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Biomedical subjects

R Hendrix

Publications and source records attributed to R Hendrix.

At least 19 recordsLinked to original sources
PubMed2005

Reducing whole-body vibration and musculoskeletal injury with a new car seat design.

A new car seat design, which allows the back part of the seat (BPS) to lower down while a protruded cushion supports the lumbar spine, was quantitatively tested to determine its effectiveness and potentials in reducing whole-body vibration (WBV) and musculoskeletal disorders in automobile drivers. Nine subjects were tested to drive with the seat in: 1) the conventional seating arrangement (Normal posture); and 2) the new seating design (without BPS (WO-BPS) posture). By reducing contact between the seat and the ischial tuberosities (ITs), the new seating design reduced both contact pressure and amplitude of vibrations transmitted through the body. Root-mean-squared values for acceleration along the z-axis at the lumbar spine and ITs significantly decreased 31.6% (p < 0.01) and 19.8% (p < 0.05), respectively, by using the WO-BPS posture. At the same time, vibration dose values significantly decreased along the z-axis of the lumbar spine and ITs by 43.0% (p < 0.05) and 34.5% (p < 0.01). This reduction in WBV allows more sustained driving than permitted by conventional seating devices, by several hours, before sustaining unacceptable WBV levels. Such seating devices, implemented in large trucks and other high-vibration vehicles, may reduce the risk of WBV-related musculoskeletal disorders among drivers.

Acceleration↗
PubMed2000

Vigorous allograft rejection in the absence of danger.

Tolerance to self is a necessary attribute of the immune system. It is thought that most autoreactive T cells are deleted in the thymus during the process of negative selection. However, peripheral tolerance mechanisms also exist to prevent development of autoimmune diseases against peripheral self-Ags. It has been proposed that T cells develop tolerance to peripheral self-Ags encountered in the absence of inflammation or "danger" signals. We have used immunodeficient Rag 1-/- mice to study the response of T cells to neo-self peripheral Ags in the form of well-healed skin and vascularized cardiac allografts. In this paper we report that skin and cardiac allografts without evidence of inflammation are vigorously rejected by transferred T cells or when recipients are reconstituted with T cells at a physiologic rate by nude bone graft transplantation. These results provide new insights into the role of inflammation or "danger" in the initiation of T cell-dependent immune responses. These findings also have profound implications in organ transplantation and suggest that in the absence of central deletional tolerance, peripheral tolerance mechanisms are not sufficient to inhibit alloimmune responses even in the absence of inflammation or danger.

Adoptive Transfer↗
PubMed1997

Analysis of the B7 costimulatory pathway in allograft rejection.

BACKGROUND: Blockade of the B7/CD28 costimulation pathway with the fusion protein, CTLA4-Ig, has been shown to prolong allograft survival in numerous rodent models, suggesting that this pathway is functionally important in the allograft rejection response. This pathway is complex and consists of at least the B7-1, B7-1a, B7-1cyt II, and B7-2 molecules on the antigen-presenting cell and CD28 and CTLA4 molecules on the T cell. METHODS: The intragraft transcript expression of the B7 molecules and their counterreceptors was defined using reverse transcriptase-polymerase chain reaction in the vascularized mouse cardiac allograft model. In addition, the functional significance of these molecules was investigated both in vitro in the mixed leukocyte response (MLR) and in vivo in the vascularized mouse cardiac allograft model. RESULTS: Intragraft expression of B7-1, B7-1a, B7-1cyt II, B7-2, CD28, and CTLA4 transcripts is up-regulated in allografts when compared with both normal untransplanted hearts and syngeneic transplants at between 5 and 12 days after transplant. Both anti-B7-1 and anti-B7-2 monoclonal antibodies alone inhibited T-cell proliferation in the MLR, however, equivalent maximal inhibition was obtained by a combination of these agents or by CTLA4-Ig. Likewise, in the mouse cardiac allograft model, both anti-B7-1 and anti-B7-2 modestly prolonged graft survival. However, an increased survival was obtained with either a combination of anti-B7-1 and anti-B7-2 or CTLA4-Ig. Blockade of the B7/CD28 pathway in the MLR using T cells from CD28 knockout mice had no effect on the proliferative response. Likewise, blockade of the B7/CD28 pathway did not effect the rate of rejection of cardiac allografts by CD28 knockout recipients. CONCLUSIONS: These data suggest that both B7-1 and B7-2 have an important role in allograft rejection in the mouse vascularized cardiac allograft model.

Animals↗
PubMed1996

Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways.

