bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating Concentrations of Soluble Receptor for AGE Are Associated With Age and AGER Gene Polymorphisms in Children With Newly Diagnosed Type 1 Diabetes
Authors: Salonen Kirsi M. , Ryhänen Samppa J. , Forbes Josephine M. , Härkönen Taina , Ilonen Jorma , Laine Antti-Pekka , Groop Per-Henrik , Knip Mikael ,   for the Finnish Pediatric Diabetes Register
Published: April 2014

OBJECTIVE
We analyzed the relationship among soluble receptor for advanced glycation end products (sRAGEs), the clinical phenotype, HLA genotype, and risk-associated single nucleotide polymorphisms (SNPs) in the AGER gene in a large population of Finnish children with newly diagnosed type 1 diabetes.

RESEARCH DESIGN AND METHODS
Samples from 2,115 clinically phenotyped children &lt;15 years of age in whom type 1 diabetes was diagnosed and 316 control subjects were analyzed for sRAGEs. Three SNPs of AGER, previously associated with HLA-DR/DQ haplotype independent diabetes risk (rs2070600, rs9469089, and rs17493811), were analyzed in 1,390 affected subjects.

RESULTS
Children with type 1 diabetes and control subjects had similar sRAGE concentrations (1,171 vs. 1,153 pg/mL, P = 0.48). There was a correlation between age at diagnosis and serum sRAGE concentrations (r = 0.10, P &lt; 0.001) among the patients but not among the control subjects. Children &lt;2 years of age had the lowest concentrations in the diabetic population (1,027 vs. 1,181 pg/mL, P &lt; 0.001) and the highest among the control subjects (1,329 vs. 1,140 pg/mL, P = 0.04). Ketoacidosis at diagnosis was associated with reduced concentrations (1,086 vs. 1,190 pg/mL, P &lt; 0.001). HLA DR3/DR4 heterozygosity and the DR3 allele were associated with reduced sRAGE concentrations. The predisposing AA genotype of rs2070600 was associated with decreased sRAGE concentrations, while the protective CC genotype of rs9469089 was linked to increased concentrations.

CONCLUSIONS
Age and AGER polymorphisms are associated with the circulating sRAGE concentration among children with type 1 diabetes. The observations of reduced sRAGE concentrations in young children, in those with ketoacidosis, and in carriers of the high-risk HLA DR3/DR4 genotype suggest that decreased sRAGE concentration reflects a more aggressive disease phenotype.
Use of programmable versus nonprogrammable shunts in the management of hydrocephalus secondary to aneurysmal subarachnoid hemorrhage: a retrospective study with cost-benefit analysis
Authors: Lee Lester , King Nicolas K. K. , Kumar Dinesh , Ng Yew Poh , Rao Jai , Ng Huiyu , Lee Kah Keow , Wang Ernest , Ng Ivan 
Published: April 2014

Object
The choice of programmable or nonprogrammable shunts for the management of hydrocephalus after aneurysmal subarachnoid hemorrhage (SAH) remains undefined. Variable intracranial pressures make optimal management difficult. Programmable shunts have been shown to reduce problems with drainage, but at 3 times the cost of nonprogrammable shunts.

Methods
All patients who underwent insertion of a ventriculoperitoneal shunt for hydrocephalus after aneurysmal SAH between 2006 and 2012 were included. Patients were divided into those in whom nonprogrammable shunts and those in whom programmable shunts were inserted. The rates of shunt revisions, the reasons for adjustments of shunt settings in patients with programmable devices, and the effectiveness of the adjustments were analyzed. A cost-benefit analysis was also conducted to determine if the overall cost for programmable shunts was more than for nonprogrammable shunts.

Results
Ninety-four patients underwent insertion of shunts for hydrocephalus secondary to SAH. In 37 of these patients, nonprogrammable shunts were inserted, whereas in 57 programmable shunts were inserted. Four (7%) of 57 patients with programmable devices underwent shunt revision, whereas 8 (21.6%) of 37 patients with nonprogrammable shunts underwent shunt revision (p = 0.0413), and 4 of these patients had programmable shunts inserted during shunt revision. In 33 of 57 patients with programmable shunts, adjustments were made. The adjustments were for a trial of functional improvement (n = 21), overdrainage (n = 5), underdrainage (n = 6), or overly sunken skull defect (n = 1). Of these 33 patients, 24 showed neurological improvements (p = 0.012). Cost-benefit analysis showed $646.60 savings (US dollars) per patient if programmable shunts were used, because the cost of shunt revision is a lot higher than the cost of the shunt.

