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Articles 1591 - 1620 of 2396

Full-Text Articles in Medicine and Health Sciences

Neutralization Of Osteopontin Attenuates Neutrophil Migration In Sepsis-Induced Acute Lung Injury, Y. Hirano, M. Aziz, W.L. Yang, Z. Wang, M. Zhou, M. Ochani, A. Khader, P. Wang Jan 2015

Neutralization Of Osteopontin Attenuates Neutrophil Migration In Sepsis-Induced Acute Lung Injury, Y. Hirano, M. Aziz, W.L. Yang, Z. Wang, M. Zhou, M. Ochani, A. Khader, P. Wang

Journal Articles

INTRODUCTION: Sepsis refers to severe systemic inflammation leading to acute lung injury (ALI) and death. Introducing novel therapies can reduce the mortality in ALI. Osteopontin (OPN), a secretory glycoprotein produced by immune reactive cells, plays a deleterious role in various inflammatory diseases. However, its role in ALI caused by sepsis remains unexplored. We hypothesize that treatment with an OPN-neutralizing antibody (anti-OPN Ab) protects mice against ALI during sepsis. METHODS: Sepsis was induced in 8-week-old male C57BL/6 mice by cecal ligation and puncture (CLP). Anti-OPN Ab or non-immunized IgG as control, at a dose of 50 mug/mouse, was intravenously injected at …

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Endoplasmic Reticulum Stress In Sepsis, M. M. Khan, W.L. Yang, P. Wang Jan 2015

Endoplasmic Reticulum Stress In Sepsis, M. M. Khan, W.L. Yang, P. Wang

Journal Articles

Sepsis is an enormous public health issue and the leading cause of death in critically ill patients in intensive care units. Overwhelming inflammation, characterized by cytokine storm, oxidative threats, and neutrophil sequestration, is an underlying component of sepsis-associated organ failure. Despite recent advances in sepsis research, there is still no effective treatment available beyond the standard of care and supportive therapy. To reduce sepsis-related mortality, a better understanding of the biological mechanism associated with sepsis is essential. Endoplasmic reticulum (ER), a subcellular organelle, is responsible for the facilitation of protein folding and assembly and involved in several other physiological activities. …

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Stimulation Of Wnt/Beta-Catenin Signaling Pathway With Wnt Agonist Reduces Organ Injury After Hemorrhagic Shock, M. Kuncewitch, W.L. Yang, A. Jacob, A. Khader, M. Giangola, Jeffrey Nicastro, G. Coppa, P. Wang Jan 2015

Stimulation Of Wnt/Beta-Catenin Signaling Pathway With Wnt Agonist Reduces Organ Injury After Hemorrhagic Shock, M. Kuncewitch, W.L. Yang, A. Jacob, A. Khader, M. Giangola, Jeffrey Nicastro, G. Coppa, P. Wang

Journal Articles

BACKGROUND: Hemorrhagic shock is a leading cause of morbidity and mortality in surgery and trauma patients. Despite a large number of preclinical trials conducted to develop therapeutic strategies against hemorrhagic shock, there is still an unmet need for effective therapy for hemorrhage patients. Wnt/beta-catenin signaling controls developmental processes and cellular regeneration owing to its central role in cell survival and proliferation. We therefore hypothesized that the activation of Wnt signaling reduces systemic injury caused by hemorrhagic shock. METHODS: Adult male Sprague-Dawley rats underwent hemorrhagic shock by controlled bleeding of the femoral artery to maintain a mean arterial pressure of 30 …

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Stimulation Of Brain Amp-Activated Protein Kinase Attenuates Inflammation And Acute Lung Injury In Sepsis, N. Mulchandani, W.L. Yang, M. M. Khan, F. Zhang, P. Marambaud, J. Nicastro, G.F. Coppa, P. Wang Jan 2015

Stimulation Of Brain Amp-Activated Protein Kinase Attenuates Inflammation And Acute Lung Injury In Sepsis, N. Mulchandani, W.L. Yang, M. M. Khan, F. Zhang, P. Marambaud, J. Nicastro, G.F. Coppa, P. Wang

