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Biomedical subjects

M Holman

Publications and source records attributed to M Holman.

At least 37 records · Page 2Linked to original sources
PubMed1994

Hypercross-linking surface IgM or IgD receptors on mature B cells induces apoptosis that is reversed by costimulation with IL-4 and anti-CD40.

Cross-linking of sIgM or sIgD receptors on mature B cells with appropriate anti-Ig Abs normally induces B cell activation and DNA synthesis. We show here that hypercross-linking of either class of sIg receptor on these cells by biotinylated, normally mitogenic anti-mu or anti-delta mAb by avidin rapidly induces unresponsiveness to heterologous anti-Ig, accompanied by DNA fragmentation characteristic of apoptosis. Apoptotic nuclei can be detected within 4 h after stimulation, but cells that survive for 12 to 16 h are abortively activated, as evidenced by increased levels of MHC class II Ags. Because the induction of B cell tolerance is known to be modulated by T cell-derived influences, we investigated the effects of two stimuli--IL-4 and ligation of CD40--that are known to affect B cell survival in this system. IL-4 partially reversed the induction of apoptosis, as did a mAb to CD40, and both reagents together caused almost complete reversal. We therefore conclude that in the absence of T cell help the extent of sIg receptor cross-linking on mature B cells determines whether the cells enter cycle or become deleted. We believe that this system represents a polyclonal model of clonal deletion of mature B cells induced by highly cross-linking Ags, such as type 2 T-independent polysaccharide Ags.

Animals↗
PubMed1994

Properties of mouse CD40: the role of homotypic adhesion in the activation of B cells via CD40.

Stimulation of human B cells via CD40 is known to induce their homotypic aggregation. We show here that anti-mouse CD40 monoclonal antibodies (mAb) also induce B cells to form large, spherical, extremely stable clusters. This clustering is markedly enhanced by co-stimulation with either interleukin-4 (IL-4) or anti-immunoglobulin (Ig). The aggregation is slow in onset, and is largely (but not completely) abrogated by anti-LFA-1 mAb, but not by mAb directed against other potentially important adhesion molecules on B cells. Anti-LFA-1 mAb also partially suppressed DNA synthesis induced by anti-CD40, but not by other B cell mitogens, suggesting that clustering is an important component of B cell activation via CD40. This concept is supported by analyses of the phenotype of clustered B cells: the cells within clusters express higher levels of various activation markers, and also more of them are in cell cycle than non-clustered cells. These results therefore suggest that CD40 stimulation may either induce B cells to secrete soluble factors which act in an autocrine way to promote B cell activation, or that clustering generates cell contact-mediated signals which are important in the activation cascade.

Animals↗
PubMed1994

Properties of mouse CD40. Ligation of CD40 activates B cells via a Ca(++)-dependent, FK506-sensitive pathway.

The immunosuppressive drugs cyclosporine A (CsA) and FK506 selectively abrogate Ca(++)-regulated activation pathways in both T cells and B cells. We show here that anti-CD40-induced murine B cell proliferation, in the presence or absence of interleukin-4 (IL-4) is, like the response to anti-immunoglobulin (Ig), abrogated by 1-5 ng/ml (concentration causing 50% inhibition ca. 1 nM) FK506. However, the effects of the drug on proliferative responses elicited by anti-Ig or anti-CD40 differ significantly: firstly, the response to anti-CD40 + IL-4 becomes completely FK506-resistant within 24 h, whilst that to anti-Ig remains sensitive significantly longer. Secondly, stimulating B cells concurrently via CD40, surface Ig (sIg) and IL-4 receptors invokes an FK506-resistant activation pathway. We previously reported that ligation of either sIg or CD40 receptors, in conjunction with IL-4, induces the transcription factor, nuclear factor of activated T cells (NF-AT) in B cells, via a CsA/FK506-sensitive pathway. However, NF-AT induction elicited by anti-Ig/anti-CD40/IL-4 is still FK506 sensitive, implying that the drug resistance of the response to these three stimuli involves additional components than NF-AT. These results indicate that CD40 activates murine B cells via a Ca(++)-dependent pathway. In agreement with this, anti-CD40 induces a modest increase in intracellular Ca++ levels in these cells, which appears to be largely due to Ca++ influx through the plasma membrane.

