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Endothelial-specific inhibition of NF-kappaB enhances functional haematopoiesis

Tue, 05/23/2017 - 4:51pm

Haematopoietic stem cells (HSCs) reside in distinct niches within the bone marrow (BM) microenvironment, comprised of endothelial cells (ECs) and tightly associated perivascular constituents that regulate haematopoiesis through the expression of paracrine factors. Here we report that the canonical NF-kappaB pathway in the BM vascular niche is a critical signalling axis that regulates HSC function at steady state and following myelosuppressive insult, in which inhibition of EC NF-kappaB promotes improved HSC function and pan-haematopoietic recovery. Mice expressing an endothelial-specific dominant negative IkappaBalpha cassette under the Tie2 promoter display a marked increase in HSC activity and self-renewal, while promoting the accelerated recovery of haematopoiesis following myelosuppression, in part through protection of the BM microenvironment following radiation and chemotherapeutic-induced insult. Moreover, transplantation of NF-kappaB-inhibited BM ECs enhanced haematopoietic recovery and protected mice from pancytopenia-induced death. These findings pave the way for development of niche-specific cellular approaches for the treatment of haematological disorders requiring myelosuppressive regimens.

Characterization of Severe Malaria in Liberian Children 5 Years Old and Younger

Tue, 05/23/2017 - 12:18pm

Malaria continues to be a challenging problem in the developing world, and the burden of this life threatening disease continues to be borne by young children living in Sub Saharan Africa. One of the biggest challenges to the prevention and control of this problem lies in accurately diagnosing malaria, and distinguishing it from the many other febrile illnesses which present in children in this age group.

Liberia is a West African country with a high burden of malaria. Very little is known about the presentation of severe malaria in children aged 5 years old and younger in Liberia. We undertook a prospective, hospital -based study of children 5 and under presenting to JKF Medical Center, the national referral hospital, with fever and signs and symptoms consistent with malaria. The aims of our study were to determine: 1) the frequency of confirmed malaria cases, 2) the frequency of non-malaria diagnoses, 3) the prevalence of anti-malarial drug resistance mutations, 4) the presence of other life threatening etiologies of febrile illness such as S. typhii and Dengue virus and 5) immunological profiling associated with severe malaria.

We analyzed clinical and laboratory data from 462 children age 5 and under who presented to the national referral hospital in Monrovia, Liberia with signs and symptoms consistent with malaria over a one year period. Key findings included determining the demographic factors most closely associated with severe malaria in this population (age > 1yr and urban environment) and those that were negatively associated with the development of severe malaria (prior episodes of malaria, use of bednets and use of anti malarial medications prior to presentation). The clinical symptoms most closely associated with severe malaria in this population were found to be headache and vomiting.

We found that 33% of children admitted and treated for severe malaria did not test positive for malaria by rapid diagnostic testing (RDT) or blood smear. These children had a case fatality rate that was 5 times higher than their RDT positive counter parts. Of the RDT negative children, 2 tested positive for salmonella typhii, but were not treated for this pathogen. Upon discharge from the hospital, 11% of children had resolved their symptoms, but had not cleared their malaria parasites.

These findings will help to identify the children who present with true severe malaria in Liberia. They also underscore the need to expand diagnostic capabilities to determine which other types of pathogens cause febrile illness in this population, so that adequate treatment can be extended to these patients.

The immunoprofiles of these children revealed 3 IgM antibodies (AMA-1, CSP and LSA-1) that were associated with the development of severe malaria. These antibodies also appear to be associated with initial infection with malaria. Such data will help to identify antigens could be potential targets for malaria vaccines, and which can play an important role in the development of new malaria diagnostics for this population.

The Relationship Between Hope, Core Self-Evaluations, Emotional Well-Being, Sexual Risk Taking, Substance Use, and Academic Performance in Freshman University Students

Tue, 05/23/2017 - 11:05am

Objective: To examine the relationship between hope, core self-evaluations, physical function, emotional well-being, health risk behaviors, and academic performance in freshman enrolled in their first year of college.

