bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load
Authors: Deeks Steven G. , Kitchen Christina M. R. , Liu Lea , Guo Hua , Gascon Ron , Narváez Amy B. , Hunt Peter , Martin Jeffrey N. , Kahn James O. , Levy Jay , McGrath Michael S. , Hecht Frederick M. 
Published: May 2004

AbstractAlthough generalized T-cell activation is an important factor in chronic HIV disease pathogenesis, its role in primary infection remains poorly defined. To investigate the effect of immune activation on T-cell changes in subjects with early HIV infection, and to test the hypothesis that an immunologic activation “set point” is established early in the natural history of HIV disease, a prospective cohort of acutely infected adults was performed. The median density of CD38 molecules on CD4+ and CD8+ T cells was measured longitudinally in 68 antiretroviral-untreated individuals and 83 antiretroviral-treated individuals. At study entry, T-cell activation was positively associated with viremia, with CD8+ T-cell activation levels increasing exponentially at plasma HIV RNA levels more than 10 000 copies/mL. Among untreated patients, the level of CD8+ T-cell activation varied widely among individuals but often remained stable within a given individual. CD8+ T-cell activation and plasma HIV RNA levels over time were independently associated with the rate of CD4+ T-cell loss in untreated individuals. These data indicate that immunologic activation set point is established early in HIV infection, and that this set point determines the rate at which CD4+ T cells are lost over time.
Immunoregulation of dendritic cells by IL-10 is mediated through suppression of the PI3K/Akt pathway and of IκB kinase activity
Authors: Bhattacharyya Sandip , Sen Pradip , Wallet Mark , Long Brian , Baldwin Albert S. , Tisch Roland 
Published: May 2004

AbstractInterleukin-10 (IL-10) has potent immunoregulatory effects on the maturation and the antigen-presenting cell (APC) function of dendritic cells (DCs). The molecular basis underlying these effects in DCs, however, is ill defined. It is well established that the transcription factor NF-κB is a key regulator of DC development, maturation, and APC function. This study was initiated to determine the effects of IL-10 on the NF-κB signaling pathway in immature DCs. IL-10 pretreatment of myeloid DCs cultured from bone marrow resulted in reduced DNA binding and nuclear translocation of NF-κB after anti-CD40 antibody or lipopolysaccharide (LPS) stimulation. Furthermore, inhibited NF-κB activation was characterized by reduced degradation, phosphorylation, or both of IκBα and IκBϵ but not IκBβ and by reduced phosphorylation of Ser536, located in the trans-activation domain of p65. Notably, IL-10–mediated inhibition of NF-κB coincided with suppressed IκB kinase (IKK) activity in vitro. Furthermore, IL-10 blocked inducible Akt phosphorylation, and inhibitors of phosphatidylinositol 3-kinase (PI3K) effectively suppressed the activation of Akt, IKK, and NF-κB. These findings demonstrate that IL-10 targets IKK activation in immature DCs and that suppressing the PI3K pathway in part mediates blockade of the pathway.
Safety and efficacy of denileukin diftitox in patients with steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation
Authors: Ho Vincent T. , Zahrieh David , Hochberg Ephraim , Micale Eileen , Levin Jesse , Reynolds Carol , Steckel Steve , Cutler Corey , Fisher David C. , Lee Stephanie J. , Alyea Edwin P. , Ritz Jerome , Soiffer Robert J. , Antin Joseph H. 
Published: May 2004

Abstract
Denileukin diftitox (Ontak), a recombinant protein composed of human interleukin 2 (IL-2) fused to diphtheria toxin, has selective cytotoxicity against activated lymphocytes expressing the high-affinity IL-2 receptor. We conducted a phase 1 study of denileukin diftitox in 30 patients with steroid refractory acute graft-versus-host disease (GVHD). Seven patients received 9 μg/kg intravenously on days 1 and 15; 18 received 9 μg/kg intravenously on days 1, 3, 5, 15, 17, and 19; and 5 received 9 μg/kg intravenously on days 1 to 5 and 15 to 19. Hepatic transaminase elevation was the dose-limiting toxicity (DLT), and dose level 2 was the maximum tolerated dose (MTD). Overall, 71% of patients responded with complete resolution (12 of 24; 50%) or partial resolution (5 of 24; 21%) of GVHD. Eight of 24 patients (33%) are alive at 6.3 to 24.6 months (median, 7.2 months). Denileukin diftitox is tolerable and has promising activity in steroid-refractory acute GVHD. (Blood. 2004;104:1224-1226)
The expanded family of class II cytokines that share the IL-10 receptor-2 (IL-10R2) chain
Authors: Donnelly Raymond P , Sheikh Faruk , Kotenko Sergei V , Dickensheets Harold 
Published: May 2004