Journal Articles

Sepsis and septic shock are enormous public health problems with astronomical financial repercussions on health systems worldwide. The central nervous system (CNS) is closely intertwined in the septic process but the underlying mechanism is still obscure. AMP-activated protein kinase (AMPK) is a ubiquitous energy sensor enzyme and plays a key role in regulation of energy homeostasis and cell survival. In this study, we hypothesized that activation of AMPK in the brain would attenuate inflammatory responses in sepsis, particularly in the lungs. Adult C57BL/6 male mice were treated with 5-aminoimidazole-4-carboxamide riboneucleotide (AICAR, 20 ng), an AMPK activator, or vehicle (normal saline) …

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Differential Alterations Of Tissue T-Cell Subsets After Sepsis, A. Sharma, W.L. Yang, S. Matsuo, P. Wang Jan 2015

Differential Alterations Of Tissue T-Cell Subsets After Sepsis, A. Sharma, W.L. Yang, S. Matsuo, P. Wang

Journal Articles

Among immune cells in responding to sepsis, macrophages and neutrophils have been extensively studied, while the contribution of T lymphocytes and natural killer T (NKT) cells is less well characterized. Here we monitored tissue specific changes of T cell subsets in male C57BL/6 mice subjected to sham operation or cecal ligation and puncture (CLP) to induce polymicrobial sepsis. Thymus, spleen, liver, lungs and blood were processed and analyzed 20h later. Total lymphocyte count showed a significant reduction in septic thymus, spleen and blood but not in lungs and liver. The septic thymi were hypocellular with severe reduction in cell numbers …

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Human Ghrelin Mitigates Intestinal Injury And Mortality After Whole Body Irradiation In Rats, Z. M. Wang, W.L. Yang, A. Jacob, M. Aziz, P. Wang Jan 2015

Human Ghrelin Mitigates Intestinal Injury And Mortality After Whole Body Irradiation In Rats, Z. M. Wang, W.L. Yang, A. Jacob, M. Aziz, P. Wang

Journal Articles

Widespread use of ionizing radiation has led to the realization of the danger associated with radiation exposure. Although studies in radiation countermeasures were initiated a half century ago, an effective therapy for a radiomitigator has not been identified. Ghrelin is a gastrointestinal hormone, and administration of ghrelin is protective in animal models of injuries including radiation combined injury. To test whether ghrelin can be protective in whole body irradiaton (WBI) alone, male Sprague Dawley (SD) rats were treated with human ghrelin (20 nmol/rat) daily for 6 days starting at either 24 h or 48 h after 10 Gray (Gy) WBI …

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Combination Of Adrenomedullin With Its Binding Protein Accelerates Cutaneous Wound Healing, J. P. Idrovo, W. L. Yang, A. Jacob, M. A. Ajakaiye, C. Cheyuo, Z. M. Wang, J. M. Prince, J. Nicastro, G.F. Coppa, P. Wang Jan 2015

Combination Of Adrenomedullin With Its Binding Protein Accelerates Cutaneous Wound Healing, J. P. Idrovo, W. L. Yang, A. Jacob, M. A. Ajakaiye, C. Cheyuo, Z. M. Wang, J. M. Prince, J. Nicastro, G.F. Coppa, P. Wang

Journal Articles

Cutaneous wound continues to cause significant morbidity and mortality in the setting of diseases such as diabetes and cardiovascular diseases. Despite advances in wound care management, there is still an unmet medical need exists for efficient therapy for cutaneous wound. Combined treatment of adrenomedullin (AM) and its binding protein-1 (AMBP-1) is protective in various disease conditions. To examine the effect of the combination treatment of AM and AMBP-1 on cutaneous wound healing, full-thickness 2.0-cm diameter circular excision wounds were surgically created on the dorsum of rats, saline (vehicle) or AM/AMBP1 (96/320 mu g kg BW) was topically applied to the …

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An Interesting Cause Of Mechanical Small Bowel Obstruction, S. A. Sathyanarayana, G. B. Deutsch, B. Friedman Jan 2015

An Interesting Cause Of Mechanical Small Bowel Obstruction, S. A. Sathyanarayana, G. B. Deutsch, B. Friedman

