bluuebunny/crossref_metadata_2025 huggingface dataset:
18-3/4 in. FullBore Wellhead System
Authors: Minassian Marc
Published: March 2009

This paper describes the development of full-bore wellheads, a new 18-3/4 in.15,000 psi W.P. system, from conception to field installation. The wellheadwhen installed has a full-bore diameter without a casing hanger landingshoulder to allow one more casing string to be run below the mudline under BOPcontrol due to this major wellhead innovation.

Introduction

Today wells are being drilled in deeper and deeper water which associates tohigher costs. More economical risk is taken to drill wells in deeper water andreaching the 'payzone' with a sufficient size production string to produce fromis more important than ever before. In addition to deeper water, there is aneed to find ways to drill in more difficult formations some of which includevarious shallow zone hazards1.

As a result of these concerns, there has been a demand to find ways to ensurethat the operators can reach the planned hole depth and/or size required toproduce from. Unforeseen hole problems that may have not been expected mayhinder reaching the depth requirements. By providing one more casing stringthan a conventional 18-3/4 in. wellhead system, a better opportunity to reachthe desired hole depth and size can be achieved.

To help solve these problems a new 18-3/4 in. wellhead system with a 36 in.conductor string was designed and implemented. A 36 in. × 18-3/4 in. wellheadsystem consists of the following casing program:Conventional:6 in. × 28 in./26 in. × 20 in. × 16 in. × 13-3/8 in. × 9-5/8 in. × 7 in.Full-bore:36 in. × 28 in./26 in. × 22 in. × 18 in. × 16 in. × 13-3/8 in. × 9-5/8 in. × 7in.

The new system adds the 18 in. string which is run under BOP control, and the20 in. becomes 22 in. hanging from the high pressure housing as shown in FigureA. The 36 in. string is jetted or cemented in place using conventional methods. The 18-3/4 in. high pressure housing is run with 22 in. casing suspended fromthe bottom and landed in the 36 in. housing and cemented in place. The 18 in.string is landed in the 22 in. string below the mudline in its respective sub. The 16 in. string is run like the 18 in. string, but it will land in anindependent sub in the 22 in. string above the 18 in. string and below the highpressure housing. The load shoulder is then set in the high pressure housing,and 13-3/8 in., 9-5/8 in. and 7 in. casing can be run and set, respectively, with each subsequent casing string landing on top of the other.

The new system provides one more casing string to the above conventionalprogram, but with reduced radial clearances between several of the strings. Furthermore, due to the tight clearances, drives the requirement for highclearance or flush joint connections. This additional string of casing helpsoperators utilize existing rig equipment sizes and capabilities1.
The Cooperative Induction of Hypoxia-Inducible Factor-1α and STAT3 during Hypoxia Induced an Impairment of Tumor Susceptibility to CTL-Mediated Cell Lysis
Authors: Noman Muhammad Zaeem , Buart Stéphanie , Van Pelt Jos , Richon Catherine , Hasmim Meriem , Leleu Nathalie , Suchorska Wictoria Maria , Jalil Abdelali , Lecluse Yann , El Hage Faten , Giuliani Massimo , Pichon Christophe , Azzarone Bruno , Mazure Nathalie , Romero Pedro , Mami-Chouaib Fathia , Chouaib Salem
Published: March 2009

Hypoxia is an essential component of tumor microenvironment. In this study, we investigated the influence of hypoxia (1% PO2) on CTL-mediated tumor cell lysis. We demonstrate that exposure of target tumor cells to hypoxia has an inhibitory effect on the CTL clone (Heu171)-induced autologous target cell lysis. Such inhibition correlates with hypoxia-inducible factor-1α (HIF-1α) induction but is not associated with an alteration of CTL reactivity as revealed by granzyme B polarization or morphological change. Western blot analysis indicates that although hypoxia had no effect on p53 accumulation, it induced the phosphorylation of STAT3 in tumor cells by a mechanism at least in part involving vascular endothelial growth factor secretion. We additionally show that a simultaneous nuclear translocation of HIF-1α and phospho-STAT3 was observed. Interestingly, gene silencing of STAT3 by small interfering RNA resulted in HIF-1α inhibition and a significant restoration of target cell susceptibility to CTL-induced killing under hypoxic conditions by a mechanism involving at least in part down-regulation of AKT phosphorylation. Moreover, knockdown of HIF-1α resulted in the restoration of target cell lysis under hypoxic conditions. This was further supported by DNA microarray analysis where STAT3 inhibition resulted in a partly reversal of the hypoxia-induced gene expression profile. The present study demonstrates that the concomitant hypoxic induction of phopho-STAT3 and HIF-1α are functionally linked to the alteration of non-small cell lung carcinoma target susceptibility to CTL-mediated killing. Considering the eminent functions of STAT3 and HIF-1α in the tumor microenvironment, their targeting may represent novel strategies for immunotherapeutic intervention.
Lymphocytes with Aberrant Expression of Fas or Fas Ligand Attenuate Immune Bone Marrow Failure in a Mouse Model
Authors: Omokaro Stephanie O. , Desierto Marie J. , Eckhaus Michael A. , Ellison Felicia M. , Chen Jichun , Young Neal S.
Published: March 2009

