Biomedical subjects

A Sher

Publications and source records attributed to A Sher.

At least 19 recordsLinked to original sources

PubMed2006

Sepsis-induced organ failure is mediated by different pathways in the kidney and liver: acute renal failure is dependent on MyD88 but not renal cell apoptosis.

Toll-like receptors (TLRs) are important in sepsis. Myeloid differentiation factor 88 (MyD88) is a key molecule involved in signal transduction by multiple TLRs. The objective of this study was to investigate the contribution of TLR4 and MyD88 to acute renal failure (ARF) induced by polymicrobial sepsis. Liver dysfunction and apoptosis in the spleen contribute to sepsis severity after cecal ligation and puncture (CLP). Therefore, we also investigated liver injury and splenic apoptosis. We used a mouse model of sepsis-induced ARF using CLP to generate polymicrobial sepsis. Despite fluid and antibiotic resuscitation the mice developed multi-organ failure, including ARF, which resembles human sepsis. We investigated the role of the TLR4 receptor by comparing C3H/HeJ mice (which lack TLR4) with C3H/He0UJ normal controls. The role of MyD88 was investigated by comparing MyD88 knockout mice (MyD88(-/-)) with wild-type controls. Following CLP, mice lacking TLR4 and wild-type mice both developed comparable ARF. However, MyD88(-/-) mice did not develop ARF compared to wild-type controls. In contrast, MyD88(-/-) mice developed liver injury comparable to wild type. After CLP, MyD88(-/-) mice had significantly reduced apoptosis in the spleen compared with wild type. Apoptosis was not detected in the kidney of wild-type or MyD88(-/-) mice after CLP. In summary, ARF induced by polymicrobial sepsis is dependent on MyD88, but not TLR4. The absence of MyD88 dissociates ARF from liver injury; liver injury is MyD88-independent. There was MyD88-dependent apoptosis in the spleen, but no apoptosis in the kidney. MyD88 may be a good drug target for some, but not all, organ dysfunctions following sepsis.

Acute Kidney Injury↗

PubMed2004

Fidelity of the ensemble code for visual motion in primate retina.

Sensory experience typically depends on the ensemble activity of hundreds or thousands of neurons, but little is known about how populations of neurons faithfully encode behaviorally important sensory information. We examined how precisely speed of movement is encoded in the population activity of magnocellular-projecting parasol retinal ganglion cells (RGCs) in macaque monkey retina. Multi-electrode recordings were used to measure the activity of approximately 100 parasol RGCs simultaneously in isolated retinas stimulated with moving bars. To examine how faithfully the retina signals motion, stimulus speed was estimated directly from recorded RGC responses using an optimized algorithm that resembles models of motion sensing in the brain. RGC population activity encoded speed with a precision of approximately 1%. The elementary motion signal was conveyed in approximately 10 ms, comparable to the interspike interval. Temporal structure in spike trains provided more precise speed estimates than time-varying firing rates. Correlated activity between RGCs had little effect on speed estimates. The spatial dispersion of RGC receptive fields along the axis of motion influenced speed estimates more strongly than along the orthogonal direction, as predicted by a simple model based on RGC response time variability and optimal pooling. on and off cells encoded speed with similar and statistically independent variability. Simulation of downstream speed estimation using populations of speed-tuned units showed that peak (winner take all) readout provided more precise speed estimates than centroid (vector average) readout. These findings reveal how faithfully the retinal population code conveys information about stimulus speed and the consequences for motion sensing in the brain.

Action Potentials↗

PubMed2003

High statistics measurement of the K+-->pi0e+nu (K+e3) branching ratio.

E865 at the Brookhaven National Laboratory AGS collected about 70 000 K(+)(e3) events to measure the K(+)(e3) branching ratio relative to the observed K+-->pi(+)pi(0), K+-->pi(0)micro(+)nu, and K+-->pi(+)pi(0)pi(0) decays. The pi(0) in all the decays was detected using the e(+)e(-) pair from pi(0)-->e(+)e(-)gamma decay and no photons were required. Using the 2002 Particle Data Group branching ratios for the normalization decays, we obtain BR(K(+)(e3(gamma)))=(5.13+/-0.02(stat)+/-0.09(syst)+/-0.04(norm))%, where K(+)(e3(gamma)) includes the effect of virtual and real photons. This result is approximately 2.3sigma higher than the current Particle Data Group value. Implications for the V(us) element of the CKM matrix, and the matrix's unitarity are discussed.