Participants: Freshman (N = 495) attending a large public university in the Northeast completed an online survey between February 1 to February 13, 2017.

Methods: Cross sectional descriptive survey. Linear regression, path analysis, and structural equation modeling procedures were performed.

Results: Core self-evaluations mediated the relationship between hope and emotional well-being and academic performance. Contrary to the hypotheses, higher hope predicted more sexual risk taking behaviors and alcohol use.

Conclusions: Core self-evaluations is an important component of hope theory. Hope Theory is useful for predicting emotional well-being, and academic performance, but not as useful for predicting drug use, alcohol use, and sexual risk taking. Hope and core self evaluations interventions are needed to improve academic performance and emotional well-being in university freshman.

Melanoma mystery

Mon, 05/22/2017 - 9:06pm

Biological variability has confounded efforts to confirm the role of PREX2 mutations in melanoma.

Setting the (Scientific) Record Straight: Molecular and Cellular Biology Responds to Postpublication Review

Mon, 05/22/2017 - 9:06pm

Though the ultimate responsibility lies with the institutions and researchers to educate the next generation of scientists in the ethics of research and publishing, scientific publishers have a contributing and important role in the maintenance and integrity of the scientific record.

Hyper- and hypo- nutrition studies of the hepatic transcriptome and epigenome suggest that PPARα regulates anaerobic glycolysis

Mon, 05/22/2017 - 9:06pm

Diet plays a crucial role in shaping human health and disease. Diets promoting obesity and insulin resistance can lead to severe metabolic diseases, while calorie-restricted (CR) diets can improve health and extend lifespan. In this work, we fed mice either a chow diet (CD), a 16 week high-fat diet (HFD), or a CR diet to compare and contrast the effects of these diets on mouse liver biology. We collected transcriptomic and epigenomic datasets from these mice using RNA-Seq and DNase-Seq. We found that both CR and HFD induce extensive transcriptional changes, in some cases altering the same genes in the same direction. We used our epigenomic data to infer transcriptional regulatory proteins bound near these genes that likely influence their expression levels. In particular, we found evidence for critical roles played by PPARα and RXRα. We used ChIP-Seq to profile the binding locations for these factors in HFD and CR livers. We found extensive binding of PPARα near genes involved in glycolysis/gluconeogenesis and uncovered a role for this factor in regulating anaerobic glycolysis. Overall, we generated extensive transcriptional and epigenomic datasets from livers of mice fed these diets and uncovered new functions and gene targets for PPARα.

Tips for Mental Health Providers Working with Southeast Asian Immigrants/Refugees [English and Vietnamese versions]

Mon, 05/22/2017 - 2:35pm

A Vietnamese translation of this tip sheet is available for download under "Additional Files" below.

Developing trusting and respectful relationships is critical to best addressing the mental health needs of Southeast Asians. This tip-sheet offers some culturally-informed strategies mental health providers can use to build strong therapeutic alliances with their Southeast Asian clients.

Gold nanoparticles stabilized with MPEG-grafted poly(l-lysine): in vitro and in vivo evaluation of a potential theranostic agent