Bone marrow (BM) and lymphocyte samples from aplastic anemia patients show up-regulated Fas and Fas-ligand (FasL) expression, respectively, supporting a relationship between immune-mediated BM destruction and the Fas apoptotic pathway. Mice with spontaneous lymphoproliferation (lpr) and generalized lymphoproliferative disease (gld) mutations exhibit abnormal expression of Fas and FasL, serving as potential models to elucidate underlying mechanisms of BM failure. We examined cellular and functional characteristics of lpr and gld mutants on the C57BL/6 (B6) background. Lymph node (LN) cells from lpr and gld mice produced less apoptosis when coincubated with C.B10-H2b/LilMcd (C.B10) BM cells in vitro. This functional difference was confirmed by infusing lpr, gld, and B6 LN cells into sublethally irradiated CB10 mice. All donor LN cells showed significant T cell expansion and activation, but only B6 LN cells caused severe BM destruction. Mice infused with gld LN cells developed mild to moderate BM failure despite receiving FasL-deficient effectors, thus suggesting the existence of alternative pathways or incomplete penetrance of the mutation. Paradoxically, mice that received Fas-deficient lpr LN cells also had reduced BM failure, likely due to down-regulation of proapoptotic genes, an effect that can be overcome by higher doses of lpr LN cells. Our model demonstrates that abnormal Fas or FasL expression interferes with the development of pancytopenia and marrow hypoplasia, validating a major role for the Fas/FasL cytotoxic pathway in immune-mediated BM failure, although disruption of this pathway does not completely abolish marrow destruction.
Expression of ADAM33 Is a Novel Regulatory Mechanism in IL-18-Secreted Process in Gastric Cancer
Authors: Kim Kyung-Eun , Song Hyunkeun , Hahm Candace , Yoon Sun Young , Park Sunyoung , Lee Ha-reum , Hur Dae Young , Kim Taesung , Kim Cherl-hyun , Bang Sa Ik , Bang Jung-Wook , Park Hyunjeong , Cho Dae-Ho
Published: March 2009

IL-18 has recently been reported to play a critical role in tumor migration, invasion, and metastasis. Because IL-18 has various biological activities after its secretion as an 18 kDa mature form, the regulation of the IL-18 secretion process is an important step in tumor progression. This study investigated the implication of IL-18 in vascular endothelial growth factor (VEGF)-D-regulated migration, along with the role of the IL-18 secretion process. VEGF-D enhanced cell migration, which was then blocked by inhibiting IL-18. VEGF-D increased IL-18 expression and secretion, suggesting that IL-18 is a critical mediator for VEGF-D-enhanced migration. VEGF-D induced a disintegrin and metalloprotease 33 (ADAM33) expression, which has a metalloproteinase domain. VEGF-D-enhanced IL-18 secretion and cell migration were inhibited by ADAM33 knock-down. Moreover, cell proliferation was considerably reduced in ADAM33 small interfering RNA transfectants. In conclusion, ADAM33 has a key role in gastric cancer pathogenesis by up-regulating IL-18 secretion process, resulting in increased cell migration and proliferation.
IL-17 Induces Monocyte Migration in Rheumatoid Arthritis
Authors: Shahrara Shiva , Pickens Sarah R. , Dorfleutner Andrea , Pope Richard M.
Published: March 2009

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease which is in part mediated by the migration of monocytes from blood to RA synovial tissue, where they differentiate into macrophages and secrete inflammatory cytokines and chemokines. The T cell cytokine IL-17 is expressed in the RA synovial tissue and synovial fluid. To better understand the mechanism by which IL-17 might promote inflammation, its role in monocyte trafficking was examined. In vivo, IL-17 mediates monocyte migration into sponges implanted into SCID mice. In vitro, IL-17 was chemotactic, not chemokinetic, for monocytes at the concentrations detected in the RA synovial fluid. Further, IL-17-induced monocyte migration was mediated by ligation to IL-17RA and RC expressed on monocytes and was mediated through p38MAPK signaling. Finally, neutralization of IL-17 in RA synovial fluid or its receptors on monocytes significantly reduced monocyte migration mediated by RA synovial fluid. These observations suggest that IL-17 may be important in recruiting monocytes into the joints of patients with RA, supporting IL-17 as a therapeutic target in RA.
New Insights into the Evolution of IFNs: Zebrafish Group II IFNs Induce a Rapid and Transient Expression of IFN-Dependent Genes and Display Powerful Antiviral Activities
Authors: López-Muñoz Azucena , Roca Francisco J. , Meseguer José , Mulero Victoriano
Published: March 2009

The IFNs and their receptors have existed in early chordates for ∼500 million years and represent the early elements in innate and adaptive immunity. Both types I and II IFNs have been discovered in fish, and type I has recently been classified into two groups based on their primary protein sequences. However, the biological activities of fish IFNs and their roles in infection are largely unknown. Using the zebrafish and manageable bacterial (Streptococcus iniae) and viral (spring viremia of carp virus) infection models, we are reporting in this study that zebrafish IFN (zfIFN) γ failed to induce antiviral and proinflammatory genes when administered in vivo, which correlates with its inability to protect the fish against bacterial and viral infections. We also found that, although both group I (i.e., zfIFN1) and group II zfIFNs (i.e., zfIFN2 and zfIFN3) displayed strong in vivo antiviral activities, only group I zfIFN was able to protect the fish against bacterial infection, which may reflect the different patterns and kinetics of immune-related genes elicited by these two groups of IFNs. Thus, group II zfIFNs induced a rapid and transient expression of antiviral genes, whereas group I zfIFN exerted a slow but more powerful induction of several antiviral and proinflammatory genes. Collectively, our results suggest nonredundant, complementary roles of type I zfIFNs in viral infections and provide evidence for a pivotal role of the recently identified group II IFN of fish in the early stages of viral infections.
Notch Regulates Cytolytic Effector Function in CD8+ T Cells
Authors: Cho Ok Hyun , Shin Hyun Mu , Miele Lucio , Golde Todd E. , Fauq Abdul , Minter Lisa M. , Osborne Barbara A.
Published: March 2009