AbstractSeveral novel interleukin (IL)-10-related cytokines have recently been discovered. These include IL-22, IL-26, and the interferon-λ (IFN-λ) proteins IFN-λ1 (IL-29), IFN-λ2 (IL-28A), and IFN-λ3 (IL-28B). The ligand-binding chains for IL-22, IL-26, and IFN-λ are distinct from that used by IL-10; however, all of these cytokines use a common second chain, IL-10 receptor-2 (IL-10R2; CRF2-4), to assemble their active receptor complexes. Thus, IL-10R2 is a shared component in at least four distinct class II cytokine-receptor complexes. IL-10 binds to IL-10R1; IL-22 binds to IL-22R1; IL-26 binds to IL-20R1; and IFN-λ binds to IFN-λR1 (also known as IL-28R). The binding of these ligands to their respective R1 chains induces a conformational change that enables IL-10R2 to interact with the newly formed ligand-receptor complexes. This in turn activates a signal-transduction cascade that results in rapid activation of several transcription factors, particularly signal transducer and activator of transcription (STAT)3 and to a lesser degree, STAT1. Activation by IL-10, IL-22, IL-26, or IFN-λ can be blocked with neutralizing antibodies to the IL-10R2 chain. Although IL-10R2 is broadly expressed on a wide variety of tissues, only a subset of these tissues expresses the ligand-binding R1 chains. The receptors for these cytokines are often present on cell lines derived from various tumors, including liver, colorectal, and pancreatic carcinomas. Consequently, the receptors for these cytokines may provide novel targets for inhibiting the growth of certain types of cancer.
Increased numbers of committed myeloid progenitors but not primitive hematopoietic stem/progenitors in mice lacking STAT6 expression
Authors: Bunting Kevin D , Yu Wen-Mei , Bradley Heath L , Haviernikova Eleonora , Kelly-Welch Ann E , Keegan Achsah D , Qu Cheng-Kui 
Published: May 2004

AbstractSignal transducer and activator of transcription-6 (STAT6) plays important roles in cytokine signaling via interleukin-4 and -13 receptors (IL-4R and IL-13R). Mice in which STAT6 has been disrupted by homologous recombination show defects in T helper cell type 2 (Th2) lymphocyte production, resulting in an accumulation of Th1 cells. In addition to defects in differentiation and proliferation of T lymphocytes, STAT6-deficient mice show increased cell-cycle activation and frequency of myeloid progenitors. Although this has been shown to be mediated through Oncostatin M production by T cells, IL-4Rα and STAT6 have also recently been found to be enriched for expression in primitive hematopoietic stem cells (HSCs) in gene expression-profiling studies. Therefore, we have investigated whether defects in hematopoietic function in mice lacking STAT6 expression extended into the primitive hematopoietic compartments of the bone marrow. Here, we report that STAT6 deficiency increased bone marrow-committed myeloid progenitors but did not alter the number of cells enriched for HSC/multipotent progenitors, primitive cobblestone area-forming cells assayed in vitro, or bone marrow short-term or long-term repopulating cells assayed in vivo. Therefore, the requirement for STAT6 activation during hematopoiesis is limited, and primitive hematopoietic cell types are insulated against possible effects of cytokine stimulation by Th1 cells.
CXCR2 inhibition suppresses hemorrhage-induced priming for acute lung injury in mice
Authors: Lomas-Neira Joanne L , Chung Chun-Shiang , Grutkoski Patricia S , Miller Edmund J , Ayala Alfred 
Published: May 2004

