bluuebunny/crossref_metadata_2025 huggingface dataset:
Egr-1 contributes to IL-1-mediated down-regulation of peroxisome proliferator-activated receptor γ expression in human osteoarthritic chondrocytes
Authors: Nebbaki Sarah-Salwa , El Mansouri Fatima Ezzahra , Afif Hassan , Kapoor Mohit , Benderdour Mohamed , Duval Nicolas , Pelletier Jean-Pierre , Martel-Pelletier Johanne , Fahmi Hassan
Published: March 2012

Introduction

Peroxisome proliferator-activated receptor (PPAR)γ has been shown to exhibit anti-inflammatory and anti-catabolic properties and to be protective in animal models of osteoarthritis (OA). We have previously shown that interleukin-1β (IL-1) down-regulates PPARγ expression in human OA chondrocytes. However, the mechanisms underlying this effect have not been well characterized. The PPARγ promoter harbors an overlapping Egr-1/specificity protein 1 (Sp1) binding site. In this study, our objective was to define the roles of Egr-1 and Sp1 in IL-1-mediated down-regulation of PPARγ expression.

Methods

Chondrocytes were stimulated with IL-1 and the expression levels of Egr-1 and Sp1 mRNAs and proteins were evaluated using real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting, respectively. The role of de novo protein synthesis was evaluated using the protein synthesis inhibitor cycloheximide (CHX). The recruitment of Sp1 and Egr-1 to the PPARγ promoter was evaluated using chromatin immunoprecipitation (ChIP) assays. The PPARγ promoter activity was analyzed in transient transfection experiments. The roles of Egr-1 and Sp1 were further evaluated using small interfering RNA (siRNA) approaches. The level of Egr-1 in cartilage was determined using immunohistochemistry.

Results

Down-regulation of PPARγ expression by IL-1 requires de novo protein synthesis and was concomitant with the induction of the transcription factor Egr-1. Treatment with IL-1 induced Egr-1 recruitment and reduced Sp1 occupancy at the PPARγ promoter. Overexpression of Egr-1 potentiated, whereas overexpression of Sp1 alleviated, the suppressive effect of IL-1 on the PPARγ promoter, suggesting that Egr-1 may mediate the suppressive effect of IL-1. Consistently, Egr-1 silencing prevented IL-1-mediated down-regulation of PPARγ expression. We also showed that the level of Egr-1 expression was elevated in OA cartilage compared to normal cartilage.

Conclusions

Our results indicate that induction and recruitment of Egr-1 contributed to the suppressive effect of IL-1 on PPARγ expression. They also suggest that modulation of Egr-1 levels in the joint may have therapeutic potential in OA.
PAX3/FOXO1 Fusion Gene Status Is the Key Prognostic Molecular Marker in Rhabdomyosarcoma and Significantly Improves Current Risk Stratification
Authors: Missiaglia Edoardo , Williamson Dan , Chisholm Julia , Wirapati Pratyaksha , Pierron Gaëlle , Petel Fabien , Concordet Jean-Paul , Thway Khin , Oberlin Odile , Pritchard-Jones Kathy , Delattre Olivier , Delorenzi Mauro , Shipley Janet
Published: March 2012

Purpose

To improve the risk stratification of patients with rhabdomyosarcoma (RMS) through the use of clinical and molecular biologic data.

Patients and Methods

Two independent data sets of gene-expression profiling for 124 and 101 patients with RMS were used to derive prognostic gene signatures by using a meta-analysis. These and a previously published metagene signature were evaluated by using cross validation analyses. A combined clinical and molecular risk-stratification scheme that incorporated the PAX3/FOXO1 fusion gene status was derived from 287 patients with RMS and evaluated.

Results

We showed that our prognostic gene-expression signature and the one previously published performed well with reproducible and significant effects. However, their effect was reduced when cross validated or tested in independent data and did not add new prognostic information over the fusion gene status, which is simpler to assay. Among nonmetastatic patients, patients who were PAX3/FOXO1 positive had a significantly poorer outcome compared with both alveolar-negative and PAX7/FOXO1-positive patients. Furthermore, a new clinicomolecular risk score that incorporated fusion gene status (negative and PAX3/FOXO1 and PAX7/FOXO1 positive), Intergroup Rhabdomyosarcoma Study TNM stage, and age showed a significant increase in performance over the current risk-stratification scheme.

Conclusion

Gene signatures can improve current stratification of patients with RMS but will require complex assays to be developed and extensive validation before clinical application. A significant majority of their prognostic value was encapsulated by the fusion gene status. A continuous risk score derived from the combination of clinical parameters with the presence or absence of PAX3/FOXO1 represents a robust approach to improving current risk-adapted therapy for RMS.
Developmental Programming: Prenatal and Postnatal Contribution of Androgens and Insulin in the Reprogramming of Estradiol Positive Feedback Disruptions in Prenatal Testosterone-Treated Sheep
Authors: Abi Salloum Bachir , Herkimer Carol , Lee James S. , Veiga-Lopez Almudena , Padmanabhan Vasantha
Published: March 2012

