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Find video protocols related to scientific articles indexed in Pubmed.
Cerebrovascular Reactivity in Young Subjects with Sleep Apnea.
Sleep
PUBLISHED: 12-20-2014
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Regional brain alterations may be involved in the pathogenesis and adverse consequences of obstructive sleep apnea (OSA). The objectives for the current study were to (1) determine cerebrovascular reactivity in the motor areas that control upper airway musculature in patients with OSA, and (2) determine whether young patients with OSA have decreased cerebrovascular reactivity in response to breath holding.
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DESCRIPTION OF A NEW SPECIES OF PARAPHARYNGODON (NEMATODA: PHARYNGODONIDAE) FROM MEXICO WITH A LIST OF CURRENT SPECIES AND KEY TO SPECIES FROM THE PANAMANIAN REGION.
J. Parasitol.
PUBLISHED: 11-20-2014
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Abstract Parapharyngodon guerreroensis n. sp. (Nematoda: Pharyngodonidae) from the large intestine of Lepidophyma smithii from Mexico is described and illustrated. A list of nominal species and a key to species from the Panamanian Region are provided. Parapharyngodon guerreroensis n. sp. is the 54th species assigned to the genus and the 9th from the Panamanian region. It differs from other species in the genus in that males possess 3 pairs of caudal papillae, an anterior cloacal lip supporting 4 digitfiorm processes, and a blunt spicule 67-104 µm in length while females possess long flexible caudal appendages.
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Civil Disobedience and Physicians - Protesting the Blockade of Medicaid.
N. Engl. J. Med.
PUBLISHED: 11-20-2014
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In April 2013, North Carolina health care professionals began joining diverse other activists in "Moral Monday" protests aiming to change the minds of the governor and state legislators about expanding Medicaid under the Affordable Care Act.
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Radiation Combined Injury Models to Study the Effects of Interventions and Wound Biomechanics.
Radiat. Res.
PUBLISHED: 11-20-2014
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In the event of a nuclear detonation, a considerable number of projected casualties will suffer from combined radiation exposure and burn and/or wound injury. Countermeasure assessment in the setting of radiation exposure combined with dermal injury is hampered by a lack of animal models in which the effects of interventions have been characterized. To address this need, we used two separate models to characterize wound closure. The first was an open wound model in mice to study the effect of wound size in combination with whole-body 6 Gy irradiation on the rate of wound closure, animal weight and survival (morbidity). In this model the addition of interventions, wound closure, subcutaneous vehicle injection, topical antiseptic and topical antibiotics were studied to measure their effect on healing and survival. The second was a rat closed wound model to study the biomechanical properties of a healed wound at 10 days postirradiation (irradiated with 6 or 7.5 Gy). In addition, complete blood counts were performed and wound pathology by staining with hematoxylin and eosin, trichrome, CD68 and Ki67. In the mouse open wound model, we found that wound size and morbidity were positively correlated, while wound size and survival were negatively correlated. Regardless of the wound size, the addition of radiation exposure delayed the healing of the wound by approximately 5-6 days. The addition of interventions caused, at a minimum, a 30% increase in survival and improved mean survival by ?9 days. In the rat closed wound model we found that radiation exposure significantly decreased all wound biomechanical measurements as well as white blood cell, platelet and red blood cell counts at 10 days post wounding. Also, pathological changes showed a loss of dermal structure, thickening of dermis, loss of collagen/epithelial hyperplasia and an increased density of macrophages. In conclusion, we have characterized the effect of a changing wound size in combination with radiation exposure. We also demonstrated that the most effective interventions mitigated insensible fluid loss, which could help to define the most appropriate requirements of a successful countermeasure.
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Enhanced performance of PTB7:PC71BM solar cells via different morphologies of gold nanoparticles.
ACS Appl Mater Interfaces
PUBLISHED: 11-20-2014
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The effects of gold nanoparticles (AuNPs) incorporated in the hole transporting layer (HTL) of Poly[[4,8-bis[(2-ethylhexyl)oxy] benzo[1,2-b:4,5-b'] dithiophene-2, 6-diyl] [3-fluoro-2-[(2-ethylhexy)carbonyl]thieno[3,4-b]thiophened iyl]] (PTB7): [6,6]-Phenyl C71 butyric acid methyl ester (PC71BM) based solar cells are being systematically investigated in terms of the optical properties, electrical properties and photovoltaic performance. The impacts of AuNPs on the optical response of the devices are modeled by finite-difference time-domain (FDTD) simulation. The size of the AuNPs used in this work is around 50-70 nm, so that 10-20 nm penetrated from the HTL into the active layer. We found that the power conversion efficiencies (PCEs) of the devices with AuNPs are significantly enhanced from 7.5%, for the control device, to 8.0%, 8.1% and 8.2% for Au nanosphere-, nanorod- and nanocube-incorporated devices respectively. Among the photovoltaic parameters of the AuNP devices, the short circuit current density (JSC) exhibits the largest improvement, which can be attributed to the improved optical properties of the devices. Based on the calculation results, the scattering cross section for the samples in the presence of AuNPs can be enhanced by a factor of ~1010-1013 and Au nanocubes exhibit superior scattering cross section compared to the Au nanospheres and nanorods with the same linear dimension. From the experimental impedance spectroscopy results, we found that the addition of AuNPs had little effect on the electrical properties of the device. The device performance is also found to be sensitive to the concentration and morphology of the AuNPs.
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Mass transfer in the biomolecular binding of a target against probe molecules on the surface of microbeads sequestered in wells in a microfluidic cell.
Lab Chip
PUBLISHED: 11-20-2014
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Diagnostic tools which screen the binding interactions of a protein target against a display of biomolecular probes to identify molecules which bind the target are central to cell proteomic studies, and to diagnostic assays. Here, we study a microfluidic design for screening interactions in which the probe molecules are hosted on microbeads sequestered in wells arranged at the bottom of a microfluidic flow channel. Assays are undertaken by streaming an analyte solution with a fluorescently labelled target through the cell, and identifying the fluorescing beads. Numerical simulations are first constructed for the analyte flow over the microbeads in the well array, and the increase in the target concentration on the microbead surface. The binding profile is expressed as a function of the ratio of the convective to the diffusive transport rates (Peclet number or Pe), and the ratio of the kinetic to the diffusive rates (Damkohler number, Da). For any Pe, as Da becomes small enough, the transport is determined by the intrinsic kinetic binding rate. As Pe increases, a thin concentration boundary layer develops over the top surface of the microbead because of the convective flow, and target binds more rapidly. However, the relatively stagnant layers of liquid in the well provide a diffusion barrier which slows the target transport, and for any Da and Pe the transport is slower than equivalent patches of probes arranged on the channel wall. Experiments are also undertaken at high Pe, using the binding of fluorescently labelled NeutrAvidin as a target to probes of its binding partner, biotin, on the microbead surface. The binding profile is compared to the simulations to measure the kinetic rate constant, and this comparison shows that the transport in the cell is not kinetically limited because of the diffusion barriers created by the stagnant liquid layer in the well. Simulations and experiments on microbeads which are only partially recessed in the well demonstrate an increase in the mass transfer rate as more of the microbead surface intersects the flow and the diffusion limitation due to the stagnant layer of liquid surrounding the bottom part of the microbead is minimized.
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The mechanochemical production of phenyl cations through heterolytic bond scission.
Faraday Discuss.
PUBLISHED: 11-20-2014
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High mechanical forces applied to polymeric materials typically induce unselective chain scission. For the last decade, mechanoresponsive molecules, mechanophores, have been designed to harness the mechanical energy applied to polymers and provide a productive chemical response. The selective homolysis of chemical bonds was achieved by incorporating peroxide and azo mechanophores into polymer backbones. However, selective heterolysis in polymer mechanochemistry is still mostly unachieved. We hypothesized that highly polarized bonds in ionic species are likely to undergo heterolytic bond scission. To test this, we examined a triarylsulfonium salt (TAS) as a mechanophore. Poly(methyl acrylate) possessing TAS at the center of the chain (PMA-TAS) is synthesized by a single electron transfer living radical polymerization (SET-LRP) method. Computational and experimental studies in solution reveal the mechanochemical production of phenyl cations from PMA-TAS. Interestingly, the generated phenyl cation reacts with its counter-anion (trifluoromethanesulfonate) to produce a terminal trifluoromethyl benzene structure that, to the best of our knowledge, is not observed in the photolysis of TAS. Moreover, the phenyl cation can be trapped by the addition of a nucleophile. These findings emphasize the interesting reaction pathways that become available by mechanical activation.
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Osteoclast Derivation from Mouse Bone Marrow.
J Vis Exp
PUBLISHED: 11-20-2014
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Osteoclasts are highly specialized cells that are derived from the monocyte/macrophage lineage of the bone marrow. Their unique ability to resorb both the organic and inorganic matrices of bone means that they play a key role in regulating skeletal remodeling. Together, osteoblasts and osteoclasts are responsible for the dynamic coupling process that involves both bone resorption and bone formation acting together to maintain the normal skeleton during health and disease. As the principal bone-resorbing cell in the body, changes in osteoclast differentiation or function can result in profound effects in the body. Diseases associated with altered osteoclast function can range in severity from lethal neonatal disease due to failure to form a marrow space for hematopoiesis, to more commonly observed pathologies such as osteoporosis, in which excessive osteoclastic bone resorption predisposes to fracture formation. An ability to isolate osteoclasts in high numbers in vitro has allowed for significant advances in the understanding of the bone remodeling cycle and has paved the way for the discovery of novel therapeutic strategies that combat these diseases. Here, we describe a protocol to isolate and cultivate osteoclasts from mouse bone marrow that will yield large numbers of osteoclasts.