AbstractPolymorphonuclear neutrophil (PMN) extravasation/sequestration in the lung and a dysregulated inflammatory response characterize the pathogenesis of acute lung injury (ALI). Previously, we have shown that hemorrhage (Hem) serves to prime PMN such that subsequent septic challenge [cecal ligation and puncture (CLP)] produces a pathological, inflammatory response and consequent lung injury in mice. Keratinocyte-derived chemokine (KC) and macrophage inflammatory protein-2 (MIP-2) are murine CXC chemokines found elevated in the lungs and plasma following Hem/CLP and have been reported by others to share a common receptor (CXCR2). Based on these data, we hypothesize that blockade of CXCR2 immediately following Hem would suppress KC and MIP-2 priming of PMN, thereby reducing the inflammatory injury observed following CLP. To assess this, Hem mice (90 min at 35±5 mmHg) were randomized to receive 0, 0.4, or 1 mg antileukinate (a hexapeptide inhibitor of CXCRs) in 100 μl phosphate-bufferd saline (PBS)/mouse subcutaneously, immediately following resuscitation (Ringer's lactate-4× drawn blood volume). Twenty-four hours post-Hem, mice were subjected to CLP and killed 24 h later. The results show that blockade of CXCR2 significantly (P&lt;0.05, Tukey's test) reduced PMN influx, lung protein leak, and lung-tissue content of interleukin (IL)-6, KC, and MIP-2 and increased tissue IL-10 levels. Plasma IL-6 was significantly decreased, and IL-10 levels increased in a dose-dependent manner compared with PBS-treated mice. A differential effect was observed in plasma levels of KC and MIP-2. KC showed a significant reduction at the 0.4 mg antileukinate dose. In contrast, plasma MIP-2 was significantly elevated at both doses compared with the PBS-treated controls. Together, these data demonstrate that blockade of CXCR2 signaling attenuates shock-induced priming and ALI observed following Hem and subsequent septic challenge in mice.
Cross-linking of MHC class I molecules on human NK cells inhibits NK cell function, segregates MHC I from the NK cell synapse, and induces intracellular phosphotyrosines
Authors: Rubio Gonzalo , Férez Xavier , Sánchez-Campillo María , Gálvez Jesús , Martí Salvador , Verdú Rocío , Hernández-Caselles Trinidad , García-Peñarrubia Pilar 
Published: May 2004

AbstractEngagement of major histocompatibility complex (MHC) class I molecules on immune cells, where they are usually highly expressed, induces signal transduction events of unclear significance. We show here that antibody-mediated cross-linking of MHC-I molecules on human natural killer (NK) cells inhibits their cytotoxic activity against tumor target cells. Inhibition by anti-MHC class I monoclonal antibody exhibits molecular specificity and is an isotype and Fc-independent process. Physical hindrance of specific molecular recognition, induction of apoptosis, or reciprocal NK cell killing, which could be induced by cross-linking of MHC I molecules, has also been ruled out as putative mechanisms of inhibition. Confocal microscopy analysis revealed that MHC class I molecules on the surface of NK cells colocalize constitutively with GM1, a marker of lipid rafts. Cross-linking of MHC class I resulted in the asymmetric redistribution of GM1-enriched raft domains, which are concentrated to the immunological synapse, and MHC I molecules, which segregate to the opposite pole. Also, the cross-linking of MHC I on NK cells induced intracellular tyrosine phosphorylations. These results suggest that MHC I molecules on NK cells could transmit inhibitory signals upon engagement with putative ligands expressed on the surface of those cells that need to be protected from natural cytotoxicity.
CCL2, a product of mice early after systemic inflammatory response syndrome (SIRS), induces alternatively activated macrophages capable of impairing antibacterial resistance of SIRS mice
Authors: Tsuda Yasuhiro , Takahashi Hitoshi , Kobayashi Makiko , Hanafusa Toshiaki , Herndon David N , Suzuki Fujio 
Published: May 2004

AbstractInfection associated with systemic inflammatory response syndrome (SIRS) is a major cause of morbidity and mortality in patients with major surgery, polytrauma, and severe burn injury. In previous studies, mice with severe pancreatitis (a mouse model of SIRS, SIRS mice) have been shown to be greatly susceptible to various infections. In the present study, a mechanism involved in the impaired resistance of SIRS mice to infectious complications was investigated. Sera from SIRS mice impaired the resistance of normal mice to infectious complications induced by cecal ligation and puncture (CLP). CC chemokine ligand 2 (CCL2) was detected in sera of SIRS mice. Resident macrophages (RMφ) cultured with SIRS mouse sera converted to alternatively activated macrophages (AAMφ), which were also demonstrated in mice treated with recombinant murine CCL2. However, AAMφ were not demonstrated in mice injected with SIRS mouse sera and anti-CCL2 monoclonal antibody (mAb) in combination. Furthermore, normal mice that received SIRS mouse sera and anti-CCL2 mAb resisted CLP-induced infectious complications. These results indicate that the resistance of SIRS mice to infectious complications is impaired by AAMφ generated from RMφ in response to SIRS-associated CCL2 production.
Cell-Specific Knockout of Steroidogenic Factor 1 Reveals Its Essential Roles in Gonadal Function
Authors: Jeyasuria Pancharatnam , Ikeda Yayoi , Jamin Soazik P. , Zhao Liping , de Rooij Dirk G. , Themmen Axel P. N. , Behringer Richard R. , Parker Keith L. 
Published: May 2004