The receptor-ligand pairs CD28-B7 and CD40-gp39 are essential for the initiation and amplification of T-cell-dependent immune responses. CD28-B7 interactions provide 'second signals' necessary for optimal T-cell activation and IL-2 production, whereas CD40-gp39 signals co-stimulate B-cell, macrophage, endothelial cell and T-cell activation. Nonetheless, blockade of either of these pathways alone is not sufficient to permit engraftment of highly immunogenic allografts. Here we report that simultaneous but not independent blockade of the CD28 and CD40 pathways effectively aborts T-cell clonal expansion in vitro and in vivo, promotes long-term survival of fully allogeneic skin grafts, and inhibits the development of chronic vascular rejection of primarily vascularized cardiac allografts. The requirement for simultaneous blockade of these pathways for effective inhibition of alloimmunity indicates that, although they are interrelated, the CD28 and CD40 pathways are critical independent regulators of T-cell-dependent immune responses.

Abatacept↗
PubMed1996

CTLA4-Ig plus bone marrow induces long-term allograft survival and donor specific unresponsiveness in the murine model. Evidence for hematopoietic chimerism.

Allograft rejection is dependent on T cell activation, which requires both the engagement of the T cell receptor by antigen in the context of the MHC molecules and costimulatory signals delivered by cell surface molecules such as B7-CD28/CTLA4 pathway. CTLA4-Ig is a fusion protein that blocks this pathway and has previously been shown to prolong both allograft and xenograft survival. The current study demonstrates markedly prolonged murine cardiac allograft survival and specific prolongation of secondary skin grafts using a combination of CTLA4-Ig plus donor bone marrow. A role for hematopoietic chimerism in the establishment of CTLA4-Ig-induced transplantation tolerance was investigated using reverse transcriptase polymerase chain reaction analysis of recipient tissues. Expression of donor-specific MHC class II transcripts in both peripheral and lymphoid tissues was demonstrated at greater than 200 days after transplant. To investigate the functional significance of this observation, heart donors, and donor bone marrow were irradiated before transplantation in CTLA4-Ig-treated recipients. A reduction in allograft survival was associated with irradiation of both the donor heart and the bone marrow. These results suggest that there may be a donor-derived radiosensitive element that enhances allograft survival in this model. Reverse transcriptase polymerase chain reaction analysis of allografts of tolerant and control animals at days 5, 8, and 12 after transplantation failed to demonstrate a dramatic difference in the expression of interleukin (IL)-2, IL-4, IL-10, and interferon-gamma message. Cytotoxicity effector transcripts were largely intact in CTLA4-Ig + bone marrow-treated recipients as they showed no decrease in intragraft granzyme, perforin, Fas, or Fas ligand transcripts during thr first 8 days after transplant. These results imply that complex mechanisms may be important for the induction and maintenance of transplantation tolerance in the CTLA4-Ig plus bone marrow murine cardiac allograft model.

Abatacept↗
PubMed1996

CD40-gp39 interactions play a critical role during allograft rejection. Suppression of allograft rejection by blockade of the CD40-gp39 pathway.

Studies in vivo have documented the importance of CD40-gp39 interactions in the development of T-dependent antibody responses to foreign and auto-antigens. In this report, we demonstrate that allograft rejection is also associated with strong induction of CD40 and gp39 transcripts. When treatment was initiated at the time of transplant, MR1, a mAb specific for gp39, induced markedly prolonged survival of fully disparate murine cardiac allografts in both naive and sensitized hosts. However, when therapy was delayed until postoperative day 5, anti-gp39 failed to prolong graft survival. Allografts from recipients treated with MR1 from the time of transplantation showed decreased expression of transcripts for the macrophage effector molecule, inducible nitric oxide synthase, but essentially unaltered expression of B7 molecules and T cell cytokine transcripts (interleukin [IL]-2, interferon-gamma, IL-10, and IL-4) relative to control allografts. In addition, alloantibody responses in the MR1-treated mice were profoundly inhibited. However, our studies using B cell-deficient mice indicated that the ability of MR1 to prolong allograft survival was not dependent on B cells. These data suggest that blockade of CD40-gp39 interactions may inhibit allograft rejection primarily by interfering with T cell help for effector functions, rather than by interference with T cell activation.

Animals↗
PubMed1996

Analysis of effector mechanisms in murine cardiac allograft rejection.