Journal Articles

Foreign body ingestion is a known cause of abdominal pain in pediatric population occurring between 6 months and 3 years of age (Wyllie Curr Opin Pediatr 18:563, 2006, Uyemura Am Fam Physician 72:287, 2005, Banerjee Indian J Pediatr 72:173, 2005). Most of the ingested foreign bodies pass spontaneously with 10-20 % requiring endoscopic retrieval, and < 1 % of cases require a surgical intervention (Wyllie Curr Opin Pediatr 18:563, 2006, Uyemura Am Fam Physician 72:287, 2005, Shivakumar Indian J Pediatr 71:689, 2004). Presence of intestinal obstruction necessitates surgical intervention to extract the ingested foreign body. Initial abdominal plain radiograph should be obtained when foreign body ingestion is suspected, which differentiates a radiopaque from radiolucent foreign bodies. A computed tomography with 3D reconstruction (3D-CT) is recommended with radiolucent foreign bodies (Uyemura Am Fam Physician 72:287, 2005, Kazam Am J Emerg Med 23:897, 2005). After 24 h of expectant management, failure of spontaneous passage requires further intervention. Timely intervention to relieve the obstruction is pivotal to prevent undue complications. We present an interesting case of a boy who ingested a radiolucent foreign body diagnosed on 3D-CT, successfully treated with surgical extraction.

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Fdg-Pet-Positive Lower-Extremity Sebaceous-Gland Carcinoma In A Patient With Muir-Torre Syndrome, B. Kviatkovsky, E. Landau, M. Siddique, S. Hossri, A. Ebaee, J.P. Attalah, A. Picon, A. Brenner Jan 2015

Fdg-Pet-Positive Lower-Extremity Sebaceous-Gland Carcinoma In A Patient With Muir-Torre Syndrome, B. Kviatkovsky, E. Landau, M. Siddique, S. Hossri, A. Ebaee, J.P. Attalah, A. Picon, A. Brenner

Journal Articles

Sebaceous-gland carcinoma can occur alone or as one of the defining features of the Muir-Torre syndrome. Cases occurring below the head and neck are extremely rare. Here we describe the case of a 70-year-old male with Muir-Torre syndrome who had a recurrent sebaceous-gland carcinoma in the left lower extremity that demonstrated 18F-FDG avidity. An 18F-FDG-avid lower-extremity sebaceous-gland carcinoma has not been previously reported.

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Combining Task-Evoked And Spontaneous Activity To Improve Pre-Operative Brain Mapping With Fmri, M. D. Fox, T. Qian, J. R. Madsen, D. Wang, M. Ge, H. C. Zuo, D. M. Groppe, A. D. Mehta, B. Hong, H. Liu, +1 Additional Author Jan 2015

Combining Task-Evoked And Spontaneous Activity To Improve Pre-Operative Brain Mapping With Fmri, M. D. Fox, T. Qian, J. R. Madsen, D. Wang, M. Ge, H. C. Zuo, D. M. Groppe, A. D. Mehta, B. Hong, H. Liu, +1 Additional Author

Journal Articles

Noninvasive localization of brain function is used to understand and treat neurological disease, exemplified by pre-operative fMRI mapping prior to neurosurgical intervention. The principal approach for generating these maps relies on brain responses evoked by a task and, despite known limitations, has dominated clinical practice for over 20years. Recently, pre-operative fMRI mapping based on correlations in spontaneous brain activity has been demonstrated, however this approach has its own limitations and has not seen widespread clinical use. Here we show that spontaneous and task-based mapping can be performed together using the same pre-operative fMRI data, provide complimentary information relevant for functional …

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Galantamine Attenuates Type 1 Diabetes And Inhibits Anti-Insulin Antibodies In Non-Obese Diabetic Mice, W. M. Hanes, P. S. Olofsson, K. Kwan, L. K. Hudson, S. S. Chavan, V. A. Pavlov, K. J. Tracey Jan 2015

Galantamine Attenuates Type 1 Diabetes And Inhibits Anti-Insulin Antibodies In Non-Obese Diabetic Mice, W. M. Hanes, P. S. Olofsson, K. Kwan, L. K. Hudson, S. S. Chavan, V. A. Pavlov, K. J. Tracey

Journal Articles

Type 1 diabetes in mice is characterized by autoimmune destruction of insulin-producing pancreatic beta cells. Disease pathogenesis involves invasion of pancreatic islets by immune cells, including macrophages and T cells, and production of antibodies to self-antigens, including insulin. Activation of the inflammatory reflex, the neural circuit that inhibits inflammation, culminates on cholinergic receptor signals on immune cells to attenuate cytokine release and inhibit B cell antibody production. Here, we show that galantamine, a centrally acting acetylcholinesterase inhibitor and an activator of the inflammatory reflex, attenuates murine experimental type 1 diabetes. Administration of galantamine to animals immunized with keyhole limpet hemocyanin …