Prenatal testosterone (T) excess compromises the estradiol (E2) positive feedback. This study tested the hypothesis that antagonizing androgen action or improving insulin sensitivity prenatally would prevent positive feedback disruptions from developing, whereas postnatal intervention with androgen antagonist or insulin sensitizer would ameliorate the severity of disruptions in prenatal T-treated females. The E2 positive feedback response was tested at 16 wk of age in the following groups of animals: 1) control, 2) prenatal T, 3) prenatal T plus the androgen antagonist, flutamide, 4) prenatal T plus insulin sensitizer, rosiglitazone, 5) prenatal T and postnatal androgen antagonist, and 6) prenatal T and postnatal insulin sensitizer (n = 7–21 animals/group). Prenatal T treatment involved the administration of T propionate (100 mg, im) twice weekly from d 30 to 90 of gestation. Prenatal interventions involved daily sc administration of androgen antagonist (15 mg/kg) or oral administration of insulin sensitizer (8 mg) for the same duration. Postnatal treatments began at 8 wk of age and involved daily oral administration of androgen antagonist (15 mg/kg) or insulin sensitizer (0.11 mg/kg). None of the prenatal/postnatal interventions increased number of animals responding or prevented the time delay in LH surge response to the E2 positive feedback challenge. In contrast, the postnatal treatment with androgen antagonist or insulin sensitizer increased total LH released in response to E2 positive feedback challenge, compared with the T animals. Overall, these interventional studies indicate that timing and magnitude of the LH surge are programmed by different neuroendocrine mechanisms with postnatal androgens and insulin determining the size and prenatal estrogen likely the timing of the LH surge.
Chromatin remodelling initiation during human spermiogenesis
Authors: De Vries Marieke , Ramos Liliana , Housein Zjwan , De Boer Peter
Published: March 2012

During the last phase of spermatogenesis, spermiogenesis, haploid round spermatids metamorphose towards spermatozoa. Extensive cytoplasmic reduction and chromatin remodelling together allow a dramatic decrease of cellular, notably nuclear volume. DNA packing by a nucleosome based chromatin structure is largely replaced by a protamine based one. At the cytoplasmic level among others the acrosome and perinuclear theca (PNT) are formed. In this study we describe the onset of chromatin remodelling to occur concomitantly with acrosome and PNT development. In spread human round spermatid nuclei, we show development of a DAPI-intense doughnut-like structure co-localizing with the acrosomal sac and sub acrosomal PNT. At this structure we observe the first gradual decrease of nucleosomes and several histones. Histone post-translational modifications linked to chromatin remodelling such as H4K8ac and H4K16ac also delineate the doughnut, that is furthermore marked by H3K9me2. During the capping phase of acrosome development, the size of the doughnut-like chromatin domain increases, and this area often is marked by uniform nucleosome loss and the first appearance of transition protein 2 and protamine 1. In the acrosome phase at nuclear elongation, chromatin remodelling follows the downward movement of the marginal ring of the acrosome. Our results indicate that acrosome development and chromatin remodelling are interacting processes. In the discussion we relate chromatin remodelling to the available data on the nuclear envelope and the linker of nucleoskeleton and cytoskeleton (LINC) complex of spermatids, suggesting a signalling route for triggering chromatin remodelling.
Mnk1 kinase activity is required for abscission
Authors: Rannou Yoann , Salaun Patrick , Benaud Christelle , Khan Jabbar , Dutertre Stéphanie , Giet Régis , Prigent Claude
Published: March 2012

Mnk1 is a serine/threonine kinase identified as a target for MAP kinase pathways. Using chemical drug, kinase-dead expression or knock down by RNA interference, we show that inhibition of Mnk1 induces the formation of multinucleated cells, which can be rescued by expressing an RNA interference resistant form of Mnk1. We found that active human Mnk1 localises to centrosomes, spindle microtubules and the midbody. Time-lapse recording of Mnk1 depleted cells display cytokinesis defects, as daughter cells fuse back together. Under inhibition of Mnk1 activity, no microtubule defect at the midbody was detected, however membrane vesicles anchorage at the midbody was impaired as lumenal-GFP positive-vesicles did not accumulate at the midbody. At the molecular level, we found that centriolin localisation was impaired at the midbody in Mnk1 depleted cells. As a consequence endobrevin, a V-SNARE protein implicated in the abscission step, was not properly localised at the midbody. Altogether our data show that Mnk1 activity is required for abscission.
Reading About the Financial Crisis: A Twenty-One-Book Review
Authors: Lo Andrew W
Published: March 2012

The recent financial crisis has generated many distinct perspectives from various quarters. In this article, I review a diverse set of twenty-one books on the crisis, eleven written by academics, and ten written by journalists and one former Treasury Secretary. No single narrative emerges from this broad and often contradictory collection of interpretations, but the sheer variety of conclusions is informative, and underscores the desperate need for the economics profession to establish a single set of facts from which more accurate inferences and narratives can be constructed. (JEL E32, E44, E52, G01, G21, G28)
Alphafetoprotein in the Dutch External Quality Assurance programme: a need for improvement
Authors: Houwert A Carolien , Lock M T W Tycho , Lentjes Eef G W M
Published: March 2012

Background

Elevated alphafetoprotein (AFP) concentrations may result from a variety of clinical conditions, but their role as an important tumour marker has been well established. There may be differences in AFP values due to laboratories using different methods, even though most methods have been calibrated with the same international standard (WHO IS 72/225). Therefore it is important to know the analytical performance of the various methods in relation to the analytical requirements for AFP measurement.

Methods

Annually, from January 2005 to July 2010, the results were analysed from the 65–75 laboratories that took part in the AFP survey of the External Quality Assurance programme of the Foundation Quality Control Medical Laboratories (the SKML/Binding Analysis) in the Netherlands.