The maturation of naive CD8+ T cells into effector CTLs is a critical feature of a functional adaptive immune system. Development of CTLs depends, in part, upon the expression of the transcriptional regulator eomesodermin (EOMES), which is thought to regulate expression of two key effector molecules, perforin and granzyme B. Although EOMES is important for effector CTL development, the precise mechanisms regulating CD8+ effector cell maturation remains poorly understood. In this study, we show that Notch1 regulates the expression of EOMES, perforin, and granzyme B through direct binding to the promoters of these crucial effector molecules. By abrogating Notch signaling, both biochemically as well as genetically, we conclude that Notch activity mediates CTL activity through direct regulation of EOMES, perforin, and granzyme B.
NK Cells Recognize and Kill Human Glioblastoma Cells with Stem Cell-Like Properties
Authors: Castriconi Roberta , Daga Antonio , Dondero Alessandra , Zona Gianluigi , Poliani Pietro Luigi , Melotti Alice , Griffero Fabrizio , Marubbi Daniela , Spaziante Renato , Bellora Francesca , Moretta Lorenzo , Moretta Alessandro , Corte Giorgio , Bottino Cristina
Published: March 2009

In this study, cancer cells were isolated from tumor specimens of nine glioblastoma patients. Glioblastoma cells, cultured under suitable culture conditions, displayed markers typical of neural stem cells, were capable of partial multilineage differentiation in vitro, and gave origin to infiltrating tumors when orthotopically injected in NOD/SCID mice. These cells, although resistant to freshly isolated NK cells, were highly susceptible to lysis mediated by both allogeneic and autologous IL-2 (or IL-15)-activated NK cells. Indeed, all stem cell-cultured glioblastoma cells analyzed did not express protective amounts of HLA class I molecules, while expressing various ligands of activating NK receptors that triggered optimal NK cell cytotoxicity. Importantly, glioblastoma stem cells expressed high levels of PVR and Nectin-2, the ligands of DNAM-1-activating NK receptor.
STIM1-Independent T Cell Development and Effector Function In Vivo
Authors: Beyersdorf Niklas , Braun Attila , Vögtle Timo , Varga-Szabo David , Galdos Ronmy Rivera , Kissler Stephan , Kerkau Thomas , Nieswandt Bernhard
Published: March 2009

Store-operated Ca2+ entry (SOCE) is believed to be of pivotal importance in T cell physiology. To test this hypothesis, we generated mice constitutively lacking the SOCE-regulating Ca2+ sensor stromal interaction molecule 1 (STIM1). In vitro analyses showed that SOCE and Ag receptor complex-triggered Ca2+ flux into STIM1-deficient T cells is virtually abolished. In vivo, STIM1-deficient mice developed a lymphoproliferative disease despite normal thymic T cell maturation and normal frequencies of CD4+Foxp3+ regulatory T cells. Unexpectedly, STIM1-deficient bone marrow chimeric mice mounted humoral immune responses after vaccination and STIM1-deficient T cells were capable of inducing acute graft-versus-host disease following adoptive transfer into allogeneic hosts. These results demonstrate that STIM1-dependent SOCE is crucial for homeostatic T cell proliferation, but of much lesser importance for thymic T cell differentiation or T cell effector functions.
Reactivation of Latent HIV-1 Infection by the Periodontopathic Bacterium Porphyromonas gingivalis Involves Histone Modification
Authors: Imai Kenichi , Ochiai Kuniyasu , Okamoto Takashi
Published: March 2009

Latently infected cells harbor the HIV-1 proviral DNA genome primarily integrated into heterochromatin, allowing the persistence of transcriptionally silent proviruses. Hypoacetylation of histone proteins by histone deacetylases (HDAC) is involved in the maintenance of HIV-1 latency by repressing viral transcription. In addition, periodontal diseases, caused by polymicrobial subgingival bacteria including Porphyromonas gingivalis, are among the most prevalent infections of mankind. Here we demonstrate the effects of P. gingivalis on HIV-1 replication. This activity could be ascribable to the bacterial culture supernatant but not to other bacterial components such as fimbriae or LPS. We found that this HIV-1-inducing activity was recovered in the lower molecular mass (<3 kDa) fraction of the culture supernatant. We also demonstrated that P. gingivalis produces high concentrations of butyric acid, acting as a potent inhibitor of HDACs and causing histone acetylation. Chromatin immunoprecipitation assays revealed that the corepressor complex containing HDAC1 and AP-4 was dissociated from the HIV-1 long terminal repeat promoter upon stimulation with bacterial culture supernatant concomitantly with the association of acetylated histone and RNA polymerase II. We thus found that P. gingivalis could induce HIV-1 reactivation via chromatin modification and that butyric acid, one of the bacterial metabolites, is responsible for this effect. These results suggest that periodontal diseases could act as a risk factor for HIV-1 reactivation in infected individuals and might contribute to the systemic dissemination of the virus.
Antigen-Specific Suppression of Inflammatory Arthritis Using Liposomes
Authors: Capini Christelle , Jaturanpinyo Montree , Chang Hsin-I , Mutalik Srinivas , McNally Alice , Street Shayna , Steptoe Raymond , O'Sullivan Brendan , Davies Nigel , Thomas Ranjeny
Published: March 2009