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Damp Signaling Is A Key Pathway Inducing Immune Modulation After Brain Injury, A. Liesz, A. Dalpke, E. Mracsko, D. J. Antoine, S. Roth, W. Zhou, H. Yang, P. P. Nawroth, K. J. Tracey, R. Veltkamp, +4 Additional Authors Jan 2015

Damp Signaling Is A Key Pathway Inducing Immune Modulation After Brain Injury, A. Liesz, A. Dalpke, E. Mracsko, D. J. Antoine, S. Roth, W. Zhou, H. Yang, P. P. Nawroth, K. J. Tracey, R. Veltkamp, +4 Additional Authors

Journal Articles

Acute brain lesions induce profound alterations of the peripheral immune response comprising the opposing phenomena of early immune activation and subsequent immunosuppression. The mechanisms underlying this brain-immune signaling are largely unknown. We used animal models for experimental brain ischemia as a paradigm of acute brain lesions and additionally investigated a large cohort of stroke patients. We analyzed release of HMGB1 isoforms by mass spectrometry and investigated its inflammatory potency and signaling pathways by immunological in vivo and in vitro techniques. Features of the complex behavioral sickness behavior syndrome were characterized by homecage behavior analysis. HMGB1 downstream signaling, particularly with RAGE, …

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Regulation Of Post-Translational Modifications Of Hmgb1 During Immune Responses, B. Lu, Y. Tang, X. Zhao, D. Antoine, X. Xiao, H. Wang, U. Andersson, T. Billiar, K. J. Tracey Jan 2015

Regulation Of Post-Translational Modifications Of Hmgb1 During Immune Responses, B. Lu, Y. Tang, X. Zhao, D. Antoine, X. Xiao, H. Wang, U. Andersson, T. Billiar, K. J. Tracey

Journal Articles

SIGNIFICANCE: High mobility group protein 1 (HMGB1) is an evolutionarily conserved and multi-functional protein. The biological function of HMGB1 depends on its cellular locations, binding partners, and redox states. Extracellular HMGB1 is a mediator of inflammation during infection or tissue injury. Immune cells actively release HMGB1 in response to infection, which in turn orchestrates both innate and adaptive immune responses. RECENT ADVANCES: Hyperacetylation of HMGB1 within its nuclear localization sequences mobilizes HMGB1 from the nucleus to the cytoplasm and subsequently promotes HMGB1 release. The redox states of the cysteines in position 23, 45 and 106 determine the biological activity of …

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A Unifying Principle Underlying The Extracellular Field Potential Spectral Responses In The Human Cortex, E. Podvalny, N. Noy, M. Harel, S. Bickel, G. Chechik, C. E. Schroeder, A. D. Mehta, M. Tsodyks, R. Malach Jan 2015

A Unifying Principle Underlying The Extracellular Field Potential Spectral Responses In The Human Cortex, E. Podvalny, N. Noy, M. Harel, S. Bickel, G. Chechik, C. E. Schroeder, A. D. Mehta, M. Tsodyks, R. Malach

Journal Articles

Electrophysiological mass potentials show complex spectral changes upon neuronal activation. However, it is unknown to what extent these complex band-limited changes are interrelated or, alternatively, reflect separate neuronal processes. To address this question, intracranial electrocorticograms (ECoG) responses were recorded in patients engaged in visuomotor tasks. We found that in the 10- to 100-Hz frequency range there was a significant reduction in the exponent chi of the 1/f(chi) component of the spectrum associated with neuronal activation. In a minority of electrodes showing particularly high activations the exponent reduction was associated with specific band-limited power modulations: emergence of a high gamma (80-100 …

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Deletion Of Stat5a/B In Vascular Smooth Muscle Abrogates The Male Bias In Hypoxic Pulmonary Hypertension In Mice: Implications In The Human Disease, Y. M. Yang, H. Yuan, J. G. Edwards, Y. Skayian, K. Ochani, E. J. Miller, P. B. Sehgal Jan 2015

