on methadone.

This objective of this study was to examine the association between a women's HIV status and specific (IDUs) characteristics of her social networks with respect to (1) number of injection drug users (2) number of drug partners and (3) number of HIV-positive contacts in her personal networks, after controlling for the respondent's demographic characteristics and drug use. Participants were recruited through posted announcements in three methadone clinics in Harlem, New York City. Individuals were considered eligible if they were enrolled as patients in one of the clinics for at least three months. A social network questionnaire modeled after the General Social Survey network section was developed by the investigators. Face-to-face interviews were conducted by trained interviewers and included demographics, drug use, self-reported HIV status of the woman and her network members, and the social network structures. Univariate analyses found that HIV-positive and HIV-negative women had different network profiles. HIV-positive women were more likely to associate with a higher number of current drug users, injection drug users, injection drug users who were HIV-positive, drug partners, drug partners who used injection drugs, and drug partners who were HIV-positive. Multivariate analyses indicated that HIV-positive respondents were more likely to associate with HIV-positive network members than their HIV-negative counterparts. The findings suggest that to better understand the spread of HIV among female drug users and to design more effective HIV/AIDS prevention programmes, efforts should move beyond focusing on individual attributes to address the contextual dynamics of social networks.

Adult↗
PubMed1998

Xenoantigens and xenoantibodies.

Major efforts are being directed towards determining and modifying the glycosylated epitopes on pig vascular endothelial cells, against which human natural antibodies are directed. Genetic engineering techniques are being used in an effort to knock out or replace the major alpha galactosyl (alpha Gal) epitopes in mice, but to-date these have been only modestly successful in prolonging functional survival of such modified organs. Competitive glycosylation involving insertion of the gene for alpha 1,2 fucosyltransferase results in reduction of alpha Gal expression but also of presentation of hitherto cryptic antigens against which natural human antibodies are directed or could develop. The introduction of the gene for N-acetylglucosaminyltransferase III has been demonstrated to significantly reduce alpha Gal expression, and the intracellular expression of single chain Fv antibodies against alpha 1,3 galactosyltransferase also represses this enzyme activity. Several other carbohydrate antigens have been identified that could act as targets for human natural antibodies, and these include Gal alpha 1-3Le(x), Hanganutziu-Deicher, Tn, and Forssman antigens. The alternative approach, namely, the depletion of the recipient's natural antibodies, is proving difficult, but techniques for inducing B cell tolerance are being explored. The induction of a state of mixed hematopoietic chimerism in alpha Gal knockout mice has resulted in tolerance to the alpha Gal antigen. Tolerance to the SLA antigens of miniature swine is also being attempted in baboons by the transfer of SLA Class II genes into baboon bone marrow cells. It is hoped that one or a combination of these approaches may overcome the problem created by the presence of pig antigens against which humans have xenoreactive antibodies.

Animals↗
PubMed1998

Depletion of anti-Gal(alpha)1-3Gal antibody in baboons by specific alpha-Gal immunoaffinity columns.

Ongoing studies at our center on facilitating transplantation of discordant xenogeneic organs are focused on tolerance induction. To abrogate hyperacute rejection, we have used adsorption methods to eliminate natural anti-Gal(alpha)1-3Gal (alphaGal) antibodies from the circulation of baboons. We have analyzed data concerning antibody removal in baboons that were 1) immunologically naive, 2) receiving conventional pharmacologic immunosuppressive therapy (IS), and 3) treated with a conditioning regimen for tolerance induction. We compared the efficiency of removing alphaGal antibody 1) by perfusion of whole blood through an alphaGal affinity column (CP; n=5) with 2) perfusion of plasma (separated from cellular components by apheresis) through an alphaGal column (CPA; n=39). Our studies demonstrate that 1) CP and CPA are equally effective in removing anti-alphaGal antibody, 2) CPA is the method of choice if multiple adsorptions are required, 3) CPA in naive animals transiently affects levels of total IgG and IgM, 4) four CPAs repeated at 2-4 day intervals in association with heavy IS reduce the pool of anti-alphaGal antibody and total Ig, and 5) splenectomy and/or IS delay the return of anti-alphaGal antibody.