Journal Article↗

PubMed2002

Experimental study of the radiative decays K+-->mu(+)nue(+)e(-) and K+-->e(+)nue(+)e(-).

Experiment 865 at the Brookhaven Alternating Gradient Synchrotron obtained 410 K+-->e(+)nue(+)e(-) and 2679 K+-->mu(+)nue(+)e(-) events including 10% and 19% background. The branching ratios were measured to be [2.48+/-0.14(stat)+/-0.14(syst)]x10(-8) (m(ee)>150 MeV) and (7.06+/-0.16+/-0.26)x10(-8) (m(ee)>145 MeV), respectively. Results for the decay form factors are presented.

Journal Article↗

PubMed2002

Positive and negative regulation of pathogen induced dendritic cell function by G-protein coupled receptors.

The induction of IL-12 from dendritic cells (DC) is a major initiating step in host resistance to intracellular pathogens. We have studied the regulation of this response using an in vivo model in which IL-12 production by splenic CD8alpha+ DC is followed after injection of a soluble extract (STAg) of the protozoan parasite Toxoplasma gondii. Our findings indicate that the potent IL-12 response observed is highly dependent on both the chemokine receptor CCR5 and G(i)-protein coupled signaling. In addition, we have examined the basis of the unresponsiveness of DC to secondary STAg injection which occurs following primary exposure to this parasite stimulus. Our results demonstrate that this refractory state correlates with the down-regulation of CCR5 expression on DC which, in turn, appears to depend on the induction of endogenous lipoxin A(4) (LXA(4)), a product of arachidonic acid metabolism. Since LXA(4) is known to also signal through a G-protein coupled receptor pathway, these findings taken together support a major role for G-protein signaling in the regulation of microbial-induced DC function.

Animals↗

PubMed2002

Drug-resistant Plasmodium falciparum infection in immigrants and non-immune travellers.

OBJECTIVE: To detect the incidence of drug-resistant Plasmodium falciparum malaria infection in immigrants and travellers in non-endemic Kuwait. METHODS: Over a period of 3 years, July 1995 to September 1998, 1352 malaria patients were enrolled in the study. Of these, 1293 were immigrants from countries where malaria is endemic and 59 were non-immune travellers with a recent history of travel to these countries. The in vitro drug sensitivity was determined in 892 patients. RESULTS: In all, 892 of 1352 (66.0%) P. falciparum isolates were successfully cultured in vitro for drug sensitivity and 419 (47.0%) isolates showed in vitro resistance to chloroquine or mefloquine. Fifty-six (13.4%) isolates were resistant to both drugs. Chloroquine resistance was observed in > 70% of the isolates from Africa and India followed by Pakistan (39.9%) and Bangladesh (35.9%). The resistance to mefloquine ranged from 26.2% in isolates from Sri Lanka to 47.5% in isolates from African countries. CONCLUSION: The study highlights the important trend in drug resistance in P. falciparum malaria in immigrants from south-east Asian and African countries.

Adult↗

PubMed2001

T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells.

Differentiation of naive CD4(+) T cells into IFN-gamma-producing T helper 1 (T(H)1) cells is pivotal for protective immune responses against intracellular pathogens. T-bet, a recently discovered member of the T-box transcription factor family, has been reported to play a critical role in this process, promoting IFN-gamma production. Although terminal T(H)1 differentiation occurs over days, we now show that challenge of mice with a prototypical T(H)1-inducing stimulus, Toxoplasma gondii soluble extract, rapidly induced IFN-gamma and T-bet; T-bet induction was substantially lower in IFN-gamma-deficient mice. Naive T cells expressed little T-bet, but this transcription factor was induced markedly by the combination of IFN-gamma and cognate antigen. Human myeloid antigen-presenting cells showed T-bet induction after IFN-gamma stimulation alone, and this induction was antagonized by IL-4 and granulocyte/macrophage colony-stimulating factor. Although T-bet was induced rapidly and directly by IFN-gamma, it was not induced by IFN-alpha, lipopolysaccharide, or IL-1, indicating that this action of IFN-gamma was specific. Moreover, T-bet induction was dependent on Stat1 but not Stat4. These data argue for a model in which IFN-gamma gene regulation involves an autocrine loop, whereby the cytokine regulates a transcription factor that promotes its own production. These findings substantially alter the current view of T-bet in IFN-gamma regulation and promotion of cell-mediated immune responses.