Deletion Of Stat5a/B In Vascular Smooth Muscle Abrogates The Male Bias In Hypoxic Pulmonary Hypertension In Mice: Implications In The Human Disease, Y. M. Yang, H. Yuan, J. G. Edwards, Y. Skayian, K. Ochani, E. J. Miller, P. B. Sehgal

Journal Articles

Chronic hypoxia typically elicits pulmonary hypertension (PH) in mice with a male-dominant phenotype. There is an opposite sex-bias in human PH with higher prevalence in women, but greater survival (the "estrogen paradox"). We investigated the involvement of STAT5a/b species, previously established to mediate sexual dimorphism in other contexts, in the sex-bias in PH. Mice with heterozygous or homozygous deletions of the STAT5a/b locus in vascular smooth muscle cells (SMC) were generated in crosses between STAT5a/bfl/fl and transgelin (SM22alpha)-Cre+/+ parents. Wild-type (wt) males subjected to chronic hypoxia showed significant PH and pulmonary arterial remodeling, with wt females showing minimal changes (a …

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Age-Dependent Alterations In The Inflammatory Response To Pulmonary Challenge, H. M. Linge, K. Ochani, K. Lin, J. Y. Lee, E. J. Miller Jan 2015

Age-Dependent Alterations In The Inflammatory Response To Pulmonary Challenge, H. M. Linge, K. Ochani, K. Lin, J. Y. Lee, E. J. Miller

Journal Articles

The aging lung is increasingly susceptible to infectious disease. Changes in pulmonary physiology and function are common in older populations, and in those older than 60 years, pneumonia is the major cause of infectious death. Understanding age-related changes in the innate and adaptive immune systems, and how they affect both pulmonary and systemic responses to pulmonary challenge are critical to the development of novel therapeutic strategies for the treatment of the elderly patient. In this observational study, we examined age-associated differences in inflammatory responses to pulmonary challenge with cell wall components from Gram-positive bacteria. Thus, male Sprague-Dawley rats, aged 6 …

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Antibodies As Mediators Of Brain Pathology, L. Brimberg, S. Mader, Y. Fujieda, Y. Arinuma, C. Kowal, B. T. Volpe, B. Diamond Jan 2015

Antibodies As Mediators Of Brain Pathology, L. Brimberg, S. Mader, Y. Fujieda, Y. Arinuma, C. Kowal, B. T. Volpe, B. Diamond

Journal Articles

No abstract provided.

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Autoantibodies In Systemic Autoimmune Diseases: Specificity And Pathogenicity, J. Suurmond, B. Diamond Jan 2015

Autoantibodies In Systemic Autoimmune Diseases: Specificity And Pathogenicity, J. Suurmond, B. Diamond

Journal Articles

In this Review we focus on the initiation of autoantibody production and autoantibody pathogenicity, with a special emphasis on the targeted antigens. Release of intracellular antigens due to excessive cell death or to ineffective clearance of apoptotic debris, modification of self-antigens during inflammatory responses, and molecular mimicry contribute to the initiation of autoantibody production. We hypothesize that those autoreactive B cells that survive and produce pathogenic autoantibodies have specificity for self-antigens that are TLR ligands. Such B cells experience both B cell receptor (BCR) activation and TLR engagement, leading to an escape from tolerance. Moreover, the autoantibodies they produce form …

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B Cells In The Aging Immune System: Time To Consider B-1 Cells, N. E. Holodick, T. L. Rothstein Jan 2015

B Cells In The Aging Immune System: Time To Consider B-1 Cells, N. E. Holodick, T. L. Rothstein

Journal Articles

The investigation of immune senescence has uncovered many changes in B cell development, maintenance, and function with increasing age. However, most of these studies have focused on conventional B cell subsets in the spleen. The B-1 cell subset is an essential arm of the innate immune system, which in general has been understudied in terms of immune senescence. Here, we review what is currently known about B cells during aging and go on to describe why B-1 cell biology is an important component of the aging immune system in the context of diseases that most affect the aged population.