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Temporal Artery Thermometry in Children Younger Than 5 Years: A Comparison With Rectal Thermometry.
Pediatr Emerg Care
PUBLISHED: 11-20-2014
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Temporal artery (TA) thermometry has come as one of the new methods for temperature measurement, especially in children in whom accurate temperature monitoring can save lives. The device which is convenient and simple to use is yet to gain popularity in several parts of the world, as there are conflicting reports of its accuracy. This study compares the accuracy of the TA thermometry in children younger than 5 years using the rectal thermometry as the gold standard.
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Laparotomy in Mice Induces Blood Cell Expression of Inflammatory and Stress Genes.
J. Interferon Cytokine Res.
PUBLISHED: 11-20-2014
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Surgical trauma induces immune and stress responses although its effects on postsurgical inflammatory and stress gene expression remain poorly characterized. This study sought to improve current scientific knowledge by investigating the effects of laparotomy on mouse blood cell inflammatory and stress gene expression. Three-month-old male C57BL/6J mice were subjected to 2% isoflurane or 2% isoflurane with laparotomy and sacrificed 4?h postintervention. Blood was collected and blood cell expression of 158 genes central to inflammatory and stress responses was assayed using quantitative polymerase chain reaction arrays. Mice subjected to isoflurane with laparotomy, compared with mice receiving isoflurane alone, had >2-fold upregulation of genes in inflammation (Osm, IL1rn, IL1b, and Csf1), oxidative stress (Hmox1), heat shock (Hspa1b), growth arrest (Cdkn1a), and DNA repair (Ugt1a2). These genes demonstrated similar expression patterns by Pearson correlation and cluster analysis. Thus, laparotomy induces coordinated, postsurgical blood cell expression of unique inflammatory and stress genes whose roles in influencing surgical outcomes need further investigation.
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How Medical Schools Can Encourage Students' Interest in Family Medicine.
Acad Med
PUBLISHED: 11-20-2014
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The discipline of family medicine is essential to improving quality and reducing the cost of care in an effective health care system. Yet the slow growth of this field has not kept pace with national demand. In their study, Rodríguez and colleagues report on the influence of the social environment and academic discourses on medical students' identification with family medicine in four countries-the United Kingdom, Canada, France, and Spain. They conclude that these factors-the social environment and discursive activity within the medical school-influence students' specialty choices. While the discourses in Canada, France, and Spain were mostly negative, in the United Kingdom, family medicine was considered a prestigious academic discipline, well paying, and with a wide range of practice opportunities. Medical students in the United Kingdom also were exposed early and often to positive family medicine role models.In the United States, academic discourses about family medicine are more akin to those in Canada, France, and Spain. The hidden curriculum includes negative messages about family medicine, and "badmouthing" primary care occurs at many medical schools. National education initiatives highlight the importance of social determinants in medical education and the integration of public health and medicine in practice. Other initiatives expose students to family medicine role models and practice during their undergraduate training and promote primary care practice through new graduate medical education funding models. Together, these initiatives can reduce the negative effects of the social environment and create a more positive discourse about family medicine.
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The Longitudinal Standardized Patient Project: Innovation From Necessity.
Acad Med
PUBLISHED: 11-20-2014
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Constraints on time and resources prevented first- and second-year medical students from having sufficient time to complete required tasks in standardized patient (SP) communication skills training sessions, and to appreciate the SP character as a "person." Case believability was limited by having each individual SP portray multiple patients in different encounters.
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Epigenetic and in vivo comparison of diverse MSC sources reveals an endochondral signature for human hematopoietic niche formation.
Blood
PUBLISHED: 11-20-2014
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In the last decade there has been a rapid expansion in clinical trials using mesenchymal stromal cells (MSCs) from a variety of tissues. However, despite similarities in morphology, immunophenotype and differentiation behavior in vitro, MSCs sourced from distinct tissues do not necessarily have equivalent biological properties. We performed a genome-wide methylation, transcription and in vivo evaluation of MSCs from human bone marrow (BM), white adipose tissue, umbilical cord and skin cultured in humanized media. Surprisingly, only BM-derived MSCs spontaneously formed a bone marrow cavity through a vascularized cartilage intermediate in vivo that was progressively replaced by hematopoietic tissue and bone. Only BM-derived MSCs exhibited a chondrogenic transcriptional program with hypomethylation and increased expression of RUNX3, RUNX2, BGLAP, MMP13 and ITGA10 consistent with a latent and primed skeletal developmental potential. The humanized MSC-derived microenvironment permitted homing and maintenance of long-term murine SLAM(+) hematopoietic stem cells (HSCs) as well as human CD34(+)/CD38(-)/CD90(+)/CD45RA(+) HSCs after cord blood transplantation. These studies underscore the profound differences in developmental potential between MSC sources independent of donor age with implications for their clinical use. We also demonstrate a tractable human niche model for studying homing and engraftment of human hematopoietic cells in normal and neoplastic states.
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Deficient Autophagy Results in Mitochondrial Dysfunction and FSGS.
J. Am. Soc. Nephrol.
PUBLISHED: 11-20-2014
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FSGS is a heterogeneous fibrosing disease of the kidney, the cause of which remains poorly understood. In most cases, there is no effective treatment to halt or retard progression to renal failure. Increasing evidence points to mitochondrial dysfunction and the generation of reactive oxygen species in the pathogenesis of CKD. Autophagy, a major intracellular lysosomal degradation system, performs homeostatic functions linked to metabolism and organelle turnover. We prevented normal autophagic pathways in nephrons of mice by mutating critical autophagy genes ATG5 or ATG7 during nephrogenesis. Mutant mice developed mild podocyte and tubular dysfunction within 2 months, profound glomerular and tubular changes bearing close similarity to human disease by 4 months, and organ failure by 6 months. Ultrastructurally, podocytes and tubular cells showed vacuolization, abnormal mitochondria, and evidence of endoplasmic reticulum stress, features that precede the appearance of histologic or clinical disease. Similar changes were observed in human idiopathic FSGS kidney biopsy specimens. Biochemical analysis of podocytes and tubules of 2-month-old mutant mice revealed elevated production of reactive oxygen species, activation of endoplasmic reticulum stress pathways, phosphorylation of p38, and mitochondrial dysfunction. Furthermore, cultured proximal tubule cells isolated from mutant mice showed marked mitochondrial dysfunction and elevated mitochondrial reactive oxygen species generation that was suppressed by a mitochondrial superoxide scavenger. We conclude that mitochondrial dysfunction and endoplasmic reticulum stress due to impaired autophagic organelle turnover in podocytes and tubular epithelium are sufficient to cause many of the manifestations of FSGS in mice.
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IAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo.
Nature
PUBLISHED: 09-30-2014
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TP53 is commonly altered in human cancer, and Tp53 reactivation suppresses tumours in vivo in mice (TP53 and Tp53 are also known as p53). This strategy has proven difficult to implement therapeutically, and here we examine an alternative strategy by manipulating the p53 family members, Tp63 and Tp73 (also known as p63 and p73, respectively). The acidic transactivation-domain-bearing (TA) isoforms of p63 and p73 structurally and functionally resemble p53, whereas the ?N isoforms (lacking the acidic transactivation domain) of p63 and p73 are frequently overexpressed in cancer and act primarily in a dominant-negative fashion against p53, TAp63 and TAp73 to inhibit their tumour-suppressive functions. The p53 family interacts extensively in cellular processes that promote tumour suppression, such as apoptosis and autophagy, thus a clear understanding of this interplay in cancer is needed to treat tumours with alterations in the p53 pathway. Here we show that deletion of the ?N isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53-deficient tumours through upregulation of IAPP, the gene that encodes amylin, a 37-amino-acid peptide co-secreted with insulin by the ? cells of the pancreas. We found that IAPP is causally involved in this tumour regression and that amylin functions through the calcitonin receptor (CalcR) and receptor activity modifying protein 3 (RAMP3) to inhibit glycolysis and induce reactive oxygen species and apoptosis. Pramlintide, a synthetic analogue of amylin that is currently used to treat type 1 and type 2 diabetes, caused rapid tumour regression in p53-deficient thymic lymphomas, representing a novel strategy to target p53-deficient cancers.
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Looking at non-communicable diseases in Uganda through a local lens: an analysis using locally derived data.
Global Health
PUBLISHED: 09-26-2014
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The demographic and nutritional transitions taking place in Uganda, just as in other low- and middle-income countries (LMIC), are leading to accelerating growth of chronic, non-communicable diseases (NCDs). Though still sparse, locally derived data on NCDs in Uganda has increased greatly over the past five years and will soon be bolstered by the first nationally representative data set on NCDs. Using these available local data, we describe the landscape of the globally recognized major NCDs- cardiovascular disease, diabetes, cancer, and chronic respiratory disease- and closely examine what is known about other locally important chronic conditions. For example, mental health disorders, spawned by an extended civil war, and highly prevalent NCD risk factors such as excessive alcohol intake and road traffic accidents, warrant special attention in Uganda. Additionally, we explore public sector capacity to tackle NCDs, including Ministry of Health NCD financing and health facility and healthcare worker preparedness. Finally, we describe a number of promising initiatives that are addressing the Ugandan NCD epidemic. These include multi-sector partnerships focused on capacity building and health systems strengthening; a model civil society collaboration leading a regional coalition; and a novel alliance of parliamentarians lobbying for NCD policy. Lessons learned from the ongoing Ugandan experience will inform other LMIC, especially in sub-Saharan Africa, as they restructure their health systems to address the growing NCD epidemic.
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Effects of minimum monitor unit threshold on spot scanning proton plan quality.
Med Phys
PUBLISHED: 09-05-2014
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To investigate the influence of the minimum monitor unit (MU) on the quality of clinical treatment plans for scanned proton therapy.