Animals↗

PubMed2001

Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity.

Lipoxins are eicosanoid mediators that show potent inhibitory effects on the acute inflammatory process. We show here that the induction of lipoxin A(4) (LXA(4)) accompanied the in vivo suppression of interleukin 12 (IL-12) responsiveness of murine splenic dendritic cells (DCs) after microbial stimulation with an extract of Toxoplasma gondii. This paralysis of DC function could not be triggered in mice that were deficient in a key lipoxygenase involved in LXA(4) biosynthesis. In addition, DCs pre-treated with LXA(4) became refractory to microbial stimulation for IL-12 production in vitro and mice injected with a stable LXA(4) analog showed reduced splenic DC mobilization and IL-12 responses in vivo. Together, these findings indicate that the induction of lipoxins in response to microbial stimulation can provide a potent mechanism for regulating DC function during the innate response to pathogens.

Animals↗

PubMed2001

New measurement of K(+)(e4) decay and the s-pave pi pi-scattering length a(0)(0).

A sample of 4 x 10(5) events from the decay K(+)-->pi(+)pi(-)e(+)nu(e) (K(e4)) has been collected in experiment E865 at the Brookhaven Alternating Gradient Synchrotron. The analysis of these data yields new measurements of the K(e4) branching ratio [(4.11+/-0.01+/-0.11) x 10(-5)], the s-wave pi pi scattering length [a(0)(0) = 0.216+/-0.013(stat)+/-0.004(syst)+/-0.005(theor)], and the form factors F, G, and H of the hadronic current and their dependence on the invariant pi pi mass.

Journal Article↗

PubMed2001

Inactivation of LRG-47 and IRG-47 reveals a family of interferon gamma-inducible genes with essential, pathogen-specific roles in resistance to infection.

The cytokine interferon (IFN)-gamma regulates immune clearance of parasitic, bacterial, and viral infections; however, the underlying mechanisms are poorly understood. Recently, a family of IFN-gamma-induced genes has been identified that encode 48-kD GTP-binding proteins that localize to the endoplasmic reticulum of cells. The prototype of this family, IGTP, has been shown to be required for host defense against acute infections with the protozoan parasite Toxoplasma gondii, but not for normal clearance of the bacterium Listeria monocytogenes and murine cytomegalovirus (MCMV). To determine whether other members of the gene family also play important roles in immune defense, we generated mice that lacked expression of the genes LRG-47 and IRG-47, and examined their responses to representative pathogens. After infection with T. gondii, LRG-47-deficient mice succumbed uniformly and rapidly during the acute phase of the infection; in contrast, IRG-47-deficient mice displayed only partially decreased resistance that was not manifested until the chronic phase. After infection with L. monocytogenes, LRG-47-deficient mice exhibited a profound loss of resistance, whereas IRG-47-deficient mice exhibited completely normal resistance. In addition, both strains displayed normal clearance of MCMV. Thus, LRG-47 and IRG-47 have vital, but distinct roles in immune defense against protozoan and bacterial infections.

Amino Acid Sequence↗

PubMed2001

Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP.

We have introduced a targeted mutation in SH2D1A/DSHP/SAP, the gene responsible for the human genetic disorder X-linked lymphoproliferative disease (XLP). SLAM-associated protein (SAP)-deficient mice had normal lymphocyte development, but on challenge with infectious agents, recapitulated features of XLP. Infection of SAP- mice with lymphocyte choriomeningitis virus (LCMV) or Toxoplasma gondii was associated with increased T cell activation and IFN-gamma production, as well as a reduction of Ig-secreting cells. Anti-CD3-stimulated splenocytes from uninfected SAP- mice produced increased IFN-gamma and decreased IL-4, findings supported by decreased serum IgE levels in vivo. The Th1 skewing of these animals suggests that cytokine misregulation may contribute to phenotypes associated with mutation of SH2D1A/SAP.