Existing therapies for rheumatoid arthritis and other autoimmune diseases are not Ag specific, which increases the likelihood of systemic toxicity. We show that egg phosphatidylcholine liposomes loaded with Ag (OVA or methylated BSA) and a lipophilic NF-κB inhibitor (curcumin, quercetin, or Bay11-7082) suppress preexisting immune responses in an Ag-specific manner. We injected loaded liposomes into mice primed with Ag or into mice suffering from Ag-induced inflammatory arthritis. The liposomes targeted APCs in situ, suppressing the cells’ responsiveness to NF-κB and inducing Ag-specific FoxP3+ regulatory T cells. This regulatory mechanism suppressed effector T cell responses and the clinical signs of full-blown Ag-induced arthritis. Thus, liposomes encapsulate Ags and NF-κB inhibitors stably and efficiently and could be readily adapted to deliver Ags and inhibitors for Ag-specific suppression of other autoimmune and allergic diseases.
Functional Silencing Is Initiated and Maintained in Immature Anti-Insulin B Cells
Authors: Henry Rachel A. , Acevedo-Suárez Carlos A. , Thomas James W.
Published: March 2009

Mechanisms of B cell tolerance act during development in the bone marrow and periphery to eliminate or restrict autoreactive clones to prevent autoimmune disease. B cells in the spleens of mice that harbor anti-insulin BCR transgenes (125Tg) are maintained in a functionally silenced or anergic state by endogenous hormone, but it is not clear when and where anergy is induced. An in vitro bone marrow culture system was therefore used to probe whether small protein hormones, a critical class of autoantigens, could interact with the BCR to induce anergy early during B cell development. Upon exposure to insulin, anti-insulin (125Tg) immature B cells show similar hallmarks of anergy as those observed in mature splenic B cells. These include BCR down-regulation, impaired proliferative responses to anti-CD40, and diminished calcium mobilization upon stimulation with BCR-dependent and independent stimuli. Inhibition of calcineurin also results in reduced immature B cell proliferation in a similar manner, suggesting a potential mechanism through which reduced intracellular calcium mobilization may be altering cellular proliferation. Signs of impairment appear after short-term exposure to insulin, which are reversible upon Ag withdrawal. This suggests that a high degree of functional plasticity is maintained at this stage and that constant Ag engagement is required to maintain functional inactivation. These findings indicate that tolerance observed in mature, splenic 125Tg B cells is initiated by insulin in the developing B cell compartment and thus highlight an important therapeutic window for the prevention of insulin autoimmunity.
Neuromodulatory Activities of CD4+CD25+ Regulatory T Cells in a Murine Model of HIV-1-Associated Neurodegeneration
Authors: Liu Jianuo , Gong Nan , Huang Xiuyan , Reynolds Ashley D. , Mosley R. Lee , Gendelman Howard E.
Published: March 2009

HIV-1-associated neurocognitive impairments are intrinsically linked to microglial immune activation, persistent viral infection, and inflammation. In the era of antiretroviral therapy, more subtle cognitive impairments occur without adaptive immune compromise. We posit that adaptive immunity is neuroprotective, serving in both the elimination of infected cells through CD8+ cytotoxic T cell activities and the regulation of neuroinflammatory responses of activated microglia. For the latter, little is known. Thus, we studied the neuromodulatory effects of CD4+ regulatory T cells (Treg; CD4+CD25+) or effector T cells in HIV-1-associated neurodegeneration. A newly developed HIV-1 encephalitis mouse model was used wherein murine bone marrow-derived macrophages are infected with a full-length HIV-1YU2/vesicular stomatitis viral pseudotype and injected into basal ganglia of syngeneic immunocompetent mice. Adoptive transfer of CD3-activated Treg attenuated astrogliosis and microglia inflammation with concomitant neuroprotection. Moreover, Treg-mediated anti-inflammatory activities and neuroprotection were associated with up-regulation of brain-derived neurotrophic factor and glial cell-derived neurotrophic factor expression and down-regulation of proinflammatory cytokines, oxidative stress, and viral replication. Effector T cells showed contrary effects. These results, taken together, demonstrate the importance of Treg in disease control and raise the possibility of their utility for therapeutic strategies.
Decreased NK Cell Frequency and Function Is Associated with Increased Risk of KIR3DL Allele Polymorphism in Simian Immunodeficiency Virus-Infected Rhesus Macaques with High Viral Loads
Authors: Bostik Pavel , Kobkitjaroen Jaruda , Tang Weining , Villinger Francois , Pereira Lara E. , Little Dawn M. , Stephenson Susan T. , Bouzyk Mark , Ansari Aftab A.
Published: March 2009

NK cells have been established as an important effector of innate immunity in a variety of viral infections. In HIV-1 infection in humans, alterations of NK cell function, frequency, and expression of various NK receptors have been reported to be associated with differential dynamics of disease progression. Expression of certain alleles of KIR3DL and KIR3DS receptors on NK cells was shown to correlate with levels of virus replication. In the SIV-infected rhesus macaque (RM) model of AIDS, several families of killer inhibitory Ig-related receptors (KIR receptors) corresponding to their human counterparts have been characterized, but only at the level of individual sequence variants. Here we define 14 different alleles of KIR3DL expressed among 38 SIV-infected RM, characterized by either high or low levels of SIV replication, by analyzing multiple sequences from individual animals and show an unequal distribution of certain alleles in these cohorts. High levels of SIV replication were associated with significant increases in KIR3DL mRNA levels in addition to decreases in both the frequency and function of NK cells in these animals. The higher frequency of inheritance of two KIR3DL alleles characterized by a single nucleotide polymorphism 159 H/Q was associated with RM that exhibited high plasma viral load. This data for the first time defines multiple alleles of KIR3DL in RM and shows an association between virus control, NK cell function and genetic polymorphisms of KIR receptors.
MEKK3 Is Essential for Lymphopenia-Induced T Cell Proliferation and Survival
Authors: Wang Xiaofang , Chang Xing , Facchinetti Valeria , Zhuang Yuan , Su Bing
Published: March 2009