Conclusions
The rate of shunt revision is lower in patients with programmable devices, and these are therefore more cost-effective. In addition, the shunt adjustments made for patients with programmable devices also resulted in better neurological outcomes.
Rapid and sensitive intraoperative detection of mutations in the isocitrate dehydrogenase 1 and 2 genes during surgery for glioma
Authors: Kanamori Masayuki , Kikuchi Atsuo , Watanabe Mika , Shibahara Ichiyo , Saito Ryuta , Yamashita Yoji , Sonoda Yukihiko , Kumabe Toshihiro , Kure Shigeo , Tominaga Teiji 
Published: April 2014

Object
Intraoperative diagnosis is important in determining the strategies during surgery for glioma. Because the mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes have diagnostic, prognostic, and predictive values, the authors assessed the feasibility and significance of a simplified method for the intraoperative detection of IDH1 and IDH2 gene mutations.

Methods
Rapid DNA extraction, amplification with conventional polymerase chain reaction (PCR) or co-amplification at lower denaturation temperature PCR (COLD-PCR), and fluorescence melting curve analysis with adjacent hybridization probes were performed for the intraoperative detection of IDH1 and IDH2 mutations in 18 cases of suspected nonneoplastic lesions and low- and high-grade gliomas and in 3 cases of radiation necrosis.

Results
DNA extraction for detection of the mutation took 60–65 minutes. The results of this assay showed complete correlation with that of Sanger sequencing. The sensitivity for detection of mutations in a background of wild-type genes was 12.5% and 2.5% in conventional PCR and COLD-PCR, respectively. The diagnosis of glioma was established in 3 of 5 cases in which definitive diagnosis was not obtained using frozen sections, and information was obtained for the discrimination of glioblastoma or glioblastoma with an oligodendroglioma component from anaplastic glioma or secondary glioblastoma. This assay also detected a small fraction of tumor cells with IDH1 mutation in radiation necrosis.

Conclusions
These methods provide important information for establishing the differential diagnosis between low-grade glioma and nonneoplastic lesions and the diagnosis for subtypes of high-grade glioma. Although tumor cells in radiation necrosis were detected with a high sensitivity, further investigation is necessary for clinical application in surgery for recurrent glioma.
Anterior cerebral artery bypass for complex aneurysms: an experience with intracranial-intracranial reconstruction and review of bypass options
Authors: Abla Adib A. , Lawton Michael T. 
Published: April 2014

Object
The authors describe their experience with intracranial-to-intracranial (IC-IC) bypasses for complex anterior cerebral artery (ACA) aneurysms with giant size, dolichoectatic morphology, or intraluminal thrombus; they determine how others have addressed the limitations of ACA bypass; and they discuss clinical indications and microsurgical technique.

Methods
A consecutive, single-surgeon experience with ACA aneurysms and bypasses over a 16-year period was retrospectively reviewed. Bypasses for ACA aneurysms reported in the literature were also reviewed.

Results
Ten patients had aneurysms that were treated with ACA bypass as part of their surgical intervention. Four patients presented with subarachnoid hemorrhage and 3 patients with mass effect symptoms from giant aneurysms; 1 patient with bacterial endocarditis had a mycotic aneurysm, and 1 patient's meningioma resection was complicated by an iatrogenic pseudoaneurysm. One patient had his aneurysm discovered incidentally. There were 2 precommunicating aneurysms (A1 segment of the ACA), 5 communicating aneurysms (ACoA), and 3 postcommunicating (A2–A3 segments of the ACA). In situ bypasses were used in 4 patients (A3-A3 bypass), interposition bypasses in 4 patients, reimplantation in 1 patient (pericallosal artery-to-callosomarginal artery), and reanastomosis in 1 patient (pericallosal artery). Complete aneurysm obliteration was demonstrated in 8 patients, and bypass patency was demonstrated in 8 patients. One bypass thrombosed, but 4 years later. There were no operative deaths, and permanent neurological morbidity was observed in 2 patients. At last follow-up, 8 patients (80%) were improved or unchanged. In a review of the 29 relevant reports, the A3-A3 in situ bypass was used most commonly, extracranial (EC)–IC interpositional bypasses were the second most common, and reanastomosis and reimplantation were used the least.