Animals↗
PubMed1994

Lack of compliance with influenza immunization for caretakers of neonatal intensive care unit patients.

BACKGROUND: Both the Centers for Disease Control and Prevention and the American Academy of Pediatrics have recommended influenza immunizations for neonatal intensive care unit staff. Compliance rates for influenza immunization among neonatal intensive care unit staff have not yet been reported. METHODS: To determine both the rates and the associated factors for compliance between 1990 and 1993 among neonatal intensive care unit nursing staff, interviews were conducted at three Hartford area hospitals by means of a structured questionnaire. RESULTS: Compliance rates at the three hospitals were 15% in 1990 to 1991, 20% in 1991 to 1992, and 17% in 1992 to 1993 (89% sampling of all nurses with direct patient care). Sixty-three percent were not immunized between 1991 and 1993, 26% were vaccinated once, 9% were vaccinated twice, and 2% were vaccinated three times within the 3-year period. Convictions regarding vaccine safety and effectiveness, concern about getting influenza, and awareness of national recommendations for annual influenza immunization were shown to be associated with vaccination compliance. Concern over exposing neonates, peer influence, pain from injection, and previous adverse reaction were not statistically significant factors differentiating compliers from noncompliers. CONCLUSIONS: There is a poor acceptance of the influenza vaccine among our neonatal intensive care unit nursing staff. Educational and research efforts directed toward influenza risks among neonates and vaccine safety and effectiveness, along with incentives to comply, may improve compliance rates.

Attitude of Health Personnel↗
PubMed1993

Causes of late graft loss after liver transplantation.

The causes of graft loss in liver transplant recipients with a graft functioning for more than 1 year post-transplant were analyzed. Of 500 liver transplants in 434 patients, 362 grafts were functioning for more than 1 year. After 1 year, 42 grafts were later lost (11.6%). Thirty-three grafts were lost by death and 9 retransplants were done with 8 patients. Of the grafts lost by death, 12 had no evidence of dysfunction. The actuarial 2- and 5-year graft survival in liver transplantation recipients with functioning grafts for more than 1 year was 91 and 83%, respectively. The graft loss rate was 3.4 times higher during the 2nd year post-transplant than during 2-5 years post-transplant. The most common causes of graft loss were chronic rejection (26.2%), recurrent hepatitis (23.8%), arterial thrombosis/stenosis (11.9%) and recurrent malignancy (9.5%). No graft was lost from acute rejection. There was no difference in timing of the graft lost between the different causes. The pretransplant diagnosis of hepatitis B, chronic rejection, and malignancy was associated with the highest frequency of late graft lost. In conclusion, long-term graft survival is good after liver transplantation in patients with a functioning graft for more than 1 year. The main causes of graft loss were chronic rejection and recurrent hepatitis. Prevention and treatment for these conditions may further improve the results after liver transplantation.

Adolescent↗
PubMed1992

The selection of portal aperture using interactively displayed Beam's Eye Sections.

Portal apertures are often defined by wax-pencil lines drawn on simulator films. The simulator-film images suffer degradation due to X ray absorption and scatter in tissues proximal to and distal to the intended target volume. We describe a method for avoiding the degradation by using a 3-D dataset to produce high-contrast section images with a user-defined orientation. The calculation of these Beam's Eye Section (BES) images requires a set of medium-to high-resolution transverse section data (the 3-D dataset), as well as a medium- to high-performance computer workstation. These CT-like section images, providing more contrast and detail than a projection (that is, a simulator or Digitally Reconstructed Radiograph [DRR]) image, should allow for more accurate selection of portal apertures. The BES image plane is oriented perpendicular to the central axis of a user-selected beam. Once the user has created a beam, the system allows the user to step along that beam with a new BES image produced at each step. Contours manually drawn on these BES images are ultimately projected onto a DRR image. The outermost segments of these sometimes crisscrossing contours (the union of all projected areas) accurately defines the portal aperture needed to encompass the target at all levels.

Computer Simulation↗
PubMed1992

Noninvasive imaging of a retrocardiac spleen. Unusual component of paraesophageal diaphragmatic hernia.