T cell homeostasis is crucial for maintaining an efficient and balanced T cell immunity. The interaction between TCR and self peptide (sp) MHC ligands is known to be the key driving force in this process, and it is believed to be functionally and mechanistically different from that initiated by the antigenic TCR stimulation. Yet, very little is known about the downstream signaling events triggered by this TCR-spMHC interaction and how they differ from those triggered by antigenic TCR stimulation. In this study, we show that T cell conditional ablation of MEKK3, a Ser/Thr kinase in the MAPK cascade, causes a significant reduction in peripheral T cell numbers in the conditional knockout mice, but does not perturb thymic T cell development and maturation. Using an adoptive mixed transfer method, we show that MEKK3-deficient T cells are severely impaired in lymphopenia-induced cell proliferation and survival. Interestingly, the Ag-induced T cell proliferation proceeds normally in the absence of MEKK3. Finally, we found that the activity of ERK1/2, but not p38 MAPK, was attenuated during the lymphopenia-driven response in MEKK3-deficient T cells. Together, these data suggest that MEKK3 may play a crucial selective role for spMHC-mediated T cell homeostasis.
Jagged1 Suppresses Collagen-Induced Arthritis by Indirectly Providing a Negative Signal in CD8+ T Cells
Authors: Kijima Mika , Iwata Akiko , Maekawa Yoichi , Uehara Hisanori , Izumi Keisuke , Kitamura Akiko , Yagita Hideo , Chiba Shigeru , Shiota Hiroshi , Yasutomo Koji
Published: March 2009

Distinct Notch ligands possess a characteristic ability in terms of functional T cell differentiation. However, the precise role or the therapeutic potential of each Notch ligand in autoimmune diseases is largely unknown. In this study, we examined whether Jagged1 modulates a collagen-induced rheumatoid arthritis (CIA) model by altering T cell responses. The injection of a soluble Jagged1-encoding plasmid, sJag1-P, before or even after initial type II collagen (CII) immunization suppressed the disease severity of CIA. However, this treatment did not suppress CII-specific CD4+ T cell proliferation and CII-specific Ab production. Depletion of either CD4+ or CD8+ T cells ameliorated CIA severity and sJag1-P further improved CIA in CD4+ but not CD8+ T cell-depleted mice. Injection of OVA and Jagged1-encoding plasmids inhibited proliferation of OVA-specific granzyme B-producing CD8+ T cells, although Jagged1 could not directly inhibit CD8+ T cell proliferation in vitro. The blockade of Jagged1 by an anti-Jagged1 Ab exacerbated CIA, whereas this effect was not observed in the absence of CD8+ T cells. These data indicate that Jagged1 is able to deliver an indirect negative signal into CD8+ T cells in vivo, which suggests its therapeutic potential in the treatment of CD8+ T cell-mediated diseases, including rheumatoid arthritis.
Villitis of Unknown Etiology Is Associated with a Distinct Pattern of Chemokine Up-Regulation in the Feto-Maternal and Placental Compartments: Implications for Conjoint Maternal Allograft Rejection and Maternal Anti-Fetal Graft-versus-Host Disease
Authors: Kim Mi Jeong , Romero Roberto , Kim Chong Jai , Tarca Adi L. , Chhauy Sovantha , LaJeunesse Christopher , Lee Deug-Chan , Draghici Sorin , Gotsch Francesca , Kusanovic Juan Pedro , Hassan Sonia S. , Kim Jung-Sun
Published: March 2009

The co-presence of histoincompatible fetal and maternal cells is a characteristic of human placental inflammation. Villitis of unknown etiology (VUE), a destructive inflammatory lesion of villous placenta, is characterized by participation of Hofbauer cells (placental macrophages) and maternal T cells. In contrast to acute chorioamnionitis of infection-related origin, the fundamental immunopathology of VUE is unknown. This study was performed to investigate the placental transcriptome of VUE and to determine whether VUE is associated with systemic maternal and/or fetal inflammatory response(s). Comparison of the transcriptome between term placentas without and with VUE revealed differential expression of 206 genes associated with pathways related to immune response. The mRNA expression of a subset of chemokines and their receptors (CXCL9, CXCL10, CXCL11, CXCL13, CCL4, CCL5, CXCR3, CCR5) was higher in VUE placentas than in normal placentas (p < 0.05). Analysis of blood cell mRNA showed a higher expression of CXCL9 and CXCL13 in the mother, and CXCL11 and CXCL13 in the fetus of VUE cases (p < 0.05). The median concentrations of CXCL9, CXCL10, and CXCL11 in maternal and fetal plasma were higher in VUE (p < 0.05). Comparison of preterm cases without and with acute chorioamnionitis revealed elevated CXCL9, CXCL10, CXCL11, and CXCL13 concentrations in fetal plasma (p < 0.05), but not in maternal plasma with chorioamnionitis. We report for the first time the placental transcriptome of VUE. A systemic derangement of CXC chemokines in maternal and fetal circulation distinguishes VUE from acute chorioamnionitis. We propose that VUE be a unique state combining maternal allograft rejection and maternal antifetal graft-vs-host disease mechanisms.
Loss of Mandibular Lymph Node Integrity Is Associated with an Increase in Sensitivity to HSV-1 Infection in CD118-Deficient Mice
Authors: Conrady Christopher D. , Thapa Manoj , Wuest Todd , Carr Daniel J. J.
Published: March 2009