Amino Acid Sequence↗

PubMed2001

A human immunodeficiency virus-transgenic mouse model for assessing interventions that block microbial-induced proviral expression.

A human immunodeficiency virus (HIV) type 1-transgenic mouse line (166) that previously showed up-regulated expression of viral proteins and infectious particles after infection with pathogenic agents was tested as a model for screening the in vitro and in vivo efficacy of inhibitors of HIV-1 immune activation. Two types of interventions were assessed: use of either the immunosuppressive drug prednisolone or an HIV-1 envelope-targeted toxin (sCD4-PE40). Both agents inhibited lipopolysaccharide-induced p24 expression by splenocytes in vitro and, when administered to transgenic mice, suppressed the induction of plasma p24, as well as the ex vivo production of p24 and infectious virus stimulated by in vivo infection with Mycobacterium avium. Moreover, HIV-1 mRNA levels in the spleen were greatly reduced in mice treated with either agent. Because HIV-1 expression cannot be induced in T lymphocytes from line 166 mice, this model may be of particular advantage for testing interventions that target virus production by non-T cell virus reservoirs.

Animals↗

PubMed2001

A heritable defect in IL-12 signaling in B10.Q/J mice. I. In vitro analysis.

B10.Q mice are normally susceptible to the induction of collagen-induced arthritis. We noted that one subline of B10.Q mice, B10.Q/J, was completely resistant to disease induction when immunized with collagen in CFA. B10.Q/J mice have a global defect in the generation of Th1 responses, and Ag-specific T cells derived from this strain failed to produce IFN-gamma. Because T cells from these mice could produce normal amounts of IFN-gamma when activated by IL-12/IL-18-independent stimuli, the defect appeared to be a failure to respond to IL-12. This defect extended to NK cells, which also failed to produce IFN-gamma when stimulated by IL-12. The capacity of NK cells, but not activated T cells, to produce IFN-gamma in response to IL-12 could be partially restored by IL-18. The expression of the IL-12R beta1- and beta2-chains on T cells and NK cells from B10.Q/J mice was normal. However, activated T cells from B10.Q/J mice did not signal normally through the IL-12R and manifested a defect in their capacity to phosphorylate Stat4. This defect was partial in that it could be overcome by increasing both the concentration of IL-12 and the incubation times in the Stat4 phosphorylation assays. Because Stat4 function is apparently intact in B10.Q/J mice, the defect in IL-12 signaling can be localized between the IL-12R complex and Stat4. This subtle abnormality in IL-12 responsiveness results in a profound defect in the generation of Th1 cells and the development of autoimmune disease.

Animals↗

PubMed2001

A heritable defect in IL-12 signaling in B10.Q/J mice. II. Effect on acute resistance to Toxoplasma gondii and rescue by IL-18 treatment.

This study documents a defect in IL-12-dependent IFN-gamma responses in a substrain (B10.Q-H2-(q)/SgJ) of B10.Q mice that manifests as an acute susceptibility to infection by the intracellular protozoan pathogen, Toxoplasma gondii. Despite robust systemic production of IL-12, infected B10.Q/J animals fail to mount an early IFN-gamma response after parasite inoculation. Genetic experiments revealed that the host resistance and IFN-gamma production defects are determined by a single autosomal recessive locus distinct from the Stat4 gene. Nonetheless, a delayed IL-12-mediated IFN-gamma response emerges in later stages of acute infection but is unable to prevent host mortality. IL-18 administration restores, in an IL-12-dependent manner, the early IFN-gamma response and host resistance of B10.Q/J animals. These in vivo studies indicate that the partially impaired IL-12 responsiveness in B10.Q/J mice can result in defective host resistance and demonstrate a therapeutic function for IL-18 in reversing a genetically based immunodeficiency in IL-12-dependent IFN-gamma production.

Acute Disease↗

PubMed2001

Malaria infection induces virus expression in human immunodeficiency virus transgenic mice by CD4 T cell-dependent immune activation.