Animals↗
PubMed1998

Comparative histopathology of hepatic allografts and xenografts in the nonhuman primate.

Liver transplantation was performed in the following groups: Group 1, baboon-to-baboon allografting (n=8) (control group); Group 2, ABO-compatible vervet monkey-to-baboon xenografting (n=8); Group 3, ABO-incompatible vervet monkey-to-baboon xenografting (n=6); Group 4, pig-to-baboon xenografting (n=2); and Group 5, pig-to-rhesus monkey xenografting (n=6). Immunosuppressive therapy (cyclosporine, cyclophosphamide, and methylprednisolone) was begun 2-7 days before liver transplantation (LTx) and continued indefinitely after LTx. The liver grafts were biopsied pre-LTx and subsequently post-LTx at approximately 1 hr, 2-3 hr, 7-10 days, 20-30 days, 60 days, 120 days, and at euthanasia or spontaneous death. There were 19 successful LTxs with grafts functioning from one hour to 123 days. No pig liver (Groups 4 and 5) survived more than 5.5 hr, as there was an immediate severe vascular response after reperfusion, typical of hyperacute rejection (congestion and hemorrhage). Vascular rejection was not seen in allografts (Group 1), but early mild-to-moderate congestion and neutrophil infiltration were present in concordant xenografts (Groups 2 and 3), which were associated with moderate deposition of immunoglobulin, C3, and fibrinogen. Lymphoid cell infiltration, bile duct damage, and portal vein endothelialitis in the portal zones occurred later in both allografts (Group 1) and concordant xenografts (Groups 2 and 3), developing earlier in the presence of ABO-incompatibility (Group 3). In concordant xenografts it was usually followed by fibrosis.

Animals↗
PubMed1998

Pharmacologic immunosuppressive therapy and extracorporeal immunoadsorption in the suppression of anti-alphaGal antibody in the baboon.

The aim of this study was to deplete baboons of anti-(alpha)galactosyl (alphaGal] antibody and attempt to maintain depletion by pharmacologic immunosuppressive therapy (PI). In 12 experiments, involving nine baboons, repeated extracorporeal immunoadsorption (EIA) was carried out by plasma perfusion through immunoaffinity columns of synthetic alphaGal trisaccharide type 6. Five of the baboons were immunologically naive and four had undergone various procedures at least 6 months previously. All, however, had recovered lymphohematopoietic function and (with one exception) had levels of anti-alphaGal antibody within the normal range. Eleven protocols included continuous i.v. cyclosporine (to maintain whole blood levels of approximately 1,600 ng/ml). In addition, in ten protocols, the baboon received one or more of the following drugs: cyclophosphamide (1-20 mg/kg/day), mycophenolate mofetil (70-700 mg/ kg/day), brequinar sodium (1-12 mg/kg/day), prednisolone (1 mg/kg/day), melphalan (0.15-0.6 mg/kg/day), methylprednisolone (125 mg/day x3), and antilymphocyte globulin (ATG) (50 mg/kg/day x3). EIA was carried out on 1-9 occasions in each study and was temporarily successful in removing all antibody. When no PI was administered, antibody returned close to pre-EIA levels within 48 hr. Cyclosporine alone delayed the rate of antibody return only slightly. While EIA was continuing on a daily or alternate day schedule, antibody levels (both IgM and IgG) were maintained at 20-45% of pre-EIA levels. Once EIA was discontinued but PI maintained, IgM rose to 40-90% and IgG to 30-60% of pre-EIA levels. In vitro testing demonstrated significant cytotoxicity to pig cells at these antibody levels. We conclude that i) EIA utilizing columns of alphaGal trisaccharide is successful in temporarily depleting baboons of anti-alphaGal antibody, but ii) none of the PI regimens tested suppressed antibody production to levels which would be expected to prevent antibody-mediated rejection of pig xenografts. Additional strategies will therefore be required if xenotransplantation is to become a clinical reality.

ABO Blood-Group System↗
PubMed1998

Hepatitis C status of heart transplant recipients.