Type I IFNs are potent antiviral cytokines that contribute to the development of the adaptive immune response. To determine the role of type I IFNs in this process in an infectious disease model, mice deficient in the type I IFN receptor (CD118−/−) were ocularly infected with HSV-1 and surveyed at times post infection in the nervous system and lymph node for virus and the host immune response. Virus titers were elevated in the trigeminal ganglia and brain stem with virus disseminating rapidly to the draining lymph node of CD118−/− mice. T cell and plasmacytoid dendritic cell infiltration into the brain stem was reduced in CD118−/− mice following infection, which correlated with a reduction in CXCL10 but not CXCL9 expression. In contrast, CXCL1 and CCL2 levels were up-regulated in the brainstem of CD118−/− mice associated with an increase in F4/80+ macrophages. By day 5 post infection, there was a significant loss in T, NK, and plasmacytoid dendritic cell numbers in the draining lymph nodes associated with an increase in apoptotic/necrotic T cells and an appreciable lack of HSV-specific CD8+ T cells. The adoptive transfer of HSV-specific TCR transgenic CD8+ T cells into CD118−/− mice at the time of infection modestly reduced viral titers in the nervous system suggesting in addition to the generation of HSV-specific CD8+ T cells, other type I IFN-activated pathways are instrumental in controlling acute infection.
Multiple distinct risk loci for nicotine dependence identified by dense coverage of the complete family of nicotinic receptor subunit (CHRN) genes
Authors: Saccone Nancy L. , Saccone Scott F. , Hinrichs Anthony L. , Stitzel Jerry A. , Duan Weimin , Pergadia Michele L. , Agrawal Arpana , Breslau Naomi , Grucza Richard A. , Hatsukami Dorothy , Johnson Eric O. , Madden Pamela A.F. , Swan Gary E. , Wang Jen C. , Goate Alison M. , Rice John P. , Bierut Laura J.
Published: March 2009

Tobacco smoking continues to be a leading cause of preventable death. Recent research has underscored the important role of specific cholinergic nicotinic receptor subunit (CHRN) genes in risk for nicotine dependence and smoking. To detect and characterize the influence of genetic variation on vulnerability to nicotine dependence, we analyzed 226 SNPs covering the complete family of 16 CHRN genes, which encode the nicotinic acetylcholine receptor (nAChR) subunits, in a sample of 1,050 nicotine‐dependent cases and 879 non‐dependent controls of European descent. This expanded SNP coverage has extended and refined the findings of our previous large‐scale genome‐wide association and candidate gene study. After correcting for the multiple tests across this gene family, we found significant association for two distinct loci in the CHRNA5–CHRNA3–CHRNB4 gene cluster, one locus in the CHRNB3–CHRNA6 gene cluster, and a fourth, novel locus in the CHRND–CHRNG gene cluster. The two distinct loci in CHRNA5–CHRNA3–CHRNB4 are represented by the non‐synonymous SNP rs16969968 in CHRNA5 and by rs578776 in CHRNA3, respectively, and joint analyses show that the associations at these two SNPs are statistically independent. Nominally significant single‐SNP association was detected in CHRNA4 and CHRNB1. In summary, this is the most comprehensive study of the CHRN genes for involvement with nicotine dependence to date. Our analysis reveals significant evidence for at least four distinct loci in the nicotinic receptor subunit genes that each influence the transition from smoking to nicotine dependence and may inform the development of improved smoking cessation treatments and prevention initiatives. © 2009 Wiley‐Liss, Inc.
Suggestive linkage at 9p22 in bipolar disorder weighted by alcohol abuse
Authors: Saunders Erika F.H. , Zhang Peng , Copeland J. Nathan , Mclnnis Melvin G. , Zöllner Sebastian
Published: March 2009

Bipolar disorder (BP) is a highly heritable disorder, however attempts to map genetic risk factors are challenging. One possible reason for these difficulties is the genetic heterogeneity of BP. Hence, focusing on clinically homogeneous families to create a genetically more homogeneous sample may increase the power of finding a specific variant. Alcohol abuse (AA) and alcohol dependence (AD) are familial in BP families, and these families may carry a specific risk variant for BP. We tested this hypothesis by performing a genome‐wide linkage scan in 638 pedigrees (1,835 individuals) from the National Institute of Mental Health Genetics Initiative for BP, weighting the evidence for linkage according to the family's frequency of AA or AD. Using AA weighting, we identified a linkage region on 9p22.2 with an NPL score of 3.23. The region had previously been identified in a meta‐analysis of linkage in bipolar disorder. We used permutation analysis to assess if weighting by AA increased the linkage signal more than expected by chance and observed a significant P‐value (P = 0.048). Therefore, the genetic risk factor for BP on 9p22.2 has an increased effect in families with high levels of AA. In summary, we present an example of using covariates such as AA and AD to define subtypes of BP, demonstrate how using such subtypes can improve the power of a linkage scan, and demonstrate statistical approaches to validate the suggested interaction. © 2009 Wiley‐Liss, Inc.
Association of the α4 integrin subunit gene (ITGA4) with autism
Authors: Correia Catarina , Coutinho Ana M. , Almeida Joana , Lontro Raquel , Lobo Cristina , Miguel Teresa S. , Martins Madalena , Gallagher Louise , Conroy Judith , Gill Michael , Oliveira Guiomar , Vicente Astrid M.
Published: March 2009

In the present work, we provide further evidence for the involvement of the integrin alpha‐4 precursor gene (ITGA4) in the etiology of autism, by replicating previous findings of a genetic association with autism in various independent populations. The ITGA4 gene maps to the autism linkage region on 2q31‐33 and is therefore a plausible positional candidate. We tested eight single nucleotide polymorphisms (SNPs) in the ITGA4 gene region for association with autism in a sample of 164 nuclear families. Evidence for association was found for the rs155100 marker (P = 0.019) and for a number of specific marker haplotypes containing this SNP (0.00053 < P < 0.022). α4 integrins are known to play a key role in neuroinflammatory processes, which are hypothesized to contribute to autism. In this study, an association was found between the ITGA4 rs1449263 marker and levels of a serum autoantibody directed to brain tissue, which was previously shown to be significantly more frequent in autistic patients than in age‐matched controls in our population. This result suggests that the ITGA4 gene could be involved in a neuroimmune process thought to occur in autistic patients and, together with previous findings, offers a new perspective on the role of integrins in the etiology of autism to which little attention has been paid so far. © 2009 Wiley‐Liss, Inc.
Free radical damage to cerebral cortex in Alzheimer's disease, microvascular brain injury, and smoking
Authors: Sonnen Joshua A. , Larson Eric B. , Gray Shelly L. , Wilson Angela , Kohama Steven G. , Crane Paul K. , Breitner John C. S. , Montine Thomas J.
Published: March 2009

