General Practitioner, Internists
22 years of experience

Accepting new patients
Southeast Torrance
22930 Crenshaw Blvd
Ste A1
Torrance, CA 90505
310-530-4281
Locations and availability (2)

Education ?

Medical School Score
Rosalind Franklin University (1988)
  • Currently 2 of 4 apples

Awards & Distinctions ?

Associations
American Board of Internal Medicine

Affiliations ?

Dr. Black is affiliated with 5 hospitals.

Hospital Affilations

Score

Rankings

  • Providence Holy Cross Medical Center
    15031 Rinaldi St, Mission Hills, CA 91345
    • Currently 4 of 4 crosses
    Top 25%
  • Little Company of Mary Hospital
    4101 Torrance Blvd, Torrance, CA 90503
    • Currently 4 of 4 crosses
    Top 25%
  • Torrance Memorial Medical Center
    3330 Lomita Blvd, Torrance, CA 90505
    • Currently 3 of 4 crosses
    Top 50%
  • Little Company of Mary-San Pedro Hospital
    1300 W 7th St, San Pedro, CA 90732
    • Currently 2 of 4 crosses
  • Prov Little Co of Mary Med Center Torrance
  • Publications & Research

    Dr. Black has contributed to 86 publications.
    Title Microcystic Meningioma Presenting As a Cystic Lesion with an Enhancing Mural Nodule in Elderly Women: Report of Three Cases.
    Date February 2012
    Journal Brain Tumor Pathology
    Excerpt

    Cystic meningioma with an enhancing mural nodule is uncommon and can present as a radiologic and clinical dilemma with wide differential. We report a series of rare and unique presentation of microcystic meningioma in three elderly women aged 76 (case 1), 72 (case 2), and 76 (case 3) years, respectively. The first patient presented with a 3-year history of vertigo and past history of carotid artery stenosis, hypertension, and hypothyroidism. The second patient presented with headache and an acute episode of weakness in her legs. The third patient presented with headache, vomiting, and confusion. Magnetic resonance imaging for these three cases showed a cystic lesion with an enhancing mural nodule in the right frontal lobe. The preoperative differential diagnoses included hemangioblastoma and well-circumscribed gliomas for the first two cases. Glioblastoma and metastatic tumor were the working diagnoses for the third case because of vasogenic brain edema and marked mass effect. The final pathological diagnosis was microcystic meningioma for all three cases. Case reports are mainly of fibrous or meningothelial meningiomas with cystic formation. Male predominance and young age are most commonly reported. Our series is unique because of the rare and unusual clinical-radiologic presentation of microcystic meningioma in elderly women.

    Title Review of Vascularized Bone Marrow Transplantation: Current Status and Future Clinical Applications.
    Date September 2007
    Journal Microsurgery
    Excerpt

    In this review, we examine the applicability of the vascularized bone marrow transplant (VBMT) as an alternative to conventional bone marrow transplantation (BMT). As a new surgical approach, the VBMT is unique by transplantation of the stromal environment that eliminates the need for an engraftment period, provides critical signaling and modulatory functions, and may potentiate tolerance induction. Thus far, VBMT studies have demonstrated an absence of graft-versus-host disease (GVHD) and robust engraftment into nonmanipulated as well as irradiated recipients with evidence of immunological tolerance. Further investigation is needed to determine the applicability of VBMT as an alternative to BMT.

    Title Multicystic, Heterogeneously Enhancing Meningioma in an Octogenerian.
    Date June 2005
    Journal British Journal of Neurosurgery
    Excerpt

    A multicystic meningioma in an octogenerian whose tissue diagnosis was ill-defined and misleading on preoperative neuroradiologic imaging is presented. Nauta has described four cyst types that can develop in cystic meningiomas. We report the first case in which three cyst types are demonstrated concurrently, describe the histopathology and surgical management. This case represents a rare variant of a common tumour in an unusual age group, and underscores the need for definitive biopsy and resection as indicated. Furthermore, the diagnosis of multicystic meningioma does not favour an aggressive histopathology in this case.

    Title Cellular Remodeling of Depopulated Bovine Ureter Used As an Arteriovenous Graft in the Canine Model.
    Date May 2004
    Journal Journal of the American College of Surgeons
    Excerpt

    BACKGROUND: One of the greatest challenges in hemodialysis access surgery is improving the durability of prosthetic grafts caused by structural deterioration. The depopulated bovine ureter SynerGraft (SG) (CryoLife, Inc) is a tissue-engineered vascular graft processed to remove the xenograft cells while maintaining an unfixed connective tissue matrix capable of autologous cell repopulation by the recipient. STUDY DESIGN: Nineteen 6-mm diameter bovine ureter SG conduits were implanted in 12 dogs as arteriovenous grafts between the carotid artery and jugular vein (n = 11) or between the femoral artery and vein (n = 8). Performance of these biologic conduits was compared with that of 15 IMPRA (Bard) ePTFE grafts implanted in 9 dogs, including 9 arteriovenous grafts between the carotid artery and jugular vein and 6 femoral artery to femoral vein grafts. After 14 days, the grafts were accessed once weekly. Histologic and immunohistochemical analyses were performed on grafts explanted between 10 to 60 weeks. RESULTS: The 6- and 12-month primary patency rates of the bovine SG were 72.6% and 58.6%, respectively, compared with 6- and 12-month primary patency for ePTFE conduits of 57.4% and 57.4%, respectively. None of the bovine SG grafts became infected, but synthetic conduits became infected within 54 days of implantation. At 10 weeks, bovine ureter SG conduit showed fibroblast cell migration and proliferation with incorporation into the surrounding subcutaneous tissue, and elongated cells expressing the contractile protein smooth muscle actin were also observed. After 24 weeks, procollagen synthesis was demonstrated in the fully colonized graft matrix. The ePTFE grafts had no evidence of cellular ingrowth and an absence of endothelium. CONCLUSIONS: The bovine SG was appropriately remodeled to its host environment through an organized process of recellularization and neovascularization. The absence of infection, similar patency rates, and cell repopulation of the matrix warrant further investigation.

    Title Acute Syringomyelia: Case Report.
    Date February 2004
    Journal Neurosurgery
    Excerpt

    OBJECTIVE AND IMPORTANCE: Syringomyelia is generally regarded as a chronic, slowly progressive disorder. We describe a case of acute dilation of the central canal of the spinal cord that presented with rapidly progressive segmental signs. CLINICAL PRESENTATION: A 29-year-old female patient who had previously undergone surgical treatment for a Chiari I malformation, syringomyelia, and hydrocephalus presented with an 8-day history of headaches, progressive paraparesis, and urinary retention. Magnetic resonance imaging scans demonstrated panventricular hydrocephalus in association with a holocord syrinx that extended to the obex. Magnetic resonance imaging scans that had been coincidentally obtained just 3 days before the onset of symptoms had revealed no evidence of hydrocephalus or syringomyelia. INTERVENTION: The patient underwent emergency revision of a failed ventriculoperitoneal shunt. Postoperatively, there was prompt resolution of the syringomyelia, hydrocephalus, and associated neurological deficits. CONCLUSION: Among patients with communicating syringomyelia, the central canal of the spinal cord participates as a "fifth ventricle" and can undergo rapid dilation in association with acute hydrocephalus. Appropriate treatment in such cases involves placement of a ventriculoperitoneal shunt.

    Title Targeted Prodrug Treatment of Her-2-positive Breast Tumor Cells Using Trastuzumab and Paclitaxel Linked by A-z-cinn Linker.
    Date February 2004
    Journal Journal of Experimental Therapeutics & Oncology
    Excerpt

    Targeting drugs for delivery and release has the potential to increase the efficacy of treatment. A bifunctional linker, A-Z-CINN Linker was used to create a targeted prodrug, A-Z-CINN 310. A-Z-CINN Linker links to a potent chemotherapeutic agent, paclitaxel, via an energy-reversible ester bond and also binds a targeting agent, the monoclonal antibody trastuzumab (Herceptin). This study demonstrates the effectiveness of a single-treatment use of A-Z-CINN 310 in decreasing tumor volume and tumor cell density of human HER-2-positive BT-474 mammary tumor cells implanted in scid mice, compared to treatment with simultaneously administered trastuzumab and paclitaxel and with saline control. After treatment with A-Z-CINN 310, some mice received light exposure at 6 h for 5 min adjacent to the tumor to cause light-accelerated release of paclitaxel. Changes in tumor volume were measured for 28 days following treatment; changes in histology were measured at 31 days. Animals treated with A-Z-CINN 310, then light, showed dose-dependent decreases in tumor volume and tumor cell density which were more rapid and extensive than those seen with A-Z-CINN 310 without light or a 10-fold higher concentration of co-administered trastuzumab plus paclitaxel. This suggests that targeted delivery of paclitaxel using A-Z-CINN 310 kills tumor cells by localized release of paclitaxel at the tumor site, which can be accelerated by light treatment. These results indicate that a targeted prodrug therapy containing trastuzumab as the targeting agent and A-Z-CINN-paclitaxel as the prodrug results in a conjugate that is more effective in killing tumor cells than equivalent concentrations of co-administered trastuzumab and paclitaxel. Targeting of a drug can reduce the dose needed for effective therapy and can increase local bioavailability. This makes targeted therapy using an A-Z-CINN prodrug delivery system feasible for treating both primary and metastatic tumors.

    Title Mechanisms of Alloimmune Tolerance Associated with Mixed Chimerism Induced by Vascularized Bone Marrow Transplants.
    Date June 2003
    Journal Cell Transplantation
    Excerpt

    Rat limb allograft recipients represent surgically induced, immediately vascularized bone marrow transplant (VBMT) chimeras. The majority of these chimeras undergo tolerance while a minority develop graft versus host disease (GVHD). T-cell chimerism and associated mechanisms of cellular immune nonresponsiveness were investigated in tolerant VBMT chimeras. A strong correlation (p < 0.01) was observed between the clinical onset of GVHD and levels of donor T-cell chimerism approximating or greater than 50%. However, stable mixed chimerism was associated with tolerance. In conclusion, three major sequential mechanisms of immune nonresponsiveness were elucidated in tolerant VBMT chimeras over time and included development of nonspecific suppressor cells (which potentially represent natural suppressor cells), maturation of antigen-specific suppressor cell circuits, and eventually putative clonal inactivation.