The records of 155 consecutive patients who underwent successful heart transplantation (HTx) were reviewed to document the incidence of hepatitis C (HCV) infection. One patient was HCV RNA positive pre-HTx, and 12 patients (8%) developed transient or permanent HCV positivity post-HTx. HCV RNA positivity was associated with biochemical features of liver injury. Liver biopsy was performed in 8, and demonstrated features of chronic hepatitis in all. Two patients died of chronic liver failure at 50 and 56 months post-HTx, respectively. Interferon therapy was given to three patients, two of whom converted to HCV negativity. This study suggests that HCV infection is more common than previously anticipated in HTx patients, and varies from a mild transient condition to a fatal chronic liver failure.

Adolescent↗
PubMed1997

Delayed xenograft rejection of pig-to-baboon cardiac transplants after cobra venom factor therapy.

BACKGROUND: This study sought to (i) investigate the efficacy of cobra venom factor (CVF) in preventing hyperacute rejection (HAR) after pig-to-baboon heart transplantation, (ii) examine the effect of additional splenectomy (Spx) and pharmacologic immunosuppression (IS), and (iii) study delayed graft rejection when HAR is avoided by complement depletion. METHODS: Eleven recipient baboons received heterotopic pig heart transplants. Three received either no therapy or IS (cyclosporine + methylprednisolone +/- cyclophosphamide +/- methotrexate) at clinically well-tolerated doses, with graft survival for only 40, 32, and 15 min, respectively. Two received CVF+/-Spx, which extended survival to 5 and 6 days, respectively. Six underwent Spx + CVF therapy + IS; graft survival was 3 hr (technical complication), 6 days (death from sepsis), 10, 12, and 22 days (vascular rejection), and <25 days (euthanized for viral pneumonia with a functioning graft that showed histopathologic features of vascular rejection). RESULTS: Dense deposition of IgM and, to a lesser extent, IgG and IgA were seen on the endothelial cells within 1 hr of transplantation, but only trace levels of complement deposition were present in CVF-treated recipients. Within approximately 5-12 days, cardiac xenografts showed progressive infiltration by mononuclear cells, consisting primarily of activated macrophages producing tumor necrosis factor-alpha and small numbers of natural killer cells; T and B cells were absent. CONCLUSIONS: We conclude that (i) CVF prevents HAR, (ii) the addition of Spx + IS delays rejection, but (iii) the early deposition of antibody leads to progressive graft injury, resulting in (iv) delayed vascular rejection. Our findings indicate that the features of delayed xenograft rejection described in small animal models also occur in the pig-to-baboon model, and that rejection may occur in a complement-independent manner from the effects of antibody and/or host macrophages.

Acute Disease↗
PubMed1997

Anti-GaL IgG antibodies in sera of newborn humans and baboons and its significance in pig xenotransplantation.

We have previously demonstrated that hyperacute rejection does not occur in a pig-to-newborn baboon heart transplant model, presumably because of low levels of cytotoxic antipig antibodies present in the serum of newborn baboons. Cytotoxic antipig antibodies are primarily directed to alpha-1,3-galactosyl (alpha Gal) residues on endothelial cell surface structures Twenty-one full-term humans and 5 full-term baboons were tested for complement mediated lysis (CML) of pig kidney (PK-15) cells and anti-alpha Gal activity with an ELISA using BSA-conjugated alpha Gal residues as target. To evaluate the significance of the anti-alpha Gal titers in vivo 5 newborn baboons underwent heterotopic pig cardiac xenotransplantation. Six of 21 human samples and 1 of 5 baboon samples demonstrated significant cytotoxicity to PK-15 cells. Twelve of 21 newborn humans had anti-alpha Gal IgG antibodies at titers of 1:80 or greater. None of the samples had anti-alpha Gal IgM. In newborn baboons, 1 of 5 sera had anti-alpha Gal IgG antibodies at titers greater than 1:80 and none of these samples had anti-alpha Gal IgM. Xenografts survived for an average of 3.6 days, even in the baboon with high anti-alpha Gal IgG titers. Analysis of the explanted grafts showed minimal evidence of complement-mediated hyperacute rejection (HAR), but prominent mononuclear cell infiltrates. In serum tested posttransplant there was an induced anti-alpha Gal response with cytotoxicity against PK-15 cells. These results show that anti-alpha Gal IgM is absent in newborn human and baboon sera, allowing pig grafts to avoid HAR. However, the presence of anti-alpha Gal IgG may be associated with mononuclear cell infiltration of the xenograft and its subsequent rejection.

