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M Holman

Publications and source records attributed to M Holman.

At least 19 recordsLinked to original sources
PubMed1999

The origin of chaos in the outer solar system

Classical analytic theories of the solar system indicate that it is stable, but numerical integrations suggest that it is chaotic. This disagreement is resolved by a new analytic theory. The theory shows that the chaos among the jovian planets results from the overlap of the components of a mean motion resonance among Jupiter, Saturn, and Uranus, and provides rough estimates of the Lyapunov time (10(7) years) and the dynamical lifetime of Uranus (10(18) years). The jovian planets must have entered the resonance after all the gas and most of the planetesimals in the protoplanetary disk were removed.

Journal Article↗
PubMed1999

Anti-CD40 antibody enhances responses to polysaccharide without mimicking T cell help.

Protection against infection with encapsulated bacteria is mediated by IgG antibodies against the capsular polysaccharides. Production of such antibodies is impaired during infancy, when susceptibility to bacterial meningitis is greatest. Recent studies have proposed the use of anti-CD40 antibody to increase responsivenesses to polysaccharide antigens. We show here that the IgG response to a model polysaccharide antigen is greatly increased, but retains thymus-independent characteristics--switching continues to be mainly to IgG3 and neither germinal centers nor memory B cells are formed. Furthermore, anti-CD40 causes striking splenomegaly in mice, which is accompanied by dramatic cellular redistribution and proliferation of dendritic cells, macrophages, T cells and endothelium, as well as B cells. These findings raise the possibility that the anti-CD40 effect is due mainly to increased activity of accessory cells that affect plasmablast growth and differentiation rather than mimicry of T cell help.

Animals↗
PubMed1999

Interaction of B cells with activated T cells reduces the threshold for CD40-mediated B cell activation.

CD154-CD40 interactions are of central importance for the induction of antibody responses to T-dependent antigens. Since most anti-CD40 mAb are only weak B cell mitogens, it is believed that under physiological conditions, signals through CD40 synergize with those from other receptors on B cells to induce B cell activation. We show here that the interaction of either normal B cells, or those from CBA/N (xid) mice, with CD3-activated primary T cells in whole spleen cell cultures markedly reduces the threshold for B cell activation via CD40. Hence, these pre-activated cells undergo vigorous proliferation when stimulated with either optimal or suboptimal concentrations of weakly mitogenic anti-CD40 mAb, or with soluble CD40 ligand. Blocking experiments indicate that the establishment of this priming effect requires stimulation via CD40 itself, plus T cell-derived IL-2. In support of this concept, only CD3/CD28-pre-activated, but not CD3-pre-activated T cells induce this effect, unless the co-cultures of B cells with the latter T cells are supplemented with IL-2. Although B cells activated in this fashion do express higher levels of CD40 than naive cells, we believe that this is insufficient to explain the observed dramatic effects on their proliferative capacity. Rather we propose that T cell-dependent B cell activation induces fundamental changes in the signalling machinery invoked by ligation of CD40. It is likely that this amplification loop could play an important role during the initiation of antibody responses to T-dependent antigens, when activated CD4 T cells only express low levels of CD154.

Animals↗
PubMed1998

Evidence for a critical role for IL-2 in CD40-mediated activation of naive B cells by primary CD4 T cells.

The interaction of CD40 on B cells with the CD40 ligand (CD40L) on preactivated CD4 T cells is critical for the initiation of T-dependent Ab responses. It is believed that signals via CD40 synergize with cytokines (e.g., IL-4 and IL-5) to drive B cell activation. However, primary T cells preactivated via CD3 alone cannot induce B cell proliferation; we have shown previously that costimulation of T cells via CD3 and CD28 stabilizes the expression of the CD40L, which we propose contributes to their capacity to act as competent helper-effector cells. Here we show that an additional, critical reason why CD3-stimulated CD40L-bearing T cells are incompetent helper cells is because they secrete insufficient IL-2. In contrast, CD28/CD3-activated T cells induce B cells to become IL-2 responsive via a combination of CD40L and IL-2-mediated signals, and these two stimuli subsequently drive B cell proliferation and IgM secretion. We therefore propose that T cells must first encounter Ag in conjunction with CD80/86 on APCs. This leads to the stable expression of CD40L and maximal secretion of IL-2, which together render primary T cells competent to activate B cells in an IL-2-dependent fashion.