Mon, 05/22/2017 - 11:55am

As the number of diagnostic and therapeutic applications utilizing gold nanoparticles (AuNPs) increases, so does the need for AuNPs that are stable in vivo, biocompatible, and suitable for bioconjugation. We investigated a strategy for AuNP stabilization that uses methoxypolyethylene glycol-graft-poly(l-lysine) copolymer (MPEG-gPLL) bearing free amino groups as a stabilizing molecule. MPEG-gPLL injected into water solutions of HAuCl4 with or without trisodium citrate resulted in spherical (Zav = 36 nm), monodisperse (PDI = 0.27), weakly positively charged nanoparticles (AuNP3) with electron-dense cores (diameter: 10.4 +/- 2.5 nm) and surface amino groups that were amenable to covalent modification. The AuNP3 were stable against aggregation in the presence of phosphate and serum proteins and remained dispersed after their uptake into endosomes. MPEG-gPLL-stabilized AuNP3 exhibited high uptake and very low toxicity in human endothelial cells, but showed a high dose-dependent toxicity in epithelioid cancer cells. Highly stable radioactive labeling of AuNP3 with (99m)Tc allowed imaging of AuNP3 biodistribution and revealed dose-dependent long circulation in the blood. The minor fraction of AuGNP3 was found in major organs and at sites of experimentally induced inflammation. Gold analysis showed evidence of a partial degradation of the MPEG-gPLL layer in AuNP3 particles accumulated in major organs. Radiofrequency-mediated heating of AuNP3 solutions showed that AuNP3 exhibited heating behavior consistent with 10 nm core nanoparticles. We conclude that PEG-pPLL coating of AuNPs confers "stealth" properties that enable these particles to exist in vivo in a nonaggregating, biocompatible state making them suitable for potential use in biomedical applications such as noninvasive radiofrequency cancer therapy.

A feasible approach to evaluate the relative reactivity of NHS-ester activated group with primary amine-derivatized DNA analogue and non-derivatized impurity

Mon, 05/22/2017 - 11:55am

Synthetic DNA analogues with improved stability are widely used in life science. The 3'and/or 5' equivalent terminuses are often derivatized by attaching an active group for further modification, but a certain amount of non-derivatized impurity often remains. It is important to know to what extent the impurity would influence further modification. The reaction of an NHS ester with primary amine is one of the most widely used options to modify DNA analogues. In this short communication, a 3'-(NH2-biotin)-derivatized morpholino DNA analogue (MORF) was utilized as the model derivatized DNA analogue. Inclusion of a biotin concomitant with the primary amine at the 3'-terminus allows for the use of streptavidin to discriminate between the products from the derivatized MORF and non-derivatized MORF impurity. To detect the MORF reaction with NHS ester, S-acetyl NHS-MAG3 was conjugated to the DNA analogue for labeling with (99m)Tc, a widely used nuclide in the clinic. It was found that the non-derivatized MORF also reacted with the S-acetyl NHS-MAG3. Radiolabeling of the product yielded an equally high labeling efficiency. Nevertheless, streptavidin binding indicated that under the conditions of this investigation, the non-derivatized MORF was five times less reactive than the amine-derivatized MORF.

Improving radiographic quality at a busy outpatient imaging center

Mon, 05/22/2017 - 11:55am

A multidisciplinary task force, including musculoskeletal radiologists and technologist leads, was established to assess and correct the large number of quality defects observed on adult musculoskeletal radiology plain radiographs (x-rays).

Dosimetric properties of high energy current (HEC) detector in keV x-ray beams

Mon, 05/22/2017 - 11:55am

We introduce a new x-ray radiation detector. The detector employs high-energy current (HEC) formed by secondary electrons consisting predominantly of photoelectrons and Auger electrons, to directly convert x-ray energy to detector signal without externally applied power and without amplification. The HEC detector is a multilayer structure composed of thin conducting layers separated by dielectric layers with an overall thickness of less than a millimeter. It can be cut to any size and shape, formed into curvilinear surfaces, and thus can be designed for a variety of QA applications. We present basic dosimetric properties of the detector as function of x-ray energy, depth in the medium, area and aspect ratio of the detector, as well as other parameters. The prototype detectors show similar dosimetric properties to those of a thimble ionization chamber, which operates at high voltage. The initial results obtained for kilovoltage x-rays merit further research and development towards specific medical applications.

Breast: Sezary Syndrome: A Unique Presentation

Mon, 05/22/2017 - 11:55am

Sezary syndrome is a subtype of cutaneous T cell lymphoma which usually presents as generalized skin disease with erytheroderma. Distal organ involvement is rare and is usually a late finding in the course of the disease. Breast involvement is extremely rare. Herein, we present a case report of a patient whose initial presentation involved an intramammary lymph node prior to the onset of more characteristic skin disease. Sezary syndrome was confirmed by cythopathologic findings.