Animals↗
PubMed1997

Juveniles' understanding of trial-related information: are they competent defendants?

There exists a national trend lowering the age to transfer children facing serious charges to adult court for trial. This study examined juvenile offenders' understanding of factual information about trials. Juveniles ages 11 through 16 experiencing their first institutional placement were administered a competence to stand trial screening measure, shown an educational videotape, and readministered the measure. Findings suggest that a majority do not have sufficient understanding for meaningful participation in their trials. Special care appears warranted with juveniles ages 13 and under, and juveniles with low average or below average IQ scores. Further, substantial training may be necessary for some juvenile offenders.

Adolescent↗
PubMed1997

Five year research update (1991-1995): evaluations for competence to stand trial.

This article reviews and evaluates publications during 1991-1995 with relevance for assessments of competence to stand trial. The review focuses specifically on articles that provide new concepts or data supported by research or case analyses. The studies are reviewed under the following headings: (a) the systemic context of competence to stand trial (CST) evaluations, (b) conceptual definitions of CST, (c) research on CST assessment methods, (d) characteristics of incompetent defendants, (e) interpretation and communication of CST evaluation data, (f) issues in CST assessment of special populations (juveniles, persons with mental retardation), and (g) treatment to restore competence. Suggestions are offered for further research to advance the quality of clinical evaluations for competence to stand trial.

Bias↗
PubMed1997

Ultrastructure changes associated with brain death in the human donor heart.

Electromicroscopic examinations were carried out on 30 myocardial biopsies taken from 22 human donor hearts immediately after excision (prestorage) or immediately before transplantation (poststorage). All electron micrographs were independently examined by two morphologists. Eleven structures were examined in each micrograph, and each structure was scored according to the degree of injury. A good interobserver correlation was obtained in 84% of the structures scored. In the prestorage left ventricular biopsies (n = 11), approximately 20%-25% showed moderate to severe ultrastructural injury. The ultrastructural injury observed in the poststorage left ventricular biopsies (n = 15) was no different from that in the prestorage group, particularly injury to the sarcomere and mitochondria. A similar degree and pattern of injury was seen in the right ventricle (n = 4). There was no evidence that an ischemic storage period of less than 6 h increased the degree of injury seen. However, there was a higher incidence of moderate to severe injury in those hearts excised from donors initially dependent on high inotropic support.

Adolescent↗
PubMed1997

Primary bronchogenic carcinoma in recipients of heart transplants.

With the exception of carcinomas of the skin and lip, carcinoma of the bronchus is the most common carcinoma that afflicts recipients of solid organ grafts. Of 859 tumors occurring in 830 recipients of thoracic organs reported to the Cincinnati Tumor Transplant Registry, 242 were carcinomas and 68 of these were bronchogenic carcinomas, which therefore made up 8% of the overall total. There are, however, relatively few reports of heart transplant patients with bronchogenic carcinoma in the literature. We present details of four patients who developed this malignancy out of a total of 196 patients who survived and have been followed up for more than 3 months at our center, an incidence of 2%. The mean period from the time of transplant to diagnosis of malignancy was 58 months (range 11-82 months). The histology was squamous or anaplastic in three cases, and adenocarcinoma in one. Immunosuppressive therapy was reduced in all cases. Resection was carried out in two patients (both of whom died 6 and 11 months later, respectively), resection was combined with chemotherapy and radiation in one patient (alive 15 months later), and therapy consisting of radiation alone was given to one patient (died within 1 month). We conclude that bronchogenic carcinoma is relatively common in patients with heart transplants and that it has a poor prognosis.

Adult↗
PubMed1997

Clinical xenotransplantation: past, present and future.