Animals↗
PubMed1998

Migrating planets

A planet orbiting in a disk of planetesimals can experience an instability in which it migrates to smaller orbital radii. Resonant interactions between the planet and planetesimals remove angular momentum from the planetesimals, increasing their eccentricities. Subsequently, the planetesimals either collide with or are ejected by the planet, reducing the semimajor axis of the planet. If the surface density of the planetesimals exceeds a critical value, corresponding to approximately 0.03 solar mass of gas inside the orbit of Jupiter, the planet will migrate inward a large distance. This instability may explain the presence of Jupiter-mass objects in small orbits around nearby stars.

Journal Article↗
PubMed1998

Gestational age can predict the need for prophylaxis with surfactant therapy.

Controversy exists as to whether prophylactic or rescue therapy with surfactant should be used in infants born at less than 30 weeks gestation. We developed the hypothesis that gestational age can be used to predict a need for prophylactic surfactant therapy. We designed this retrospective study to determine whether there was a gestational age below which one could accurately predict the need for prophylactic surfactant therapy in almost all infants and limit unnecessary treatment of infants. We conducted a retrospective study of infants born at 23-34 weeks' gestation to determine the frequency with which surfactant therapy was used in a rescue strategy at each gestational age, and to ascertain the sensitivity, specificity, and predictive values of gestational age as a predictor of the use of surfactant therapy. There was a significant inverse correlation between gestational age and the proportion of infants treated with surfactant (r = -0.923, p < 0.001). A gestational age cut-off of 26 completed weeks' had a positive predictive value of 85% and a specificity of 96% for the need for surfactant therapy. We conclude that gestational age can be used to predict a need for surfactant therapy in premature infants. At our institution, the failure to attain 26 completed weeks' gestation will accurately predict the need for surfactant therapy and will result in unnecessary treatment of very few infants. We suggest that each institution caring for very low birth weight infants should examine its population to determine the gestational age at which they can accurately predict the need for prophylaxis with surfactant therapy.

Gestational Age↗
PubMed1998

Further evidence for allergic pathophysiology in allergic fungal sinusitis.

Controversy continues over whether allergic fungal sinusitis represents a true allergy, an infection, or a point somewhere along a spectrum between allergy and infection. The present study describes two experiments that add weight to the argument that allergic fungal sinusitis (AFS) is truly an immunologically mediated hypersensitivity and not a form of infection. In the first experiment, eight patients with Bipolaris culture-positive AFS were prospectively evaluated with Bipolaris antigen skin testing and with inhibition radioallergosorbent (RAST) and enzyme-linked immunosorbent assay (ELISA) for Bipolaris-specific IgE and IgG antibodies. The Bipolaris AFS cases were compared with 10 control patients with no history of AFS. All eight AFS cases demonstrated positive skin testing to Bipolaris and in addition, all tested positive by RAST and ELISA for IgE and IgG Bipolaris antibodies, respectively. In the control group one patient had a positive skin test, ELISA, and RAST and one additional patient had a positive ELISA only. Good correlation was noted between skin test, RAST, and ELISA results. In the second experiment, sinus mucosa from 14 AFS patients and 10 control patients with other forms of surgical sinus disease was analyzed by immunohistocytochemistry for the eosinophilic inflammatory mediators major basic protein (MBP) and eosinophil derived neurotoxin (EDN) and the neutrophil mediator neutrophil elastase. All AFS cases demonstrated evidence of eosinophilic mediator release, and MBP and EDN predominated over neutrophil elastase. In the control group eosinophil and neutrophil mediator release in sinus mucosa was equal. The two experiments support the concept that AFS is an antigen-triggered, IgE- and IgG-mediated hypersensitivity response with a late-phase inflammatory reaction involving release of eosinophilic mediators.

Adolescent↗
PubMed1997

The effects of IFN-gamma on CD40-mediated activation of B cells from X-linked immunodeficient or normal mice.

