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Yochum C.L.,Environmental and Occupational Health science Institute | Bhattacharya P.,Rutgers University | Patti L.,Rutgers University | Mirochnitchenko O.,UMDNJ RWJMS | And 2 more authors.
Behavioural Brain Research | Year: 2010

Autism is a heterogeneous, behaviorally defined developmental disorder with unknown etiology but thought to be the result of environmental insult acting upon the developing brain of a genetically susceptible individual. Approximately 30% of individuals with autism have normal development up to the age of about 30 months after which they experience behavioral regression and lose previously acquired motor, cognitive and social skills. Early post-natal toxicant administration to mice has been used to model autistic regression. To test the hypothesis that genetically altered mice might be more sensitive to toxicant exposure early in life, mice with a deletion of glutathione-S-transferaseM1 (GSTM1; a gene associated with increased risk of autism that codes for an enzyme involved in the management of toxicant-induced oxidative stress) and wild-type controls were exposed to valproic acid (VPA; a toxicant known to cause autism-like behavioral deficits that, in part, are mediated through oxidative stress) on post-natal day 14. VPA treatment caused significant increases in apoptosis in granule cells of the hippocampus and cerebellum. There was a genotype by treatment by sex interaction with wild-type females exhibiting significantly fewer apoptotic cells in these regions compared to all other groups. VPA treatment also resulted in long-lasting deficits in social behaviors and significant alterations in brain chemistry. VPA-treated GSTM1 knockout animals performed significantly fewer crawl-under behaviors compared to saline-treated knockout animals as well as wild-type controls receiving either treatment. Collectively, these studies indicate that VPA-treatment causes cerebellar and hippocampal apoptosis and that having the wild-type GSTM1 genotype may confer protection against VPA-induced neuronal death in female mice. © 2010 Elsevier B.V.

Aung L.L.,UMDNJ RWJMS | Dhib-Jalbut S.,UMDNJ RWJMS | Balashov K.,UMDNJ RWJMS
Journal of Neuroimmunology | Year: 2010

Plasmacytoid dendritic cells (pDCs) are present in peripheral blood, leptomeninges and demyelinating lesions in patients with multiple sclerosis (MS). The ability of pDCs to produce chemokines and express the chemokine receptor CCR7 in MS is not known.We studied pDCs in MS patients and healthy subjects. The ability of pDCs to up-regulate CCR7 was significantly increased in untreated MS patients as compared to healthy subjects. IFN-beta treatment significantly inhibited TLR9 agonist-specific secretion of chemokines, which are ligands for CCR5-positive Th1 cells (CCL3, CCL4, and CCL5), and impaired TLR9 agonist-induced up-regulation of CCR7 and IFN-alpha in MS patients. This finding represents a new immunomodulatory effect of IFN-beta in patients with multiple sclerosis. © 2010 Elsevier B.V.

Baumann B.M.,UMDNJ RWJMS | Chen E.H.,University of California at San Francisco | Chen E.H.,University of Pennsylvania | Mills A.M.,University of Pennsylvania | And 4 more authors.
Annals of Emergency Medicine | Year: 2011

Study objective We describe patient perceptions of computed tomography (CT) and their understanding of radiation exposure and risk. Methods This was a cross-sectional study of acute abdominal pain patients aged 18 years or older. Confidence in medical evaluations with increasing levels of laboratory testing and imaging was rated on a 100-point visual analog scale. Knowledge of radiation exposure was ascertained when participants compared the radiation dose of one abdomen-pelvis CT with 2-view chest radiography. To assess cancer risk knowledge, participants rated their agreement with these factual statements: "Approximately 2 to 3 abdominal CTs give the same radiation exposure as experienced by Hiroshima survivors" and "2 to 3 abdominal CTs over a person's lifetime can increase cancer risk." Previous CT was also assessed. Results There were 1,168 participants, 67% women and mean age 40.7 years (SD 15.9 years). Median confidence in a medical evaluation without ancillary testing was 20 (95% confidence interval [CI] 16 to 25) compared with 90 (95% CI 88 to 91) when laboratory testing and CT were included. More than 70% of participants underestimated the radiation dose of CT relative to chest radiography, and cancer risk comprehension was poor. Median agreement with the Hiroshima statement was 13 (95% CI 10 to 16) and 45 (95% CI 40 to 45) with the increased lifetime cancer risk statement. Seven hundred ninety-five patients reported receiving a previous CT. Of 365 patients who reported no previous CT, 142 (39%) had one documented in our electronic medical record. Conclusion Patients are more confident when CT imaging is part of their medical evaluation but have a poor understanding of the concomitant radiation exposure and risk and underestimate their previous imaging experience. © 2010 American College of Emergency Physicians.