Results

The Elecsys/Modular (36%) and the Immulite 2000/2500 (29%) are the methods used most. The methods show, on average, up to 15% positive and 12% negative bias, compared with the all-laboratory trimmed mean. Of the laboratories using the Immulite or the Elecsys/Modular analyser, over 70% show sufficient analytical performance to meet the Fraser criterion for method imprecision. Of the laboratories using a different method, over 50% do not meet this criterion.

Conclusions

AFP immunoassays suffer from method bias, even though all methods have been calibrated with the same international standard. Some of the methods used show insufficient performance.
Compression Hosiery for Occupational Leg Symptoms and Leg Volume: A Randomized Crossover Trial in a Cohort of Hairdressers
Authors: Blazek C , Amsler F , Blaettler W , Keo H H , Baumgartner I , Willenberg T
Published: March 2012

Objective:

Occupational leg symptoms are highly prevalent in the general population and impair the psychic state of health. We investigated hairdressers, a cohort exposed to prolonged standing during work, in a randomized crossover trial. We hypothesized that hairdressers wearing low-strength compression hosiery would benefit from less leg volume increase and discomfort.

Methods:

One hundred and eight hairdressers were randomized to wear medical compression stockings (MCS; 15–20 mmHg) in a crossover study. The effect of MCS on symptoms and on lower leg volume was compared with no compression treatment. Symptoms were assessed with a comprehensive questionnaire, categorized using factor analysis with varimax rotation and correlated with leg volume changes.

Results:

Wearing MCS reduced the symptom score for pain and feelings of swelling (range 0–4) by an average of 0.22 (12%, P < 0.001). Sleep disturbance, feeling of unattractive legs and depressiveness improved with MCS compared with no MCS. Subjects initially obliged to refrain from wearing stockings showed a significant decrease of pain and feelings of swelling as well (by 0.10 [6%], P = 0.015). Wearing MCS was associated with a decrease of lower leg volume by an average of 19 mL ( P < 0.001), with preference in older hairdressers ( P < 0.001). The effects of wearing MCS on symptoms and on leg volume were not correlated with each other.

Conclusions:

Individuals working in a standing profession experience leg pain, feelings of swelling, heaviness and various other disturbing feelings. These symptoms can be alleviated by wearing low-strength MCS.
Catheter-directed foam sclerotherapy for insufficiency of the great saphenous vein: occlusion rates and patient satisfaction after one year
Authors: Williamsson C , Danielsson P , Smith L
Published: March 2012

Objectives

This study aims to describe a technique for catheter-directed foam sclerotherapy (CDS) of great saphenous vein (GSV) insufficiency and report occlusion rate and patient satisfaction after a single treatment.

Methods

About 100 patients were included. The GSV was accessed at knee level. With the method of Tessari 10 mL sclerosant foam was made (2 mL 3% polidocanol and 8 mL air) and delivered along the GSV while the catheter was withdrawn. At two weeks and at one year after treatment the patients were evaluated.

Results

CDS was successfully performed in 94 of the 100 patients. After one year, 84% of the patients were satisfied. Seventy percent of the GSV were completely occluded, 14% were partly occluded and 15% were recanalized. No serious side-effects occurred.

Conclusions

CDS is safe. Patient satisfaction is very satisfying and the occlusion rate is promising after a single treatment. Repeated treatments and technical development may achieve higher occlusion rates.
Endovenous laser ablation with and without high ligation compared with high ligation and stripping in the treatment of great saphenous varicose veins: initial results of a multicentre randomized controlled trial
Authors: Flessenkämper I , Hartmann M , Stenger D , Roll S
Published: March 2012

Objectives:

To compare reflux recurrences at the saphenofemoral junction after endovenous laser ablation (EVLA) with or without high ligation with high ligation and stripping (HL/ST) of the great saphenous vein (GSV) in patients with varicosity of the GSV.

Design:

Multicentre, randomized, three-arm, parallel trial.

Material and Methods:

Patients with varicosity of the GSV were randomized to one of three groups: HL/ST, laser ablation (980 nm) or a combination of laser ablation with high ligation (EVLA/HL). Patients were examined clinically and by ultrasound pre- and postoperatively and after two months. The primary endpoint of this ongoing study is the inguinal venous reflux (IVR) in the proximal section of the GSV after two years. We present data after two months. Secondary endpoints include postoperative ecchymosis, pain or discomfort, saphenous syndrome. Groups were compared by chi-squared test.

Results:

A total of 449 patients were randomized; mean age 48 years and 71.2% were women. Postoperative ecchymosis developed among 69.2% in the HL/ST group, in 50.4% of the EVLA group and in 50.3% of the EVLA/HL group ( P = 0.0007). Postoperative pain after one day occurred in 32.7% in the HL/ST group. Discomfort occurred after surgery in 37.3% in the EVLA group, and in 50.0% in the EVLA/HL group ( P = 0.0069). Early postoperative nervus saphenous syndrome developed in 0.6% in the HL/ST group, in 3.7% in the EVLA group and in 6.1% in the EVLA/HL group ( P = 0.0341). After two months, IVR persisted in 38 cases (8.5%) in the laser group, in 10 (2.2%) in the EVLA/HL group and none in the HL/ST group ( P = 0.6800).