To test the capacity of malaria parasites to trigger virus expression in vivo, human immunodeficiency virus (HIV) transgenic mice were infected with Plasmodium chabaudi chabaudi clone AS. Splenocytes recovered during peak parasitemia showed a dramatic elevation in viral p24 production that returned to baseline by day 15 and failed to rebound at recrudescence or after reinfection. The major sources of virus expression were antigen-presenting cells (APCs) rather than T lymphocytes. Nevertheless, T cells from infected mice stimulated with plasmodial antigen triggered 5-10-fold increases in p24 production from dendritic cells in vitro, which suggests that viral induction stems from interaction of malaria-specific T lymphocytes with HIV-expressing APCs. Indeed, depletion of CD4 T cells resulted in a 70% reduction in the p24 response stimulated by malaria in vivo. These findings demonstrate the ability of Plasmodium species to immunologically activate latently integrated HIV in vivo but suggest that this process may be restricted to acute infection.

Animals↗

PubMed2001

In vivo CD40-CD154 (CD40 ligand) interaction induces integrated HIV expression by APC in an HIV-1-transgenic mouse model.

Because of their relative resistance to viral cytopathic effects, APC can provide an alternative reservoir for latently integrated HIV. We used an HIV-transgenic mouse model in which APC serve as the major source of inducible HIV expression to study mechanisms by which integrated virus can be activated in these cells. When admixed with transgenic APC, activated T lymphocytes provided a major contact-dependent stimulus for viral protein expression in vitro. Using blocking anti-CD154 mAb as well as CD154-deficient T cells, the HIV response induced by activated T lymphocytes was demonstrated to require CD40-CD154 interaction. The role of this pathway in the induction of HIV expression from APC in vivo was further studied in an experimental model involving infection of the HIV-transgenic mice with PLASMODIUM: chabaudi parasites. Enhanced viral production by dendritic cells and macrophages in infected mice was associated with up-regulated CD40 expression. More importantly, in vivo treatment with blocking anti-CD154 mAb markedly reduced viral expression in P. chabaudi-infected animals. Together, these findings indicate that immune activation of integrated HIV can be driven by the costimulatory interaction of activated T cells with APC. Because chronic T cell activation driven by coinfections as well as HIV-1 itself is a characteristic of HIV disease, this pathway may be important in sustaining viral expression from APC reservoirs.

Animals↗

PubMed2001

Th1/Th2 effector choice in parasitic infection: decision making by committee.

Parasitic infections frequently result in highly polarized CD4+ T cell responses characterized by dominant Th1 or Th2 cytokine production profiles. Although previously thought to be strictly dependent on signaling by the differentiative cytokines, IL-12 and IL-4, recent data indicate that this polarization may be primarily decided instead by a series of different factors intrinsic to the pathogen-antigen-presenting-cell interaction that influence T cell priming.

Animals↗

PubMed2001

Mice infected with Schistosoma mansoni develop a novel non-T-lymphocyte suppressor population which inhibits virus-specific CTL induction via a soluble factor.

We previously observed that Schistosoma mansoni-infected mice were deficient in their ability to mount a CTL response to unrelated viral antigens and to clear a vaccinia viral infection. Here, we explore the mechanism of that deficiency. Mixing experiments showed that splenocytes from S. mansoni-infected mice actively suppress stimulation in vitro of both viral-peptide specific CTL in spleen cells from virus-infected mice, and allospecific CTL. The mechanism of suppression involves at least in part a soluble factor, in that it can occur across a 0.4-microm membrane which prohibits direct cell contact. However, the inhibition is not alleviated by blocking with antibodies to IL-4, IL-10 or TGF-beta. Fractionation of the splenocyte population from S. mansoni-infected mice shows that the suppression is mediated by a non-B, non-T cell that expresses CD16 and Mac-1, but not FcepsilonR or NK1.1. This represents a novel suppressor population that is distinct from the FcepsilonRI(+) populations of non-B, non-T cells in the spleens of S. mansoni-infected mice that provide a major source of IL-4 in these animals. Similar cells in schistosome-infected humans could affect susceptibility to other infections or responsiveness to vaccines.

Animals↗