The ability to use animal organs, such as from the pig, for the purposes of transplantation in humans, would clearly overcome the major shortage of human organs that greatly restricts transplantation programmes worldwide. Recent experimental advances have raised the possibility of renewed attempts at organ xenotransplantation in humans within the near future. Previous clinical experience, dating back to 1906, is briefly reviewed. The problems that still require resolution include the immunological barrier, the risk of transferring infectious agents with the transplanted organ, and uncertainty as to whether the transplanted animal organ will function satisfactorily in the human environment. Ironically, the answers to some of these problems may only be provided when clinical xenotransplantation is undertaken.

Animals↗
PubMed1996

In vivo immunoadsorption of antipig antibodies in baboons using a specific Gal(alpha)1-3Gal column.

The major role of anti-alphaGal antibodies in the hyperacute rejection of pig organs by humans and baboons has been clearly demonstrated. Spacered alpha-galactose disaccharide (Gal(alpha1)-3Gal) hapten was produced by chemical synthesis and covalently attached to a flexible, hydrophilic polymer (PAA), which in turn was covalently coupled to macroporous glass beads, forming an immunoadsorbent that is mechanically and chemically stable and can be sterilized. The extracorporeal immunoadsorption (EIA) of anti-alphaGal antibodies using this column has been investigated in vivo in 3 baboons. In Baboon 1 (which had hyperacutely rejected a pig heart transplant 4 months previously, was not splenectomized, and did not receive any pharmacologic immunosuppression) the levels of anti-alphaGal antibody and antipig IgM and IgG, as well as serum cytotoxicity, fell significantly after each of 3 EIAs but were not eliminated. Serum cytotoxicity, antipig immunoglobulin and anti-alphaGal antibody rose steeply within 24 hr of the final EIA, suggesting that the return of cytotoxicity was associated with anti-alphaGa1 antibody. In Baboons 2 and 3 (which were immunologically naive and splenectomized, and received triple drug immunosuppressive therapy) serum cytotoxicity was totally eliminated and anti-alphaGal antibody and antipig IgM and IgG levels were greatly reduced by courses of EIA. In Baboon 2, cytotoxicity and all antibody levels remained negligible for approximately one week after the final (fourth) daily EIA. In Baboon 3, cytotoxicity and antibody levels were maintained low by intermittent EIA (over a period of 13 days) for almost 3 weeks, although antipig IgM began to rebound 4 days after the final EIA. We conclude that, in an immunosuppressed, splenectomized baboon, repeated EIA using a specific alphaGal disaccharide column will reduce antipig and anti-alphaGal antibody levels and serum cytotoxicity significantly for several days. This reduction in cytotoxicity will almost certainly be sufficient to delay the hyperacute rejection of a transplanted pig organ, but further studies are required to investigate whether it will be sufficient to allow accommodation to develop.

Acrylic Resins↗
PubMed1996

Glycans derived from porcine stomach mucin are effective inhibitors of natural anti-alpha-galactosyl antibodies in vitro and after intravenous infusion in baboons.

The current shortage of donor organs has stimulated investigation of pig-to-human xenotransplantation as a practical alternative to allotransplantation. However, a major obstacle to this xenotransplantation is hyperacute rejection, which is believed to be initiated by the interaction of natural anti-alpha-galactosyl (alphaGal) antibodies with alphaGal epitopes on pig vascular endothelium. Previously, we reported that neutral oligosaccharides derived from porcine stomach mucin (PSM) are effective inhibitors of human anti-alphaGal IgG in vitro. We now report that O-glycans derived from PSM by beta-elimination (PSMO) reduce the cytotoxicity of both baboon and human sera to pig kidney (PK15) cells in vitro. Crude PSM had some inhibitory effect in vitro, but PSMO were more than 100 times more potent. Moreover, 1 microg/ml of beta-eliminated PSMO that bound to an immunoaffinity column of anti-alphaGal antibodies were four times more efficient than total PSMO in protecting PK15 cells from the cytotoxic effect of baboon or human sera. Blood recovered from baboons after intravenous infusion of PMSO also showed significant protection of PK15 cells. We conclude that PSMO eluted from an anti-alphaGal immunoaffinity column demonstrate potent inhibitory effects against baboon and human serum cytotoxicity to PK15 cells in vitro and when administered intravenously. PSM may provide a cheap and readily available source of glycans that will be of therapeutic value in the prevention of hyperacute rejection.

Animals↗