Conclusions
Anterior cerebral artery aneurysms requiring bypass are rare and can be revascularized in a variety of ways. Anterior cerebral artery aneurysms, more than any other aneurysms, require a thorough survey of patient-specific anatomy and microsurgical options before deciding on an individualized management strategy. The authors' experience demonstrates a preference for IC-IC reconstruction, but EC-IC bypasses are reported frequently in the literature. The authors conclude that ACA bypass with indirect aneurysm occlusion is a good alternative to direct clip reconstruction for complex ACA aneurysms.
La compréhension de la maltraitance
Authors: Labache Lucette 
Published: April 2014

Depuis plus d’une dizaine d’années de pratique de la formation sur la connaissance des départements d’outre-mer, j’ai noté la récurrence d’un thème particulier, la maltraitance chez les originaires des Antilles. En effet, le public est de plus en plus demandeur d’éclaircissements sur les « châtiments corporels », sur les « brutalités » physiques et psychologiques que les parents migrants antillais exerceraient sur leurs enfants. Les appréciations portées par les professionnels en contact avec cette population sont révélatrices d’un amalgame très vite réduit à une vision culturaliste. L’objet de cet article est de montrer comment les apports de l’anthropologie et la clinique peuvent servir à comprendre un cas de maltraitance.
A Postmigrational Switch among Skin-Derived Dendritic Cells to a Macrophage-Like Phenotype Is Predetermined by the Intracutaneous Cytokine Balance
Authors: de Gruijl Tanja D. , Sombroek Claudia C. , Lougheed Sinéad M. , Oosterhoff Dinja , Buter Jan , van den Eertwegh Alfons J. M. , Scheper Rik J. , Pinedo Herbert M. 
Published: April 2014

AbstractMigration of dendritic cells (DC) to secondary lymphoid organs under proinflammatory conditions coincides with their maturation and acquisition of T cell stimulatory abilities. In contrast, impaired activation of DC, e.g., in tumor-conditioned environments, may hamper their activation and possibly their subsequent migration to lymph nodes, leading to either immunological tolerance or ignorance, respectively. In this study, the influence of cytokines in the peripheral skin microenvironment on the activation state of migrating cutaneous DC was assessed using an ex vivo human skin explant model. We observed a phenotypic shift from mature CD83+ DC to immature CD14+ macrophage-like cells within 7 days subsequent to migration from unconditioned skin. These macrophage-like cells displayed a poor T cell stimulatory ability and lacked expression of CCR7, thus precluding their migration to paracortical T cell areas in the lymph nodes. The balance of suppressive and stimulatory cytokines during the initiation of migration decided the postmigrational fate of DC with IL-10 accelerating and GM-CSF and IL-4 preventing the phenotypic switch, which proved irreversible once established. These observations indicate that, in immunosuppressed environments, a postmigrational DC-to-macrophage shift may hinder T cell activation, but also that it may be prevented by prior conditioning of the tissue microenvironment by GM-CSF and/or IL-4.
Regulation of Microtubule Formation in Activated Mast Cells by Complexes of γ-Tubulin with Fyn and Syk Kinases
Authors: Sulimenko Vadym , Dráberová Eduarda , Sulimenko Tetyana , Macůrek Libor , Richterová Vĕra , Dráber Petr , Dráber Pavel 
Published: April 2014

AbstractAggregation of the high-affinity IgE receptors (FcεRIs) on the surface of granulated mast cells initiates a chain of signaling events culminating in the release of allergy mediators. Although microtubules are involved in mast cell degranulation, the molecular mechanism that controls microtubule rearrangement after FcεRI triggering is poorly understood. In this study, we show that the activation of bone marrow-derived mast cells (BMMCs) induced by FcεRI aggregation or treatment with pervanadate leads to a rapid polymerization of microtubules. This polymerization was not dependent on the presence of Lyn kinase as determined by experiments with BMMCs isolated from Lyn-negative mice. One of the key regulators of microtubule polymerization is γ-tubulin. Immunoprecipitation experiments revealed that γ-tubulin from activated cells formed complexes with Fyn and Syk protein tyrosine kinases and several tyrosine phosphorylated proteins from both wild-type and Lyn−/− BMMCs. Pretreatment of the cells with Src-family or Syk-family selective tyrosine kinase inhibitors, PP2 or piceatannol, respectively, inhibited the formation of microtubules and reduced the amount of tyrosine phosphorylated proteins in γ-tubulin complexes, suggesting that Src and Syk family kinases are involved in the initial stages of microtubule formation. This notion was corroborated by pull-down experiments in which γ-tubulin complex bounds to the recombinant Src homology 2 and Src homology 3 domains of Fyn kinase. We propose that Fyn and Syk kinases are involved in the regulation of binding properties of γ-tubulin and/or its associated proteins, and thus modulate the microtubule nucleation in activated mast cells.
Antiangiogenic and Antitumor Activities of IL-27
Authors: Shimizu Motomu , Shimamura Mariko , Owaki Toshiyuki , Asakawa Masayuki , Fujita Koji , Kudo Motoshige , Iwakura Yoichiro , Takeda Yasutaka , Luster Andrew D. , Mizuguchi Junichiro , Yoshimoto Takayuki 
Published: April 2014