Multiple effector cells have been implicated in transplant rejection, including cytotoxic T cells, B cells, macrophages and NK cells. The purpose of this study was to examine the effector pathways which are critical to murine cardiac allograft rejection. RT-PCR (reverse transcriptase-polymerase chain reaction) analysis of syngeneic and allogeneic vascularized heterotopic cardiac grafts at 5, 8 and 12 days following transplantation demonstrate constitutive expression of Fas in both the syngeneic and allogeneic grafts as well as in normal heart. However, FasL, granzyme, and perforin expression were shown to be up-regulated on days 5-12 in the allograft with no expression in syngeneic grafts or in normal hearts. We have recently analyzed the functional significance of T cell cytotoxic pathways and found that neither the Fas nor CD8+ cytotoxic pathways are required for murine cardiac allograft rejection. In light of these results, we investigated the functional significance of other effector cells in the rejection process. B cell deficient C57BL/10-IgHtm1Cgn mice rejected cardiac allografts from normal donors at control rate. Finally, RT-PCR was used to analyze the expression of macrophage effector transcripts in allograft rejection. Transcripts for iNOS (inducible nitric oxide synthase) and TNF alpha (tumor necrosis factor-alpha) were up-regulated on days 5-12 in untreated allografts with undetectable expression in normal heart or syngeneic grafts. These results demonstrate that effective allograft rejection can occur in the absence of B cells and T cell cytotoxicity pathways suggesting that other effector pathways, such as delayed-type hypersensitivity responses by macrophages, may be critical for allograft rejection.

Animals↗
PubMed1995

Fas-mediated cytotoxicity. An immunoeffector or immunoregulatory pathway in T cell-mediated immune responses?

Fas/Fas ligand interactions serve as a signaling pathway for apoptosis (1-3), an important regulatory mechanism in the development and function of the immune system (4-9). Recent evidence that Fas-dependent apoptosis is also an important mode of T cell cytotoxicity (10-13) suggested that Fas might play a critical role in the effector phase of T-dependent immune responses, such as allograft rejection. We observed that Fas transcripts are constitutively expressed in syngeneic and allogeneic murine cardiac transplants, while Fas ligand (FasL) is up-regulated only in rejecting allografts. Surprisingly, the absence of an intact Fas/FasL pathway did not alter the tempo of allograft rejection, even CD4-dependent rejection. These results indicate that Fas/FasL interactions are not essential mediators of T cell-induced allograft damage. Rather, as suggested in other studies, the Fas pathway may be principally involved in the regulation of clonal expansion and subsequent contraction of T cell populations during immune responses.

Animals↗
PubMed1994

Regulation of immunostimulatory function and costimulatory molecule (B7-1 and B7-2) expression on murine dendritic cells.

Dendritic cells (DC) play a critical role in the initiation of T cell-mediated immune responses, and express costimulatory molecules that are required for optimal activation of unprimed T cells. Studies on the regulation of the costimulatory molecules on DC have produced evidence from several systems that GM-CSF can up-regulate expression of CTLA4 counter receptor (CTLA4-CR) (but not intercellular adhesion molecule 1 (ICAM-1) and heat stable Ag (HsAg)) on DC. This is demonstrated on splenic DC, Langerhans cells, kidney DC in culture, and in a skin-explant culture system, in which the increased expression of CTLA4-CR on Langerhans cells (LC) occurs concomitantly with their migration out of skin. Interestingly, despite the ability of both GM-CSF and IFN-gamma to increase CTLA4-CR and maintain similar levels of ICAM-1, HsAg, and MHC molecule expression, the functional consequences of these cytokines on splenic DC are distinctly different. GM-CSF enhances the ability of DC to stimulate both T cell proliferation and cytokine release, whereas IFN-gamma causes no increase in immunostimulatory function. Further analysis of the CTLA4-CR on these cell populations by using the GL-1 and IG10 mAbs has shown that GM-CSF-cultured DC express high levels of both B7-1 and B7-2, whereas IFN-gamma-cultured DC express increased levels of only B7-2. These results suggest that optimal stimulation of unprimed T cells to proliferate and release cytokines may require participation of both of these CTLA4 counter receptors, and confirm the importance of GM-CSF for the maturation of DC into potent stimulators of T cell activation.

Abatacept↗
PubMed1993

Growth pressure can drive early chick lens geometries.

Over a number of morphological stages during chick lens morphogenesis, a flat plate of cuboidal ectodermal cells infolds to form a deep cup of tall, pyramidal lenticular cells. This invagination process is accompanied by asynchronous cellular multiplication over a basal region constrained by an adhesive extracellular matrix. A lens placode is formed as the cells crowd into columnar "palisades." A lens cup forms as the cells pyramidalize owing to basal nuclear movements. Invagination ends when the opening into the lens cup is closed to form a lens vesicle. In this paper, equations are developed that provide a quantitative, mathematical formulation of an earlier theory that explains this invagination as a growth driven process. The equations take into account the lens cell cycle, the extracellular matrix, and nuclear migratory behaviors. Based on the equations, geometries simulating the morphological stages and the cell cycle phases are generated for the 1st day of lens development. The mathematical formulation of lens invagination helps demonstrate how growth pressure alone can be the primary driving force for tissue folding. In this view, recruitment occurs before the shape changes; and cell-autonomous mechanisms of invagination, involving the cytoskeleton or differential adhesion alone, offer inadequate explanations of these changes.