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Childhood Stress Exposure Among Preadolescents With and Without Family Histories of Substance Use Disorders.
Psychol Addict Behav
PUBLISHED: 08-18-2014
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Having a family history of substance use disorders (FH+) increases risk for developing a substance use disorder. This risk may be at least partially mediated by increased exposure to childhood stressors among FH+ individuals. However, measures typically used to assess exposure to stressors are narrow in scope and vary across studies. The nature of stressors that disproportionately affect FH+ children and how these stressors relate to later substance use in this population are not well understood. The purpose of this study was to assess exposure to a broad range of stressors among FH+ and FH- children to better characterize how exposure to childhood stressors relates to increased risk for substance misuse among FH+ individuals. A total of 386 children (305 FH+, 81 FH-; ages 10-12) were assessed using the Stressful Life Events Schedule before the onset of regular substance use. Both the number and severity of stressors were compared. Preliminary follow-up analyses were done for 53 adolescents who subsequently reported initiation of substance use. FH+ children reported more frequent and severe stressors than did FH- children, specifically in the areas of housing, family, school, crime, peers, and finances. Additionally, risk for substance use initiation during early adolescence was influenced directly by having a family history of substance use disorders and also indirectly through increased exposure to stressors among FH+ individuals. In conclusion, FH+ children experience greater stress across multiple domains, which contributes to their risk for substance misuse and related problems during adolescence and young adulthood. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
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Alkyne mechanochemistry: putative activation by transoidal bending.
Chem. Commun. (Camb.)
PUBLISHED: 08-06-2014
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We investigated the use of mechanical stress to bend carbon-carbon triple bonds. Formation of an isoquinoline after reaction with a benzyl azide trap points towards a nucleophilic addition mechanism, differentiating mechanochemical trans-bending of ? bonds from the typical reactivity observed for cisoidal bending of triple bonds in strained cyclic alkynes.
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Unshielded asymmetric transmit-only and endorectal receive-only radiofrequency coil for (23) Na MRI of the prostate at 3 tesla.
J Magn Reson Imaging
PUBLISHED: 07-30-2014
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To develop and optimize radiofrequency (RF) hardware for the detection of endogenous sodium ((23) Na) by 3.0 Tesla (T) MRI in the human prostate.
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Thermal Assisted Oxygen Annealing for High Efficiency Planar CH3NH3PbI3 Perovskite Solar Cells.
Sci Rep
PUBLISHED: 07-30-2014
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We report investigations on the influences of post-deposition treatments on the performance of solution-processed methylammonium lead triiodide (CH3NH3PbI3)-based planar solar cells. The prepared films were stored in pure N2 at room temperature or annealed in pure O2 at room temperature, 45°C, 65°C and 85°C for 12?hours prior to the deposition of the metal electrodes. It is found that annealing in O2 leads to substantial increase in the power conversion efficiencies (PCEs) of the devices. Furthermore, strong dependence on the annealing temperature for the PCEs of the devices suggests that a thermally activated process may underlie the observed phenomenon. It is believed that the annealing process may facilitate the diffusion of O2 into the spiro-MeOTAD for inducing p-doping of the hole transport material. Furthermore, the process can result in lowering the localized state density at the grain boundaries as well as the bulk of perovskite. Utilizing thermal assisted O2 annealing, high efficiency devices with good reproducibility were attained. A PCE of 15.4% with an open circuit voltage (VOC) 1.04?V, short circuit current density (JSC) 23?mA/cm(2), and fill factor 0.64 had been achieved for our champion device.
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Increased Forebrain Activations in Youths with Family Histories of Alcohol and Other Substance Use Disorders Performing a Go/NoGo Task.
Alcohol. Clin. Exp. Res.
PUBLISHED: 06-21-2014
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Youths with a family history of alcohol and other drug use disorders (FH+) are at a greater risk of developing substance use disorders than their peers with no such family histories (FH-), and this increased risk may be related to impaired maturation of forebrain circuitry. FH+ individuals have shown altered forebrain activity at rest and while performing cognitive tasks. However, it is not fully understood how forebrain activity is altered in FH+ individuals, and ultimately how these alterations may contribute to substance use disorder risk.
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Descending the sanitation ladder in urban Uganda: evidence from Kampala Slums.
BMC Public Health
PUBLISHED: 06-09-2014
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While the sanitation ladder is useful in analysing progressive improvements in sanitation, studies in Uganda have not indicated the sanitation barriers faced by the urban poor. There are various challenges in shared latrine use, cleaning and maintenance. Results from Kampala city indicate that, failure to clean and maintain sanitation infrastructure can lead to a reversal of the potential benefits that come with various sanitation facilities.
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Outcomes and toxicities of stereotactic body radiation therapy for non-spine bone oligometastases.
Pract Radiat Oncol
PUBLISHED: 06-04-2014
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Stereotactic body radiation therapy (SBRT) is being applied more widely for oligometastatic disease. This technique is now being used for non-spine bony metastases in addition to liver, spine, and lung. However, there are few studies examining the toxicity and outcomes of SBRT for non-spine bone metastases.
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New species of Bakeria (Nematoda; Strongylida; Molineidae), new species of Falcaustra (Nematoda; Ascaridida; Kathlaniidae) and other helminths in Cnemaspis mcguirei (Sauria; Gekkonidae) from Peninsular Malaysia.
Acta Parasitol.
PUBLISHED: 06-03-2014
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Two new nematode species, Bakeria schadi sp. nov. and Falcaustra malaysiaia sp. nov. from the gastrointestinal tract of McGuire's rock gecko, Cnemaspis mcguirei (Sauria: Gekkonidae) collected in Peninsular Malaysia are described. The two species now assigned to Bakeria are separated on the bases of male bursa type and location of the excretory pore: type II in B. schadi sp. nov. and type I in B. bakeri; location of excretory pore, anterior to nerve ring in B. schadi sp. nov. and posterior to nerve ring in B. bakeri. Falcaustra malaysiaia sp. nov. is most similar to F. chabaudi, F. concinnae, F. condorcanquii, F. barbi, F. dubia, and F. tchadi in that these 7 species possess 1 pseudosucker, 1 median papilla plus 10 pairs caudal papillae, and spicules with lengths between 1 and 2 mm. F. barbi and F. tchadi lack adcloacal papillae; the remaining 5 species possess 1 pair of adcloacal papillae. Falcaustra chabaudi is known from Nearctic salamanders; F. concinnae from Nearctic turtles; F. condorcanquii from Neotropical frogs, F. dubia from Oriental frogs, and F. malaysiaia sp. nov. from Oriental geckos. Two additional species of Nematoda were found, Cosmocerca ornata and Meteterakis singaporensis. Cnemaspis mcguirei represents a new host record for Cosmocerca ornata and Meteterakis singaporensis.
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Complications of adjustable gastric banding surgery for obesity.
Am Fam Physician
PUBLISHED: 05-29-2014
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Laparoscopic adjustable gastric banding procedures have a favorable risk-benefit profile and are increasingly important as part of the overall management of obesity. These procedures are effective at inducing weight loss and improving comorbid conditions, including diabetes mellitus, hypertension, and sleep apnea. Laparoscopic adjustable gastric banding has several typical complications, and family physicians should recognize these as part of a team-based approach to the management of obesity. Gastric band slippage, port or tubing malfunction, stomal obstruction, band erosion, pouch dilation, and port infection are examples of complications that may occur after laparoscopic adjustable gastric banding. Upper gastrointestinal tract imaging is often required to diagnose these complications. Some complications can be managed in the primary care setting through behavioral diet modification or removal of fluid from the band (band deflation); however, other complications require surgical repair or removal of the band.
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Highly permeable silicon membranes for shear free chemotaxis and rapid cell labeling.
Lab Chip
PUBLISHED: 05-23-2014
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Microfluidic systems are powerful tools for cell biology studies because they enable the precise addition and removal of solutes in small volumes. However, the fluid forces inherent in the use of microfluidics for cell cultures are sometimes undesirable. An important example is chemotaxis systems where fluid flow creates well-defined and steady chemotactic gradients but also pushes cells downstream. Here we demonstrate a chemotaxis system in which two chambers are separated by a molecularly thin (15 nm), transparent, and nanoporous silicon membrane. One chamber is a microfluidic channel that carries a flow-generated gradient while the other chamber is a shear-free environment for cell observation. The molecularly thin membranes provide effectively no resistance to molecular diffusion between the two chambers, making them ideal elements for creating flow-free chambers in microfluidic systems. Analytical and computational flow models that account for membrane and chamber geometry, predict shear reduction of more than five orders of magnitude. This prediction is confirmed by observing the pure diffusion of nanoparticles in the cell-hosting chamber despite high input flow (Q = 10 ?L min(-1); vavg ~ 45 mm min(-1)) in the flow chamber only 15 nm away. Using total internal reflection fluorescence (TIRF) microscopy, we show that a flow-generated molecular gradient will pass through the membrane into the quiescent cell chamber. Finally we demonstrate that our device allows us to expose migrating neutrophils to a chemotactic gradient or fluorescent label without any influence from flow.
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Evaluating the benefits of incorporating traditional birth attendants in HIV prevention of mother to child transmission service delivery in Lilongwe, Malawi.