Evidence supports a pathogenic role for free radical injury to brain in Alzheimer's disease; however, clinical trial results are only mildly encouraging. Examining brains from The Adult Changes in Thought study offers a unique perspective. Selectively increased free radical damage to cerebral cortex was associated with Alzheimer's disease, microvascular brain injury, and current smoking, but not with antioxidant supplement usage. Our results support suppression of free radical injury to brain as a therapeutic target for Alzheimer's disease and microvascular brain injury; however, future clinical trials should consider other antioxidants or doses than those identified in our study. Ann Neurol 2009;65:226–229
Medullary pain facilitating neurons mediate allodynia in headache‐related pain
Authors: Edelmayer Rebecca M. , Vanderah Todd W. , Majuta Lisa , Zhang En‐Tan , Fioravanti Beatriz , De Felice Milena , Chichorro Juliana G. , Ossipov Michael H. , King Tamara , Lai Josephine , Kori Shashi H. , Nelsen Andrew C. , Cannon Keri E. , Heinricher Mary M. , Porreca Frank
Published: March 2009

Objective

To develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches. To explore neural mechanisms underlying cephalic and extracephalic allodynia.

Methods

Inflammatory mediators (IM) were applied to the dura of unanesthetized rats via previously implanted cannulas, and sensory thresholds of the face and hind‐paws were characterized.

Results

IM elicited robust facial and hind‐paw allodynia, which peaked within 3 hours. These effects were reminiscent of cutaneous allodynia seen in patients with migraine or other primary headache conditions, and were reversed by agents used clinically in the treatment of migraine, including sumatriptan, naproxen, and a calcitonin gene–related peptide antagonist. Consistent with clinical observations, the allodynia was unaffected by a neurokinin‐1 antagonist. Having established facial and hind‐paw allodynia as a useful animal surrogate of headache‐associated allodynia, we next showed that blocking pain‐facilitating processes in the rostral ventromedial medulla (RVM) interfered with its expression. Bupivacaine, destruction of putative pain‐facilitating neurons, or block of cholecystokinin receptors prevented or significantly attenuated IM‐induced allodynia. Electrophysiological studies confirmed activation of pain‐facilitating RVM “on” cells and transient suppression of RVM “off” cells after IM.

Interpretation

Facial and hind‐paw allodynia associated with dural stimulation is a useful surrogate of pain associated with primary headache including migraine and may be exploited mechanistically for development of novel therapeutic strategies for headache pain. The data also demonstrate the requirement for activation of descending facilitation from the RVM for the expression of cranial and extracranial cutaneous allodynia, and are consistent with a brainstem generator of allodynia associated with headache disorders. Ann Neurol 2009;65:184–193
Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy
Authors: Banno Haruhiko , Katsuno Masahisa , Suzuki Keisuke , Takeuchi Yu , Kawashima Motoshi , Suga Noriaki , Takamori Motoko , Ito Mizuki , Nakamura Tomohiko , Matsuo Koji , Yamada Shinichi , Oki Yumiko , Adachi Hiroaki , Minamiyama Makoto , Waza Masahiro , Atsuta Naoki , Watanabe Hirohisa , Fujimoto Yasushi , Nakashima Tsutomu , Tanaka Fumiaki , Doyu Manabu , Sobue Gen
Published: March 2009

Objective

Spinal and bulbar muscular atrophy (SBMA) is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). Animal studies have shown that the pathogenesis of SBMA is dependent on serum testosterone level. This study is aimed at evaluating the efficacy and safety of androgen deprivation by leuprorelin acetate in patients with SBMA.

Methods

Fifty SBMA patients underwent subcutaneous injections of leuprorelin acetate or placebo in a randomized, placebo‐controlled trial for 48 weeks, followed by an open‐label trial for an additional 96 weeks, in which 19 patients of the leuprorelin group and 15 of the placebo group received leuprorelin acetate. The patients who did not participate in the open‐label trial were also followed up for the 96‐week period (UMIN000000474).

Results

Leuprorelin acetate significantly extended the duration of cricopharyngeal opening in videofluorography and decreased mutant AR accumulation in scrotal skin biopsy. The patients treated with leuprorelin acetate for 144 weeks exhibited significantly greater functional scores and better swallowing parameters than those who received placebo. Autopsy of one patient who received leuprorelin acetate for 118 weeks suggested that androgen deprivation inhibits the nuclear accumulation or stabilization, or both, of mutant AR in the motor neurons of the spinal cord and brainstem.

Interpretation

These observations suggest that administration of leuprorelin acetate suppresses the deterioration of neuromuscular impairment in SBMA by inhibiting the toxic accumulation of mutant AR. The results of this phase 2 trial support the start of large‐scale clinical trials of androgen deprivation for SBMA. Ann Neurol 2009;65:140–150
Lacunar stroke is associated with diffuse blood–brain barrier dysfunction
Authors: Wardlaw Joanna M. , Doubal Fergus , Armitage Paul , Chappell Francesca , Carpenter Trevor , Muñoz Maniega Susana , Farrall Andrew , Sudlow Cathie , Dennis Martin , Dhillon Baljean
Published: March 2009

Objective

Lacunar stroke is common (25% of ischemic strokes) and mostly because of an intrinsic cerebral microvascular disease of unknown cause. Although considered primarily to be an ischemic process, the vessel and tissue damage could also be explained by dysfunctional endothelium or blood–brain barrier (BBB) leak, not just ischemia. We tested for subtle generalized BBB leakiness in patients with lacunar stroke and control patients with cortical ischemic stroke.