    Title Cryopreservation Prevents Arterial Allograft Dilation.
    Date April 2003
    Journal Annals of Vascular Surgery
    Excerpt

    Historically, immune-mediated degradation and subsequent aneurysm formation have limited the usefulness of cryopreserved arterial allografts. This study tested the hypothesis that modern cryopreserved arterial allografts are protected from immune-mediated dilation. Abdominal aortas were harvested from anesthetized rats (Lewis and Brown-Norway) for immediate implantation or cryopreservation. Subsequently, Lewis rats underwent infrarenal aortic replacement with either an acutely harvested or a cryopreserved graft. There were four experimental groups: (1) acutely harvested isografts (Iso; n = 6), (2) cryopreserved isografts (C-Iso; n = 6), (3) cryopreserved allografts (C-Allo; n = 6), and (4) acutely harvested allografts (Allo; n = 6). All grafts were explanted at 8 weeks. A video camera and edge detection software were used to measure systolic and diastolic in vivo graft diameter (d). Measurement of arterial blood pressure (p) allowed calculation of compliance (Dd/Dp). Tail-cuff plethysmography was used to assess graft patency at 1 week. Graft diameter and blood pressure measurements were repeated at harvest. All harvested grafts were examined histologically. Our results showed that cryopreservation prevented immune-mediated dilation in arterial allografts in our 8-week rat implant model. Furthermore, the compliance of the cryopreserved grafts and was similar to that of controls. Further investigation is needed to delineate the exact mechanism of these potential clinically significant findings.

    Title Recellularization of Heart Valve Grafts by a Process of Adaptive Remodeling.
    Date March 2002
    Journal Seminars in Thoracic and Cardiovascular Surgery
    Excerpt

    The objective of this study was to investigate if function and durability of connective tissue grafts stems from in vivo revascularization and recellularization. Viability is important for durable valve performance, demonstrated by pulmonary autografts. A pattern of in vivo recellularization occurs in xenogeneic or allogeneic heart valves decellularized prior to implantation, dictated by the tissue matrix and functional biomechanics. Porcine or sheep heart valves were decellularized with the SynerGraft antigen reduction process (a common treatment process to remove all histologically demonstrable leaflet cells), and implanted as pulmonary (n = 11) or aortic valve (n = 9) replacements in sheep. Sheep allograft pulmonary valves (n = 4) were implanted as pulmonary valve replacements. Recellularization was evaluated histologically after 3, 4, 5, 6, and 11 months, with cell phenotypes identified using specific antibodies. SynerGraft heart valves were progressively recellularized beginning with an initial cellular infiltrate, and subsequent repopulation with mature interstitial cells. This process occurs in the conduit and then in the leaflet, and is associated with revascularization of the graft. Functional, fully developed fibrocytes, actively synthesizing type I procollagen (antibody probe) were present within 3 months. As the process matured cell density and distribution became similar to native valve leaflets with localization of smooth muscle actin positive cells at the ventricularis/spongiosa interface. After 11 months, leaflet explants had no detectable inflammatory cells, were as much as 80% repopulated, and had a distribution of smooth muscle actin positive cells similar to that of the natural leaflet. SynerGraft- treated heart valve implants are repopulated by a process typical of adaptive remodeling following implantation. This antigen reduction treatment is the first successful tissue engineering effort obtaining an implant with mature recipient cells capable of matrix protein synthesis. Normal early valve function and durability is maintained.

    Title Incipient Erosion of Biostabilized Sediments Examined Using Particle-field Optical Holography.
    Date October 2001
    Journal Environmental Science & Technology
    Excerpt

    Laser holography allows images of three-dimensional space at ultra-high resolution to be recorded onto photographic plates. Recorded scenes can be "replayed" with a second laser beam into free space and optically "interrogated" using either a microscope or a camera by sequentially focusing on increasing distances from the hologram in the field of view (optical sectioning). From these sections, information on the relative locations and orientation in space of suspended particles as well as the morphology of particles can be obtained. This paper examines the utility of "in-line" laser holography to discriminate the size and the morphology of sand particles eroded under turbulent shear flow during benthic sediment transport. The influence of a commercially available adhesive polymer (xanthan gum, derived from the bacterium Xanthomonas campestris) on sediment stability and resuspended particle morphology is described. The major implications for carbon and sediment cycling within estuaries are highlighted.

    Title Decellularized Human Valve Allografts.
    Date June 2001
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: Variable performance of allograft tissues in children and some adults may be linked to an immune response and could be mitigated by reducing implant antigenicity. METHODS: As endothelial and fibroblast cells are the likely source of valve antigenicity, human (CryoValve SG) and sheep pulmonary valves were decellularized using the SynerGraft treatment process. Treated valves were evaluated in vitro using histochemical, biomechanical, and hydrodynamic methods, and compared with standard cryopreserved valves. Four SynerGraft-treated and two cryopreserved sheep pulmonary valves were implanted as root replacements in the right ventricular outflow tract of growing sheep and monitored echocardiographically and histologically at 3 and 6 months. CryoValve SG human pulmonary valves were implanted in 36 patients. RESULTS: SynerGraft treatment reduced tissue antigen expression but did not alter human valve biomechanics or strength. Decellularized sheep allograft valves were functional during the implantation period, and, they became progressively recellularized with recipient cells. In humans, CryoValve SG pulmonary valves did not provoke a panel reactive antibody response. CONCLUSIONS: SynerGraft decellularization leaves the physical properties of valves unaltered and substantially diminishes antigen content. Reduction in implant cellularity enables host recellularization of the matrix, which should favorably impact long-term graft durability.

    Title Transformation of Nonvascular Acellular Tissue Matrices into Durable Vascular Conduits.
    Date June 2001
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: Prosthetic grafts commonly used for vascular reconstruction are limited to synthetics and cross-linked tissue grafts. Within these devices, graft infections are common, compliance mismatch is significant, and handling qualities are poor. Natural biological tissues that are unfixed have been shown to resist infections and be durable and compliant. A natural biological matrix that could be remodeled appropriately after implantation would be a desirable graft for vascular reconstruction. METHODS: SynerGraft tissue engineering strategies have been used to minimize antigenicity and produce stable unfixed vascular grafts from nonvascular bovine tissues. These grafts have replaced the abdominal aortas of 8 dogs that have been followed for up to 10 months. RESULTS: Early evaluation indicates rapid recellularization by recipient smooth muscle actin positive cells, which become arranged circumferentially, into the media. Arterioles were present in the adventitial areas and endothelial cells were seen to cover lumenal surfaces. After 10 months, grafts were patent and not aneurysmal. CONCLUSIONS: These data indicate that SynerGraft processing of animal tissues is capable of producing stable vascular conduits that exhibit long-term functionality in other species.

    Title Cellular Mechanisms of Alloimmune Non-responsiveness in Tolerant Mixed Lymphocyte Chimeras Induced by Vascularized Bone Marrow Transplants.
    Date April 2001
    Journal Transplant International : Official Journal of the European Society for Organ Transplantation
    Excerpt

    It has been demonstrated that the development of stable mixed lymphocyte chimerism is associated with alloimmune tolerance induction in vascularized bone marrow transplant (VBMT) recipients. The underlying mechanisms of immune non-responsiveness in tolerant VBMT chimeras remains unclear. Our VBMT model involves the transplantation of a parental donor limb (Lewis rats) onto a hybrid (Lewis x Brown Norway) F1 recipient. Tolerogenic mechanisms and cellular immune regulation to self and host allodeterminants were investigated during the early post-transplant phase of tolerance induction. Flow cytometric analysis of sIg+-depleted experimental peripheral blood lymphocytes from tolerant VBMT recipients demonstrated low level stable mixed immune chimerism. Chimeric cells tested for responsiveness against self-LEW determinants showed activated proliferation and immune dysregulation 30 days post-transplantation. However, direct immunocytolytic activity against LEW determinants was not found. Tolerant chimeras also demonstrated elevated cellular proliferation and cytolytic responses against host-specific BN allodeterminants at 30 days. Consistent with these in vitro findings, limited clinical signs compatible with GVH reactivity were evident in vivo at this time. Following this initial period, the tolerant VBMT animals returned to normal clinical condition and remained otherwise healthy throughout the study. Consistent with these results, VBMT chimeras then showed declining proliferative responses from the elevated values seen at 30 days against self-LEW determinants. Proliferative and immunocytolytic responses also decreased against host-specific BN allodeterminants from peak levels at 30 days. In conclusion, these results provide evidence that the initial phases of tolerance induction in VBMT chimeras consist of self- and alloimmune regulation that follow an early period of immune dysregulation. Sequential phases of immune dysregulation and re-regulation elucidated in VBMT stable mixed chimeras within the first 100-day period may represent important mechanisms of tolerance induction.

    Title Mechanisms of Unresponsiveness Associated with Pretransplant Blood Transfusion-cyclosporine-induced Mixed Lymphocyte Chimerism.
    Date April 2001
    Journal Transplant International : Official Journal of the European Society for Organ Transplantation
    Excerpt

    Multiple pretransplant blood transfusions while under limited daily cyclosporine cover (PTBT-CsA) induce extensive rat renal allograft survival and antigen-specific non-responsiveness. The underlying mechanisms of this extensive allograft survival are not yet fully understood. We hypothesized that one of the potential contributing mechanisms to tolerance induction in PTBT-CsA-treated kidney recipients is the development of stable mixed chimerism, putatively due to the proliferation of stem cells capable of haematopoiesis in the transfused blood. BN rats served as whole blood and kidney donors. LEW rats served as recipients of the PTBT-CsA protocol and BN kidney transplants. Three weekly transfusions were given under concomitant limited CsA cover. Following these multiple primary sensitizations, antigen-specific splenic cellular responsiveness in vivo was normal in comparison with naive animals. However, these experimental splenocytes were non-specifically suppressed against third-party allodeterminants. At 100 days post-transplantation (T100) following tolerance induction to kidney allografts (secondary challenge), in vivo adoptive transfer experiments demonstrated the existence of potent splenic suppressor cells. In vitro suppressor cell assays confirmed that these cells were non-specific suppressor cells. However, following chimerism stabilization at T130, splenic antigen-specific suppressor cells became exclusively expressed in the tolerant animals, replacing the non-specific suppressor cells. At this time, splenic microchimerism was at peak levels and remained stable from T100 to T130. In conclusion, these findings demonstrate that sequential mechanisms of suppressor cell network expression are induced within a chimeric environment by blood-CsA immune modulation. Stable mixed lymphocyte chimerism and related immunomodulatory mechanisms may, therefore, play an important tolerogenic role in blood-CsA-induced non-responsiveness and in the beneficial effect of blood transfusion.