AbstractKnockout (KO) mice lacking the orphan nuclear receptor steroidogenic factor 1 (SF-1, officially designated Nr5a1) have a compound endocrine phenotype that includes adrenal and gonadal agenesis, impaired expression of pituitary gonadotropins, and structural abnormalities of the ventromedial hypothalamic nucleus. To inactivate a conditional SF-1 allele in the gonads, we targeted the expression of Cre recombinase with a knock-in allele of the anti-Müllerian hormone type 2 receptor locus. In testes, Cre was expressed in Leydig cells. The testes of adult gonad-specific SF-1 KO mice remained at the level of the bladder and were markedly hypoplastic, due at least partly to impaired spermatogenesis. Histological abnormalities of the testes were seen from early developmental stages and were associated with markedly decreased Leydig cell expression of two essential components of testosterone biosynthesis, Cyp11a and the steroidogenic acute regulatory protein. In females, the anti-Müllerian hormone type 2 receptor-Cre allele directed Cre expression to granulosa cells. Although wild-type and SF-1 KO ovaries were indistinguishable during embryogenesis and at birth, adult females were sterile and their ovaries lacked corpora lutea and contained hemorrhagic cysts resembling those in estrogen receptor α and aromatase KO mice. Collectively, these studies establish definitively that SF-1 expression in the gonads is essential for normal reproductive development and function.
Anti-Thrombin III in the Management of Hematopoietic Stem-Cell Transplantation—Associated Toxicity
Authors: Ibrahim Rami B , Peres Edward , Dansey Roger , Abidi Muneer H , Abella Esteban M , Klein Jared 
Published: May 2004

OBJECTIVE: To describe the evidence assessing the use of anti-thrombin III (AT-III) in the management of toxicity associated with hematopoietic stem-cell transplantation (HSCT)—conditioning regimens. DATA SOURCES: Clinical literature was accessed through conference proceedings, EMBASE, the Cochrane database, and MEDLINE (1966-December 2003). STUDY SELECTION AND DATA EXTRACTION: Case reports, small case series, case—control and cohort studies, and randomized controlled trials of AT-III in HSCT were evaluated. Publications examining AT-III use in the non-HSCT setting were also explored. Key search terms included AT-III, transplantation, and veno-occlusive disease (VOD). DATA SYNTHESIS: Severe VOD and ensuing multiple organ dysfunction is associated with high mortality in HSCT. A low AT-III level has been shown to correlate with the development of organ dysfunction. Phase II trials, case series, and one small, randomized, placebo-controlled study suggest a benefit when AT-III therapy is instituted early in the course of VOD/multiple organ dysfunction syndrome. In all of these reports, AT-III use was devoid of adverse events. CONCLUSIONS: Although further studies are needed to ascertain the optimal target level, method, and duration of administration, AT-III is still a viable alternative for the treatment of severe VOD and ensuing multiple organ dysfunction.
Emtricitabine: A Once-Daily Nucleoside Reverse Transcriptase Inhibitor
Authors: Modrzejewski Krysten A , Herman Ronald A 
Published: May 2004

OBJECTIVE: To review the pharmacology, virology, pharmacokinetics, safety, and efficacy of the nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine. DATA SOURCES: English-language reports were accessed using MEDLINE (1966-June 2003) and the Iowa Drug Information Service database (1966-June 2003) using emtricitabine and Coviracil as key words. (Coviracil was the proposed trade name for the product prior to approval.) The Internet was also searched using the terms HIV/AIDS conferences, then emtricitabine within the conference proceedings. STUDY SELECTION AND DATA EXTRACTION: Abstracts, posters, and oral presentations from scientific conferences, both published and unpublished, were included. Preference was given to published controlled trials. Studies providing a description of the pharmacology, virology, effectiveness, safety, or pharmacokinetics of emtricitabine were used in this review. DATA SYNTHESIS: Emtricitabine is an NRTI used to treat HIV-1 infection. Once-daily administration can decrease pill burden and potentially increase adherence to multidrug HIV therapy. Further, emtricitabine has shown equivalent or improved outcomes compared with lamivudine and stavudine. CONCLUSIONS: Emtricitabine is a safe and effective option for HIV-1 infection in adults as part of a multidrug regimen. It may be a better alternative than lamivudine for once-daily therapy because of its extended intracellular half-life and better than lamivudine and stavudine because of a possibly decreased potential for drug resistance.
Successful Treatment of Staphylococcus Epidermidis Hip Prosthesis Infection with Oral Linezolid
Authors: Mogenet Ingrid , Raetz-Dillon Sabine , Canonge Jean-Marie , Archambaud Maryse , Bonnet Eric 
Published: May 2004