Afr J Reprod Health
PUBLISHED: 05-07-2014
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The objective of our intervention was to examine the benefits of incorporating traditional birth attendants (TBA) in HIV Prevention of Mother to Child Transmission (PMTCT) service delivery. We developed a training curriculum for TBAs related to PMTCT and current TBA roles in Malawi. Fourteen TBAs and seven TBA assistants serving 4 urban health centre catchment areas were assessed, trained and supervised. Focus group discussions with the TBAs were conducted after implementation of the program. From March 2008 to August 2009, a total of 4017 pregnant women visited TBAs, out of which 2133 (53.1%) were directly referred to health facilities and 1,884 (46.9%) women delivered at TBAs and subsequently referred. 168 HIV positive women were identified by TBAs. Of these, 86/168 (51.2%) women received nevirapine and 46/168 (27.4%) HIV exposed infants received nevirapine. The challenges in providing PMTCT services included lack of transportation for referrals and absence of a reporting system to confirm the woman's arrival at the health center. Non-disclosure of HIV status by patients to the TBAs resulted in inability to assist nevirapine uptake. TBAs, when trained and well-supervised, can supplement efforts to provide PMTCT services in communities.
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The influence of visual information on multi-muscle control during quiet stance: a spectral analysis approach.
Exp Brain Res
PUBLISHED: 05-06-2014
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Standing upright requires the coordination of neural drives to a large set of muscles involved in controlling human bipedal stance (i.e., postural muscles). The coordination may deteriorate in situations where standing is performed under more challenging circumstances, such as standing on a smaller base of support or not having adequate visual information. The present study investigates the role of common neural inputs in the organization of multi-muscle synergies and the effects of visual input disruption to this mechanism of control. We analyzed the strength and distribution of correlated neural inputs (measured by intermuscular coherence) to six postural muscles previously recognized as components of synergistic groups involved in the maintenance of the body's vertical positioning. Two experimental conditions were studied: quiet bipedal stance performed with opened eyes (OEs) and closed eyes (CEs). Nine participants stood quietly for 30 s while the activity of the soleus, biceps femoris, lumbar erector spinae, tibialis anterior, rectus femoris, and rectus abdominis muscles were recorded using surface electrodes. Intermuscular (EMG-EMG) coherence was estimated for 12 muscle pairs formed by these muscles, including pairs formed solely by either posterior, anterior, or mixed (one posterior and one anterior) muscles. Intermuscular coherence was only found to be significant for muscle pairs formed solely by either posterior or anterior muscles, and no significant coherence was found for mixed muscle pairs. Significant intermuscular coherence was only found within a distinct frequency interval bounded between 1 and 10 Hz when visual input was available (OEs trials). The strength of correlated neural inputs was similar across muscle pairs located in different joints but executing a similar function (pushing body either backward or forward) suggesting that synergistic postural groups are likely formed based on their functional role instead of their anatomical location. Absence of visual information caused a significant decrease in intermuscular coherence. These findings are consistent with the hypothesis that correlated neural inputs are a mechanism used by the CNS to assemble synergistic muscle groups. Further, this mechanism is affected by interruption of visual input.
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Effects of CP-900691, a novel peroxisome proliferator-activated receptor ?, agonist on diabetic nephropathy in the BTBR ob/ob mouse.
Lab. Invest.
PUBLISHED: 05-02-2014
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Piperidine-based peroxisome proliferator-activated receptor-? agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP-900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the Black and Tan, BRachyuric (BTBR) ob/ob mouse model of type 2 diabetes mellitus. Four-week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3?mg/kg per day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria, and urinary excretion of 8-epi PGF(2?), a product of the nonenzymatic metabolism of arachidonic acid and whose production is elevated in oxidative stress, in BTBR WT mice. In BTBR ob/ob mice, CP reduced plasma triglycerides and non-esterified fatty acids, fasting blood glucose, body weight, and plasma interleukin-6, while concomitantly improving insulin resistance. Despite these beneficial metabolic effects, CP had no effect on elevated plasma insulin, 8-epi PGF(2?) excretion, and albuminuria, and surprisingly, did not ameliorate the development of diabetic nephropathy, having no effect on the accumulation of renal macrophages, glomerular hypertrophy, and increased mesangial matrix expansion. In addition, CP did not increase plasma high-density lipoprotein in BTBR ob/ob mice, while paradoxically increasing total cholesterol levels. These findings indicate that 8-epi PGF(2?), possibly along with hyperinsulinemia and inflammatory and dysfunctional lipoproteins, is integral to the development of diabetic nephropathy and should be considered as a potential target of therapy in the treatment of diabetic nephropathy.
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New species of Gorgoderina (Digenea; Gorgoderidae) and other helminths in Euphlyctis cyanophlyctis (Anura: Dicroglossidae) from Dehradun, (Uttarakhand), India.
Acta Parasitol.
PUBLISHED: 04-18-2014
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Gorgoderina spinosa sp. nov. (Digenea, Gorgoderidae) from the bladder of the water skipper, Euphlyctis cyanophlyctis (Anura, Dicroglossidae), from Dehradun, India is described and illustrated. Gorgoderina spinosa is the 6th Indian species assigned to the genus and is separated from its congeners based upon the morphology of vitelline glands and the presence of a spinose integument. Two additional digenean species, Diplodiscus amphichrus and Ganeo tigrinus, and 3 nematode species, Cosmocerca kalesari, Gendria chauhani, and unidentified larvae were found. Diplodiscus amphichrus, Ganeo tigrinus, Cosmocerca kalesari, and Gendria chauhani have previously been reported to infect Indian individuals of Euphlyctis cyanophlyctis.
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ATP promotes extracellular matrix biosynthesis of intervertebral disc cells.
Cell Tissue Res.
PUBLISHED: 04-11-2014
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We have recently found a high accumulation of extracellular adenosine triphosphate (ATP) in the center of healthy porcine intervertebral discs (IVD). Since ATP is a powerful extracellular signaling molecule, extracellular ATP accumulation might regulate biological activities in the IVD. The objective of this study was therefore to investigate the effects of extracellular ATP on the extracellular matrix (ECM) biosynthesis of porcine IVD cells isolated from two distinct anatomical regions: the annulus fibrosus (AF) and nucleus pulposus (NP). ATP treatment significantly promotes ECM deposition and corresponding gene expression (aggrecan and type II collagen) by both cell types in three-dimensional agarose culture. A significant increase in ECM accumulation has been found in AF cells at a lower ATP treatment level (20 ?M) compared with NP cells (100 ?M), indicating that AF cells are more sensitive to extracellular ATP than NP cells. NP cells also exhibit higher ECM accumulation and intracellular ATP than AF cells under control and treatment conditions, suggesting that NP cells are intrinsically more metabolically active. Moreover, ATP treatment also augments the intracellular ATP level in NP and AF cells. Our findings suggest that extracellular ATP not only promotes ECM biosynthesis via a molecular pathway, but also increases energy supply to fuel that process.
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Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation.
J. Immunol.
PUBLISHED: 04-07-2014
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Systemic lupus erythematosus is a multisystem autoimmune disease characterized by autoantibodies targeting nucleic acid-associated Ags. The endosomal TLRs TLR7 and TLR9 are critical for generation of Abs targeting RNA- or DNA-associated Ags, respectively. In murine lupus models, deletion of TLR7 limits autoimmune inflammation, whereas deletion of TLR9 exacerbates disease. Whether B cell or myeloid TLR7/TLR9 signaling is responsible for these effects has not been fully addressed. In this study, we use a chimeric strategy to evaluate the effect of B cell-intrinsic deletion of TLR7 versus TLR9 in parallel lupus models. We demonstrate that B cell-intrinsic TLR7 deletion prevents RNA-associated Ab formation, decreases production of class-switched Abs targeting nonnuclear Ags, and limits systemic autoimmunity. In contrast, B cell-intrinsic TLR9 deletion results in decreased DNA-reactive Ab, but increased Abs targeting a broad range of systemic autoantigens. Further, we demonstrate that B cell-intrinsic TLR9 deletion results in increased systemic inflammation and immune complex glomerulonephritis, despite intact TLR signaling within the myeloid compartment. These data stress the critical importance of dysregulated B cell-intrinsic TLR signaling in the pathogenesis of systemic lupus erythematosus.
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Glomerular disease: looking beyond pathology.
Clin J Am Soc Nephrol
PUBLISHED: 04-03-2014
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The National Institute of Diabetes and Digestive and Kidney Diseases-supported Kidney Research National Dialogue asked the scientific community to formulate and prioritize research objectives aimed at improved understanding of kidney function and disease progression. Over the past 2 years, 1600 participants posted almost 300 ideas covering all areas of kidney disease. An overriding theme that evolved through these discussions is the need to move beyond pathology to take advantage of basic science and clinical research opportunities to improve diagnostic classification and therapeutic options for people with primary glomerular disease. High-priority research areas included focus on therapeutic targets in glomerular endothelium and podocytes, regenerating podocytes through developmental pathways, use of longitudinal phenotypically defined disease cohorts to improve classification schemes, identifying biomarkers, disease-specific therapeutics, autoantibody triggers, and changing the clinical research culture to promote participation in clinical trials. Together, these objectives provide a path forward for improving clinical outcomes of glomerular disease.
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Mechanically triggered heterolytic unzipping of a low-ceiling-temperature polymer.
Nat Chem
PUBLISHED: 03-27-2014
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Biological systems rely on recyclable materials resources such as amino acids, carbohydrates and nucleic acids. When biomaterials are damaged as a result of aging or stress, tissues undergo repair by a depolymerization-repolymerization sequence of remodelling. Integration of this concept into synthetic materials systems may lead to devices with extended lifetimes. Here, we show that a metastable polymer, end-capped poly(o-phthalaldehyde), undergoes mechanically initiated depolymerization to revert the material to monomers. Trapping experiments and steered molecular dynamics simulations are consistent with a heterolytic scission mechanism. The obtained monomer was repolymerized by a chemical initiator, effectively completing a depolymerization-repolymerization cycle. By emulating remodelling of biomaterials, this model system suggests the possibility of smart materials where aging or mechanical damage triggers depolymerization, and orthogonal conditions regenerate the polymer when and where necessary.