    Title Transpecies Heart Valve Transplant: Advanced Studies of a Bioengineered Xeno-autograft.
    Date January 2001
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: Tissue engineering approaches utilizing biomechanically suitable cell-conductive matrixes should extend xenograft heart valve performance, durability, and growth potential to an extent presently attained only by the pulmonary autograft. To test this hypothesis, we developed an acellular, unfixed porcine aortic valve-based construct. The performance of this valve has been evaluated in vitro under simulated aortic conditions, as a pulmonary valve replacement in sheep, and in aortic and pulmonary valve replacement in humans. METHODS: SynerGraft porcine heart valves (CryoLife Inc, Kennesaw, GA) were constructed from porcine noncoronary aortic valve cusp units consisting of aorta, noncoronary aortic leaflet, and attached anterior mitral leaflet (AML). After treatment to remove all histologically demonstrable leaflet cells and substantially reduce porcine cell-related immunoreactivity, three valve cusps were matched and sewn to form a symmetrical root utilizing the AML remnants as the inflow conduit. SynerGraft valves were evaluated by in vitro hydrodynamics, and by in vivo implants in the right ventricular outflow tract of weanling sheep for up to 336 days. Cryopreserved allograft valves served as control valves in both in vitro and in vivo evaluations. Valves were also implanted as aortic valve replacements in humans. RESULTS: In vitro pulsatile flow testing of the SynerGraft porcine valves demonstrated excellent valve function with large effective orifice areas and low gradients equivalent to a normal human aortic valve. Implants in sheep right ventricular outflow tracts showed stable leaflets with up to 80% of matrix recellularization with host fibroblasts and/or myofibroblasts, and with no leaflet calcification over 150 days, and minimal deposition at 336 days. Echocardiography studies showed normal hemodynamic performance during the implantation period. The human implants have proven functional for over 9 months. CONCLUSIONS: A unique heart valve construct has been engineered to achieve the equivalent of an autograft. Short-term durability of these novel implants demonstrates for the first time the possibility of an engineered autograft.

    Title The Synergraft Valve: a New Acellular (nonglutaraldehyde-fixed) Tissue Heart Valve for Autologous Recellularization First Experimental Studies Before Clinical Implantation.
    Date February 2000
    Journal Seminars in Thoracic and Cardiovascular Surgery
    Excerpt

    The durability of current bioprosthetic heart valves is diminished by glutaraldehyde-associated leaflet calcification or by the associated absence of a cellular component capable of repair of wear-related damage. As a novel tissue engineering approach to improving replacement heart valve durability, we have developed a decellularization process to replace the use of cross-linking to limit xenograft antigenicity. The effectiveness of this process was assessed in a weanling sheep right ventricular outflow tract reconstruction model where valve function, calcification, and recellularization were examined. Porcine aortic valves were decellularized by a process designed to remove all histologically demonstrable leaflet cells. Stentless, bioprosthetic valves were fabricated from acellular tissues, cryopreserved, sterilized, and then implanted as pulmonary valve replacements in 4- to 6-month old female Suffolk sheep. Sheep aortic valves were implanted as allograft control subjects. After 150 days, the grafts were explanted and assessed histologically and by atomic absorption spectrophotometry for calcium content. All valves were hemodynamically functional at explant. Histological examination showed intact leaflets with in-growth of host fibroblastoid cells in all explanted porcine valves and no evidence of calcification. Porcine leaflet calcium content was unchanged over the duration of the implant (1.0+/-1.2 vs 1.5+/-1.8 mg/g dry weight, P = ns). Decellularization can stabilize xenogenic heart valves. Lack of calcification of acellular aortic leaflets suggests that prolonged durability of such valves is attainable without the use of cross-linking agents. The repopulation of the leaflet matrix offers additional promise of durability based on revitalization of the graft in vivo.

    Title Site-specific Immunosuppression: Mechanisms of Cellular Immunosuppression That Are Operative at Local and Systemic Levels.
    Date February 2000
    Journal The Journal of Burn Care & Rehabilitation
    Excerpt

    The cellular mechanisms by which topical cyclosporine A (tCsA) induces site-specific immunosuppression were investigated. Experiments were designed to elucidate how cyclosporine A (CsA) suppresses activated immunocytes in animals that are undergoing local alloactivation and concomitant tCsA immune suppression. Lewis rats received dual Lewis x Brown Norway rat skin allografts; the rats were treated with systemic CsA (sCsA) at 8 mg/kg/day for 10 days after grafting and then tCsA and vehicle thereafter. CsA added to mixed lymphocyte reactions 24 hours after culture initiation modeled the local effects of CsA on alloactivated immunocytes, and tCsA in conjunction with limited sCsA prolonged local skin allograft survival. CsA inhibited both antigen-specific and nonspecific activated alloresponses of immunocytes from animals that had received allografts and that underwent limited sCsA treatment only in a dose-dependent manner. When tCsA had been applied, immunocyte responses to a nonspecific antigen were extremely CsA-resistant as compared with those induced by antigen-specific suppression. However, this nonspecific alloresponse was fully suppressible with the use of elevated CsA doses (66 microg/mL); thus alloresponding immunocytes were significantly more sensitive to CsA if they were challenged with the donor antigen and preexposed to limited sCsA followed by tCsA in vivo.

    Title Composite Tissue Allografts in Rats: Iv. Graft-versus-host Disease in Recipients of Vascularized Bone Marrow Transplants.
    Date October 1999
    Journal Plastic and Reconstructive Surgery
    Excerpt

    This laboratory has used a composite tissue allograft model as a vehicle for studies on a new type of bone marrow transplant, the vascularized bone marrow transplant. The model consists of a rat hind limb transplant that incorporates integumentary musculoskeletal, and lymphopoietic tissues. These transplants, in comparison with conventional marrow transplants, have the advantage of providing a syngeneic microenvironment and immediate engraftment of both mature and progenitor hemopoietic cells at the time of transplantation. The characteristics of graft-versus-host disease were studied in this model. Lewis X Brown Norway F1 (LBN RT-1(1+n)) rats received hind limbs from Lewis (LEW RT-1(1)) donors (n = 19). Animals were observed daily for signs of graft-versus-host disease. Necropsies were performed. A minority of animals developed lethal disease (7 of 19 recipients) and demonstrated cachexia with concomitant histopathologic changes of the disease. Acute and chronic groups emerged with distinct clinical courses, which are similar to other models of this disease. Recipients of vascularized bone marrow transplants (limb transplants) showed clinical and histopathologic changes of the disease. The transplants may be used as a model of graft-versus-host disease in humans. Most interestingly, the transplant has a lower incidence of disease compared with other methods of bone marrow transplantation and represents an alternative to conventional bone marrow transplantation, which deserves further exploration. It may be possible to develop a new technique for bone marrow transplantation based on this surgical approach. It is proposed that the transfer of vascularized blocks of bone/marrow into prospective recipients as opposed to cellular bone marrow transplants may be preferable.

    Title Tissue Modifications.
    Date October 1998
    Journal Transplantation Proceedings
    Title A Rapid and Sensitive Cellular Enzyme-linked Immunoabsorbent Assay (celisa) for the Detection and Quantitation of Antibodies Against Cell Surface Determinants. Ii. Optimal Reagent Concentrations and Predictive Analysis.
    Date September 1997
    Journal Cell Transplantation
    Excerpt

    A cellular enzyme-linked immunosorbent assay (CELISA) was developed for the detection and quantification of antibodies elicited against allogeneic cell surface determinants. The technique uses a solid-phase cell matrix created by fixing cells with a mild formalin solution onto the bottom of a 96-well microtiter plate. A primary layer of alloantisera is first reacted against rat target cells. The secondary antibody, peroxidase conjugated antirat IgG, is then added to each well and serves as the second sandwich layer. Optimal reagent concentrations were determined by serial dilution analysis of various cell concentrations and secondary antibody dilutions. It was found that 200,000 cells per well was the optimal target cell concentration. However, 100,000 cells per well was also sufficient to run the assay with acceptable performance characteristics. Even lower cell concentrations of 10,000 and 20,000 cells/well, although not optimal, also produced acceptable results. Secondary antibody concentration with respect to the optimal cell concentration was determined to be 1:500. At 200,000 cells per well and a 1:500 secondary antibody dilution, the assay presented excellent coefficients of determination and high positive to negative ratios. The reaction was found to be very sensitive in yielding high antibody titers with low background levels and could be defined mathematically as a linear-log function. Titers of multiple unknown alloantibody samples were easily and accurately predicted in an automated manner by regression analysis form known standards. This immunoassay will be useful in studies of cell surface determinant expression and quantitation of antibodies reactive to such markers.

    Title Use of Regression Analysis and Flow Cytometry for Determining Levels of Mixed Semiallogeneic Immune Chimerism.
    Date January 1997
    Journal Journal of Investigative Surgery : the Official Journal of the Academy of Surgical Research
    Excerpt

    It has been shown that tolerance or specific immunologic nonresponsiveness in various lymphohemopoietic transplant models can be associated with the development of mixed lymphoid chimerism. As a specific example, composite tissue (limb) allografts were studied as a model for vascularized bone marrow transplantation (VBMT) and it was demonstrated that development of stable cellular immune chimerism is associated with long-term allograft survival. Recently, studies were initiated using a new parental to hybrid VBMT model, but the detection of donor cells is complicated, due to the fact that they share one parental allotypic determinant. Therefore, regression analysis with a flow cytometric immunofluorescent staining assay was evaluated for the assessment of cellular lymphoid chimerism in donor parental to hybrid (P-->F1) lymphohemopoietic transplant models. Standard curves consisting of known mixed populations of parental donor (Lewis, LEW) and hybrid host F1 (Lew x BN, LBN) lymphocytes were established. Standard curves were analyzed by linear regression statistics and excellent coefficients of determination (r > .881) were obtained for all standard curves. A highly statistically significant (p < .016) linear relationship between level of donor cell chimerism (independent variable) and percent stained (dependent variable) was determined. The technique was then evaluated using the parental to hybrid VBMT model. Levels of donor LEW lymphoid chimerism in all VBMT LBN recipients were successfully assessed by regression analysis and inverse prediction using distinct recipient allodeterminant markers. In conclusion, this technique was proven to be reliable and accurate for the detection of of chimerism in parental to F1 lymphohemopoietic allograft models.