Yip D.,UMDNJ RWJMS | Drachtman R.,Cancer Institute of New Jersey | Amorosa L.,Metabolism and Nutrition | Trooskin S.,UMDNJ RWJMS
Pediatric Blood and Cancer | Year: 2010

Thyroid carcinomas are an uncommon entity in childhood. We report a case of papillary thyroid cancer presenting as Horner syndrome in a 14 year-old child, which is the only reported such case in the pediatric population. Pediatr Blood Cancer. © 2010 Wiley-Liss, Inc.

Schlesinger N.,UMDNJ RWJMS
Expert Opinion on Biological Therapy | Year: 2012

Introduction: Gout is a painful inflammatory arthritis with a prevalence of approximately 4% in the United States, affecting an estimated 8.3 million adults. The past 20 years have shown significant increases in the number of patients with gout and its incidence may still be increasing. Current treatment options to control the pain and inflammation of acute gout include nonsteroidal anti-inflammatory drugs, colchicine and corticosteroids, although patients are often unresponsive to, intolerant of, or have contraindications for, these therapies. Additional treatment options are therefore needed for this population with difficult-to-treat gout.Areas covered: Currently available and investigational anti-inflammatory agents for acute and chronic gout will briefly be reviewed. Canakinumab, a fully human monoclonal anti-interleukin (IL)-1β antibody that selectively blocks IL-1β and that is being investigated for the treatment of gout, will be discussed in greater detail.Expert opinion: Canakinumab has been found to be superior to triamcinolone acetonide in acute gout and to colchicine in gout attack prophylaxis in reducing pain and risk of new gout attacks. Canakinumab's long half-life contributes to its prolonged anti-inflammatory effects. © 2012 Informa UK, Ltd.

Kim S.,UMDNJ RWJMS | DeStefano M.,UMDNJ RWJMS | Oh W.,UMDNJ RWJMS | Wu C.-C.,UMDNJ RWJMS | And 5 more authors.
Molecular Cell | Year: 2012

The mammalian target of rapamycin (mTOR) integrates signals from nutrients and insulin via two distinct complexes, mTORC1 and mTORC2. Disruption of mTORC2 impairs the insulin-induced activation of Akt, an mTORC2 substrate. Here, we found that mTORC2 can also regulate insulin signaling at the level of insulin receptor substrate-1 (IRS-1). Despite phosphorylation at the mTORC1-mediated serine sites, which supposedly triggers IRS-1 downregulation, inactive IRS-1 accumulated in mTORC2-disrupted cells. Defective IRS-1 degradation was due to attenuated expression and phosphorylation of the ubiquitin ligase substrate-targeting subunit, Fbw8. mTORC2 stabilizes Fbw8 by phosphorylation at Ser86, allowing the insulin-induced translocation of Fbw8 to the cytosol where it mediates IRS-1 degradation. Thus, mTORC2 negatively feeds back to IRS-1 via control of Fbw8 stability and localization. Our findings reveal that in addition to persistent mTORC1 signaling, heightened mTORC2 signals can promote insulin resistance due to mTORC2-mediated degradation of IRS-1. © 2012 Elsevier Inc.

Su B.,Yale University | Jacinto E.,UMDNJ RWJMS
Critical Reviews in Biochemistry and Molecular Biology | Year: 2011

The mechanistic (or mammalian) target of rapamycin (mTOR), an evolutionarily conserved protein kinase, orchestrates cellular responses to growth, metabolic and stress signals. mTOR processes various extracellular and intracellular inputs as part of two mTOR protein complexes, mTORC1 or mTORC2. The mTORCs have numerous cellular targets but members of a family of protein kinases, the protein kinase (PK)A/PKG/PKC (AGC) family are the best characterized direct mTOR substrates. The AGC kinases control multiple cellular functions and deregulation of many members of this family underlies numerous pathological conditions. mTOR phosphorylates conserved motifs in these kinases to allosterically augment their activity, influence substrate specificity, and promote protein maturation and stability. Activation of AGC kinases in turn triggers the phosphorylation of diverse, often overlapping, targets that ultimately control cellular response to a wide spectrum of stimuli. This review will highlight recent findings on how mTOR regulates AGC kinases and how mTOR activity is feedback regulated by these kinases. We will discuss how this regulation can modulate downstream targets in the mTOR pathway that could account for the varied cellular functions of mTOR. © 2011 Informa Healthcare USA, Inc.