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Combining diffusion tensor imaging and magnetic resonance spectroscopy to study reduced frontal white matter integrity in youths with family histories of substance use disorders.
Hum Brain Mapp
PUBLISHED: 03-24-2014
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Individuals with a family history of substance use disorder (FH+) show impaired frontal white matter as indicated by diffusion tensor imaging (DTI). This impairment may be due to impaired or delayed development of myelin in frontal regions, potentially contributing to this population's increased risk for developing substance use disorders. In this study, we examined high angular resolution DTI and proton magnetic resonance spectroscopy data from the anterior corona radiata were collected in 80 FH+ and 34 FH- youths (12.9?±?1.0 years old). White matter integrity indices included fractional anisotropy (FA), N-acetylaspartate (NAA), and total choline (tCho). Lower FA suggests decreased myelination. Decreased NAA coupled with higher tCho suggests impaired build-up and maintenance of cerebral myelin and consequently greater breakdown of cellular membranes. We found FH+ youths had lower FA (P?
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Quinic acid derivative KZ-41 exhibits radiomitigating activity in preclinical models of radiation injury.
Drug Dev. Res.
PUBLISHED: 03-21-2014
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Acute radiation syndrome is induced when a significant portion of the body receives high-dose, as well as high-dose rate, radiation. We have previously identified a quinic acid-based derivative, KZ-41, that protects from radiation injury. Further preclinical efficacy studies were conducted to determine the radiomitigating activity of KZ-41. C57BL/6 mice received total body irradiation (TBI-LD??/??, ¹³?Cs; ?2?min) followed by either normal saline or KZ-41 (100?mg/kg sc ?26?h post-TBI). KZ-41 increased 30-day survival by approximately 45% compared with vehicle controls (P?
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Cells of renin lineage take on a podocyte phenotype in aging nephropathy.
Am. J. Physiol. Renal Physiol.
PUBLISHED: 03-19-2014
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Aging nephropathy is characterized by podocyte depletion accompanied by progressive glomerulosclerosis. Replacement of terminally differentiated podocytes by local stem/progenitor cells is likely a critical mechanism for their regeneration. Recent studies have shown that cells of renin lineage (CoRL), normally restricted to the kidney's extraglomerular compartment, might serve this role after an abrupt depletion in podocyte number. To determine the effects of aging on the CoRL reserve and if CoRL moved from an extra- to the intraglomerular compartment during aging, genetic cell fate mapping was performed in aging Ren1cCre × Rs-ZsGreen reporter mice. Podocyte number decreased and glomerular scarring increased with advanced age. CoRL number decreased in the juxtaglomerular compartment with age. There was a paradoxical increase in CoRL in the intraglomerular compartment at 52 and 64 wk of age, where a subset coexpressed the podocyte proteins nephrin, podocin, and synaptopodin. Transmission electron microscopy studies showed that a subset of labeled CoRL in the glomerulus displayed foot processes, which attached to the glomerular basement membrane. No CoRL in the glomerular compartment stained for renin. These results suggest that, despite a decrease in the reserve, a subpopulation of CoRL moves to the glomerulus after chronic podocyte depletion in aging nephropathy, where they acquire a podocyte-like phenotype. This suggests that they might serve as adult podocyte stem/progenitor cells under these conditions, albeit in insufficient numbers to fully replace podocytes depleted with age.
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Assessment of whole brain white matter integrity in youths and young adults with a family history of substance-use disorders.
Hum Brain Mapp
PUBLISHED: 03-14-2014
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Individuals with a family history of substance use disorders (FH+) are at a greater risk of developing substance use disorders than their peers with no such family histories (FH-) and this vulnerability is proportional to the number of affected relatives (FH density). The risk for developing substance use disorders peaks during adolescence to early adulthood in the general population, and that is thought to be related to delayed maturation of frontocortical and frontostriatal functional circuits. We hypothesized that FH+ youth and young adults have impaired myelination of frontocortical and frontostriatal white matter tracts. We examined fractional anisotropy (FA) data in 80 FH+ and 34 FH- youths (12.9?±?1.0 years) and in 25 FH+ and 30 FH- young adults (24.3?±?3.4 years). FH+ youths had lower FA values in both frontocortical and frontostriatal tracts as well as parietocortical tracts including the anterior, superior and posterior corona radiata and the superior frontal-occipital fasciculus. Moreover, FA values in these tracts were negatively correlated with FH density. FH+ adults had lower FA values in two frontocortical tracts: the genu of the corpus callosum and anterior corona radiata and also significant negative correlations between FA and FH density in these same tracts. In both groups, lower FA values corresponded to higher radial diffusivity suggesting reduced axonal myelination. We interpreted our findings as evidence for impaired myelination of frontal white matter that was proportional to FH density. Our data suggest that deficits may partially resolve with age, paralleling an age-related decline in risk for developing substance use disorders. Hum Brain Mapp 35:5401-5413, 2014. © 2014 Wiley Periodicals, Inc.
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Gender variations in access, choice to use and cleaning of shared latrines; experiences from Kampala Slums, Uganda.
BMC Public Health
PUBLISHED: 03-04-2014
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Sanitation is one of the most intimate issues that affect women, especially in slums of developing countries. There are few studies that have paid attention to the gender variations in access, choice to use and cleaning of shared latrines in slums.
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New species of Orientatractis (Nematoda: Atractidae), new species of Rondonia (Nematoda: Atractidae) and other helminths in Austrochaperina basipalmata (Anura: Microhylidae) from Papua New Guinea.
Acta Parasitol.
PUBLISHED: 02-26-2014
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Two new nematode species, Orientatractis hamabatrachos sp. nov. and Rondonia batrachogena sp. nov. (Nematoda: Atractidae), from the gastrointestinal tract of Austrochaperina basipalmata (Anura: Microhylidae) collected in Papua New Guinea are described. Orientatractis hamabatrachos sp. nov. is characterized by the presence of the cephalic end armed with 4 wellsclerotized structures, consisting of 2 "horns" extending outward and downward and immediately below a single well-sclerotized spine. It differs from 5 congeners in spicule lengths and caudal papillae arrangements. Rondonia batrachogena sp. nov. is characterized by the presence of a female cloaca. It differs from 2 congeners primarily in body size. Orientatractis hamabatrachos sp. nov. and Rondonia batrachogena sp. nov. represent the first species assigned to either genus found to infect anurans or to occur in the Australo-Papuan region.
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Cosmocercoides himalayanus sp. nov. (Nematoda, Cosmocercidae) in Duttaphrynus himalayanus (Amphibia, Anura) from Dehradun (Uttarakhand), India.
Acta Parasitol.
PUBLISHED: 02-26-2014
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Cosmocercoides himalayanus sp. nov. (Nematoda, Cosmocercidae) from the large intestine of Duttaphrynus himalayanus (Amphibia, Anura) from Dehradun, India is described and illustrated. Cosmocercoides himalayanus sp. nov. represents the 21st species assigned to the genus and the 9th species from the Oriental biogeographical region. Cosmocercoides himalayanus sp. nov. differs from the previously described Oriental species in number and position of rosette papillae; it is the only species possessing 24 or more rosette papillae to have 4 postcloacal papillae. In addition, a list of species assigned to Cosmocercoides is provided; however, C. fotedari Arya, 1992 is removed from the genus and until further study is considered a species inquirenda.
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Feasibility of multianimal hyperpolarized (13) C MRS.
Magn Reson Med
PUBLISHED: 02-19-2014
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There is great potential for real-time investigation of metabolism with MRS and hyperpolarized (HP) (13) C agents. Unfortunately, HP technology has high associated costs and efficiency limitations that may constrain in vivo studies involving many animals. To improve the throughput of preclinical investigations, we evaluate the feasibility of performing HP MRS on multiple animals simultaneously.
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Separating the dosimetric consequences of changing tumor anatomy from positional uncertainty for conventionally fractionated lung cancer patients.
Pract Radiat Oncol
PUBLISHED: 02-17-2014
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To separate the dosimetric consequences of changing tumor volume from positional uncertainty for patients undergoing conventionally fractionated lung radiation therapy (RT) and to quantify which factor has a larger impact on dose to target volumes and organs at risk (OAR).
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Stress, substance abuse, and addiction.
Curr Top Behav Neurosci
PUBLISHED: 02-11-2014
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Experiencing stressful life events is reciprocally associated with substance use and abuse. The nature of these relationships varies based on the age of stress exposure and stage of substance use involvement. This chapter reviews the developmental and biological processes involved in the relationship of stress exposure and substance use initiation, substance use maintenance and relapse, and response to substance abuse treatment. Special emphasis is given to describing the various stress-related mechanisms involved in substance use and abuse, highlighting the differences between each of these phases of drug use and drawing upon current research to make suggestions for treatments of substance use disorder (SUD) patients. Stress is inherent to the experience of life and, in many situations, unavoidable. Through ongoing research and treatment development, there is the potential to modify the relationship of stress with ongoing substance use and abuse.
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Delay discounting differentiates pre-adolescents at high and low risk for substance use disorders based on family history.
Drug Alcohol Depend
PUBLISHED: 01-24-2014
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Youth with family histories of substance use disorders (FH+) are at increased risk for developing substance use disorders relative to those without such histories (FH-). FH+ individuals show deficits in impulse control that parallel those in individuals with substance use disorders. Elucidating how specific components of impulse control are affected in FH+ pre-adolescents would advance our understanding of how deficits in impulse control relate to risk of substance use disorders.
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A new species of Spauligodon (Nematoda: Oxyuroidea: Pharyngodonidae) in Cyrtodactylus bintangrendah (Sauria: Gekkonidae) from Peninsular Malaysia.