    Title Chemotherapeutic Treatment of Malignant Chordoma in Children.
    Date October 1996
    Journal Journal of Pediatric Hematology/oncology : Official Journal of the American Society of Pediatric Hematology/oncology
    Excerpt

    PURPOSE: We describe the effect of multiagent chemotherapy for malignant chordoma. Previous reports of other patients with malignant chordoma treated with chemotherapy as well as other therapeutic interventions are reviewed. PATIENTS AND METHODS: We describe a 19-month-old girl with unresectable cervical chordoma metastatic to the lungs at diagnosis treated with multiagent systemic chemotherapy. CNS disease was diagnosed after one course of therapy, and intrathecal chemotherapy was then administered. CONCLUSIONS: Ifosfamide and doxorubicin were efficacious in a patient with advanced metastatic disease, producing significant disease regression. The addition of intrathecal or intraventricular therapy with hydrocortisone, ARA-C, and methotrexate was effective in controlling CNS disease due to chordoma. There was no apparent benefit from the use of actinomycin-D, cyclophosphamide and vincristine nor the combination of cisplatin and 5-fluorouracil or high-dose methotrexate.

    Title Graft-versus-host Disease in Limb Transplantation: Digital Image Analysis of Bone Marrow and Tgf-beta Expression in Situ Using a Novel 3-d Microscope.
    Date September 1996
    Journal Transplantation Proceedings
    Excerpt

    A subpopulation of parental to hybrid VBMT recipients developed characteristic clinical and histopathologic manifestations of GVHD. These changes are similar to those seen in human GVHD secondary to bone marrow transplantation. Human GVHD also manifests itself in an acute and chronic manner. Only a minority (30% to 40%) of animals developed lethal GVHD in our model. Those animals developing GVHD had a significantly (P < .0001) higher expression of TGF-beta in situ compared to the tolerant subpopulation. The differential expression of TGF-beta may represent an important mechanism of immune dysregulation associated with GVHD in CTA recipients.

    Title Overview of a 10-year Experience on Methods and Compositions for Inducing Site-specific Immunosuppression with Topical Immunosuppressants.
    Date June 1996
    Journal Transplantation Proceedings
    Excerpt

    Methods and formulations have been successfully developed to bring about site-specific immune suppression of local T-cell-mediated immune responses involved in contact hypersensitivity, skin allograft rejection, and, putatively, autoimmune inflammatory conditions such as psoriasis. The induction of site-specific immune suppression results in reduced systemic pharmacology and toxicity. Certain formatulations have been devised that can effect dramatic transdermal drug delivery and systemic immunopharmacology. Local site-specific or systemic efficacy by transdermal delivery can be dependent upon carrier composition with respect to the hydrophilic/lipophilic nature of the solvent system, active principal solubilization, and concentration. Multiple classes of active immunosuppressive agents can be successfully combined to produce novel and extremely potent topical drugs. Specifically, either cyclosporine or rapamycin inhibit local inflammatory/immune responses by topical application to skin tissue in vivo. Rapamycin is particularly efficacious during the late local inflammatory/immune phase. Cyclosporine is particularly efficacious during the early local inflammatory-immune phase. Also, skin allograft survival may be prolonged via topical use of CyA, alone and in combination with other anti-inflammatory agents. This includes combined immunosuppressant and steroidal anti-inflammatory agents that can produce synergistic results. Systemic immunity in these instances is normal. Expression of MHC class I and MHC class II molecules is dramatically decreased in these CyA/steroid SITE-treated grafts. In summary, the induction of local immune suppression at the tissue site and focal responding immunocytes can result in surprising efficacy when used in conjunction with limited systemic administration, which could have significant immunologic and clinical ramifications.

    Title Angiographic Demonstration of Reversible Cerebral Vasospasm in Porphyric Encephalopathy.
    Date January 1996
    Journal Ajnr. American Journal of Neuroradiology
    Title Spleen Mixed Leukocyte Chimerism and Induction of Tolerance in Rat Renal Allograft Recipients Conditioned with Donor-specific Blood Transfusions and Cyclosporine.
    Date September 1995
    Journal Transplantation Proceedings
    Title Site-specific Immune Suppression with Topical Cyclosporine. Synergism with Combined Topical Corticosteroid Added During the Maintenance Phase.
    Date July 1995
    Journal Transplantation
    Title Hemorrhagic Subependymal Giant Cell Astrocytoma.
    Date June 1995
    Journal Pediatric Radiology
    Excerpt

    We describe the CT and MR findings in a patient diagnosed with tuberous sclerosis after presenting with a hemorrhagic subependymal giant cell astrocytoma (SEGCA). While these tumors are not uncommon in tuberous sclerosis, hemorrhage into them is extremely rare.

    Title Current State of Composite Tissue and Limb Allo-transplantation: Do Present Data Justify Clinical Application?
    Date April 1995
    Journal Transplantation Proceedings
    Title Digital Image Analysis of Major Histocompatibility Complex Class I and Class Ii Expression During Site-specific Immune Suppression with Topical Cyclosporine.
    Date April 1995
    Journal Transplantation Proceedings
    Title A Rapid and Sensitive Cellular Enzyme-linked Immunoabsorbent Assay (celisa) for the Detection and Quantitation of Antibodies Against Cell Surface Determinants. I. A Comparison of Cell Fixation and Storage Techniques.
    Date October 1992
    Journal Journal of Immunological Methods
    Excerpt

    A solid phase cellular ELISA was designed and evaluated for the detection of antibodies specific for cell surface determinants. It was hypothesized that certain fixation and freezing procedures would result in stabilization of cell structures for prevention of antigen diffusion and extraction during washing procedures. This would assure assay accuracy and convenient sample management. It was hypothesized that fixation with certain reagents prior to analysis would not alter antigenicity of antibody targeted epitopes. In order to improve the preservation of the cells following cell binding to the solid phase matrix while still retaining antigenicity and morphology, a series of fixatives and storage procedures were screened to determine which were best suited for CELISA. Methanol, washing buffer (WB), Hanks' balanced salt solution (HBSS), and 0.5% formalin in HBSS were examined by comparing their relative cell binding capacity and the subsequent cell morphology. In consideration of all variables, fixation in 0.5% formalin provided the best maintenance of cell antigenicity, morphology, binding, and was associated with consistent results. Cells used immediately after fixation and fixed cells used after storage at -80 degrees C for up to 12 months were compared to determine if long term storage affected antigenicity. Since frozen cells and fresh cells demonstrated statistically identical positive to negative ratios and consistency of antibody binding, it was determined that long term frozen storage of formalin-fixed cells did not adversely affect antibody binding capacity to cell surface determinants.

    Title Lethal Cyclosporine Associated Toxicity in the Rabbit: Similar Findings in Two Distant and Independent Transplant Laboratories.
    Date July 1992
    Journal Journal of Clinical & Laboratory Immunology
    Excerpt

    A collaborative study was initiated between Basel and Irvine Laboratories named above in an attempt to characterize a unique and lethal gastrointestinal toxicity in rabbits associated with cyclosporine administration. Data from both laboratories were combined and analyzed. The rate of weight loss in CsA treated rabbits was found to be a significant linear function of the dose. In addition, animal survival decreased and showed a dose-dependent linear relationship to CsA use. Grossly, all of the animals presented with full stomachs, incompletely digested, dry, hard, rabbit chow. Histopathology could not provide any insight into the mechanisms of this gross finding and remain unclear. The complete similarity of clinical and histopathological results in distant independent laboratories confirms the specificity of this CsA associated toxicity in the rabbit.

    Title Lumbar Synovial Cysts Eroding Bone.
    Date June 1992
    Journal Ajnr. American Journal of Neuroradiology
    Title Aneurysm of the Azygos Pericallosal Artery: Diagnosis by Mr Imaging and Mr Angiography.
    Date June 1992
    Journal Ajnr. American Journal of Neuroradiology
    Title Evaluation of the Lumbar Spine in Patients with Glycogen Storage Disease: Ct Demonstration of Patterns of Paraspinal Muscle Atrophy.
    Date February 1992
    Journal Ajnr. American Journal of Neuroradiology
    Excerpt

    CT studies of the lumbar spine were performed in 19 patients with glycogen storage disease. Nine of 10 patients with McArdle's disease and seven of nine patients with acid maltase deficiency demonstrated posterior paraspinal muscle atrophy out of proportion to their ages. In addition, the psoas muscles were spared in all 10 patients with McArdle's disease and were involved with atrophy in seven of the nine patients with acid maltase deficiency. We conclude that when patients with low back pain-or asymptomatic patients-demonstrate otherwise unexplained atrophy of the paraspinal muscles the diagnosis of glycogen storage disease should be considered. Furthermore, when the psoas muscles are spared, the specific diagnosis of McArdle's disease is suggested.

    Title Venous Sinus Thrombosis As a Cause of Parenchymal and Intraventricular Hemorrhage in the Full-term Neonate.
    Date January 1992
    Journal Clinical Imaging
    Excerpt

    A case of parenchymal and intraventricular hemorrhage in a full-term neonate is reported. The underlying cause in our patient is thought to be related to cerebral sinovenous occlusive disease secondary to Protein C deficiency, a rare coagulopathy.

    Title Congenital Spondylolisthesis of the 6th Cervical Vertebra: Ct Findings.
    Date April 1991
    Journal Journal of Computer Assisted Tomography
    Excerpt

    The CT demonstration of a case of congenital spondylolisthesis of the C6 vertebral body is reported. This entity includes bilateral bony defects in the pars interarticularis regions, deranged facet joints, as well as a midline bony cleft in the spinous process. This congenital deformity should be recognized and not mistaken for traumatic spondylolisthesis.

    Title Mechanisms of Site-specific Immunosuppression.
    Date March 1991
    Journal Transplantation Proceedings
    Title Mechanisms of Prior Blood Transfusion-cyclosporine-induced Tolerance: a Potential Role for Immune-cellular Chimerism.
    Date March 1991
    Journal Transplantation Proceedings
    Excerpt

    Skin allografts were not enhanced by prior conditioning of blood and CyA (5 or 10 mg/kg/d). However, when BM-CyA pretreatment was used, SA survival was significantly prolonged (CyA, 5 or 10 mg/kg/d). In examining differences between the BT-CyA and BM-CyA protocols, equivocal levels of donor microchimerism (1.5%) were found in the spleens of BT-CyA conditioned recipients at the time of transplantation (day 0). In contrast, highly significant levels of splenic donor chimerism (17.2%) developed at day 0 for the BM-CyA pretransplant recipients. Skin-allograft prolongation under the BM-CyA protocol implied that the effect may be linked to the existence of a donor-specific stem-cell population in the recipient animal.