Conclusions:

After two months IVR was more often seen in both EVLA groups compared with the HL/ST group. There were significantly more postoperative ecchymosis in the HL/ST. Postoperative pain occurred significantly more often in the EVLA/HL group. Peri- and postoperative data showed significant differences between the three groups. For definitive results concerning the primary endpoint of IVR the later follow-up has to be waited for.
Epidemiology, risk factors and sequelae of venous thromboembolism
Authors: Wong P , Baglin T
Published: March 2012

The aim of this review was to discuss the epidemiology, risk factors and sequelae of venous thromboembolism (VTE). VTE has an incidence of 1–2 per 1000 people annually. The risk of VTE increases with age and is highest in Caucasians and African Americans. Combined oral contraceptives (COC), especially the third-generation COCs, have been strongly implicated in VTE. Hospitalized patients, especially patients with underlying malignancy and undergoing surgery, have a host of risk factors for VTE. Thrombophilia can predispose an individual to VTE but indiscriminate testing for thrombophilia in patients presenting with VTE is not indicated. VTE can have serious chronic sequelae in the form of post-thrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTPH). The risk of PTS and CTPH is increased with recurrent deep vein thrombosis and pulmonary embolism, respectively. Mortality from VTE can be as high as 21.6% at one year. Patients who had an episode of VTE have a high risk of subsequent VTE and this risk is highest in patients who had a first VTE event associated with malignancy. A good understanding of the epidemiology and risk factors of VTE will enable the treating medical practitioners to identify patients at risk and administer appropriate VTE prophylaxis to prevent the longterm consequences of VTE.
Thrombosis: simplified
Authors: Sarvananthan T , Das S
Published: March 2012

The devastating consequences of venous thromboembolism have forever provided the impetus to explore safe and effective treatment strategies. To date, the pathophysiology and mechanism of thrombosis have been extensively studied and details of new thrombophilic conditions are continually being discovered. Although there has been extensive research detailing various predispositions to thrombosis, uncertainties regarding their appropriate management continue. This review aims to highlight the various challenges involved in identifying those at risk; provide appropriate management options; and lastly present the current views on the development of new anticoagulants that are competing to replace the traditional agents.
Cancer-related venous thromboembolic disease: current management and areas of uncertainty
Authors: Radhakrishna G , Berridge D
Published: March 2012

The relationship between cancer and venothromboembolic events is a complex, multifactorial process which is still not fully understood and therefore the use of current generic guidelines may be inadequate. Current management of cancer-related VTE may be suboptimal because of the lack of cancer-specific studies into the role of primary prophylaxis in both ambulant and non-ambulant cancer patients. Further research into developing cancer-specific risk assessment tools and the choice, dose and duration of prophylaxis is required. The management of confirmed symptomatic VTE in cancer patients is outlined but certain controversies remain. Areas for further research include the management of asymptomatic unsuspected VTE events, recurrent VTE events on treatment and the role of IVC filters and other treatment options are required. This paper attempts to cover some of the recent developments and areas of uncertainty surrounding the management of cancer-related VTE.
Management of proximal deep vein thrombosis
Authors: Nyamekye I , Merker L
Published: March 2012

Iliofemoral DVT constitutes approximately 20–25% of lower limb DVT and represents a specific subgroup of patients at highest risk for post-thrombotic syndrome (PTS). Anticoagulation alone has no significant thrombolytic activity and has not impact on PTS prevention.

Early thrombus removal has reduced PTS in uncontrolled reports and reviews but major trials are awaited. The optimal timing for treatment appear to be thrombus <2 weeks old and, methods for thrombus removal include direct open or suction thrombectomy, catheter directed thrombolysis (CDT), with or without percutaneous mechanical thrombectomy (PMT) devices. Three principle types of PMT device are in use (rotational, rheolytic and ultrasound enhanced devices) and are combined with CDT in pharmocomechanical thrombolysis (PhMT) to enhance early thrombus removal. These devices have individual device specific attributes and side effects that are additional to the bleeding complications of thrombolysis.

A number of additional interventions may be utilised to the improve results of CDT and PhMT. IVC filter deployment to reduce periprocedural PE, is supported by little evidence unless an indication for its use already exists. However, balloon venoplasty and vein stents undoubtedly vein patency after treatment.

Early thrombus removal comes with additional upfront costs derived from devices, imaging and critical care bed usage. However, significant potential savings from reduction in PTS and rethrombosis rates may reduce overall societal costs.

This review focuses on iliofemoral thrombosis, however, the less commonly encountered but clinically important subclavian vein thrombosis is also discussed.
Pregnancy-associated venous thrombosis
Authors: Kesteven P , Hanley J , Loughney A D
Published: March 2012

Pregnant women are at an increased risk of venous thromboembolism (VTE) and the consequences of an acute event in pregnancy can be debilitating, long-lasting or fatal. Screening for risk factors early in pregnancy and the provision of thromboprophylaxis are useful ways of preventing VTE in some women, but even when performed diligently, acute events are likely to remain common for the foreseeable future. It is therefore important for obstetric and non-obstetric clinicians to recognize the symptoms and signs of deep vein thrombosis and pulmonary embolism in pregnancy, to understand how a diagnosis can be reached in an effective yet safe manner and to be aware of the available treatment modalities.
Pri-miR-17-92a transcript folds into a tertiary structure and autoregulates its processing
Authors: Chakraborty Saikat , Mehtab Shabana , Patwardhan Anand , Krishnan Yamuna
Published: March 2012