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Brain Metabolism And Autoantibody Titres Predict Functional Impairment In Systemic Lupus Erythematosus, M. Mackay, C. C. Tang, B. T. Volpe, C. Aranow, P. J. Mattis, R. A. Korff, B. Diamond, D. Eidelberg Jan 2015

Brain Metabolism And Autoantibody Titres Predict Functional Impairment In Systemic Lupus Erythematosus, M. Mackay, C. C. Tang, B. T. Volpe, C. Aranow, P. J. Mattis, R. A. Korff, B. Diamond, D. Eidelberg

Journal Articles

OBJECTIVE: We investigated whether systemic lupus erythematosus (SLE) disease duration or serology associate with abnormal regional glucose metabolism as measured with [(18)F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and deficits on neuropsychological testing. METHODS: Subjects with SLE with stable disease activity, without brain damage or clinical symptoms of neuropsychiatric (NP) SLE, stratified by disease duration (short-term (ST)-SLE=disease/=10 years), underwent clinical assessments, neuropsychological testing, resting FDG-PET scan imaging and measurement of serum titres of antibody to N-methyl-d-aspartate receptor (DNRAb). FDG-PET scans were compared with age-matched and gender-matched healthy controls. RESULTS: Subjects with LT-SLE demonstrated hypometabolism in the prefrontal and premotor cortices that correlated …

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The Brighter (And Evolutionarily Older) Face Of The Metabolic Syndrome: Evidence From Trypanosoma Cruzi Infection In Cd-1 Mice, W. Brima, D. J. Eden, S. F. Mehdi, M. Bravo, M. M. Wiese, J. Stein, V. Almonte, D. Zhao, J. Roth, F. Nagajyothi, +5 Additional Authors Jan 2015

The Brighter (And Evolutionarily Older) Face Of The Metabolic Syndrome: Evidence From Trypanosoma Cruzi Infection In Cd-1 Mice, W. Brima, D. J. Eden, S. F. Mehdi, M. Bravo, M. M. Wiese, J. Stein, V. Almonte, D. Zhao, J. Roth, F. Nagajyothi, +5 Additional Authors

Journal Articles

BACKGROUND: Infection with Trypanosoma cruzi, the protozoan parasite that causes Chagas disease, results in chronic infection that leads to cardiomyopathy with increased mortality and morbidity in endemic regions. In a companion study, our group found that a high-fat diet (HFD) protected mice from T. cruzi-induced myocardial damage and significantly reduced post-infection mortality during acute T. cruzi infection. METHODS: In the present study metabolic syndrome was induced prior to T. cruzi infection by feeding a high fat diet. Also, mice were treated with anti-diabetic drug metformin. RESULTS: In the present study, the lethality of T. cruzi (Brazil strain) infection in CD-1 …

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Calhm1 Deletion In Mice Affects Glossopharyngeal Taste Responses, Food Intake, Body Weight, And Life Span, G. Hellekant, J. Schmolling, P. Marambaud, T. A. Rose-Hellekant Jan 2015

Calhm1 Deletion In Mice Affects Glossopharyngeal Taste Responses, Food Intake, Body Weight, And Life Span, G. Hellekant, J. Schmolling, P. Marambaud, T. A. Rose-Hellekant

Journal Articles

Stimulation of Type II taste receptor cells (TRCs) with T1R taste receptors causes sweet or umami taste, whereas T2Rs elicit bitter taste. Type II TRCs contain the calcium channel, calcium homeostasis modulator protein 1 (CALHM1), which releases adenosine triphosphate (ATP) transmitter to taste fibers. We have previously demonstrated with chorda tympani nerve recordings and two-bottle preference (TBP) tests that mice with genetically deleted Calhm1 (knockout [KO]) have severely impaired perception of sweet, bitter, and umami compounds, whereas their sour and salty tasting ability is unaltered. Here, we present data from KO mice of effects on glossopharyngeal (NG) nerve responses, TBP, …

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The Cation Channel Trpv2 Is A New Suppressor Of Arthritis Severity, Joint Damage, And Synovial Fibroblast Invasion, T. Laragione, K. F. Cheng, M. R. Tanner, M. He, C. Beeton, Y. Al-Abed, P. S. Gulko Jan 2015

The Cation Channel Trpv2 Is A New Suppressor Of Arthritis Severity, Joint Damage, And Synovial Fibroblast Invasion, T. Laragione, K. F. Cheng, M. R. Tanner, M. He, C. Beeton, Y. Al-Abed, P. S. Gulko