    Title Vascularized Bone Marrow Transplantation (vbmt): Induction of Stable Mixed T-cell Chimerism and Transplantation Tolerance in Unmodified Recipients.
    Date March 1991
    Journal Transplantation Proceedings
    Excerpt

    In this preliminary report, our model of VBMT across a semiallogeneic barrier consistently brings about antigen-specific host tolerance with absence of GVHD in the majority of recipients. No immunologic or radiologic intervention was utilized. These results emphasized a potentially important mechanism for low-level stable mixed lymphoid chimerism (SMLC) in tolerance induction, independent of immune suppressive effects due to irradiation or immunopharmacologic intervention.

    Title Development of Stable Mixed T Cell Chimerism and Transplantation Tolerance Without Immune Modulation in Recipients of Vascularized Bone Marrow Allografts.
    Date December 1990
    Journal Transplantation
    Excerpt

    A consistent majority (62.5%) of immunologically unmodified rat recipients transplanted with vascularized hind-limb bone marrow allografts across a semiallogeneic transplant barrier developed tolerance with absence of graft-versus-host disease. A minority of recipients (37.5%) demonstrated lethal GVHD. Transplantation tolerance in the majority was associated with the induction of stable low-level mixed T cell chimerism, including donor CD5+, CD4+, and CD8+ lymphocytes. Chimeras were specifically immune nonresponsive to host alloantigenic determinants. These results emphasized a potentially important mechanism for low-level stable mixed lymphoid chimerism (SMLC) in tolerance induction, independent of immune suppressive effects due to irradiation or immunopharmacologic intervention. These vascularized bone marrow transplantation (VBMT) results may establish the experimental foundation for a novel approach to stem cell transfer and bone marrow transplantation.

    Title Induction of Long-term Rat Renal Allograft Survival: a Specific Synergistic Effect of Limited Pretransplant Cyclosporine Combined with Multiple Nonspecific Blood Transfusions.
    Date August 1990
    Journal Transplantation Proceedings
    Title Two New Composite Tissue Allograft Models in Rats to Study Neuromuscular Functional Return.
    Date July 1990
    Journal Transplantation Proceedings
    Title Long-term Residual Cyclosporine Levels Following Short-term Administration in Various Allograft Models Demonstrating Extensive Survival Prolongation.
    Date July 1990
    Journal Transplantation Proceedings
    Title Site-specific Suppression of Cell-mediated Immunity by Cyclosporine.
    Date May 1990
    Journal The Journal of Investigative Dermatology
    Excerpt

    In this study, it was demonstrated that site-specific suppression of T-cell-mediated immune responsiveness could indeed be achieved by topical application of cyclosporine. Evidence for site-specific immune suppression was obtained from a dual skin allograft model in rats. These animals were given an initial 10-d systemic treatment of CsA. Subsequently, one allograft was treated with topical CsA and the other was treated with the vehicle alone. Anti-inflammatory efficacy and prolonged skin allograft survival were observed both grossly and histopathologically in the presence of topically administered CsA, while contralateral vehicle-treated control grafts underwent vigorous rejection. Systemic lymphocyte DNA synthesis following Con-A and PHA stimulation was normal to elevated. Therefore, systemic T-cell-mediated immunity appeared unaffected or possibly activated even with concomitant topical CsA treatment. CsA levels were low systemically, and showed relative site-specificity in terms of tissue concentration. In conclusion, this study indicates that topical CsA is capable of locally suppressing a strong T-cell-mediated immune response after an initial short-term systemic dose of CsA. Furthermore, certain putative autoimmune and inflammatory diseases of the skin, such as psoriasis and eczematous dermatitis, which may share common mechanisms of action compared to skin allograft rejection should likewise benefit from topical CsA treatment.

    Title Aneurysms and Vascular Malformations.
    Date April 1990
    Journal Topics in Magnetic Resonance Imaging : Tmri
    Excerpt

    Intracranial aneurysms and vascular malformations are frequently detected following intracranial hemorrhages. A CT scan is the most sensitive method of detecting acute subarachnoid, parenchymal, and intraventricular hemorrhages. Small aneurysms are inconsistently visualized on MR scans. Angiography remains the standard for complete and accurate depiction of patent aneurysms, as well as of arteriovenous and venous malformations that have not thrombosed. Giant and thrombosed aneurysms present as mass lesions and are frequently detected when MR is used as a screening examination. Often MRI characterizes these lesions better than CT or angiography. Patients with vascular malformations who have focal neurologic symptoms without hemorrhage are best evaluated with MRI. Patent vascular malformations demonstrating flow void and other flow-related phenomena are readily demonstrated. Occult vascular malformations, including thrombosed arteriovenous, venous, and cavernous malformations and telangiectasia, are also best detected by MRI and are not visible on angiography.

    Title Reconstructive Allotransplantation: Considerations Regarding Integumentary/musculoskeletal Grafts, Cyclosporine, Wound Coverage in Thermal Injury, and the Immune Response.
    Date April 1990
    Journal The Journal of Burn Care & Rehabilitation
    Excerpt

    With the advent of cyclosporine, a powerful and selective immunosuppressant, comes resurgence of a long-sought goal: to transplant modules of allointegumentary/musculoskeletal tissues or components thereof for the repair of peripheral tissue defects. Because these modules of integumentary and/or musculoskeletal tissue are actually composites of various tissues, they are also known as composite tissue allografts. The immediate goal of the studies reviewed herein is to lay the foundation in transplant immunobiology for the clinical exploitation of composite tissue allografts. The objective of these continuing studies is to induce permanent acceptance of composite tissue allografts. The value of such grafts lies in their potential for complete functional and cosmetic restoration in the surgical reconstruction of tissue after full-thickness burn injury. The initial results of basic experiments with cyclosporine are extremely encouraging in regard to the clinical potential for integumentary/musculoskeletal grafts in reconstructive allotransplantation.

    Title The Effects of Testicular Trauma on Fertility in the Lewis Rat and Comparisons to Isoimmunized Recipients of Syngeneic Sperm.
    Date March 1990
    Journal The Journal of Urology
    Excerpt

    Adult male Lewis (LEW) rats were used to investigate the effects of unilateral testicular trauma on fertility. Comparisons were made between normal and experimental rats immunized with syngeneic sperm in Complete Freund's Adjuvant (CFA). Matings within the three groups yielded offspring to all normal males, no offspring to the immunized rats, and 27% (3/11) fertility in the trauma group (p less than 0.001). The contralateral testis demonstrated decreased volumes, various degrees of aspermatogenesis and smaller seminiferous tubular diameters, in both the trauma and immunized groups compared to the controls. Similar histopathologic findings of chronic granulomatous inflammation within contralateral testes in both the trauma and immunized groups suggested a common immune etiology for infertility via possible disruption of the blood-testis barrier.

    Title Partial Tolerance in Rat Renal Allograft Recipients Following Multiple Blood Transfusions and Concomitant Cyclosporine.
    Date February 1990
    Journal Transplantation
    Excerpt

    Multiple prior administrations of donor-strain blood while under limited cyclosporine cover, consistently induce extensive rat renal allograft survival and transplantation tolerance. Yet it was hypothesized that some chronic rejection mechanisms were nevertheless operative since consistent but nonprogressive minor renal dysfunction was observed long-term. A histopathologic study on these putative tolerant rats was undertaken to test this hypothesis. Twenty long-term LEW recipients of BN renal allografts receiving the blood-CsA regimen were examined histopathologically at day 100 post-transplant. Sixteen control LEW recipients receiving only a BN renal allograft were studied acutely at day 7 posttransplant. The control recipients demonstrated a range of lesions consistent with previous studies on acute renal allograft rejection in the rat. However, tolerant recipients demonstrated mild-to-moderate lesions consistent with chronic mechanisms of rejection including the following: moderate focal interstitial mononuclear inflammatory cellular infiltration, with periglomerular and perivascular accumulation; occasional arteriolar luminal obliteration and glomerular atrophy; focal areas of moderate interstitial fibrosis; mild interstitial hemorrhage; mild-to-moderate tubular atrophy; and focal tubular necrosis. Previously our laboratory has documented that tissue-specific renal basement membrane antigens may be responsible for inciting this pattern of focal chronic interstitial inflammation. However, from the present histopathologic studies, it would appear likely that chronic rejection mechanisms in these recipients, which were defined as tolerant by immunologic criteria, involve both tissue-specific and MHC determinants. Therefore, induction of transplantation tolerance in these indefinite survivors is partial or incomplete.

    Title Histochemical Properties of Muscle Allografts Enhanced Via Cyclosporine.
    Date December 1989
    Journal Transplantation
    Excerpt

    Until recently, the transplantation of skeletal muscle across a major histocompatibility barrier has proved difficult. However, with the advent of cyclosporine (CsA), it has become possible to achieve extended survival across such histocompatibility barriers. To date, very little is known about the histochemical, biochemical, immunological or contractile properties of long-term-surviving muscle allografts. Consequently, it was the focus of this study to histochemically examine muscle allografts prolonged with CsA and determine the cross-sectional area of fast glycolytic muscle fibers. Measurements of cross-sectional area were made because they are an important correlate to the amount of tension a muscle can generate. Animals were assigned randomly to one of three groups: control (normal) (n = 5), syngeneic (n = 4), and allogeneic (n = 4). Muscle allografts were performed by transplanting the gastrocnemius of an ACI rat (RT1a) hindlimb into the hindlimb of a Lewis rat (LEW;RT1(1]. The syngeneic model consisted of an ACI-to-ACI transplant. Animals in the allograft group were given CsA (8 mg/kg/day) until the time of sacrifice. At approximately 100 days following transplantation, both syngeneic and allogeneic muscles were removed from the recipient, and quickly frozen in isopentane cooled by liquid nitrogen. Muscle fibers were classified as slow-oxidative (SO), fast-oxidative-glycolytic (FOG), or fast-glycolytic (FG) based upon their staining for myofibrillar ATPase and NADH-dehydrogenase. From each muscle, the cross-sectional area of approximately 175 FG muscle fibers was determined. The fast-glycolytic muscle fibers of both the syngeneic and allogeneic grafts demonstrated a substantial decrease in cross-sectional area. The mean value (+/- SD) for the fibers of the allografted muscle was 1165 +/- 533 microns 2. The mean (+/- SD) fiber cross-sectional area for the fibers of the syngeneic muscle was 973 +/- 421 microns 2. These values contrast with a mean (+/- SD) value of 3552 +/- 601 microns 2 for fibers from age-matched control animals. The differences between the syngeneic and allogeneic muscles were not significant (P greater than 0.05). However, both exhibited significant (P less than 0.01) atrophy compared with the control muscle.