Methods

We recruited patients with lacunar and mild cortical stroke. We assessed BBB leak in gray matter, white matter, and cerebrospinal fluid, at least 1 month after stroke, using magnetic resonance imaging before and after intravenous gadolinium. We measured tissue enhancement for 30 minutes after intravenous gadolinium by two image analysis approaches (regions of interest and tissue segmentation). We compared the enhancement (leak) between lacunar and cortical patients, and associations with key variables, using general linear modeling.

Results

We recruited 51 lacunar and 46 cortical stroke patients. Signal enhancement after gadolinium was higher in lacunar than cortical stroke patients in white matter (p < 0.001) and cerebrospinal fluid (p < 0.003) by both analysis methods, independent of other variables. Signal enhancement after gadolinium was also associated with increasing age and enlarged perivascular spaces, but these did not explain the lacunar‐cortical difference.

Interpretation

Patients with lacunar stroke have subtle, diffuse BBB dysfunction in white matter. Further studies are required to determine the relative contributions of BBB dysfunction and/or ischemia to the microvascular and brain abnormalities in lacunar stroke. Ann Neurol 2009;65:194–202
Reperfusion normalizes motor activation patterns in large‐vessel disease
Authors: Chmayssani Mohamad , Lazar Ronald M. , Hirsch Joy , Marshall Randolph S.
Published: March 2009

Objective

Hemodynamic impairment in one hemisphere has been shown to trigger ipsilateral motor activation in the opposite hemisphere on functional imaging. We hypothesized that reversing the hypoperfusion would normalize the motor activation pattern.

Methods

We studied four patients with high‐grade stenosis and impaired vasomotor reactivity (VMR) but no stroke. Functional magnetic resonance imaging motor activation pattern before and after VMR normalization was compared with seven healthy control subjects scanned at an interval of 3 months using voxel‐wise statistical parametric maps and region of interest analysis. Subjects performed a repetitive hand closure task in synchrony with 1Hz metronome tone. We used repeated‐measures analysis of variance to compute the interaction between group (patients/control subjects) and time by obtaining the average blood oxygen level dependent signal of three motor regions of interest in each hemisphere.

Results

Two patients normalized their VMR after spontaneous resolution of dissection, and two after revascularization procedures. Both voxel‐wise statistical maps and region of interest analysis showed that VMR normalization was associated in each case with a reduction in the atypical activation in the hemisphere opposite to the previously hypoperfused hemisphere (p < 0.001).

Interpretation

In the presence of a physiological stressor such as hypoperfusion, the brain is capable of dynamic functional reorganization to the opposite hemisphere that is reversible when normal blood flow is restored. These findings are important to our understanding of the clinical consequences of hemodynamic failure and the role of the ipsilateral hemisphere in maintaining normal neurological function. Ann Neurol 2009;65:203–208
Decreased cerebrospinal fluid Aβ42 correlates with brain atrophy in cognitively normal elderly
Authors: Fagan Anne M. , Head Denise , Shah Aarti R. , Marcus Daniel , Mintun Mark , Morris John C. , Holtzman David M.
Published: March 2009

Objective

For therapies for Alzheimer's disease (AD) to have the greatest impact, it will likely be necessary to treat individuals in the “preclinical” (presymptomatic) stage. Fluid and neuroimaging measures are being explored as possible biomarkers of AD pathology that could aid in identifying individuals in this stage to target them for clinical trials and to direct and monitor therapy. The objective of this study was to determine whether cerebrospinal fluid (CSF) biomarkers for AD suggest the presence of brain damage in the preclinical stage of AD.

Methods

We investigated the relation between structural neuroimaging measures (whole‐brain volume) and levels of CSF amyloid‐β (Aβ)40, Aβ42, tau, and phosphorylated tau181 (ptau181), and plasma Aβ40 and Aβ42 in well‐characterized research subjects with very mild and mild dementia of the Alzheimer type (n = 29) and age‐matched, cognitively normal control subjects (n = 69).

Results

Levels of CSF tau and ptau181, but not Aβ42, correlated inversely with whole‐brain volume in very mild and mild dementia of the Alzheimer type, whereas levels of CSF Aβ42, but not tau or ptau181, were positively correlated with whole‐brain volume in nondemented control subjects.

Interpretation

Reduction in CSF Aβ42, likely reflecting Aβ aggregation in the brain, is associated with brain atrophy in the preclinical phase of AD. This suggests that there is toxicity associated with Aβ aggregation before the onset of clinically detectable disease. Increases in CSF tau (and ptau181) are later events that correlate with further structural damage and occur with clinical onset and progression. Ann Neurol 2009;65:176–183
Katalyse in der Totalsynthese von Bryostatin 16
Authors: Miller Aubry K.
Published: March 2009

Mit zwei Additionen zum Produkt: Eine Totalsynthese von Bryostatin 16 zeichnet sich durch zwei Übergangsmetall‐katalysierte Additionen aus. Die erste liefert Ring B und ermöglicht die Zuordnung seiner relativen Konfiguration; die zweite schließt den Makrocyclus mithilfe einer seltenen Isomerisierung. Die beiden Reaktionen benötigen weder Substrataktivierung, noch bilden sie Nebenprodukte. Die Makrocyclisierung ist eine effiziente Alternative zu traditionellen Verfahren.

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