Journal Articles

Little is known about the regulation of arthritis severity and joint damage in rheumatoid arthritis (RA). Fibroblast-like synoviocytes (FLS) have a central role in joint damage and express increased levels of the cation channel Trpv2. We aimed at determining the role of Trpv2 in arthritis. Treatment with Trpv2-specific agonists decreased the in vitro invasiveness of FLS from RA patients and arthritic rats and mice. Trpv2 stimulation suppressed IL-1beta-induced expression of MMP-2 and MMP-3. Trpv2 agonists, including the new and more potent LER13, significantly reduced disease severity in KRN serum- and collagen-induced arthritis, and reduced histologic joint damage, synovial inflammation, and …

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Defects In Germinal Center Selection In Sle, M. Woods, Y. R. Zou, A. Davidson Jan 2015

Defects In Germinal Center Selection In Sle, M. Woods, Y. R. Zou, A. Davidson

Journal Articles

Germinal centers (GCs) are the primary site at which clonal expansion and affinity maturation of B cells occur. B cells encounter antigen and receive T cell help in the GC light zone (LZ) and then migrate to the dark zone where they proliferate and undergo somatic mutation before cycling back to the LZ for further rounds of selection. Tolerance to autoantigens is frequently lost de novo as GC B cells undergo class switching and somatic mutation. This loss of tolerance is regulated by a variety of mechanisms including cell death, failure to compete for T cell help, and failure to …

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Enrichment Of Genetic Variants For Rheumatoid Arthritis Within T-Cell And Nk-Cell Enhancer Regions, J. Freudenberg, P. Gregersen, W. Li Jan 2015

Enrichment Of Genetic Variants For Rheumatoid Arthritis Within T-Cell And Nk-Cell Enhancer Regions, J. Freudenberg, P. Gregersen, W. Li

Journal Articles

To identify disease-causative variants, we intersected the published results of a metaanalysis of genome-wide association studies (GWAS) for rheumatoid arthritis (RA) with the set of enhancer regions for 71 primary cell types that was provided by the FANTOM consortium. We first retrieved all single nucleotide polymorphisms (SNPs) that are associated (P < 5 x 10(8)) with RA in the GWAS meta-analysis and that are located in any of these enhancer regions. After excluding the major histocompatibility complex (MHC) region, we identified 50 such RA-associated SNPs that are located in enhancer regions. Enhancer sets from different cell types were then compared with each other for their number of RA-associated SNPs by permutation analysis. This analysis showed that RA-associated SNPs are preferentially located in enhancers from several immunological cell types. In particular, we see a strong relative enrichment in enhancer regions that are active in T cells (P < 0.001) and NK cells (P < 0.001). Several loci display multiple RA-associated SNPs in tight linkage disequilibrium that are located within the same or neighboring enhancers. These haplotypes may have a greater likelihood to influence enhancer activity than any SNP on its own. Taken together, these results support the hypothesis that RA-causative variants often act through altering the activity of immune cell enhancers. The enrichment in T-cell and NK-cell enhancer regions indicates that expression changes in these cell types are particularly relevant for the pathogenesis of RA. The specific SNPs that account for this enrichment can be used as a basis for focused genotype-phenotype studies of these cell types.

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Excessive Antigen Reactivity May Underlie The Clinical Aggressiveness Of Chronic Lymphocytic Leukemia Stereotyped Subset #8, M. Gounari, S. Ntoufa, B. Apollonio, N. Papakonstantinou, M. Ponzoni, C. C. Chu, D. Rossi, G. Gaidano, N. Chiorazzi, P. Ghia, +1 Additional Author Jan 2015

Excessive Antigen Reactivity May Underlie The Clinical Aggressiveness Of Chronic Lymphocytic Leukemia Stereotyped Subset #8, M. Gounari, S. Ntoufa, B. Apollonio, N. Papakonstantinou, M. Ponzoni, C. C. Chu, D. Rossi, G. Gaidano, N. Chiorazzi, P. Ghia, +1 Additional Author

Journal Articles

Subset #8 is a distinctive subset of patients with chronic lymphocytic leukemia (CLL) defined by the expression of stereotyped IGHV4-39/IGKV1(D)-39 B-cell receptors. Subset #8 patients experience aggressive disease and exhibit the highest risk for Richter transformation among all CLL. In order to obtain biological insight into this behavior, we profiled the antigen reactivity and signaling capacity of subset #8 vs other clinically aggressive stereotyped subsets, namely subsets #1 and #2. Twenty-seven monoclonal antibodies (mAbs) from subsets #1, #2, and #8 CLL clones were prepared as recombinant human immunoglobulin G1 and used as primary antibodies in enzyme-linked immuno-sorbent assays against representatives …