J. Parasitol.
PUBLISHED: 01-22-2014
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Spauligodon bintangensis n. sp. from the intestines of Cyrtodactylus bintangrendah (Gekkonidae) from Peninsular Malaysia is described and illustrated. Spauligodon bintangensis n. sp. represents the 51st species assigned to the genus and the first species from the Oriental Region. The new species is most similar to Spauligodon atlanticus, Spauligodon eremiasi, and Spauligodon occidentalis, but is easily separated by position of vulva, prebulbar in S. atlanticus and S. occidentalis , postbulbar in the new species, and location of lateral alae; in S. eremiasi, the lateral alae occur only in the fourth quarter of the body, whereas in the new species the lateral alae begin just posterior to lips.
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A sensitive and fast LC-MS/MS method for determination of ?-receptor agonist JP-49b: application to a pharmacokinetic study in rats.
J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.
PUBLISHED: 01-17-2014
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Ocular administration of the beta (?)-adrenergic receptor agonist JP-49b prevents retinopathy-like damage in a preclinical rat model of diabetes. Importantly, JP-49b did not induce characteristic ?-adrenergic agonist-related side effects (e.g., left ventricular damage), which led to the hypothesis that JP-49b systemic exposure was minimal following ocular administration. To test this hypothesis, a sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to study the preclinical pharmacokinetics of JP-49b in rats. Animals received either a single periocular or intravenous injection of JP-49b (10mg/kg) and plasma and tissue samples were obtained. JP-49b and fenoterol hydrobromide (internal standard, IS) were isolated by liquid-liquid extraction and extracts were analyzed by reversed-phase liquid chromatography on a C18 column using a gradient elution (acetic acid in water and methanol). A triple quadrupole mass spectrometer operating in the positive electrospray ionization mode with multiple reaction monitoring was used to detect JP-49b and IS transitions of m/z 346.4?195.1 and 304.1?134.9. The method was validated for selectivity, linearity, accuracy, and precision in rat vitreous humor, tissue homogenates, and plasma. Following intravenous administration, JP-49b was found to have a rapid clearance (36±5.8L/h/kg), high volume of distribution (244±51.5L/kg) and a terminal half-life of 4.8±1.6h. JP-49b was rapidly absorbed and extensively distributed into ocular tissue following topical administration. However, JP-49b was undetectable in heart tissue 24h after ocular administration. High local drug concentrations coupled with minimal systemic exposure following ocular administration supports further testing of JP-49b as a localized therapy for diabetic retinopathy.
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Antiretroviral pharmacokinetics in mothers and breastfeeding infants from 6 to 24 weeks post-partum: results of the BAN Study.
Antivir. Ther. (Lond.)
PUBLISHED: 01-10-2014
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An intensive, prospective, open-label pharmacokinetic (PK) study in a subset of HIV-infected mothers and their uninfected infants enrolled in the Breastfeeding, Antiretroviral and Nutrition (BAN) Study was performed to describe drug exposure and antiviral response.
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Modulation of radiation injury response in retinal endothelial cells by quinic acid derivative KZ-41 involves p38 MAPK.
PLoS ONE
PUBLISHED: 01-01-2014
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Radiation-induced damage to the retina triggers leukostasis, retinal endothelial cell (REC) death, and subsequent hypoxia. Resultant ischemia leads to visual loss and compensatory retinal neovascularization (RNV). Using human RECs, we demonstrated that radiation induced leukocyte adhesion through mechanisms involving p38MAPK, p53, and ICAM-1 activation. Additional phenotypic changes included p38MAPK-dependent tyrosine phosphorylation of the focal adhesion scaffolding protein, paxillin (Tyr118). The quinic acid derivative KZ-41 lessened leukocyte adhesion and paxillin-dependent proliferation via inhibition of p38MAPK-p53-ICAM-1 signaling. Using the murine oxygen-induced retinopathy (OIR) model, we examined the effect of KZ-41 on pathologic RNV. Daily ocular application of a KZ-41-loaded nanoemulsion significantly reduced both the avascular and neovascular areas in harvested retinal flat mounts when compared to the contralateral eye receiving vehicle alone. Our data highlight the potential benefit of KZ-41 in reducing both the retinal ischemia and neovascularization provoked by genotoxic insults. Further research into how quinic acid derivatives target and mitigate inflammation is needed to fully appreciate their therapeutic potential for the treatment of inflammatory retinal vasculopathies.
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Diagnosis and management of physical abuse in children.
Am Fam Physician
PUBLISHED: 12-25-2013
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Child abuse is the third leading cause of death in children between one and four years of age, and almost 20% of child homicide victims have contact with a health care professional within a month of their death. Therefore, family physicians are in an ideal position to detect and intervene in cases of suspected child maltreatment. There is currently insufficient evidence that screening parents or guardians for child abuse reduces disability or premature death. Assessment for physical abuse involves evaluation of historical information and physical examination findings, as well as radiographic and laboratory studies, if indicated. The history should be obtained in a nonaccusatory manner and should include details of any injuries or incidents, the patients medical and social history, and information from witnesses. The physical examination should focus on bruising patterns, injuries or findings concerning for abuse, and palpation for tenderness or other evidence of occult injury. Skeletal survey imaging is indicated for suspected abuse in children younger than two years. Imaging may be indicated for children two to five years of age if abuse is strongly suspected. Detailed documentation is crucial, and includes photographing physical examination findings. Physicians are mandated by law to report child abuse to the local child protective services or law enforcement agency. After a report is made, the child protection process is initiated, which involves a multidisciplinary team approach.
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Determinants of Mortality in a Combined Cohort of 501 Patients With HIV-Associated Cryptococcal Meningitis: Implications for Improving Outcomes.
Clin. Infect. Dis.
PUBLISHED: 12-06-2013
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Background.?Cryptococcal meningitis (CM) is a leading cause of death in individuals infected with human immunodeficiency virus (HIV). Identifying factors associated with mortality informs strategies to improve outcomes. Methods.?Five hundred one patients with HIV-associated CM were followed prospectively for 10 weeks during trials in Thailand, Uganda, Malawi, and South Africa. South African patients (n = 266) were followed for 1 year. Similar inclusion/exclusion criteria were applied at all sites. Logistic regression identified baseline variables independently associated with mortality. Results.?Mortality was 17% at 2 weeks and 34% at 10 weeks. Altered mental status (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.7-5.9), high cerebrospinal fluid (CSF) fungal burden (OR, 1.4 per log10 colony-forming units/mL increase; 95% CI, 1.0-1.8), older age (>50 years; OR, 3.9; 95% CI, 1.4-11.1), high peripheral white blood cell count (>10 × 10(9) cells/L; OR, 8.7; 95% CI, 2.5-30.2), fluconazole-based induction treatment, and slow clearance of CSF infection were independently associated with 2-week mortality. Low body weight, anemia (hemoglobin <7.5 g/dL), and low CSF opening pressure were independently associated with mortality at 10 weeks in addition to altered mental status, high fungal burden, high peripheral white cell count, and older age. In those followed for 1 year, overall mortality was 41%. Immune reconstitution inflammatory syndrome occurred in 13% of patients and was associated with 2-week CSF fungal burden (P = .007), but not with time to initiation of antiretroviral therapy (ART). Conclusions.?CSF fungal burden, altered mental status, and rate of clearance of infection predict acute mortality in HIV-associated CM. The results suggest that earlier diagnosis, more rapidly fungicidal amphotericin-based regimens, and prompt immune reconstitution with ART are priorities for improving outcomes.
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In vivo production of novel vitamin D2 hydroxy-derivatives by human placentas, epidermal keratinocytes, Caco-2 colon cells and the adrenal gland: Metabolism of vitamin D2.
Mol. Cell. Endocrinol.
PUBLISHED: 11-27-2013
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We investigated the metabolism of vitamin D2 to hydroxyvitamin D2 metabolites ((OH)D2) by human placentas ex-utero, adrenal glands ex-vivo and cultured human epidermal keratinocytes and colonic Caco-2 cells, and identified 20(OH)D2, 17,20(OH)2D2, 1,20(OH)2D2, 25(OH)D2 and 1,25(OH)2D2 as products. Inhibition of product formation by 22R-hydroxycholesterol indicated involvement of CYP11A1 in 20- and 17-hydroxylation of vitamin D2, while use of ketoconazole indicated involvement of CYP27B1 in 1? -hydroxylation of products. Studies with purified human CYP11A1 confirmed the ability of this enzyme to convert vitamin D2 to 20(OH)D2 and 17,20(OH)2D2. In placentas and Caco-2 cells, production of 20(OH)D2 was higher than 25(OH)D2 while in human keratinocytes the production of 20(OH)D2 and 25(OH)D2 were comparable. HaCaT keratinocytes showed high accumulation of 1,20(OH)2D2 relative to 20(OH)D2 indicating substantial CYP27B1 activity. This is the first in vivo evidence for a novel pathway of vitamin D2 metabolism initiated by CYP11A1 and modified by CYP27B1, with the product profile showing tissue- and cell-type specificity.
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Physiological and pharmacokinetic effects of oral 1,3-dimethylamylamine administration in men.
BMC Pharmacol Toxicol
PUBLISHED: 09-30-2013
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1,3-dimethylamylamine (DMAA) has been a component of dietary supplements and is also used within "party pills," often in conjunction with alcohol and other drugs. Ingestion of higher than recommended doses results in untoward effects including cerebral hemorrhage. To our knowledge, no studies have been conducted to determine both the pharmacokinetic profile and physiologic responses of DMAA.
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BLT-humanized C57BL/6 Rag2-/-?c-/-CD47-/- mice are resistant to GVHD and develop B- and T-cell immunity to HIV infection.