MicroRNAs control gene expression either by RNA transcript degradation or translational repression. Expressions of miRNAs are highly regulated in tissues, disruption of which leads to disease. How this regulation is achieved and maintained is still largely unknown. MiRNAs that reside on clustered or polycistronic transcripts represent a more complex case where individual miRNAs from a cluster are processed with different efficiencies despite being cotranscribed. To shed light on the regulatory mechanisms that might be operating in these cases, we considered the long polycistronic primary miRNA transcript pri-miR-17-92a that contains six miRNAs with diverse functions. The six miRNA domains on this cluster are differentially processed to produce varying amounts of resultant mature miRNAs in different tissues. How this is achieved is not known. We show, using various biochemical and biophysical methods coupled with mutational studies, that pri-miR-17-92a adopts a specific three-dimensional architecture that poses a kinetic barrier to its own processing. This tertiary structure could create suboptimal protein recognition sites on the pri-miRNA cluster due to higher-order structure formation.
Discerning Trends in Multiplex Immunoassay Technology with Potential for Resource-Limited Settings
Authors: Gordon Julian , Michel Gerd
Published: March 2012

BACKGROUND

In the search for more powerful tools for diagnoses of endemic diseases in resource-limited settings, we have been analyzing technologies with potential applicability. Increasingly, the process focuses on readily accessible bodily fluids combined with increasingly powerful multiplex capabilities to unambiguously diagnose a condition without resorting to reliance on a sophisticated reference laboratory. Although these technological advances may well have important implications for the sensitive and specific detection of disease, to date their clinical utility has not been demonstrated, especially in resource-limited settings. Furthermore, many emerging technological developments are in fields of physics or engineering, which are not readily available to or intelligible to clinicians or clinical laboratory scientists.

CONTENT

This review provides a look at technology trends that could have applicability to high-sensitivity multiplexed immunoassays in resource-limited settings. Various technologies are explained and assessed according to potential for reaching relevant limits of cost, sensitivity, and multiplex capability. Frequently, such work is reported in technical journals not normally read by clinical scientists, and the authors make enthusiastic claims for the potential of their technology while ignoring potential pitfalls. Thus it is important to draw attention to technical hurdles that authors may not be publicizing.

Immunochromatographic assays, optical methods including those involving waveguides, electrochemical methods, magnetorestrictive methods, and field-effect transistor methods based on nanotubes, nanowires, and nanoribbons reveal possibilities as next-generation technologies.
Netrin/DCC Signaling Guides Olfactory Sensory Axons to Their Correct Location in the Olfactory Bulb
Authors: Lakhina Vanisha , Marcaccio Christina L. , Shao Xin , Lush Mark E. , Jain Roshan A. , Fujimoto Esther , Bonkowsky Joshua L. , Granato Michael , Raper Jonathan A.
Published: March 2012

Olfactory sensory neurons expressing particular olfactory receptors project to specific reproducible locations within the bulb. The axonal guidance cues that organize this precise projection pattern are only beginning to be identified. To aid in their identification and characterization, we generated a transgenic zebrafish line, OR111-7:IRES:Gal4, in which a small subset of olfactory sensory neurons is labeled. Most sensory neurons expressing theOR111-7transgene project to a specific location within the bulb, the central zone protoglomerulus, while a smaller number project to the lateral glomerulus 1 protoglomerulus. Inhibiting Netrin/DCC (deleted in colorectal cancer) signaling perturbs the ability of OR111-7-expressing axons to enter the olfactory bulb and alters their patterns of termination within the bulb. The Netrin receptor DCC is expressed in olfactory sensory neurons around the time that they elaborate their axons, netrin1a is expressed near the medial-most margin of the olfactory bulb, and netrin1b is expressed within the ventral region of the bulb. Loss of Netrin/DCC signaling components causes some OR111-7-expressing sensory axons to wander posteriorly after exiting the olfactory pit, away from netrin-expressing areas in the bulb. OR111-7-expressing axons that enter the bulb target the central zone less precisely than normal, spreading away from netrin-expressing regions. These pathfinding errors can be corrected by the reexpression of DCC withinOR111-7transgene-expressing neurons in DCC morphant embryos. These findings implicate Netrins as the only known attractants for olfactory sensory neurons, first drawing OR111-7-expressing axons into the bulb and then into the ventromedially positioned central zone protoglomerulus.
A Septal-Hypothalamic Pathway Drives Orexin Neurons, Which Is Necessary for Conditioned Cocaine Preference
Authors: Sartor Gregory C. , Aston-Jones Gary S.
Published: March 2012

Orexins (also called hypocretins) have been shown to be importantly involved in reward and addiction, but little is known about the circuitry that regulates orexin neuronal activity during drug-seeking behaviors. Here, we examined inputs to the lateral hypothalamus (LH) orexin cell field from the lateral septum (LS) using tract-tracing and Fos immunohistochemistry after cocaine (10 mg/kg) conditioned place preference (CPP) in Sprague Dawley rats. We found that neurons in rostral LS (LSr) that project to LH are Fos-activated in proportion to cocaine CPP, and that inhibition of LSr neurons with local baclofen and muscimol microinjection (0.3/0.03 nmol) blocks expression of Fos in LH orexin cells and cocaine preference. In addition, using local inactivation in LS and orexin antisense morpholinos in LH, we found that LSr influences on LH orexin neurons are critical for the expression of cocaine preference. These results indicate that LSr activates LH orexin neurons during cocaine place preference, and that this circuit is essential for expression of cocaine place preference.
ChondrolectinMediates Growth Cone Interactions of Motor Axons with an Intermediate Target
Authors: Zhong Zhen , Ohnmacht Jochen , Reimer Michell M. , Bach Ingolf , Becker Thomas , Becker Catherina G.
Published: March 2012