Animals↗
PubMed1991

The use of T2 distribution to study tumor extent and heterogeneity in head and neck cancer.

Demarcation of the extent of malignant tissue is essential for planning a course of radiotherapy. MR images may provide additional information for delineating the target volume because of the large difference in the proton magnetic resonance relaxation times between normal and malignant tissues. In 13 patients with head and neck tumors the distribution of the proton spin-spin relaxation times, T2, at 1.5 Tesla were evaluated throughout the physician designated target volume and normal surrounding tissue. The T2 values within the tumor were always elevated compared with normal tissue, the highest values being in the nominal center of the tumor and decreasing toward the periphery. The regional distribution of T2 values within the tumor is a measure of the tissue heterogeneity within the tumor volume. In addition, the large differences in T2 relaxation times between normal and disease tissues were used in a computer algorithm to automatically demarcate the boundary of abnormal tissue in each axial MRI section. This potentially could significantly expedite the time required to identify the target volume on multiple sections and thus remove one of the major time constraints for 3D treatment planning.

Head and Neck Neoplasms↗
PubMed1991

Compression therapy of limb edema using hydrostatic pressure of mercury.

A new apparatus for the treatment of edema of the extremities is described. The extremity is placed in a cylindrical vertical tank and isolated by a circumferential synthetic rubber membrane. The equipment is programmed to create a mold of the extremity using a slurry of plastic granules from a reservoir. Mercury is then pumped between the mold and the extremity, thereby exerting a pressure gradient on the extremity equal to the hydrostatic pressure of the mercury column. A computerized program forms the mold and runs several compression cycles for each treatment session. Twelve patients were treated (8 upper extremities, 4 lower extremities) on a weekly or semiweekly basis. Progress was followed with computed axial tomography scans, as well as measurements and photographs. Ten patients experienced significant immediate decrease in edema with each treatment. Wrapping or elastic support was required to prevent the return of edema between treatments. No pain, skin injury, or other complication of treatment was noted. The apparatus can safely provide short-term, immediate, significant improvement of extremity edema. Further studies will be necessary to determine long-term benefit.

Bandages↗
PubMed1988

Stress proteins are immune targets in leprosy and tuberculosis.

To understand the immune response to infection by tuberculosis and leprosy bacilli and to develop improved vaccines, the nature of antigens that are involved in humoral and cell-mediated immunity was investigated. We have determined that five immunodominant protein antigens under study are homologues of stress proteins. This finding and observations with other pathogens suggest that infectious agents may respond to the host environment by producing stress proteins and that these proteins can be important immune targets. We postulate that abundant and highly conserved stress proteins may have "immunoprophylactic" potential for a broad spectrum of human pathogens.

Amino Acid Sequence↗
PubMed1986

Purification and properties of the groES morphogenetic protein of Escherichia coli.

The morphogenesis of lambda proheads is governed by the products of at least four bacteriophage-coded genes (B, C, E and Nu3) and two host-coded genes (groES (mopB) and groEL (mopA)). Earlier genetic experiments indicated that the phenotypes of some of the groES- mutations could be suppressed by mutations in the groEL gene, suggesting an interaction between the two groE proteins in vivo (Tilly, K., and Georgopoulos, C. P. (1982) J. Bacteriol. 149, 1082-1088). The Mr 15,000 groES protein was overproduced and purified to homogeneity by monitoring its presence after polyacrylamide gel electrophoresis. Both gel filtration on an AcA34 sizing column and glycerol gradient centrifugation indicate that the groES protein possesses an oligomeric structure of Mr 80,000. In agreement, electron microscopic pictures of the purified groES protein show that it possesses a symmetrical ring-like structure. The sequence of the first five amino acids and the overall composition of the purified protein match those predicted by the nucleotide sequence of the groES gene. The following results implicate a physical association between the groES and groEL proteins in vitro. The groES protein inhibits the weak ATPase activity of the groEL protein, with a maximal effect seen at a 1:1 molar ratio; the two proteins cosediment during glycerol gradient centrifugation in the presence of ATP and Mg2+; and the groES protein binds specifically to a groEL-affinity column. These results help explain why mutations in either of the groE genes exhibit similar phenotypes with respect to both lambda and bacterial growth.

Adenosine Triphosphatases↗
PubMed1982

The B66.0 protein of Escherichia coli is the product of the dnaK+ gene.

B66.0 is one of the most abundant proteins of Escherichia coli. Its relative rate of synthesis is highly regulated depending on temperature and the growth rate of the culture. We identified the B66.0 protein to be the dnaK+ structural gene product since dnaK756 mutant bacteria synthesized a B66.0 protein with a more acidic isoelectric point.

Bacterial Proteins↗