Technical Note: Nanometric organic photovoltaic thin film detectors for dose monitoring in diagnostic x-ray imaging

Mon, 05/22/2017 - 11:55am

PURPOSE: To fabricate organic photovoltaic (OPV) cells with nanometric active layers sensitive to ionizing radiation and measure their dosimetric characteristics in clinical x-ray beams in the diagnostic tube potential range of 60-150 kVp.

METHODS: Experiments were designed to optimize the detector's x-ray response and find the best parameter combination by changing the active layer thickness and the area of the electrode. The OPV cell consisted of poly (3-hexylthiophene-2,5-diyl): [6,6]-phenyl C61 butyric acid methyl ester photoactive donor and acceptor semiconducting organic materials sandwiched between an aluminum electrode as an anode and an indium tin oxide electrode as a cathode. The authors measured the radiation-induced electric current at zero bias voltage in all fabricated OPV cells.

RESULTS: The net OPV current as a function of beam potential (kVp) was proportional to kVp(-0.5) when normalized to x-ray tube output, which varies with kVp. Of the tested configurations, the best combination of parameters was 270 nm active layer thicknesses with 0.7 cm(2) electrode area, which provided the highest signal per electrode area. For this cell, the measured current ranged from approximately 0.7 to 2.4 nA/cm(2) for 60-150 kVp, corresponding to about 0.09 nA-0.06 nA/mGy air kerma, respectively. When compared to commercial amorphous silicon thin film photovoltaic cells irradiated under the same conditions, this represents 2.5 times greater sensitivity. An additional 40% signal enhancement was observed when a 1 mm layer of plastic scintillator was attached to the cells' beam-facing side.

CONCLUSIONS: Since both OPVs can be produced as flexible devices and they do not require external bias voltage, they open the possibility for use as thin film in vivo detectors for dose monitoring in diagnostic x-ray imaging.

Effect of Non-Alignment/Alignment of Attenuation Map Without/With Emission Motion Correction in Cardiac SPECT/CT

Mon, 05/22/2017 - 11:55am

PURPOSE: We investigate the differences without/with respiratory motion correction in apparent imaging agent localization induced in reconstructed emission images when the attenuation maps used for attenuation correction (from CT) are misaligned with the patient anatomy during emission imaging due to differences in respiratory state.

METHODS: We investigated use of attenuation maps acquired at different states of a 2 cm amplitude respiratory cycle (at end-expiration, at end-inspiration, the center map, the average transmission map, and a large breath-hold beyond range of respiration during emission imaging) to correct for attenuation in MLEM reconstruction for several anatomical variants of the NCAT phantom which included both with and without non-rigid motion between heart and sub-diaphragmatic regions (such as liver, kidneys etc). We tested these cases with and without emission motion correction and attenuation map alignment/non-alignment.

RESULTS: For the NCAT default male anatomy the false count-reduction due to breathing was largely removed upon emission motion correction for the large majority of the cases. Exceptions (for the default male) were for the cases when using the large-breathhold end-inspiration map (TI_EXT), when we used the end-expiration (TE) map, and to a smaller extent, the end-inspiration map (TI). However moving the attenuation maps rigidly to align the heart region, reduced the remaining count-reduction artifacts. For the female patient count-reduction remained post motion correction using rigid map-alignment due to the breast soft-tissue misalignment. Quantitatively, after the transmission (rigid) alignment correction, the polar-map 17-segment RMS error with respect to the reference (motion-less case) reduced by 46.5% on average for the extreme breathhold case. The reductions were 40.8% for end-expiration map and 31.9% for end-inspiration cases on the average, comparable to the semi-ideal case where each state uses its own attenuation map for correction.