AbstractIL-27 is a novel IL-6/IL-12 family cytokine playing an important role in the early regulation of Th1 responses. We have recently demonstrated that IL-27 has potent antitumor activity, which is mainly mediated through CD8+ T cells, against highly immunogenic murine colon carcinoma. In this study, we further evaluated the antitumor and antiangiogenic activities of IL-27, using poorly immunogenic murine melanoma B16F10 tumors, which were engineered to overexpress single-chain IL-27 (B16F10 + IL-27). B16F10 + IL-27 cells exerted antitumor activity against not only s.c. tumor but also experimental pulmonary metastasis. Similar antitumor and antimetastatic activities of IL-27 were also observed in IFN-γ knockout mice. In NOD-SCID mice, these activities were decreased, but were still fairly well-retained, suggesting that different mechanisms other than the immune response are also involved in the exertion of these activities. Immunohistochemical analyses with Abs against vascular endothelial growth factor and CD31 revealed that B16F10 + IL-27 cells markedly suppressed tumor-induced neovascularization in lung metastases. Moreover, B16F10 + IL-27 cells clearly inhibited angiogenesis by dorsal air sac method, and IL-27 exhibited dose-dependent inhibition of angiogenesis on chick embryo chorioallantoic membrane. IL-27 was revealed to directly act on HUVECs and induce production of the antiangiogenic chemokines, IFN-γ-inducible protein (IP-10) and monokine induced by IFN-γ. Finally, augmented mRNA expression of IP-10 and monokine induced by IFN-γ was detected at the s.c. B16F10 + IL-27 tumor site, and antitumor activity of IL-27 was partially inhibited by the administration of anti-IP-10. These results suggest that IL-27 possesses potent antiangiogenic activity, which plays an important role in its antitumor and antimetastatic activities.
TCR-Dependent Cell Response Is Modulated by the Timing of CD43 Engagement
Authors: Fierro Nora A. , Pedraza-Alva Gustavo , Rosenstein Yvonne 
Published: April 2014

AbstractBinding of Ag by the Ag receptor in combination with other stimuli provided by costimulatory receptors triggers the expansion and differentiation of T lymphocytes. However, it is unclear whether the time when costimulatory molecules interact with their counterreceptors with regards to Ag recognition leads to different T cell responses. Provided that the coreceptor molecule CD43 is a very abundant molecule evenly distributed on the membrane of T cell surface protruding 45 nm from the cell, we hypothesized that CD43 is one of the first molecules that interacts with the APC and thus modulates TCR activation. We show that engaging CD43 before or simultaneously with the TCR inhibited Lck-Src homology 2 domain containing phosphatase-1 interaction, preventing the onset of a negative feedback loop on TCR signals, favoring high levels of IL-2, cell proliferation, and secretion of proinflammatory cytokines and chemokines. In contrast, the intracellular signals resulting of engaging the TCR before CD43 were insufficient to induce IL-2 production and cell proliferation. Interestingly, when stimulated through the TCR and CD28, cells proliferated vigorously, independent of the order with which molecules were engaged. These results indicate that CD43 induces a signaling cascade that prolongs the duration of TCR signaling and support the temporal summation model for T cell activation. In addition to the strength and duration of intracellular signals, our data underscore temporality with which certain molecules are engaged as yet another mechanism to fine tune T cell signal quality, and ultimately immune function.
BTNL2, a Butyrophilin-Like Molecule That Functions to Inhibit T Cell Activation
Authors: Nguyen Thang , Liu Xikui K. , Zhang Yongliang , Dong Chen 
Published: April 2014