    Title Serologic Properties of the Triple Antibody-sandwich-lymphocyte-agglutination Assay (tasla).
    Date July 1989
    Journal Journal of Clinical & Laboratory Immunology
    Excerpt

    Detailed studies concerning the serologic properties of the triple antibody-sandwich-lymphocyte-agglutination (TASLA) assay are described herin. The technique is a sensitive one based on sandwiching three layers of antibody onto the target cell. Two different test systems were utilized which included xeno- and allogeneic models. In the xenogeneic test system, rabbit-anti-DA lymphocyte xenosera served as the primary antibody sandwich layer. Goat-anti-rabbit and swine-anti-goat IgG served as the secondary and tertiary antibody sandwich layers, respectively. In the rat allogeneic test system, LEW-anti-BN rat lymphocyte allosera served as the primary antibody layer. Rabbit-anti-rat and goat-anti-rabbit IgG served as the secondary and tertiary antibody sandwich layers, respectively. Several different experiments were run with varying numbers of antibody sandwich layers, and differing concentrations within each layer. The lymphocyte agglutination reaction was then evaluated by regression analysis. Regardless of the number or concentration of antibody sandwich layers, it was found that the reaction could be functionally defined mathematically, by regression analysis. A secondary or tertiary antibody sandwich layer increased assay sensitivity. The level of lymphocyte agglutination was found to be both a linear function of the number of antibody sandwich layers and the concentration of each utilized. In addition, the serological properties of the TASLA assay were extended to the rat allogeneic test system and was again functionally defined mathematically by regression analysis.

    Title Use of Regression Analysis and the Complement-dependent Cytotoxicity Typing Assay for Predicting Lymphoid Chimerism.
    Date December 1988
    Journal Journal of Immunological Methods
    Excerpt

    The complement-dependent cytotoxicity typing assay was studied for its accuracy in determining the presence of donor lymphocytes within standard chimeric donor/host cell combinations. Regression analysis of the data was utilized to evaluate the chimera assay. Excellent coefficients of determination (r2 greater than 0.90) were obtained for all standard curves, and a significant (P less than 0.001) linear relationship was established between percent cytotoxicity (dependent variable) and level of donor target cell chimerism (independent variable) for each regression equation. A highly significant (P less than 0.001) linear function was also established between percent cytotoxicity and concentration of donor target bone marrow cells. Regression coefficients (slopes) approached, but did not show complete unity (range; b = 0.86-0.95). Therefore, levels of cytotoxicity were not directly equivalent to levels of donor cell chimerism. A more accurate assessment of donor lymphoid chimerism would be provided by regression analysis of standard donor/host cell independent variables and inverse prediction. Significant estimates of peripheral donor lymphoid chimerism in putative mixed chimeric recipients were successfully made by this technique.

    Title Comparative Studies of Fk506 with Cyclosporine.
    Date October 1988
    Journal Transplantation
    Title The Development of Humoral Immunity to Tissue-specific Tubular Basement Membrane Alloantigens After Renal Transplantation Across the Major Histocompatibility Barrier in Rats Immunomodulated with Blood Transfusions and Cyclosporin.
    Date August 1988
    Journal Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (new York, N.y.)
    Excerpt

    The development of a humoral immune response to the tubular basement membrane (TBM) alloantigen of Brown-Norway (BN) rat kidneys was studied after transplantation of BN rat kidneys into bilaterally nephrectomized Lewis (LEW) rats. The LEW rat recipients consisted of four groups receiving no form of immunosuppression, pretransplantation cyclosporin alone, or pretransplantation donor-specific or donor-nonspecific transfusions combined with cyclosporin. The latter two regimens induce indefinite allograft survival in the majority of recipients. Circulating antibody to collagenase-solubilized BN rat renal basement membrane (CS-BN-RBM) was present in all four groups of transplant recipients within 1 week after transplantation, and no significant differences in antibody levels were noted between rats receiving no immunosuppression (survival of 1-2 weeks) and the groups of rats who received various immunosuppressive regimens and survived longer. Circulating antibody to BN-CS-RBM continued to increase in quantity in the cyclosporin-treated group until the time of death (2-10 weeks post-transplantation). In the much longer lived combined transfusion and cyclosporin-treated groups, circulating antibody to BN-CS-RBM generally attained a maximum at approximately 2 to 4 months post-transplantation and then plateaued or decreased somewhat before the time of death (3-16 months post-transplantation). No correlation was found between quantity of circulating anti-BN-CS-RBM antibody and post-transplantation survival. Comparative study of the quantity of circulating antibody to BN-CS-RBM (the presumed nephritogenic antigen of experimental tubulointerstitial nephritis in the BN rat) in serum from transplant recipients as compared to serum from BN rats with severe experimental tubulointerstitial nephritis (TIN) (as induced by immunization with heterologous TBM antigens) demonstrated a greater quantity of potentially nephritogenic antibody circulating in transplant recipients than in BN rats with experimental TIN. Histologically, the transplanted kidneys in immunomodulated recipients demonstrated focal chronic interstitial inflammatory infiltrates with tubular atrophy and relative sparing of the glomeruli. The development of immune responses to tissue-specific alloantigens may become of clinical significance as graft-survival times are increased.

    Title Pathologic Alterations in the Skin Component of Composite Tissue and Skin Allografts Treated with Cyclosporine.
    Date July 1988
    Journal Transplantation Proceedings
    Title Comparison of Kidney, Composite Tissue, and Skin Allograft Survival in Rats Prolonged by Donor Blood and Concomitant Limited Cyclosporine.
    Date July 1988
    Journal Transplantation Proceedings
    Title Ct of the Brain is Alive and Well.
    Date June 1988
    Journal Radiology
    Title Dose Response of Cyclosporine-treated Composite Tissue Allografts in a Strong Histoincompatible Rat Model.
    Date June 1988
    Journal Transplantation Proceedings
    Title Neuromuscular Capabilities in Long-term Composite Tissue Allografts.
    Date June 1988
    Journal Transplantation Proceedings
    Title Lymphocyte Chimerism in a Full Allogeneic Composite Tissue (rat-limb) Allograft Model Prolonged with Cyclosporine.
    Date June 1988
    Journal Transplantation Proceedings
    Excerpt

    LEW recipients of ACI vascularized hind limb allografts were analyzed for lymphoid chimerism by a complement-dependent cytotoxicity assay using antisera produced across this strain combination. In assessing the technique, two LEW recipients of sublethal irradiation (400 rad), ACI bone-marrow allografts, and CsA exhibited mixed lymphoid chimerism 23 days posttransplant. Short-term CsA-treated CTA recipients that were assayed at various times following transplantation and underwent subacute rejection did not demonstrate any significant mixed lymphoid chimerism. Long-term CsA-treated CTA recipients that were assayed at various times prior to 100 days posttransplant also did not demonstrate any significant mixed lymphoid chimerism. However, following extensive CTA survival (greater than 100 days) significant mixed donor-host lymphocyte chimerism became evident in the peripheral blood, and in one recipient a large quantity of donor bone marrow remained viable in the ACI limb allograft at necropsy (greater than 200 days posttransplant). The development of donor-host lymphocyte chimerism and a wasting syndrome that followed long-term CTA survival was suggestive of GVHD.

    Title Transdermal Application of Cyclosporine Prolongs Skin Allograft Survival.
    Date June 1988
    Journal Transplantation Proceedings
    Title Cyclosporine-induced Long-term Allograft Survival and Its Potential in Posttrauma Tissue Replacement.
    Date March 1988
    Journal The Journal of Burn Care & Rehabilitation
    Excerpt

    This report is a partial review of our work to date concerning the use of cyclosporine and integumentary/musculoskeletal allografts for posttrauma tissue replacement. Our ultimate goals for such allografts are their lifesaving capabilities in addition to their utilization in functional and aesthetic surgical reconstructions. The potential for such a treatment regimen to produce anatomical replacement of lost parts is a primary motivating reason to pursue such studies. Permanent host-accepted integumentary/musculoskeletal allografts would appear to offer much greater promise in comparison with recent synthetic and cultured tissue replacements. Summarized topics covered in this review include short- and long-term use of cyclosporine in a 30% body surface area rat burn model; bacterial studies in this model; primary wound excision and use of cyclosporine in a massive 80% body surface area rat burn model; pathological skin alterations in cyclosporine-treated rats; the synergistic immunosuppressive effects of prior blood transfusions and cyclosporine; long-term residual cyclosporine levels assayed in various long-term surviving allograft-recipients; and the use of cyclosporine and cadaver skin allografts to treat massive full-thickness burns in patients.

    Title Cyclosporine and Skin Allografts for the Treatment of Thermal Injury. Ii. Development of an Experimental Massive Third-degree Burn Model Demonstrating Extensive Graft Survival.
    Date February 1988
    Journal Transplantation
    Excerpt

    We have previously reported the successful treatment and apparent development of skin allograft tolerance in a patient sustaining massive burns, utilizing skin allografts and cyclosporine. We now report the experimental correlate via successful achievement of a 75% body surface area (BSA) scald burn cyclosporine-skin allograft model in Lewis (LEW) rats. Cyclosporine (8 mg/kg/day) was given to the experimental animals daily for the first 20 days and then three times a week thereafter. Two experimental groups were studied: one received standard posttrauma care and the second critical posttrauma care. Controls (n = 22) and experimental groups 1 (n = 28) and 2 (n = 4) had average survival times of 13.8 +/- 12.8 days, 44.2 +/- 132.5 days, and 172.0 +/- 19.4 days, respectively. The allografts on the surviving experimental animals appeared normal and healthy and had nearly perfect hair growth. These results indicate that the model follows the clinical burn wound course, and treatment of massive burns with primary excision, skin allografts, and low doses of cyclosporine could provide immediate and complete functional repair of the burn wound.