Schlesinger N.,UMDNJ RWJMS
Seminars in Arthritis and Rheumatism | Year: 2012

Objectives: The management of gouty arthritis is focused on treating pain and inflammation associated with acute flares and preventing further acute flares and urate crystal deposition. A challenge associated with the successful management of gouty arthritis is an increased risk of acute flares during the first months after initiation of urate-lowering therapy (ULT). This increase in flare frequency can occur regardless of the choice of ULT and is linked to suboptimal patient adherence to ULT. Current treatment recommendations for the use of prophylaxis are limited. There are no definitive recommendations as to which agents should be used or for how long therapy is beneficial after starting ULT. This article aims to improve awareness of the importance of gouty arthritis flare prophylaxis when initiating ULTand to summarize current recommendations and clinical findings related to the efficacy and safety of currently available and investigational new therapies. Methods: This review discusses the pathophysiology of acute gouty arthritis flares during initiation of ULT and examines the literature on the use of anti-inflammatory prophylaxis for reduction of these flares. Results: It has recently become clear that, even when the patient is asymptomatic, chronic inflammation is often present in patients with chronic gouty arthritis. Chronic anti-inflammatory therapy should therefore be added to chronic ULT. Prophylaxis with colchicine as well as with nonsteroidal antiinflammatory drugs (NSAIDs) during ULT initiation can reduce the incidence and severity of gouty arthritis flares substantially; however, safety concerns associated with colchicine and NSAIDs may limit their use. Conclusion: When colchicine and NSAIDs are contraindicated or poorly tolerated, rilonacept and canakinumab, interleukin-1 inhibitors in trials, may prove to be useful alternatives for flare prevention. (Of note, although both inhibit the IL-1β pathway, rilonacept also binds to IL-1α and IL-1RA, in contrast to canakinumab, which binds selectively to IL-1β). © 2012 Elsevier Inc.

Pediatric Cardiology | Year: 2012

The effect of patent ductus arteriosus (PDA) treatment with cyclooxygenase (COX) inhibitors (indomethacin [INDO] and ibuprofen [IBU]) on regional oxygenation requires further clarification. The authors hypothesized that both INDO and IBU reduce regional tissue oxygenation in preterm neonates with PDA but that the risk is not uniform for different tissues and other factors may contribute. Regional cerebral (rSO2-C), renal (rSO2-R), and mesenteric (rSO2-M) tissue oxygenation measured by near-infrared spectroscopy and peripheral arterial oxygen saturation measured by pulse oximetry were recorded simultaneously before, during, and after treatment with the first dose of INDO or IBU in very preterm-born infants with PDA. Tissue-specific fractional oxygen extraction (FOE) was calculated using the rSO2-C, rSO2-R, rSO2-M, and corresponding SpO2 measurements. The findings showed a significant reduction in rSO2-C, rSO2-R, and rSO2-M and an increase in regional FOE after treatment with COX inhibitors in approximately one third of the 38 enrolled infants, which were associated with increased baseline regional tissue oxygen saturation (p < 0.01). However, the infants with posttreatment reduction of tissue oxygenation had significantly lower baseline rSO 2-C (66.7 ± 8.1 vs 69.7 ± 8.1 %), rSO2-R (55.2 ± 10.8 vs 62.7 ± 11.8 %) and especially rSO2-M (37.8 ± 11.4 vs 46.7 ± 16.0 %) than the neonates with unchanged or increased tissue oxygenation. The two groups did not differ in terms of the risk for posttreatment reduction in regional tissue oxygenation with respect to either INDO or IBU treatment and their respective blood levels. Treatment of PDA with either INDO or IBU is associated with a 30-40 % risk for a reduction in regional tissue oxygenation, which is more pronounced in mesenteric tissue than in cerebral or renal tissue. Despite the inconsistency, reduction of regional tissue oxygenation in preterm infants with PDA is more likely associated with the administration of INDO than with the administration of IBU. © 2012 Springer Science+Business Media, LLC.

Hwang E.S.,UMDNJ RWJMS | Thiagarajan G.,UMDNJ RWJMS | Parmar A.S.,UMDNJ RWJMS | Brodsky B.,UMDNJ RWJMS
Protein Science | Year: 2010

The standard collagen triple-helix requires a perfect (Gly-Xaa-Yaa) n sequence, yet all nonfibrillar collagens contain interruptions in this tripeptide repeating pattern. Defining the structural consequences of disruptions in the sequence pattern may shed light on the biological role of sequence interruptions, which have been suggested to play a role in molecular flexibility, collagen degradation, and ligand binding. Previous studies on model peptides with 1- and 4-residue interruptions showed a localized perturbation within the triple-helix, and this work is extended to introduce natural collagen interruptions up to nine residue in length within a fixed (Gly-Pro-Hyp) n peptide context. All peptides in this set show decreases in triple-helix content and stability, with greater conformational perturbations for the interruptions longer than five residue. The most stable and least perturbed structure is seen for the 5-residue interruption peptide, whose sequence corresponds to a Gly to Ala missense mutation, such as those leading to collagen genetic diseases. The triple-helix peptides containing 8- and 9-residue interruptions exhibit a strong propensity for self-association to fibrous structures. In addition, a small peptide modeling only the 9-residue sequence within the interruption aggregates to form amyloid-like fibrils with antiparallel b-sheet structure. The 8- and 9-residue interruption sequences studied here are predicted to have significant cross-β aggregation potential, and a similar propensity is reported for ∼10% of other naturally occurring interruptions. The presence of amyloidogenic sequences within or between triple-helix domains may play a role in molecular association to normal tissue structures and could participate in observed interactions between collagen and amyloid. Published by Wiley-Blackwell. © 2010 The Protein Society.

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