The C-type lectin chondrolectin (chodl) represents one of the major gene products dysregulated in spinal muscular atrophy models in mice. However, to date, no function has been determined for the gene. We have identifiedchodland other novel genes potentially involved in motor axon differentiation, by expression profiling of transgenically labeled motor neurons in embryonic zebrafish. To enrich the profile for genes involved in differentiation of peripheral motor axons, we inhibited the function of LIM-HDs (LIM homeodomain factors) by overexpression of a dominant-negative cofactor, thereby rendering labeled axons unable to grow out of the spinal cord. Importantly, labeled cells still exhibited axon growth and most cells retained markers of motor neuron identity. Functional tests ofchodl, by overexpression and knockdown, confirm crucial functions of this gene for motor axon growthin vivo. Indeed, knockdown ofchodlinduces arrest or stalling of motor axon growth at the horizontal myoseptum, an intermediate target and navigational choice point, and reduced muscle innervation at later developmental stages. This phenotype is rescued bychodloverexpression, suggesting that correct expression levels ofchodlare important for interactions of growth cones of motor axons with the horizontal myoseptum. Combined, these results identify upstream regulators and downstream functions ofchodlduring motor axon growth.
HDAC6 Regulates Glucocorticoid Receptor Signaling in Serotonin Pathways with Critical Impact on Stress Resilience
Authors: Espallergues Julie , Teegarden Sarah L. , Veerakumar Avin , Boulden Janette , Challis Collin , Jochems Jeanine , Chan Michael , Petersen Tess , Deneris Evan , Matthias Patrick , Hahn Chang-Gyu , Lucki Irwin , Beck Sheryl G. , Berton Olivier
Published: March 2012

Genetic variations in certain components of the glucocorticoid receptor (GR) chaperone complex have been associated with the development of stress-related affective disorders and individual variability in therapeutic responses to antidepressants. Mechanisms that link GR chaperoning and stress susceptibility are not well understood. Here, we show that the effects of glucocorticoid hormones on socioaffective behaviors are critically regulated via reversible acetylation of Hsp90, a key component of the GR chaperone complex. We provide pharmacological and genetic evidence indicating that the cytoplasmic lysine deacetylase HDAC6 controls Hsp90 acetylation in the brain, and thereby modulates Hsp90–GR protein–protein interactions, as well as hormone- and stress-induced GR translocation, with a critical impact on GR downstream signaling and behavior. Pet1-Cre-driven deletion of HDAC6 in serotonin neurons, the densest HDAC6-expressing cell group in the mouse brain, dramatically reduced acute anxiogenic effects of the glucocorticoid hormone corticosterone in the open-field, elevated plus maze, and social interaction tests. Serotonin-selective depletion of HDAC6 also blocked the expression of social avoidance in mice exposed to chronic social defeat and concurrently prevented the electrophysiological and morphological changes induced, in serotonin neurons, by this murine model of traumatic stress. Together, these results identify HDAC6 inhibition as a potential new strategy for proresilience and antidepressant interventions through regulation of the Hsp90–GR heterocomplex and focal prevention of GR signaling in serotonin pathways. Our data thus uncover an alternate mechanism by which pan-HDAC inhibitors may regulate stress-related behaviors independently of their action on histones.
Early Binding of Gaze, Gesture, and Emotion: Neural Time Course and Correlates
Authors: Conty Laurence , Dezecache Guillaume , Hugueville Laurent , Grèzes Julie
Published: March 2012

Communicative intentions are transmitted by many perceptual cues, including gaze direction, body gesture, and facial expressions. However, little is known about how these visual social cues are integrated over time in the brain and, notably, whether this binding occurs in the emotional or the motor system. By coupling magnetic resonance and electroencephalography imaging in humans, we were able to show that, 200 ms after stimulus onset, the premotor cortex integrated gaze, gesture, and emotion displayed by a congener. At earlier stages, emotional content was processed independently in the amygdala (170 ms), whereas directional cues (gaze direction with pointing gesture) were combined at ∼190 ms in the parietal and supplementary motor cortices. These results demonstrate that the early binding of visual social signals displayed by an agent engaged the dorsal pathway and the premotor cortex, possibly to facilitate the preparation of an adaptive response to another person's immediate intention.
Wakefulness Affects Synaptic and Network Activity by Increasing Extracellular Astrocyte-Derived Adenosine
Authors: Schmitt L. Ian , Sims Robert E. , Dale Nicholas , Haydon Philip G.
Published: March 2012

Loss of sleep causes an increase in sleep drive and deficits in hippocampal-dependent memory. Both of these responses are thought to require activation of adenosine A1 receptors (adorA1Rs) and release of transmitter molecules including ATP, which is rapidly converted to adenosine in the extracellular space, from astrocytes in a process termed gliotransmission. Although it is increasingly clear that astrocyte-derived adenosine plays an important role in driving the homeostatic sleep response and the effects of sleep loss on memory (Halassa et al., 2009; Florian et al., 2011), previous studies have not determined whether the concentration of this signaling molecule increases in response to wakefulness. Here, we show that the level of adorA1R activation increases in response to wakefulness in mice (Mus musculus). We found that this increase affected synaptic transmission in the hippocampus and modulated network activity in the cortex. Direct biosensor-based measurement of adenosine showed that the net extracellular concentration of this transmitter increased in response to normal wakefulness and sleep deprivation. Genetic inhibition of gliotransmission prevented this increase and attenuated the wakefulness-dependent changes in synaptic and network regulation by adorA1R. Consequently, we conclude that wakefulness increases the level of extracellular adenosine in the hippocampus and that this increase requires the release of transmitters from astroctyes.
Bidirectional Relationship between Functional Connectivity and Amyloid-β Deposition in Mouse Brain
Authors: Bero Adam W. , Bauer Adam Q. , Stewart Floy R. , White Brian R. , Cirrito John R. , Raichle Marcus E. , Culver Joseph P. , Holtzman David M.
Published: March 2012