OBJECTIVE: To report a case of Staphylococcus epidermidis infection of a hip prosthesis successfully treated with oral linezolid. CASE SUMMARY: A 46-year-old woman developed methicillin-resistant S. epidermidis (MRSE) infection of her prosthetic hip. She received oral linezolid 600 mg twice daily for one month; after that time, the biological inflammatory markers returned to normal. DISCUSSION: One of the most serious complications of arthroplasty is joint prosthesis infection. It is mainly caused by gram-positive bacteria, in particular those of the genus staphylococcus. The increasing prevalence of gram-positive cocci that are resistant to antimicrobial agents has complicated the treatment of serious infections. CONCLUSIONS: Oral linezolid appears to be an effective and well-tolerated treatment option for hip prosthesis infections due to MRSE.
Rash Associated with Piperacillin/Tazobactam Administration in Infectious Mononucleosis
Authors: LeClaire Aimée C , Martin Craig A , Hoven Ardis D 
Published: May 2004

OBJECTIVE: To report a case of piperacillin/tazobactam-induced rash in a patient with infectious mononucleosis. CASE SUMMARY: A 25-year-old white man developed a rash while receiving piperacillin/tazobactam 3.375 g intravenously every 6 hours and gentamicin for osteomyelitis complicating a left femur fracture secondary to a motorcycle accident. Due to progression of the rash following additional doses of piperacillin/tazobactam during hospitalization, the patient's antimicrobial regimen was changed to vancomycin and meropenem. Subsequently, a mononucleosis spot test was positive, and both Epstein—Barr virus (EBV) immunoglobulin (Ig) G and IgM antibodies were positive. The rash rapidly resolved with the discontinuation of piperacillin/tazobactam. DISCUSSION: Although the development of rash following the administration of several different antimicrobials, especially ampicillin, has been previously reported, this is the first report of piperacillin/tazobactam-induced rash in infectious mononucleosis. The rash is generally self-limiting and usually resolves within days of discontinuing the causative antimicrobial agent. An altered drug metabolism or an immune-mediated process has been suggested as the potential mechanism for rash development. CONCLUSIONS: Prior reports of antimicrobial-induced rash in infectious mononucleosis and a positive laboratory diagnosis of EBV in our patient with no history of penicillin allergy support the identification of piperacillin/tazobactam as the inducer of the rash. According to the Naranjo probability scale, the association of piperacillin/tazobactam with the rash was classified as probable.
Pharmacist and Physician Collaboration in the Patient's Home
Authors: Amruso Nadia A , O'Neal Michael L 
Published: May 2004

OBJECTIVE: To review the historical perspective and current incidence of home visits by physicians and pharmacists, discuss the concept of pharmacists providing care “incident-to” the physician, and introduce a new endeavor of collaborative, incident-to home visits by a pharmacist and physician. DATA SOURCES: A literature search was performed using MEDLINE (1966-May 2003). The search terms used were home visit, house call, incident-to, collaborative care, physician, and pharmacist. STUDY SELECTION AND DATA EXTRACTION: All pertinent articles were evaluated. DATA SYNTHESIS: Home visits were once considered a hallmark of patient care, but have decreased to an average of 0.4 home visits per week for primary care physicians. Home visits are essential for patients unable to commute to the office due to a disability or illness. However, home visits also allow the physician to determine how conditions affect a patient's everyday life, in addition to assessing the living environment. Minimal documented evidence exists of pharmacists making home visits and no documented evidence exists of pharmacists and physicians collaboratively making home visits. The pharmacist complements the value of the visit by assessing medication appropriateness as well as medication administration, storage, accessibility, and adherence. CONCLUSIONS: Current practice styles often compromise services that were once paramount to patient care, as evidenced by a decline in home visits. Recent trends in health care attempt to compensate for high-volume practices and managed care restrictions. A collaborative relationship between a pharmacist and physician with visits into the patient's home is a movement toward improved continuity of care.