B cell activation induced by cross-linking of CD40 is enhanced by costimulation with certain T cell-derived cytokines (generally Th2 type), most notably IL-4. We show here that the induction of DNA synthesis in normal mouse B cells by anti-CD40 mAb is also significantly enhanced by supernatants from anti-CD3-activated Th1 cells or from primary T cells. In both instances the costimulatory activity is specifically abrogated by neutralizing Abs against IFN-gamma. B cells from CBA/N immunodeficient (xid) mice are markedly hyporesponsive to most anti-CD40 Abs, even in the presence of IL-4. These cells do, however, synthesize DNA when stimulated by anti-CD40 plus supernatants from anti-CD3-stimulated primary T cells, by anti-CD40 plus IFN-gamma (but not IL-4), or by fixed, activated Th1 T cells. In all these instances, the mitogenic response of xid B cells is crucially dependent on the presence of IFN-gamma. This cytokine also enhanced CD40-induced homotypic adhesion of normal and xid B cells and potentiated CD40-mediated protection of B cells from spontaneous apoptosis. These data, therefore, indicate that IFN-gamma plays an essential role in the activation of B cells by Th1 T cells and by naive T cells during the initiation of primary Ab responses. The results with CBA/N B cells further suggest that the xid mutation selectively affects their capacity to respond to Th2-derived signals, for reasons that remain unclear.

Adjuvants, Immunologic↗
PubMed1997

A re-evaluation of the effects of X-linked immunodeficiency (xid) mutation on B cell differentiation and function in the mouse.

CBA/N (xid) mice have a point mutation in Bruton's tyrosine kinase (btk), which results in their failure to respond to T-independent type 2 (TI-2) antigens, and to several B cell mitogens [most notably anti-immunoglobulin (Ig)] in vitro. They have reduced numbers of peripheral (B2) B cells, which are regarded as being phenotypically and functionally immature. We show here that adult CBA/N mice in fact have two distinct B cell populations: some 60% of the cells are CD23+ HSAlo sIgDhi and hence resemble recirculating, follicular (RF) B cells from normal mice, except that they are sIgMhi. The remaining 40% of xid B cells are CD23- HSAhi sIgD-/lo and resemble immature transitional (TR) B cells. TR B cells from xid mice do not synthesize DNA when cultured with lipopolysaccharide (LPS), whereas those from normal mice do so. Only the RF cells from either xid or normal mice proliferate in response to ligation of CD40. In neonatal normal mice the emergence of mitogen responsiveness followed the chronological sequence LPS-->anti-CD40-->anti-Ig approximately anti-CD38. The same developmental sequence was seen with B cells from xid mice (for LPS and anti-CD40), but it occurred at a significantly slower tempo and this correlated with the later appearance of RF-type cells. TR xid B cells express very low levels of bcl-2 and we conclude that these cells resemble very immature (bone marrow) B cells, rather than normal transitional cells. We, therefore, propose that the xid mutation imposes a multistage brake on B cell differentiation in the mouse. The available data suggest that btk is required for the positive selection of B cells throughout their differentiation in the periphery. This in turn implies that low level signaling via surface Ig is needed throughout this process in order for peripheral B cells to become functionally mature.

Animals↗
PubMed1996

Adverse effect of donor vasopressor support on immediate and one-year kidney allograft function.

BACKGROUND: This purpose of this study was to determine if there was a significant difference between the rates of acute tubular necrosis (ATN) and long-term graft survival in renal allografts procured from donors requiring inotropic support (DRIS) and those from donors not requiring inotropic support. METHODS: Eighty-two consecutive cadaveric renal transplant patients were prospectively followed in our local procurement area, the Delaware Valley Transplant Program. Forty-eight patients received organs from DRIS (> 10 mcg/kg per minute of dopamine, dobutamine, epinephrine, and norepinephrine alone or in combination), and 34 did not. RESULTS: Allografts from the non-DRIS group had an immediate function rate of 82.4% and a 1-year function rate of 91.2%. In comparison, the DRIS grafts had an immediate function rate of 58.3% and a 1-year function rate of 72.9%. These differences were statistically significant. The mean serum creatinine in the non-DRIS group was 1.46 +/- 0.58 mg/dl, whereas in the DRIS cohort it was 1.89 +/- 0.93 mg/dl. CONCLUSIONS: Kidneys transplanted from DRIS had significantly (1) poorer immediate function, (2) worse 1-year survival rates, and (3) higher serum creatinine at 1 year. We conclude that recipients receiving organs from donors requiring inotropic support are at a higher risk of developing ATN after surgery and experience reduced 1-year function.

Adolescent↗
PubMed1996

Unilobar intrahepatic lithiasis 22 years after cholecystectomy.

Complaints of right upper quadrant pain, jaundice, and fever in the postcholecystectomy patient provide the physician with a challenging diagnosis. This case concerns a patient with intrahepatic lithiasis and fibrotic atrophy of the right lobe 22 years after open cholecystectomy.

Bile Ducts, Intrahepatic↗
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↗