Brain region-specific deposition of extracellular amyloid plaques principally composed of aggregated amyloid-β (Aβ) peptide is a pathological signature of Alzheimer's disease (AD). Recent human neuroimaging data suggest that resting-state functional connectivity strength is reduced in patients with AD, cognitively normal elderly harboring elevated amyloid burden, and in advanced aging. Interestingly, there exists a striking spatial correlation between functional connectivity strength in cognitively normal adults and the location of Aβ plaque deposition in AD. However, technical limitations have heretofore precluded examination of the relationship between functional connectivity, Aβ deposition, and normal aging in mouse models. Using a novel functional connectivity optical intrinsic signal (fcOIS) imaging technique, we demonstrate that Aβ deposition is associated with significantly reduced bilateral functional connectivity in multiple brain regions of older APP/PS1 transgenic mice. The amount of Aβ deposition in each brain region was associated with the degree of local, age-related bilateral functional connectivity decline. Normal aging was associated with reduced bilateral functional connectivity specifically in retrosplenial cortex. Furthermore, we found that the magnitude of regional bilateral functional correlation in young APP/PS1 mice before Aβ plaque formation was proportional to the amount of region-specific plaque deposition seen later in older APP/PS1 mice. Together, these findings suggest that Aβ deposition and normal aging are associated with region-specific disruption of functional connectivity and that the magnitude of local bilateral functional connectivity predicts regional vulnerability to subsequent Aβ deposition in mouse brain.
The Politics of Children's Health Insurance Policy
Authors: Tope Daniel , Hickman Lisa N.
Published: March 2012

What is the relationship between state-level politics and the resources devoted to children's health insurance programs (CHIP)? The authors asses this question by drawing on theories from the power resources, institutionalist, logic of industrialism, and racial threat schools of thought. The authors find that each approach offers some explanatory power for per capita CHIP spending. In particular, Republican strength in state legislatures and governorships are associated with diminished CHIP spending. Professionalized state legislatures, strong state financial capacities, and states with a legacy of social policy innovation were linked to greater CHIP spending. States with more uninsured children tended to spend more per capita. And states with greater numbers of blacks spent less per capita. But there was no similar effect for Hispanics. The authors conclude that an array of forces at the state level figure prominently in cross-state inequality and the prospects for social citizenship.
Media Consumption, Perceptions of Crime Risk and Fear of Crime: Examining Race/Ethnic Differences
Authors: Callanan Valerie J.
Published: March 2012

This study compares the impact of multiple forms of crime-related media across white, Latino, and African American respondents on their perception of crime risk in their neighborhoods and fear of crime, using a state-wide survey of 3,712 Californians. The findings indicate some difference in the impact of crime-related media by different media forms and across race/ethnic groups. Consumption of local television news significantly elevated perceptions of risk and fear of crime for all groups. Crime-based reality programs produced equivalent fear, but the effects of newspaper and crime drama consumption were more variable. Realistic television content about crime was most influential on viewers' perceptions of and responses to crime than fictional accounts or newspapers.
Novel candidate genes of thyroid tumourigenesis identified in Trk-T1 transgenic mice
Authors: Heiliger Katrin-Janine , Hess Julia , Vitagliano Donata , Salerno Paolo , Braselmann Herbert , Salvatore Giuliana , Ugolini Clara , Summerer Isolde , Bogdanova Tatjana , Unger Kristian , Thomas Gerry , Santoro Massimo , Zitzelsberger Horst
Published: March 2012

For an identification of novel candidate genes in thyroid tumourigenesis, we have investigated gene copy number changes in aTrk-T1transgenic mouse model of thyroid neoplasia. For this aim, 30 thyroid tumours fromTrk-T1transgenics were investigated by comparative genomic hybridisation. Recurrent gene copy number alterations were identified and genes located in the altered chromosomal regions were analysed by Gene Ontology term enrichment analysis in order to reveal gene functions potentially associated with thyroid tumourigenesis. In thyroid neoplasms fromTrk-T1mice, a recurrent gain on chromosomal bands 1C4–E2.3 (10.0% of cases), and losses on 3H1–H3 (13.3%), 4D2.3–E2 (43.3%) and 14E4–E5 (6.7%) were identified. The genesTwist2,Ptma,Pde6d,Bmpr1b,Pdlim5,Unc5c,Srm,Trp73,Ythdf2,Taf12andSlitrk5are located in these chromosomal bands. Copy number changes of these genes were studied by fluorescencein situhybridisation on 30 human papillary thyroid carcinoma (PTC) samples and altered gene expression was studied by qRT-PCR analyses in 67 human PTC. Copy number gains were detected in 83% of cases forTWIST2and in 100% of cases forPTMAandPDE6D. DNA losses ofSLITRK1andSLITRK5were observed in 21% of cases and ofSLITRK6in 16% of cases. Gene expression was significantly up-regulated forUNC5CandTP73and significantly down-regulated forSLITRK5in tumours compared with normal tissue. In conclusion, a global genomic copy number analysis of thyroid tumours fromTrk-T1transgenic mice revealed a number of novel gene alterations in thyroid tumourigenesis that are also prevalent in human PTCs.
The risk of metachronous cancers in patients with small-intestinal carcinoid tumors: a US population-based study
Authors: Amin Sunil , Warner Richard R P , Itzkowitz Steven H , Kim Michelle Kang
Published: March 2012

