Gating the radical hemoglobin to macrophages: the anti-inflammatory role of CD163, a scavenger receptor

Efficient extracellular hemoglobin (Hb) clearance is essential to prevent oxidative- and nitrosative-mediated toxicity. CD163 belongs to group B of the scavenger receptor cysteine-rich (SRCR) protein family found on the surface of monocytes and macrophages and is responsible for Hb-haptoglobin (Hp) complex uptake. Hb uptake by CD163 was thought to proceed exclusively through an Hp-dependent pathway. However, Hb can interact directly with CD163 via a low affinity binding when Hp is absent. As a result, a two-phase hypothesis of Hb clearance by monocytes/macrophages suggests that Hp-Hb binding to CD163 is the primary mechanism of plasma Hb clearance, while clearance of Hb by direct binding to CD163 is secondary to Hp depletion. The authors have considered the ligand specificity of CD163 in human macrophages and in a heterologous gene expression model to demonstrate that Hb is effectively endocytosed by CD163 in the absence of Hp. Additionally, the authors have considered Hb-based oxygen carriers (HBOCs) administration as a unique situation during which direct CD163 uptake may be relevant as a mechanism of clearance. However, the nature of chemical modifications introduced onto the Hb molecule and/or oxidative changes induced in the protein appear to influence the extent of CD163 interaction and cellular uptake. Here, an overview and novel insights into the role of CD163 in Hb redox inactivation and clearance are provided.     

Fibrosarcoma of the cervical spine.

The clinical and radiographic presentation of fibrosarcoma of the third cervical segment is presented. Conventional radiographic examination and advanced imaging in this case revealed destruction of the C3 vertebral body and neural arch with extension into the spinal canal and paravertebral soft tissues. Surgical pathology revealed a pre- and postoperative diagnosis of fibrosarcoma.     

Endoscopic ultrasound in the evaluation of pancreatic neoplasms-solid and cystic: A review

Pancreatic neoplasms have a wide range of pathology, from pancreatic adenocarcinoma to cystic mucinous neoplasms. Endoscopic ultrasound(EUS) with or without fine needle aspiration(FNA) is a helpful diagnostic tool in the work-up of pancreatic neoplasms. Its utility in pancreatic malignancy is well known. Over the last two decades EUS-FNA has become a procedure of choice for diagnosis of pancreatic adenocarcinoma. EUS-FNA is highly sensitive and specific for solid lesions, with sensitivities as high as 80%-95% for pancreatic masses and specificity as high as 75%-100%. Multiple aspects of the procedure have been studied to optimize the rate of diagnosis with EUS-FNA including cytopathologist involvement, needle size, suctioning and experience of endoscopist. Onsite pathology is one of the most important elements in increasing diagnostic yield rate in EUS-FNA. EUS-FNA is valuable in diagnosing rare and atypical pancreatic neoplasms including neuroendocrine, lymphoma and metastatic disease. As more and more patients undergo cross sectional imaging, cystic lesions of the pancreas are becoming a more common occurrence and EUS-FNA of these lesions can be helpful for differentiation. This review covers the technical aspects of optimizing pancreatic neoplasm diagnosis rate, highlight rare pancreatic neoplasms and role of EUS-FNA, and also outline the important factors in diagnosis of cystic lesions by EUS-FNA.     

How to support me in connected learning: Youth perspectives on adult supportive behavior and its benefits

This study examined the various ways adults engage and support youth in connected learning settings, which are focused on supporting youth in their interests or passions. Youth from 5 Chicago community‐based, out‐of‐school time (OST) programs participated in focus groups on the topic of adult–youth relationships. Participants reported characteristics and behaviors of supportive adults as well as the outcomes associated with those behaviors. Analyses revealed that the following characteristics of adults enabled engagement and relationship development: (a) mutual respect, (b) genuine interest, (c) ongoing communication and friendship, and (d) going above and beyond. Youth also identified the specific ways that adults supported them: (a) guidance and motivation, (b) skill‐based support, (c) role modeling, (d) connecting, (e) emotional support, and (f) cultivating youth voice. Finally, participants reported the following outcomes related to such support: (a) social capital, (b) a sense of empowerment and control of their futures, and (c) a sense of acceptance and validation. This study is a contribution to the literature on adult–youth relationships in connected learning sites and draws attention to the potential socioemotional and instructional benefits of such programs. Our study also highlights the various ways that adults in OST programs can successfully engage youth and form relationships.     