Blood
PUBLISHED: 09-10-2013
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The use of C57BL/6 Rag2(-/-)?c(-/-) mice as recipients for xenotransplantation with human immune systems (humanization) has been problematic because C57BL/6 SIRP? does not recognize human CD47, and such recognition is required to suppress macrophage-mediated phagocytosis of transplanted human hematopoietic stem cells (HSCs). We show that genetic inactivation of CD47 on the C57BL/6 Rag2(-/-)?c(-/-) background negates the requirement for CD47-signal recognition protein ? (SIRP?) signaling and induces tolerance to transplanted human HSCs. These triple-knockout, bone marrow, liver, thymus (TKO-BLT) humanized mice develop organized lymphoid tissues including mesenteric lymph nodes, splenic follicles and gut-associated lymphoid tissue that demonstrate high levels of multilineage hematopoiesis. Importantly, these mice have an intact complement system and showed no signs of graft-versus-host disease (GVHD) out to 29 weeks after transplantation. Sustained, high-level HIV-1 infection was observed via either intrarectal or intraperitoneal inoculation. TKO-BLT mice exhibited hallmarks of human HIV infection including CD4(+) T-cell depletion, immune activation, and development of HIV-specific B- and T-cell responses. The lack of GVHD makes the TKO-BLT mouse a significantly improved model for long-term studies of pathogenesis, immune responses, therapeutics, and vaccines to human pathogens.
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Safety and Pharmacokinetics of Intravenous Zanamivir Treatment in Hospitalized Adults With Influenza: An Open-label, Multicenter, Single-Arm, Phase II Study.
J. Infect. Dis.
PUBLISHED: 08-27-2013
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Background.?Intravenous zanamivir is a neuraminidase inhibitor suitable for treatment of hospitalized patients with severe influenza.Methods.?Patients were treated with intravenous zanamivir 600 mg twice daily, adjusted for renal impairment, for up to 10 days. Primary outcomes included adverse events (AEs), and clinical/laboratory parameters. Pharmacokinetics, viral load, and disease course were also assessed.Results.?One hundred thirty patients received intravenous zanamivir (median, 5 days; range, 1-11) a median of 4.5 days (range, 1-7) after onset of influenza; 83% required intensive care. The most common influenza type/subtype was A/H1N1pdm09 (71%). AEs and serious AEs were reported in 85% and 34% of patients, respectively; serious AEs included bacterial pulmonary infections (8%), respiratory failure (7%), sepsis or septic shock (5%), and cardiogenic shock (5%). No drug-related trends in safety parameters were identified. Protocol-defined liver events were observed in 13% of patients. The 14- and 28-day all-cause mortality rates were 13% and 17%. No fatalities were considered zanamivir related. Pharmacokinetic data showed dose adjustments for renal impairment yielded similar zanamivir exposures. Ninety-three patients, positive at baseline for influenza by quantitative polymerase chain reaction, showed a median decrease in viral load of 1.42 log10 copies/mL after 2 days of treatment.Conclusions.?Safety, pharmacokinetic and clinical outcome data support further investigation of intravenous zanamivir.Clinical Trials Registration.?NCT01014988.
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End group characterization of poly(phthalaldehyde): surprising discovery of a reversible, cationic macrocyclization mechanism.
J. Am. Chem. Soc.
PUBLISHED: 08-20-2013
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End-capped poly(phthalaldehyde) (PPA) synthesized by anionic polymerization has garnered significant interest due to its ease of synthesis and rapid depolymerization. However, alternative ionic polymerizations to produce PPA have been largely unexplored. In this report, we demonstrate that a cationic polymerization of o-phthalaldehyde initiated by boron trifluoride results in cyclic PPA in high yield, with high molecular weight, and with extremely high cyclic purity. The cyclic structure is confirmed by NMR spectroscopy, MALDI-TOF mass spectrometry, and triple-detection GPC. The cyclic polymers are reversibly opened and closed under the polymerization conditions. Owing to PPAs low ceiling temperature, cyclic PPA is capable of chain extension to larger molecular weights, controlled depolymerization to smaller molecular weights, or dynamic intermixing with other polymer chains, both cyclics and end-capped linears. These unusual properties endow the system with great flexibility in the synthesis and isolation of pure cyclic polymers of high molecular weight. Further, we speculate that the absence of end groups enhances the stability of cyclic PPA and makes it an attractive candidate for lithographic applications.
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Patterns of body composition among HIV-infected, pregnant Malawians and the effects of famine season.
Matern Child Health J
PUBLISHED: 08-09-2013
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We describe change in weight, midupper arm circumference (MUAC), arm muscle area (AMA) and arm fat area (AFA) in 1130 pregnant HIV-infected women with CD4 counts > 200 as part of the BAN Study ( www.thebanstudy.org ), a randomized, controlled clinical trial to evaluate antiretroviral and nutrition interventions to reduce mother-to-child transmission of HIV during breast feeding. In a longitudinal analysis, we found a linear increase in weight with a mean rate of weight gain of 0.27 kgs/week, from baseline (12 to 30 weeks gestation) until the last follow-up visit (32-38 weeks). Analysis of weight gain showed that 17.1% of the intervals between visits resulted in a weight loss. In unadjusted models, MUAC and AMA increased and AFA declined during late pregnancy. Based on multivariable regression analysis, exposure to the famine season resulted in larger losses in AMA [-0.08, 95% CI -0.14, -0.02; p = 0.01] while AFA losses occurred irrespective of season [-0.55, 95%: -0.95, -0.14, p = 0.01]. CD4 was associated with AFA [0.21, 95% CI 0.01, 0.41, p = .04]. Age was positively associated with MUAC and AMA. Wealth was positively associated with MUAC, AFA, and weight. While patterns of anthropometric measures among HIV-infected, pregnant women were found to be similar to those reported for uninfected women in sub-Saharan Africa, effects of the famine season among undernourished, Malawian women are of concern. Strategies to optimize nutrition during pregnancy for these women appear warranted.
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Do pluripotent stem cells exist in adult mice as very small embryonic stem cells?
Stem Cell Reports
PUBLISHED: 08-06-2013
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Very small embryonic-like stem cells (VSELs) isolated from bone marrow (BM) have been reported to be pluripotent. Given their nonembryonic source, they could replace blastocyst-derived embryonic stem cells in research and medicine. However, their multiple-germ-layer potential has been incompletely studied. Here, we show that we cannot find VSELs in mouse BM with any of the reported stem cell potentials, specifically for hematopoiesis. We found that: (1) most events within the "VSEL" flow-cytometry gate had little DNA and the cells corresponding to these events (2) could not form spheres, (3) did not express Oct4, and (4) could not differentiate into blood cells. These results provide a failure to confirm the existence of pluripotent VSELs.
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Losartan reverses permissive epigenetic changes in renal glomeruli of diabetic db/db mice.
Kidney Int.
PUBLISHED: 08-05-2013
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Epigenetic mechanisms such as chromatin histone H3 lysine methylation and acetylation have been implicated in diabetic vascular complications. However, histone modification profiles at pathologic genes associated with diabetic nephropathy in vivo and their regulation by the angiotensin II type 1 receptor (AT1R) are not clear. Here we tested whether treatment of type 2 diabetic db/db mice with the AT1R blocker losartan not only ameliorates diabetic nephropathy, but also reverses epigenetic changes. As expected, the db/db mice had increased blood pressure, mesangial hypertrophy, proteinuria, and glomerular expression of RAGE and PAI-1 vs. control db/+ mice. This was associated with increased RNA polymerase II recruitment and permissive histone marks as well as decreased repressive histone marks at these genes, and altered expression of relevant histone modification enzymes. Increased MCP-1 mRNA levels were not associated with such epigenetic changes, suggesting post-transcriptional regulation. Losartan attenuated key parameters of diabetic nephropathy and gene expression, and reversed some but not all the epigenetic changes in db/db mice. Losartan also attenuated increased H3K9/14Ac at RAGE, PAI-1, and MCP-1 promoters in mesangial cells cultured under diabetic conditions. Our results provide novel information about the chromatin state at key pathologic genes in vivo in diabetic nephropathy mediated in part by AT1R. Thus, combination therapies targeting epigenetic regulators and AT1R could be evaluated for more effective treatment of diabetic nephropathy.Kidney International advance online publication, 2 October 2013; doi:10.1038/ki.2013.387.
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Isolation of pluripotent neural crest-derived stem cells from adult human tissues by connexin-43 enrichment.
Stem Cells Dev.
PUBLISHED: 07-27-2013
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Identification and isolation of pluripotent stem cells in adult tissues represent an important advancement in the fields of stem cell biology and regenerative medicine. For several years, research has been performed on the identification of biomarkers that can isolate stem cells residing in neural crest (NC)-derived adult tissues. The NC is considered a good model in stem cell biology as cells from it migrate extensively and contribute to the formation of diverse tissues in the body during organogenesis. Migration of these cells is modulated, in part, by gap junction communication among the cell sheets. Here we present a study in which, selection of connexin 43 (Cx43) expressing cells from human adult periodontal ligament yields a novel pluripotent stem cell population. Cx43? periodontal ligament stem cells express pluripotency-associated transcription factors OCT4, Nanog, and Sox2, as well as NC-specific markers Sox10, p75, and Nestin. When injected in vivo into an immunodeficient mouse model, these cells were capable of generating teratomas with tissues from the three embryological germ layers: endoderm, mesoderm, and ectoderm. Furthermore, the cells formed mature structures of tissues normally arising from the NC during embryogenesis such as eccrine sweat glands of the human skin, muscle, neuronal tissues, cartilage, and bone. Immunohistochemical analysis confirmed the human origin of the neoplastic cells as well as the ectodermal and endodermal nature of some of the structures found in the tumors. These results suggest that Cx43 may be used as a biomarker to select and isolate the remnant NC pluripotent stem cells from adult human tissues arising from this embryological structure. The isolation of these cells through routine medical procedures such as wisdom teeth extraction further enhances their applicability to the regenerative medicine field.