Small-intestinal carcinoids (SIC) are the most common small-bowel malignancies. We sought to determine the risk of developing SIC before and after other primary malignancies (PM) and the prognosis of patients with SIC, with and without another PM. We used the Surveillance, Epidemiology, and End Results database to identify patients diagnosed with SICs between 1973 and 2007. Multiple primary-standardized incidence ratios were calculated as an approximation of relative risk (RR) to explore the association of SICs with metachronous malignancies. Survival analysis was performed using Kaplan–Meier methods and Cox proportional-hazard models. Among 8331 patients with SICs, 2424 (29%) had another PM at some time. The most common sites were prostate (26.2%), breast (14.3%), colon (9.1%), lung/bronchus (6.3%), and bladder (5.3%). Overall, 67% of patients had a PM diagnosed before SIC (pre-SIC), 33% after SIC (post-SIC), and 8% had a PM both before and after SIC. Among the pre-SIC group, the risk of future SIC was increased after cancers of the small bowel (RR 11.86 (95% CI: 6.13–20.72)), esophagus (4.05 (1.10–10.36)), colon (1.39 (1.05–1.81)), kidney (1.93 (1.12–3.09)), prostate (1.38 (1.17–1.62)), and leukemia (2.15 (1.18–3.61)). Among the post-SIC group, there was an increased risk of future PM of the small bowel (8.78 (4.54–15.34)), liver (2.49 (1.08–4.91)), prostate (1.25 (1.0–1.53)), and thyroid (2.73 (1.10–5.62)). Compared to patients with only SIC, those with a PM pre-SIC had worse mean survival (57.9 vs 40.9 months, HR 1.55 (1.42–1.69), P<0.001). In conclusion, almost one-third of patients with SICs have an associated metachronous primary tumor. When these primaries occur prior to (but not after) the SIC diagnosis, the prognosis is worse than with an initial SIC. The type of malignancies associated with SICs may guide future screening efforts.
Involvement of the transepithelial calcium transport disruption and the formation of epididymal stones in roosters
Authors: Oliveira André Gustavo , Aquino Diêgo Junior Queiroga , Mahecha Germán Arturo Bohórquez , Oliveira Cleida Aparecida
Published: March 2012

Epididymal lithiasis is a dysfunction of unknown origin characterized by the formation of calcium stones into the lumen of efferent ductules of roosters. Affected animals present an imbalance in the hormonal responsive systems that regulate the expression of proteins involved in the transepithelial calcium transport, as TRPV6, CaBP-D28K, NCX1, and PMCA. Because the efferent ductules are the major site of fluid and calcium reabsorption in excurrent ducts, it was hypothesized that impairment in local calcium homeostasis would lead to lithiasis. To test this hypothesis, we addressed the expression of these proteins in the epididymal region of affected animals. The present study focused on the investigation of the occurrence, tissue distribution, and physiological impact of the transepithelial calcium transport in roosters under normal and pathological conditions. The results showed that affected roosters presented a significant increase in TRPV6 and CaBP-D28k levels, whereas NCX1 and PMCA were not changed. Such alterations were more conspicuous in the proximal efferent ductules, in which was also observed accumulation of calcium within the epithelial cells. These findings provided the first evidences for the involvement of alteration in the expression of proteins essential for calcium reabsorption as a plausible mechanism for the formation of calcium stones within efferent ductules.
Risk Factor Changes for Sudden Infant Death Syndrome After Initiation of Back-to-Sleep Campaign
Authors: Trachtenberg Felicia L. , Haas Elisabeth A. , Kinney Hannah C. , Stanley Christina , Krous Henry F.
Published: March 2012

OBJECTIVE:

To test the hypothesis that the profile of sudden infant death syndrome (SIDS) changed after the Back-to-Sleep (BTS) campaign initiation, document prevalence and patterns of multiple risks, and determine the age profile of risk factors.

METHODS:

The San Diego SIDS/Sudden Unexplained Death in Childhood Research Project recorded risk factors for 568 SIDS deaths from 1991 to 2008 based upon standardized death scene investigations and autopsies. Risks were divided into intrinsic (eg, male gender) and extrinsic (eg, prone sleep).

RESULTS:

Between 1991–1993 and 1996–2008, the percentage of SIDS infants found prone decreased from 84.0% to 48.5% (P < .001), bed-sharing increased from 19.2% to 37.9% (P < .001), especially among infants <2 months (29.0% vs 63.8%), prematurity rate increased from 20.0% to 29.0% (P = .05), whereas symptoms of upper respiratory tract infection decreased from 46.6% to 24.8% (P < .001). Ninety-nine percent of SIDS infants had at least 1 risk factor, 57% had at least 2 extrinsic and 1 intrinsic risk factor, and only 5% had no extrinsic risk. The average number of risks per SIDS infant did not change after initiation of the BTS campaign.

CONCLUSIONS:

SIDS infants in the BTS era show more variation in risk factors. There was a consistently high prevalence of both intrinsic and especially extrinsic risks both before and during the Back-to-Sleep era. Risk reduction campaigns emphasizing the importance of avoiding multiple and simultaneous SIDS risks are essential to prevent SIDS, including among infants who may already be vulnerable.