The findings on chest roentgenograms, cardiac ultrasound, computed tomography (CT), and radionuclide liver-spleen scan are described in a 54-year-old man with a paraesophageal diaphragmatic hernia. The CT revealed the spleen as a solid mass with a notched border adjacent to the intrathoracic retrocardiac stomach. The radionuclide scan showed splenic uptake above the diaphragm. The diagnosis in this case, which, to our knowledge, is the first such reported case, was confirmed at surgery.

Esophagus↗
PubMed1990

In vivo 5-HIAA release from the anterior hypothalamus in the ovariectomized and estradiol treated rat following perfusion with progesterone.

In the present study the frequency and magnitude of the release of 5-Hydroxyindoleacetic Acid (5-HIAA) was measured from the anterior hypothalamus of ovariectomized (OVX) and OVX rats treated with estradiol (E2). Female, Holtzman strain rats were maintained on a photoperiod of 14 H light from 0100 to 1500 H and experiments performed from 0900 to 1700 H. Animals exhibiting four-day estrous cycles (250-300 gms) were OVX (20 days recovery) and a push-pull-cannula (PPC) implanted and stereotaxically aimed at the SCN region in the anterior hypothalamus. Following a 7-10 day recovery push-pull-perfusion (PPP) experiments were performed on either OVX females or on OVX females in which a silastic E2 implant (150 micrograms E2/ml. sesame oil), was placed sc 48 H prior to PPP. In other experiments progesterone (P4) was perfused in a pulsatile manner over the SCN region of the anterior hypothalamus. The overall average 5-HIAA release in the OVX treated rats (548 +/- 358 pg/10 min.) was similar to that in the OVX E2 group (694 +/- 148 pg/10 min). The average period of 5-HIAA release was (48.2 +/- 5.5 min) in the OVX group and (56.0 +/- 9.8 min) in the OVX E2 group. These results indicate that exposure of long term OVX rats (20 days) to E2 has no effect on the release or period of 5-HIAA release from serotonergic terminals concentrated in the SCN of the anterior hypothalamus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Activation and proliferation signals in mouse B cells. IX. Protein kinase C activators synergize with non-mitogenic anti-immunoglobulin antibodies to drive B cells into G1.

Intact (IgG) rabbit anti-Ig antibodies, unlike F(ab')2 fragments, do not induce DNA synthesis in murine B cells. The F(ab')2 antibodies induce prolonged breakdown of phosphatidylinositol bisphosphate, and hence activation of protein kinase C (PKC) in B cells, whilst the non-mitogenic antibodies stimulate an abortive response. In order to investigate the role of PKC in B-cell activation, the cells were cultured with combinations of F(ab')2 or intact anti-Ig together with the PKC-activating phorbol esters PDB or PMA. Both these agents synergized with intact anti-Ig to drive resting B cells into the G1 phase of the cell cycle. This is in line with the concept that intact anti-Ig does not induce substantial cell cycle progression in B cells because it fails to cause sufficient activation of PKC. The Ca2+ signal generated by this ligand is apparently sufficient to synergize with PKC activation by phorbol esters to induce B cells to progress into G1. However, the combination of phorbol esters with either form of anti-Ig failed to stimulate B cells to synthesize DNA. This probably reflects the capacity of these agents to inhibit DNA synthesis stimulated by F(ab')2 anti-Ig.

Animals↗
PubMed1988

Central venous blood oxygen saturation: an early, accurate measurement of volume during hemorrhage.