    Title Cyclosporine and Skin Allografts for the Treatment of Thermal Injury. I. Extensive Graft Survival with Low-level Long-term Administration and Prolongation in a Rat Burn Model.
    Date February 1988
    Journal Transplantation
    Excerpt

    The hypothesis tested in the present and accompanying study is that an effective treatment for severe burns involves early excision of necrotic tissue followed by skin allografting and cyclosporine (CsA) immunosuppressive therapy. LEW (RT1) rats served as recipients of thermal injury and/or skin allografts. BN x LEW F1 (LBN, RT1(l+n)) rats served as skin donors. LEW burn recipients received a hot water (90 degrees C for 10 sec) 30% body surface area (BSA) full-thickness burn. As expected, LEW recipients treated with CsA (25 mg/kg/day for 20 days) demonstrated significant graft prolongation compared with controls (P less than 0.005). Skin graft survival was similarly prolonged in LEW recipients undergoing burn injury, primary wound excision, and CsA administration compared with burn-skin allograft controls (P less than 0.001). Mortality was not increased in the thermal injury-CsA-treated recipients compared with burn controls. A final experiment was initiated to investigate how low-level long-term (greater than 100 days) maintenance CsA treatment influenced skin allograft survival for possible future consideration in burn trauma. Recipients receiving skin allografts plus CsA (20 days, 8mg/kg/day, followed by every other day thereafter) did not reject their grafts. However, a possible early sign of rejection (a single small ulcerative lesion) was noted in five of these long-term CsA-treated animals at a mean of 34 +/- 11 (SD) days. The lesion in these animals did not progress any further during CsA administration. Histopathologic study of selected animals removed from the CsA maintenance regimen for greater than 50 days following long-term administration revealed a number of interesting chronic lesions similar to those previously reported in the skin component of composite tissue (limb) allografts following long-term low-level CsA intervention. In conclusion, CsA was very successful in preventing rejection of skin allografts in a rat burn model without apparent adverse effects.

    Title Decreased Reactivity of Allosera Against Target Lymphocytes Obtained Following Thermal Injury or Long-term Cyclosporine Treatment.
    Date January 1988
    Journal Clinical Immunology and Immunopathology
    Excerpt

    We speculated that two diverse causes of potent cell-mediated immune suppression, cyclosporine (CsA) and thermal trauma, may demonstrate some similar actions, and thus tested whether either could alter antisera reactivity against allogeneic target lymphocytes. Target splenocytes from 40% body surface area full-thickness burned Brown-Norway (BN) rats demonstrated significant (P = 0.004) decreased reactivity (agglutination) with antisera produced across a full allogeneic barrier (RT1 major histocompatibility complex (MHC) and non-MHC) compared to control splenocytes. Depression of allogeneic splenic target cell reactivity against Lewis (LEW)-anti-BN allosera was similarly observed using lymphocytes from long-term CsA-treated rats (P = 0.004). The decreased reactivity induced by burn trauma was transferable to pooled normal splenocytes or blood lymphocytes by preincubation with burn plasma (P less than 0.001), and was confirmed by a cellular enzyme-linked immunosorbent assay (CELISA) (P = 0.003). In summary, a similarity consisting of decreased antibody reactivity against lymphocytes from either burned or long-term CsA-treated animals was demonstrated. These results suggested that lymphocyte cell surface allogeneic determinants and their expression and/or availability were altered by either regimen.

    Title Inferior Vena Cava Pseudothrombus in Computed Tomography Using a Contrast Medium Power Injector: a Potential Pitfall.
    Date December 1987
    Journal Journal of Computer Assisted Tomography
    Excerpt

    Of 276 patients undergoing CT using a power injector to deliver contrast material, 71 (26%) demonstrated a pseudothrombus in the suprarenal inferior vena cava. This occurs much more commonly than in patients injected by hand and is a potential pitfall in interpreting these scans.

    Title Two-dimensional Immunoelectrophoretic Analysis of Urinary Ultraconcentrates: Antigenic Differences Between Bladder Cancer Positive Patients, Normal Individuals, and Patients with Urinary Tract Infections.
    Date December 1987
    Journal Journal of Surgical Oncology
    Excerpt

    Urine ultraconcentrates (100-fold) from bladder cancer patients, patients suffering from urinary tract infection, and normal individuals were analyzed using polyacrylamide gel electrophoresis (PAGE) and two-dimensional immunoelectrophoresis. A combined sample of normal urine was resolved into 1 to 3 protein bands by PAGE, whereas a single concentrated bladder cancer urine was resolved into 10-12 protein bands. Yet, this same concentrated urine sample was resolved into 17-20 antigen peaks by two-dimensional immunoelectrophoresis (2DIEP) against antihuman serum. A significant (P less than 0.05) increase was observed in the relative antigen concentration when comparing 2DIEP profiles of bladder cancer urines to normal controls. A significant increase in the relative antigen concentration and the number of antigen peaks was also found when comparing immunoelectrophoretic patterns obtained from ultraconcentrated urine specimens of bladder cancer positive urine and normal controls using a rabbit antibladder cancer urine antisera (P less than 0.002 and P less than 0.02, respectively). In addition, significant (P less than 0.02) antigenic differences were found when comparing concentrated urine samples from bladder cancer positive individuals to those with urinary tract infection. The bladder cancer group demonstrated 8/9 positive results for relative antigen concentrations greater than 3.0. Fifteen of 16 normal or urinary tract infected individuals combined had relative antigen concentrations less than 3.0. These differences were highly significant (P less than 0.001). No differences were found between concentrated bladder cancer and normal urine specimens tested against rabbit antinormal urine antisera.

    Title Alzheimer's Disease: Making the Diagnosis.
    Date December 1987
    Journal American Family Physician
    Excerpt

    Alzheimer's disease accounts for about 60 percent of dementia cases. Misdiagnosis of the treatable dementias can have devastating results. Pseudodementia accompanying major depression and chronic cognitive dysfunction due to psychoactive drugs are among the most commonly missed diagnoses. Although cortical atrophy is regularly found on computed tomographic scans in Alzheimer's disease, it is not necessarily diagnostic. A relatively distinct onset of cognitive impairment is not characteristic of Alzheimer's disease.

    Title Burn Depth Evaluation with Fluorometry: is It Really Definitive?
    Date December 1987
    Journal The Journal of Burn Care & Rehabilitation
    Excerpt

    Clinical evaluation of burn depth soon after injury is subjective, based on gross visual assessment. Previous investigators have quantified this process using fluorometry. Their studies show fluorescein levels in full-thickness burns to be far below control levels and partial-thickness burns to be about 60% of nonburned skin. In both rat and human models, 59 burn sites (eight rats) and 37 burn sites (seven patients) were assessed. Readings were taken for three hours on the rats and one hour on the patients during the first 48 hours, and the procedure was repeated for five days postburn. Maximum values during these periods were determined for burn and nonburn sites, and background levels were subtracted from these values. The rate of fluorescein uptake and the peak times for burn and nonburn sites were then compared. Actual depth of burn was determined by whether or not healing had occurred. The results showed no significant difference between partial-thickness and full-thickness burns using fluorometry, as standard deviations in both models for both depths of burn were large. Therefore, fluorometry did not provide a definitive evaluation of burn depth. These results differ from those reported by previous investigators.

    Title Prior Administration of Donor-strain Epidermal Cells or Macrophages to Enhance Survival of Rat Hind-limb Allografts.
    Date December 1987
    Journal Transplantation
    Title Extensive Prolongation of Rat Renal Allograft Survival Following Donor or Nonspecific Transfusions and Concomitant Immunosuppressant.
    Date July 1987
    Journal Transplantation
    Excerpt

    We report here a marked beneficial effect upon rat renal allograft survival transplanted across a strong histocompatibility barrier (BN----LEW) by pretransplant concomitant donor-strain blood transfusion (DST) and CsA treatment. Comparisons between recipient groups treated with pretransplant nonspecific blood (NST) and concomitant cyclosporine (CsA) or azathioprine (Aza) administration were also made. LEW recipients receiving only a BN renal allograft survived for a geometric average time of 8.9 days. Recipients receiving 1 ml of donor blood at weekly intervals, each week for three weeks prior to transplantation, demonstrated a geometric mean survival time (GMST) of 40.5 days. Recipients receiving this same regimen and concurrent CsA cover (5 mg/kg/day) starting 7 days prior to the first transfusion with discontinuation 5 days prior to transplantation showed extensive prolongation (greater than 100 days). Recipients treated with only CsA cover survived for a GMST of 34.4 days. LEW recipients receiving 1 ml of nonspecific blood at weekly intervals (DA, BUF, WKY, respectively) each week for 3 weeks prior to transplantation were prolonged to 27.7 days. Recipients treated with this same regimen while under CsA cover also demonstrated extended prolongation (greater than 100 days). Recipients receiving multiple donor blood transfusions under Aza (2 mg/kg/day) cover demonstrated lesser prolongation (22.8 days). Recipients receiving the multiple nonspecific blood protocol under Aza cover showed similar prolongation (38.6 days). Recipients treated only with Aza did not show prolonged survival (9.3 days). These differences in survival were considered significant among the 9 transplant groups as determined by ANOVA (P less than 0.001). The majority of recipient groups showed relatively poor renal function over their life spans, independent of whether prolongation occurred. Yet, renal function in the NST or particularly the DST groups covered by pretransplant CsA, demonstrated the best renal function in our laboratory over many years of investigations using the BN----LEW combination. In conclusion, there was a dramatic synergistic beneficial effect of prior multiple DST or NST specific to CsA, as opposed to another immunopharmacologic agent, Aza.

    Title Evaluation of the Rat Renal Allograft Model in Comparison to Man: a Physiological Perspective.
    Date September 1986
    Journal The Journal of Urology
    Excerpt

    Fabre has previously questioned the rat kidney allograft model from an immunologic perspective and raised some important considerations. The present study addresses further the fidelity of the rat renal allograft model from a physiologic rather than immunologic perspective. We reviewed several rat renal allograft studies from several laboratories, including our own, that followed BUN or urea levels during renal failure. Also examined were several studies from the literature concerning patient survival and uremia. The percentage of patient and rat survival was plotted against maximal BUNs attained. The frequency of survival was significantly (p less than 0.05) increased in the rats by comparison to the patient population over a range of median BUNmax values. Additional human data that were utilized for analysis included a group of 16 patients who experienced renal failure and subsequently chose not to undergo dialysis. Comparing the mean BUN at death in rats from our laboratory to this patient population, we found that there was a significant difference (p less than 0.001, 292 +/- 142 mg./dl. versus 127 +/- 51 mg./dl., respectively). When all of the rat data was combined, including results from the literature, and compared to the patients, a significant (p less than 0.001) increase in BUN at death was confirmed (204 +/- 95 versus 127 +/- 51, respectively). We also found that 82% of the rats that died with uremia possessed BUNs greater than 200 mg./dl. at some time during their course. In contrast, only one of the 16 patients (6%) that died with uremia demonstrated BUN levels as great as this. Although the rats frequently (13%) went on to indefinite survival after experiencing high levels of uremia, the vast majority did not. We conclude that the rats exhibit superior ability to tolerate high concentrations of urea in comparison to man. However, as a group, they demonstrated little ability to sustain their uremic condition for prolonged periods. This latter consideration is of utmost importance, since most renal transplant studies base their conclusions on length of animal survival following organ allograft failure due to rejection. We feel this is a salient feature of the rat renal allograft model.