CONCLUSIONS: Two main conclusions are that even rigid emission motion correction to rigidly align the heart region to the attenuation map helps in average cases to reduce the count-reduction artifacts and secondly, within the limits of the study (ex. rigid correction) when there is lung tissue inferior to the heart as with the NCAT phantom employed in this study endexpiration maps (TE) might best be avoided as they may create more artifacts than the end-inspiration (TI) maps.

Monte Carlo simulation of a prototypical patient dosimetry system for fluoroscopic procedures

Mon, 05/22/2017 - 11:55am

The purpose of this study is to investigate feasibility of a novel real-time dosimetry method for fluoroscopically guided interventions utilizing thin-film detector arrays in several potential locations with respect to the patient and x-ray equipment. We employed Monte Carlo (MC) simulation to establish the fluoroscopic beam model to determine dosimetric quantities directly from measured doses in thin-film detector arrays at three positions: A-attached to the x-ray source, B-on the couch under the patient and C-attached to the fluoroscopic imager. Next, we developed a calibration method to determine skin dose at the entry of the beam ([Formula: see text]) as well as the dose distribution along each ray of the beam in a water-equivalent patient model. We utilized the concept of water-equivalent thickness to determine the dose inside the patient based on doses measured outside of the patient by the thin-film detector array layers: (a) A, (b) B, or (c) B and C. In the process of calibration we determined a correction factor that characterizes the material-specific response of the detector, backscatter factor and attenuation factor for slab water phantoms of various thicknesses. Application of this method to an anthropomorphic phantom showed accuracy of about 1% for [Formula: see text] and up to about 10% for integral dose along the beam path when compared to a direct simulation of dose by MC.

Comparison of the scanning linear estimator (SLE) and ROI methods for quantitative SPECT imaging

Mon, 05/22/2017 - 11:54am

In quantitative emission tomography, tumor activity is typically estimated from calculations on a region of interest (ROI) identified in the reconstructed slices. In these calculations, unpredictable bias arising from the null functions of the imaging system affects ROI estimates. The magnitude of this bias depends upon the tumor size and location. In prior work it has been shown that the scanning linear estimator (SLE), which operates on the raw projection data, is an unbiased estimator of activity when the size and location of the tumor are known. In this work, we performed analytic simulation of SPECT imaging with a parallel-hole medium-energy collimator. Distance-dependent system spatial resolution and non-uniform attenuation were included in the imaging simulation. We compared the task of activity estimation by the ROI and SLE methods for a range of tumor sizes (diameter: 1-3 cm) and activities (contrast ratio: 1-10) added to uniform and non-uniform liver backgrounds. Using the correct value for the tumor shape and location is an idealized approximation to how task estimation would occur clinically. Thus we determined how perturbing this idealized prior knowledge impacted the performance of both techniques. To implement the SLE for the non-uniform background, we used a novel iterative algorithm for pre-whitening stationary noise within a compact region. Estimation task performance was compared using the ensemble mean-squared error (EMSE) as the criterion. The SLE method performed substantially better than the ROI method (i.e. EMSE(SLE) was 23-174 times lower) when the background is uniform and tumor location and size are known accurately. The variance of the SLE increased when a non-uniform liver texture was introduced but the EMSE(SLE) continued to be 5-20 times lower than the ROI method. In summary, SLE outperformed ROI under almost all conditions that we tested.

Novel DNA Polymer for Amplification Pretargeting

Mon, 05/22/2017 - 11:54am

In this Letter, different from conventional pretargeting, an additional novel DNA polymer with multiple copies of a target was first designed to be administrated between the antitumor antibody, and the labeled effector served as an amplification pretargeting strategy. Two phosphorothioate DNA strands, a bridging and a target strand, were hybridized to form a polymer. Polymer size, as a function of molar ratios, was then monitored by size exclusion HPLC and electrophoretic mobility shift assay. Moreover, binding efficiency of polymers with the radiolabeled effector and polymer size after hybridization were measured by HPLC as well. As the polymer was expected to produce more binding sites that would be targeted by effectors, amplification pretargeting can greatly improve accumulation of effectors in tumor. This novel proof-of-concept was then well demonstrated by the in vitro test of signal amplification in antibody-binding protein L coated plate and LS174T cells. Compared to conventional pretargeting, significantly increasing radioactive signal was observed in this designed amplification pretargeting, which would serve as a useful paradigm of the potential of oligomer polymers to improve pretargeting and other related approaches.