Abstract
B7 family members regulate T cell activation and tolerance. Although butyrophilin proteins share sequence homology with the B7 molecules, it is unclear whether they have any function in immune responses. In the present study, we characterize an MHC class II gene-linked butyrophilin family member, butyrophilin-like 2 (BTNL2), the mutation of which has been recently associated with the inflammatory autoimmune diseases sarcoidosis and myositis. Mouse BTNL2 is a type I transmembrane protein with two pairs of Ig-like domains separated by a heptad peptide sequence. BTNL2 mRNA is highly expressed in lymphoid tissues as well as in intestine. To characterize the function of BTNL2, we produced a BTNL2-Ig fusion protein. It recognized a putative receptor whose expression on B and T cells was significantly enhanced after activation. BTNL2-Ig inhibited T cell proliferation and TCR activation of NFAT, NF-κB, and AP-1 signaling pathways. BTNL2 is thus the first member of the butyrophilin family that regulates T cell activation, which has implications in immune diseases and immunotherapy.
T Cell-Independent, TLR-Induced IL-12p70 Production in Primary Human Monocytes
Authors: Bekeredjian-Ding Isabelle , Roth Susanne Ilona , Gilles Stefanie , Giese Thomas , Ablasser Andrea , Hornung Veit , Endres Stefan , Hartmann Gunther 
Published: April 2014

AbstractIL-12p70 is a key cytokine for the induction of Th1 immune responses. IL-12p70 production in myeloid cells is thought to be strictly controlled by T cell help. In this work we demonstrate that primary human monocytes can produce IL-12p70 in the absence of T cell help. We show that human monocytes express TLR4 and TLR8 but lack TLR3 and TLR7 even after preincubation with type I IFN. Simultaneous stimulation of TLR4 and TLR8 induced IL-12p70 in primary human monocytes. IL-12p70 production in peripheral blood myeloid dendritic cells required combined stimulation of TLR7/8 ligands together with TLR4 or with TLR3 ligands. In the presence of T cell-derived IL-4, but not IFN-γ, stimulation with TLR7/8 ligands was sufficient to stimulate IL-12p70 production. In monocytes, type I IFN was required but not sufficient to costimulate IL-12p70 induction by TLR8 ligation. Furthermore, TLR8 ligation inhibited LPS-induced IL-10 in monocytes, and LPS alone gained the ability to stimulate IL-12p70 in monocytes when the IL-10 receptor was blocked. Together, these results demonstrate that monocytes are licensed to synthesize IL-12p70 through type I IFN provided via the Toll/IL-1R domain-containing adaptor inducing IFN-β pathway and the inhibition of IL-10, both provided by combined stimulation with TLR4 and TLR8 ligands, triggering a potent Th1 response before T cell help is established.
Differential Activation of IFN Regulatory Factor (IRF)-3 and IRF-5 Transcription Factors during Viral Infection
Authors: Cheng Tsu-Fan , Brzostek Sabrina , Ando Osamu , Van Scoy Sarah , Kumar K. Prasanna , Reich Nancy C. 
Published: April 2014

Abstract
Members of the IFN regulatory factor (IRF) family regulate gene expression critical to immune response, hemopoiesis, and proliferation. Although related by homology at their N-terminal DNA-binding domain, they display individual functional properties. The distinct properties result from differences in regulated expression, response to activating signals, and interaction with DNA regulatory elements. IRF-3 is expressed ubiquitously and is activated by serine phosphorylation in response to viral infection or TLR signaling. Evidence indicates that the kinases TANK-binding kinase 1 and inhibitor of NF-κB kinase-ε specifically phosphorylate and thereby activate IRF-3. We evaluated the contribution of another member of the IRF family, IRF-5, during viral infection since prior studies provided varied results. Analysis of phosphorylation, nuclear translocation, dimerization, binding to CREB-binding protein, recognition of DNA, and induction of gene expression were used comparatively with IRF-3 as a measure of IRF-5 activation. IRF-5 was not activated by viral infection; however, expression of TANK-binding kinase 1 or inhibitor of NF-κB kinase-ε did provide clear activation of IRF-5. IRF-5 is therefore distinct in its activation profile from IRF-3. However, similar to the biological effects of IRF-3 activation, a constitutively active mutation of IRF-5 promoted apoptosis. The apoptosis was inhibited by expression of Bcl-xL but not a dominant-negative mutation of the Fas-associated death domain. These studies support the distinct activation profiles of IRF-3 in comparison to IRF-5, but reveal a potential shared biological effect.