    Title Prolonged Viability of Human Skin Xenografts in Rats by Cyclosporine.
    Date June 1986
    Journal The Journal of Investigative Dermatology
    Excerpt

    The immunosuppressant cyclosporine (CSA) has shown usefulness in both animal and human transplantation. The present study investigated the effect of CSA in human to rat skin xenografts. Recipient rats received either a fresh split-thickness (0.020 in.) or full-thickness graft obtained from plastic surgery, or frozen cadaver skin. The graft bed of recipient Lewis rats was prepared by full-thickness excision. Animals were maintained on CSA 25 mg/kg/day X 50 days, followed by 12.5 mg/kg 2 X/week. Control animals received an equivalent volume of vehicle. All animals receiving split-thickness grafts and treated with CSA maintained their grafts significantly longer (up to 255 days) than controls. The 2 CSA-treated full-thickness grafts and the 10 vehicle-treated controls showed clinical and microscopic signs of rejection at a mean of 6.4 days. Histologic examination of successful grafts showed areas of viable epidermis with a negligible inflammatory infiltrate. There was some loss of normal polarity and occasional apoptotic pigmented basal cells. The dermis revealed moderate fibrosis, probably secondary to the surgical procedure. Graft viability was confirmed by autoradiography. Immunohistochemical staining for S-100 protein revealed morphologic alteration of suprabasilar dendritic (Langerhans-indeterminate) cells, as well as their existence in xenografts at 12 weeks posttransplantation. Toxicities reflected by weight loss and blood chemistries were felt to be dose-dependent. This in vivo model may provide a means for testing percutaneous drug penetration and pharmacokinetics in human skin, and for observing the immune component of explanted cutaneous neoplasms and dermatoses.

    Title Composite Tissue (limb) Allografts in Rats. Iii. Development of Donor-host Lymphoid Chimeras in Long-term Survivors.
    Date February 1986
    Journal Transplantation
    Excerpt

    Eight LEW rat recipients possessing long-term-surviving (206-701 days) LBN vascularized hind limb allografts (CTAs) were tested for donor-host lymphoid chimerism. The recipients received various cyclosporine (CsA) treatment protocols in order to induce indefinite CTA acceptance. Histological examination of long-term-surviving CTAs demonstrated normal-appearing bone marrow in the donor limb. Lymphocytes isolated from host hemopoietic tissues (peripheral blood and/or spleen) by ficoll-hypaque density gradient centrifugation were tested against LEW-anti-BN antisera. Comparisons were made to standard curves employing various known concentrations of LBN and LEW cell combinations. The level of lymphocyte agglutination (dependent variable) showed a significant (P less than 0.025-0.005) linear relationship to the concentration of LBN donor cells (independent variable) present. Lymphocyte suspensions isolated from long-term CTA host peripheral blood and/or spleen showed a mean of 19.7% (+/- 9.7-95% confidence interval) donor LBN mononuclear cells present. Thus, it appeared that lymphoid cells originated from, and/or were released from LBN donor bone marrow into the circulation, resulting in chimeric repopulation of hemopoietic tissues. The presence of donor immunocytes in these limb allograft recipients may have been beneficial, and thus could have helped contribute to the long-term CTA survival observed.

    Title Long-term Skin Allograft Survival After Short-term Cyclosporin Treatment in a Patient with Massive Burns.
    Date February 1986
    Journal Lancet
    Excerpt

    In a child with extensive burns, cyclosporin was given to extend the survival of cadaveric skin allografts obtained from numerous unmatched donors. No evidence of graft rejection was seen, either during treatment or in the 2 years after cyclosporin was withdrawn.

    Title A Pair of Five-day Flaps: Early Division of Distant Pedicles After Serial Cross-clamping and Observation with Oximetry and Fluorometry.
    Date February 1986
    Journal Annals of Plastic Surgery
    Excerpt

    In each of 2 recent patients with distant pedicles (one a groin flap and the other a cross-leg flap), we were able to perform the final division and detachment of the flap on the fifth postoperative day. Cross-clamping was used to create intermittent periods of ischemia. The periods of ischemia were progressively increased until the time of division. Fluorometry with intravenous fluorescein played a role in deciding when to divide the flap. The patients were discharged from the hospital on the sixth and seventh days, respectively. Trimming was done on an outpatient basis.

    Title Immunosurgery.
    Date May 1985
    Journal Clinics in Plastic Surgery
    Excerpt

    After being leaders in the field of transplantation, plastic surgeons became inactive in this field. Interest is reviving with the advent of the new immunosuppressant drug cyclosporine, as well as new knowledge of the immune mechanism. New generations of immunosuppressive drugs may allow allografting in patients with massive burns, limb transplants, and possibly even allografts of facial structures.

    Title Composite Tissue (limb) Allografts in Rats. I. Dose-dependent Increase in Survival with Cyclosporine.
    Date May 1985
    Journal Transplantation
    Excerpt

    The dose-response effect of cyclosporine on rat limb transplant prolongation was investigated across the LBN-to-LEW histocompatibility barrier. This composite tissue allograft model has been shown to represent a strong transplantation barrier. Median limb allograft survival times increased in a dose-dependent manner with low cyclosporine doses, and then reached a plateau at higher levels. The cyclosporine dose that produced half-maximal survival based on a 20-day treatment was only 3.7 mg/kg/day. Histopathology revealed that the rejection process was distinctly different in limb allografts treated with cyclosporine compared with non-cyclosporine-treated controls. Rejection appeared to be delayed or partly arrested in certain areas of cyclosporine-treated limb allografts. These studies represent an initial step in laying the experimental foundation for clinical transplantation of composite tissue allografts using cyclosporine-induced immune suppression.

    Title Composite Tissue (limb) Allografts in Rats. Ii. Indefinite Survival Using Low-dose Cyclosporine.
    Date May 1985
    Journal Transplantation
    Excerpt

    Cyclosporine has reawakened interest in transplantation of peripheral composite tissue allografts (CTA) of skin, muscle, bone, vessel, and nerves. The purpose of this study was to examine whether cyclosporine could produce indefinite survival of CTA. Two groups of LEW recipients of LBN limb transplants were given different long-term treatments of cyclosporine. Tolerance was achieved in many of the animals. Several possibilities for the mechanism of this tolerance are discussed.

    Title Transcutaneous Oxygen and Flaps.
    Date November 1984
    Journal Plastic and Reconstructive Surgery
    Title A Comparison of Hemostatic Agents in Microvascular Surgery.
    Date May 1983
    Journal Journal of Microsurgery
    Excerpt

    The hemostatic abilities of oxidized cellulose, gelatin powder, microfibrillar collagen, and expanded polytetrafluoroethylene cuffs were compared on anastomoses of the femoral vessels in rats. The intraoperative hemostatic time and patency were recorded. Vessels that were patent intraoperatively were examined at various intervals postoperatively to determine patency and to detect the development of abnormalities, and specimens for examination under a scanning electron microscope were obtained. Microfibrillar collagen was found to be superior in maintaining patency and in ease of use. The PTFE cuffs demonstrated the shortest hemostatic times, but they produced distortion of the vessels several weeks after surgery. The authors conclude that microfibrillar collagen is the best overall hemostatic agent and have continued to use it experimentally and clinically with no complications.

    Title Efforts to Enhance Survival of Limb Allografts by Prior Administration of Whole Blood in Rats Using a New Survival End-point.
    Date February 1983
    Journal Journal of Microsurgery
    Excerpt

    Injecting whole blood into the recipient before surgery can significantly prolong renal transplant survival in rats. Therefore, experiments were performed in rats to study the effects of prior administration of whole blood on the survival of limb allografts. Tests to quantitate survival of the allografts included monitoring the internal temperature of the leg, assaying serum creatine kinase levels, and testing for alloantibodies. Lewis recipients of (BN x LEW)F1 limb transplants that received 1 ml of BN or (BN x LEW)F1 whole blood before surgery had mean survival times that were longer compared with controls as measured by a 10 F change in temperature. In a test-retest experiment, decline of temperature proved to be a reliable quantitative determination of limb allograft survival since a difference of only 5.6% was observed in the mean number of days of graft survival between two separate groups of control Lewis recipients. Moreover, combined data demonstrated that control Lewis recipients of (BN x LEW)F1 limb allografts averaged 24.0 days of graft survival based on a 10 F decline in temperature with a 95% confidence interval of +/- 6.3 days. It is concluded that prior administration of whole blood can produce significant prolongation of survival in organ transplantation, but it is not as effective in enhancing survival of limb allografts. It is also concluded that internal temperature measurement of limb allografts is an easy, effective, and quantitative method of monitoring rejection.

    Title Cosmas and Damian in the Laboratory.
    Date March 1982
    Journal The New England Journal of Medicine
    Title Transcutaneous Po2 in Flaps: a New Method of Survival Prediction.
    Date August 1980
    Journal Plastic and Reconstructive Surgery
    Excerpt

    We have shown a new clinical method for flap monitoring. This new method is noninvasive, continuous, quantitative, easy, and commercially available. If any oxygen can be detected or if there is a response to increased FIO2, flap survival is assured.

    Title Transcutaneous Po2 Monitoring of Flap Circulation Following Surgery.
    Date May 1980
    Journal Birth Defects Original Article Series
    Excerpt

    In a series of rabbit experiments, tcPO2 was found to be a very sensitive indicator of flap viability, reflecting minute-to-minute changes in physiology. It is safe, reproducible, and easily verified by comparing flap tcPO2 to a control site and by measuring response to increased FIO2. Transcutaneous PO2 measurements should prove a valuable tool in flap research and in monitoring pedicle flaps and microvascular tissue transfers.

    Title Investigation of Transcutaneous O2--co2 Sensors and Their Application on Human Adults and Newborns.
    Date May 1980
    Journal Birth Defects Original Article Series

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