Multifocal Langerhans Cell Histiocytosis in an Adult

Mon, 05/22/2017 - 11:54am

Eosinophilic granuloma (EG) is the most common and benign form of the spectrum of disorders referred to as Langerhans cell histiocytosis (LCH). Langerhans cell histiocytosis is primarily regarded as a pediatric disease, with few adult cases of multifocal EG of bone reported. We report a case of multifocal EG in a 48-year-old woman, who presented with right knee pain. Radiographs showed a small lytic lesion in the medial femoral condyle. Diagnosis was confirmed by ultrasound-guided biopsy. She had had a previous EG lesion excised from her skull. Whole-body bone scan demonstrated a new skull lesion in the right diploic space, which was confirmed by magnetic resonance imaging. The patient underwent curettage, bone grafting, and prophylactic internal fixation of the right distal femur lesion. The skull lesion was treated with repeat craniectomy. Two years later, she developed a new lesion in the right distal femoral metaphysis, which was treated with intralesional corticosteroid injections. Now, more than 1 year later, the patient is pain-free with no evidence of new or recurrent disease. Because multifocal EG is a rare diagnosis in adults, appropriate clinical suspicion, in combination with radiographic findings and histologic examination, is essential for correct diagnosis and treatment.

What to Expect When They are Expecting: Magnetic Resonance Imaging of the Acute Abdomen and Pelvis in Pregnancy

Mon, 05/22/2017 - 11:54am

In this article, we discuss the challenges in the diagnosis of acute abdominopelvic pain in pregnant patients, role of imaging, and advantages of MRI over other modalities. Methods consist of pictorial review. We review the differential diagnoses and illustrate the MRI findings in pregnant patients with acute abdominopelvic pain, including gastrointestinal, gynecologic, urologic, and vascular etiologies.

Phenoxide-Bridged Zinc(II)-Bis(dipicolylamine) Probes for Molecular Imaging of Cell Death

Mon, 05/22/2017 - 11:54am

Cell death is involved in many pathological conditions, and there is a need for clinical and preclinical imaging agents that can target and report cell death. One of the best known biomarkers of cell death is exposure of the anionic phospholipid phosphatidylserine (PS) on the surface of dead and dying cells. Synthetic zinc(II)-bis(dipicolylamine) (Zn2BDPA) coordination complexes are known to selectively recognize PS-rich membranes and act as cell death molecular imaging agents. However, there is a need to improve in vivo imaging performance by selectively increasing target affinity and decreasing off-target accumulation. This present study compared the cell death targeting ability of two new deep-red fluorescent probes containing phenoxide-bridged Zn2BDPA complexes. One probe was a bivalent version of the other and associated more strongly with PS-rich liposome membranes. However, the bivalent probe exhibited self-quenching on the membrane surface, so the monovalent version produced brighter micrographs of dead and dying cells in cell culture and also better fluorescence imaging contrast in two living animal models of cell death (rat implanted tumor with necrotic core and mouse thymus atrophy). An (111)In-labeled radiotracer version of the monovalent probe also exhibited selective cell death targeting ability in the mouse thymus atrophy model, with relatively high amounts detected in dead and dying tissue and low off-target accumulation in nonclearance organs. The in vivo biodistribution profile is the most favorable yet reported for a Zn2BDPA complex; thus, the monovalent phenoxide-bridged Zn2BDPA scaffold is a promising candidate for further development as a cell death imaging agent in living subjects.