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Functional Loss Of I Kappa B Epsilon Leads To Nf-Kappa B Deregulation In Aggressive Chronic Lymphocytic Leukemia, L. Mansouri, L. A. Sutton, V. Ljungstrom, S. Bondza, L. Arngarden, S. Bhoi, X. J. Yan, N. Chiorazzi, R. Rosenquist, +25 Additional Authors Jan 2015

Functional Loss Of I Kappa B Epsilon Leads To Nf-Kappa B Deregulation In Aggressive Chronic Lymphocytic Leukemia, L. Mansouri, L. A. Sutton, V. Ljungstrom, S. Bondza, L. Arngarden, S. Bhoi, X. J. Yan, N. Chiorazzi, R. Rosenquist, +25 Additional Authors

Journal Articles

NF-kappa B is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-kappa B pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes I kappa B epsilon, a negative regulator of NF-kappa B in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic …

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Fundamental Role Of C1q In Autoimmunity And Inflammation, M. Son, B. Diamond, F. Santiago-Schwarz Jan 2015

Fundamental Role Of C1q In Autoimmunity And Inflammation, M. Son, B. Diamond, F. Santiago-Schwarz

Journal Articles

C1q, historically viewed as the initiating component of the classical complement pathway, also exhibits a variety of complement-independent activities in both innate and acquired immunity. Recent studies focusing on C1q's suppressive role in the immune system have provided new insight into how abnormal C1q expression and bioactivity may contribute to autoimmunity. In particular, molecular networks involving C1q interactions with cell surface receptors and other ligands are emerging as mechanisms involved in C1q's modulation of immunity. Here, we discuss the role of C1q in controlling immune cell function, including recently elucidated mechanisms of action, and suggest how these processes are critical …

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The Hiv Protease Inhibitor Saquinavir Inhibits Hmgb1 Driven Inflammation By Targeting The Interaction Of Cathepsin V With Tlr4/Myd88, J. P. Pribis, Y. Al-Abed, H. Yang, D. Gero, H. Xu, M. F. Montenegro, E. M. Bauer, S. Kim, K. J. Tracey, T. R. Billiar, +5 Additional Authors Jan 2015

The Hiv Protease Inhibitor Saquinavir Inhibits Hmgb1 Driven Inflammation By Targeting The Interaction Of Cathepsin V With Tlr4/Myd88, J. P. Pribis, Y. Al-Abed, H. Yang, D. Gero, H. Xu, M. F. Montenegro, E. M. Bauer, S. Kim, K. J. Tracey, T. R. Billiar, +5 Additional Authors

Journal Articles

Extracellular HMGB1 (disulfide form), via activation of Toll-Like-Receptor (TLR4)-dependent signaling, is a strong driver of pathologic inflammation in both acute and chronic conditions. Identification of selective inhibitors of HMGB1-TLR4 signaling could offer novel therapies that selectively target proximal endogenous activators of inflammation. A cell-based screening strategy led us to identify first generation HIV-protease inhibitors (PI) as potential inhibitors of HMGB1-TLR4 driven cytokine production. Here we report, that the first-generation HIV-PI saquinavir (SQV), as well as a newly identified mammalian protease inhibitor STO33438 (334), potently block disulfide HMGB1 induced TLR4 activation, as assayed by the production of TNF-alpha by human monocyte-derived …

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Hmgb1-Driven Inflammation And Intimal Hyperplasia After Arterial Injury Involves Cell-Specific Actions Mediated By Tlr4, J. Cai, H. Yuan, Q. Wang, H. Yang, Yousef Al-Abed, Z. Hua, J. Wang, D. Chen, Kevin J. Tracey, A. F. Chen, +7 Additional Authors Jan 2015

Hmgb1-Driven Inflammation And Intimal Hyperplasia After Arterial Injury Involves Cell-Specific Actions Mediated By Tlr4, J. Cai, H. Yuan, Q. Wang, H. Yang, Yousef Al-Abed, Z. Hua, J. Wang, D. Chen, Kevin J. Tracey, A. F. Chen, +7 Additional Authors

Journal Articles

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