Accurate and relatively simple monitoring is essential in managing patients with multiple injuries, and becomes particularly important when there is substantial occult blood loss. Tachycardia, said to occur following a 15% blood loss, is generally regarded as the first reliable sign of hemorrhage. However, heart rate is a nonspecific parameter which is affected by factors other than changing intravascular volume. The purpose of this study was to evaluate available means of monitoring volume status and to identify the parameter which is the earliest and most reliable indication of blood loss. Sixteen mongrel dogs were anesthetized and bled by increments of 3% of their total blood volume until the onset of sustained hypotension or a 25% blood loss. All dogs were monitored with a Swan-Ganz catheter and an arterial line. Vital signs, full hemodynamic parameters, and arterial and mixed venous blood gases were measured after each 3% blood loss. Statistical analysis of the data demonstrated that only Cardiac Index and Mixed Venous Oxygen Saturation showed linearity as function of measure blood loss. Linear regression analysis generated r values that ranged from 0.85-0.99 with a mean of 0.95 for Mixed Venous Oxygen Saturation; r values for Cardiac Index ranged from 0.39-0.98 with a mean of 0.85. Furthermore, all dogs had increased tissue oxygen extraction after 3-6% blood loss. Because Central Venous Blood Oxygen Saturation mirrors Mixed Venous Oxygen Saturation and is easily and rapidly measured, we extended our study by repeating all of the previously measured parameters, with the addition of CVP blood gases in an unanesthetized animal model.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Selective effects of cholera toxin on the activation of mouse B cells by different polyclonal activators.

Murine B cells were stimulated in vitro with anti-immunoglobulin (Ig) antibodies, lipopolysaccharide, or with various combinations of phorbol dibutyrate and ionomycin. Very low concentrations (ca. 10(-14) M) of cholera toxin inhibited anti-Ig-stimulated DNA synthesis, while the response to LPS was only abrogated by 2 X 10(4)-10(5)-fold greater concentrations of the toxin. Earlier responses in anti-Ig-stimulated B cells, such as increases in Ia antigen levels, were not affected by the toxin. Protein kinase C-activating phorbol esters, together with Ca2+ ionophores, are believed to stimulate DNA synthesis in lymphocytes by mimicking the two second messengers resulting from ligation of the antigen receptors. However, concentrations of cholera toxin which totally abolish anti-Ig-induced B cell proliferation significantly enhanced DNA and RNA synthesis induced by phorbol dibutyrate plus ionomycin. The results are discussed in terms of possible effects of cholera toxin on guanine nucleotide-binding (G) proteins controlling receptor coupling to second messenger-generating systems in B cells.

Animals↗
PubMed1987

B-cell-stimulatory factor 1 reverses Fc receptor-mediated inhibition of B-lymphocyte activation.

Intact (IgG class) rabbit anti-immunoglobulin antibodies are not mitogenic for mouse B cells but inhibit proliferation induced by F(ab')2 anti-Fab fragment antibodies (anti-Ig). In addition, cross-linkage of Fc and surface immunoglobulin receptors on B cells by intact anti-Ig inhibits inositol phospholipid breakdown (but not Ca2+ flux) resulting from ligation of antigen receptors. This system, therefore, provides a polyclonal model for B-cell inactivation by antigen-antibody complexes. T-cell-derived B-cell-stimulatory factor 1 acts synergistically with submitogenic concentrations of F(ab')2 anti-Ig to induce B-cell proliferation. We show here that B-cell-stimulatory factor 1 and intact anti-Ig also induce B cells to synthesize DNA. However, B-cell-stimulatory factor 1 does not induce inositol phospholipid breakdown, does not mobilize Ca2+ in B cells, nor does it influence the magnitude of these responses provoked by intact anti-Ig.

Animals↗
PubMed1986

Effects of cyclosporine on responses of murine B cells to T cell-derived lymphokines.

Cyclosporine (CS) inhibits the stimulation of both T and B lymphocytes by certain agents, but not by others. Here we have studied the effects of the drug on the responses of murine B cells to T cell-derived B cell growth and differentiation factors. We show that activation of resting B cells by B cell-stimulatory factor-1 (BSF-1) is resistant to CS, whereas stimulation by anti-Ig antibodies is not, which is in agreement with earlier findings. Furthermore, B cell proliferation elicited by co-stimulation with anti-Ig plus BSF-1 remains drug susceptible. In contrast, the stimulation of large (presumably preactivated) B cells by B cell growth factor II to synthesize DNA or to secrete Ig is inhibited by low concentrations of CS. These results therefore contrast with earlier findings with human B cells, and with those using T cells from various species, which showed that the responses of preactivated cells to growth factors are resistant to the drug. It thus appears that in the mouse CS can affect all stages of B cell stimulation.

Animals↗