EBV LMP2A affects LMP1-mediated NF-kappaB signaling and survival of lymphoma cells by regulating TRAF2 expression

A mechanism used by Epstein-Barr virus (EBV) for in vitro transformation of B cells into lymphoblastoid cell lines (LCLs) is activation of the NF-kappaB pathway, which is largely mediated by the EBV latent membrane protein 1 (LMP1). LMP1 is coexpressed with LMP2A in many EBV-associated lymphoid malignancies. Since inhibition of NF-kappaB leads to apoptosis of EBV-infected LCLs and lymphoma cell lines, we sought to determine whether LMP1 alone, or in combination with other viral proteins, is responsible for initiating NF-kappaB activation in these cells, thereby playing a role in cell survival. We found that suppression of LMP1 by RNA interference results in inhibition of basal NF-kappaB and induction of apoptosis. Unexpectedly, knockdown of LMP2A also resulted in comparable decrease of NF-kappaB activity and apoptosis. We report that LMP2A protein controls the expression of TRAF2 mRNA, which in turn is necessary for signaling by LMP1. Our data contrast with previous studies showing that transfected LMP1 can signal in the absence of LMP2A or TRAF2, and demonstrate that both LMP2A and TRAF2 are required for survival in naturally infected lymphoma cells and LCLs. These results also support LMP1, LMP2A, and TRAF2 as potential therapeutic targets in a subset of EBV-associated lymphoid malignancies.     

Angiogenesis-independent cardioprotection in FGF-1 transgenic mice

OBJECTIVE: This study was performed to evaluate the cardioprotective role of acidic fibroblast growth factor-1 (FGF-1) in transgenic mice with cardiac-specific overexpression of human FGF-1. METHODS: Mice were subjected to coronary artery occlusion for 15-75 min with a continuously recorded 3-lead electrocardiogram (ECG). Infarct size was measured and ERK-1 and -2 activity was assessed by Western blot analysis. Creatine kinase and lactate dehydrogenase activity as marker for cell viability were measured in isolated ventricular myocytes subjected to simulated ischemia. RESULTS: Infarct development was markedly delayed in transgenics with first signs of myocardial infarction visible at 45 min after coronary artery occlusion compared to 15 min in wildtype. Maximal infarct size (60% of risk area) did not differ, but transgenics reached maximal infarction after 75 min compared to 45 min in wildtype animals. ECG revealed delayed Q-wave development and delayed ST-segment elevation in transgenics. Creatine kinase and lactate dehydrogenase release was significantly attenuated from isolated transgenic myocytes at 4 and 8 h after simulated ischemia. The delay in infarct development is partially due to a constitutive higher expression of the extracellular signal-regulated kinases ERK-1 and -2 in the myocardium of transgenics. Additionally, injection of the ERK-1/2 inhibitor UO126 decreased the cardioprotective effect of FGF-1. CONCLUSION: Cardiac specific overexpression of FGF-1 provides cardioprotection at the level of the cardiac myocyte, independent from angiogenesis, and at least partially mediated via activation of the mitogen activated protein kinase (MAP) ERK-1 and -2.     

MLST of housekeeping genes captures geographic population structure and suggests a European origin of Borrelia burgdorferi

Lyme borreliosis, caused by the tick-borne bacterium Borrelia burgdorferi, has become the most common vector-borne disease in North America over the last three decades. To understand the dynamics of the epizootic spread and to predict the evolutionary trajectories of B. burgdorferi, accurate information on the population structure and the evolutionary relationships of the pathogen is crucial. We, therefore, developed a multilocus sequence typing (MLST) scheme for B. burgdorferi based on eight chromosomal housekeeping genes. We validated the MLST scheme on B. burgdorferi specimens from North America and Europe, comprising both cultured isolates and infected ticks. These data were compared with sequences for the commonly used genetic markers rrs-rrlA intergenic spacer (IGS) and the gene encoding the outer surface protein C (ospC). The study demonstrates that the concatenated sequences of the housekeeping genes of B. burgdorferi provide highly resolved phylogenetic signals and that the housekeeping genes evolve differently compared with the IGS locus and ospC. Using sequence data, the study reveals that North American and European populations of B. burgdorferi correspond to genetically distinct populations. Importantly, the MLST data suggest that B. burgdorferi originated in Europe rather than in North America as proposed previously.