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Multi-muscle control during bipedal stance: an EMG-EMG analysis approach.
Exp Brain Res
PUBLISHED: 07-22-2013
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Posture and postural reactions to mechanical perturbations require the harmonic modulation of the activity of multiple muscles. This precision can become suboptimal in the presence of neuromuscular disorders and result in higher fall risk and associated levels of comorbidity. This study was designed to investigate neurophysiological principles related to the generation and distribution of inputs to skeletal muscles previously recognized as a synergistic group. Specifically, we investigated the current hypothesis that correlated neural inputs, as measured by intermuscular coherence, are the mechanism used by the central nervous system to coordinate the formation of postural muscle synergies. This hypothesis was investigated by analyzing the strength and distribution of correlated neural inputs to postural muscles during the execution of a quiet stance task. Nine participants, 4 females and 5 males, mean age 29.2 years old (±6.1 SD), performed the task of standing while holding a 5-kg barbell in front of their bodies at chest level. Subjects were asked to maintain a standing position for 10 s while the activity of three postural muscles was recorded by surface electrodes: soleus (SOL), biceps femoris (BF), and lumbar erector spinae (ERE). EMG-EMG coherence was estimated for three muscle pairs (SOL/BF, SOL/ERE, and BF/ERE). Our choice of studying these muscles was made based on the fact that they have been reported as components of a functional (synergistic) muscle group that emerges during the execution of bipedal stance. In addition, an isometric contraction can be easily induced in this muscle group by simply adding a weight to the bodys anterior aspect. The experimental condition elicited a significant increase in muscle activation levels for all three muscles (p < 0.01 for all muscles). EMG-EMG coherence analysis revealed significant coherence within two distinct frequency bands, 0-5 and 5-20 Hz. Significant coherence within the later frequency band was also found to be significantly uniformly distributed across the three muscle pairs. These findings are interpreted as corroborative with the idea of a hierarchic system of control where the controller may use the generation of common neural inputs to reduce the number of variables it manipulates.
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Paracrine activation of hepatic stellate cells in platelet-derived growth factor C transgenic mice: Evidence for stromal induction of hepatocellular carcinoma.
Int. J. Cancer
PUBLISHED: 07-16-2013
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Cirrhosis is the primary risk factor for the development of hepatocellular carcinoma (HCC), yet the mechanisms by which cirrhosis predisposes to carcinogenesis are poorly understood. Using a mouse model that recapitulates many aspects of the pathophysiology of human liver disease, we explored the mechanisms by which changes in the liver microenvironment induce dysplasia and HCC. Hepatic expression of platelet-derived growth factor C (PDGF-C) induces progressive fibrosis, chronic inflammation, neoangiogenesis and sinusoidal congestion, as well as global changes in gene expression. Using reporter mice, immunofluorescence, immunohistochemistry and liver cell isolation, we demonstrate that receptors for PDGF-CC are localized on hepatic stellate cells (HSCs), which proliferate, and transform into myofibroblast-like cells that deposit extracellular matrix and lead to production of growth factors and cytokines. We demonstrate induction of cytokine genes at 2 months, and stromal cell-derived hepatocyte growth factors that coincide with the onset of dysplasia at 4 months. Our results support a paracrine signaling model wherein hepatocyte-derived PDGF-C stimulates widespread HSC activation throughout the liver leading to chronic inflammation, liver injury and architectural changes. These complex changes to the liver microenvironment precede the development of HCC. Further, increased PDGF-CC levels were observed in livers of patients with nonalcoholic fatty steatohepatitis and correlate with the stage of disease, suggesting a role for this growth factor in chronic liver disease in humans. PDGF-C transgenic mice provide a unique model for the in vivo study of tumor-stromal interactions in the liver.
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Clonal precursor of bone, cartilage, and hematopoietic niche stromal cells.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 07-15-2013
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Organs are composites of tissue types with diverse developmental origins, and they rely on distinct stem and progenitor cells to meet physiological demands for cellular production and homeostasis. How diverse stem cell activity is coordinated within organs is not well understood. Here we describe a lineage-restricted, self-renewing common skeletal progenitor (bone, cartilage, stromal progenitor; BCSP) isolated from limb bones and bone marrow tissue of fetal, neonatal, and adult mice. The BCSP clonally produces chondrocytes (cartilage-forming) and osteogenic (bone-forming) cells and at least three subsets of stromal cells that exhibit differential expression of cell surface markers, including CD105 (or endoglin), Thy1 [or CD90 (cluster of differentiation 90)], and 6C3 [ENPEP glutamyl aminopeptidase (aminopeptidase A)]. These three stromal subsets exhibit differential capacities to support hematopoietic (blood-forming) stem and progenitor cells. Although the 6C3-expressing subset demonstrates functional stem cell niche activity by maintaining primitive hematopoietic stem cell (HSC) renewal in vitro, the other stromal populations promote HSC differentiation to more committed lines of hematopoiesis, such as the B-cell lineage. Gene expression analysis and microscopic studies further reveal a microenvironment in which CD105-, Thy1-, and 6C3-expressing marrow stroma collaborate to provide cytokine signaling to HSCs and more committed hematopoietic progenitors. As a result, within the context of bone as a blood-forming organ, the BCSP plays a critical role in supporting hematopoiesis through its generation of diverse osteogenic and hematopoietic-promoting stroma, including HSC supportive 6C3(+) niche cells.
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The Effect of Cotrimoxazole Prophylactic Treatment on Malaria, Birth Outcomes, and Postpartum CD4 Count in HIV-Infected Women.
Infect Dis Obstet Gynecol
PUBLISHED: 06-19-2013
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Background. Limited data exist on cotrimoxazole prophylactic treatment (CPT) in pregnant women, including protection against malaria versus standard intermittent preventive therapy with sulfadoxine-pyrimethamine (IPTp). Methods. Using observational data we examined the effect of CPT in HIV-infected pregnant women on malaria during pregnancy, low birth weight and preterm birth using proportional hazards, logistic, and log binomial regression, respectively. We used linear regression to assess effect of CPT on CD4 count. Results. Data from 468 CPT-exposed and 768 CPT-unexposed women were analyzed. CPT was associated with protection against malaria versus IPTp (hazard ratio: 0.35, 95% Confidence Interval (CI): 0.20, 0.60). After adjustment for time period this effect was not statistically significant (adjusted hazard ratio: 0.66, 95% CI: 0.28, 1.52). Among women receiving and not receiving CPT, rates of low birth weight (7.1% versus 7.6%) and preterm birth (23.5% versus 23.6%) were similar. CPT was associated with lower CD4 counts 24 weeks postpartum in women receiving (-77.6?cells/ ? L, 95% CI: -125.2, -30.1) and not receiving antiretrovirals (-33.7?cells/ ? L, 95% CI: -58.6, -8.8). Conclusions. Compared to IPTp, CPT provided comparable protection against malaria in HIV-infected pregnant women and against preterm birth or low birth weight. Possible implications of CPT-associated lower CD4 postpartum warrant further examination.
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Mitigation of radiation injury by selective stimulation of the LPA(2) receptor.
Biochim. Biophys. Acta
PUBLISHED: 06-13-2013
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Due to its antiapoptotic action, derivatives of the lipid mediator lysophosphatidic acid (LPA) provide potential therapeutic utility in diseases associated with programmed cell death. Apoptosis is one of the major pathophysiological processes elicited by radiation injury to the organism. Consequently, therapeutic explorations applying compounds that mimic the antiapoptotic action of LPA have begun. Here we present a brief account of our decade-long drug discovery effort aimed at developing LPA mimics with a special focus on specific agonists of the LPA(2) receptor subtype, which was found to be highly effective in protecting cells from apoptosis. We describe new evidence that 2-((3-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)propyl)thio)benzoic acid (GRI977143), a prototypic nonlipid agonist specific to the LPA(2) receptor subtype, rescues apoptotically condemned cells in vitro and in vivo from injury caused by high-dose ?-irradiation. GRI977143 shows the features of a radiomitigator because it is effective in rescuing the lives of mice from deadly levels of radiation when administered 24h after radiation exposure. Our findings suggest that by specifically activating LPA(2) receptors GRI977143 activates the ERK1/2 prosurvival pathway, effectively reduces Bax translocation to the mitochondrion, attenuates the activation of initiator and effector caspases, reduces DNA fragmentation, and inhibits PARP-1 cleavage associated with ?-irradiation-induced apoptosis. GRI977143 also inhibits bystander apoptosis elicited by soluble proapoptotic mediators produced by irradiated cells. Thus, GRI977143 can serve as a prototype scaffold for lead optimization paving the way to more potent analogs amenable for therapeutic exploration. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.
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A New Species of Strongyluris (Nematoda: Heterakidae) from the Lizard, Lophognathus temporalis (Sauria: Agamidae) from Papua New Guinea.
J. Parasitol.
PUBLISHED: 06-12-2013
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Abstract :? Strongyluris dracocola n. sp. from the intestine of Lophognathus temporalis collected in Papua New Guinea is described and illustrated. Strongyluris dracocola n. sp. represents the 32nd species assigned to the genus and the sixth from the Australo-Papuan region. It can be easily separated from the other Australo-Papuan species because it is the only species to have an unpaired median papilla adjacent to the sucker.
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A lipobead microarray assembled by particle entrapment in a microfluidic obstacle course and used for the display of cell membrane receptors.
Lab Chip
PUBLISHED: 06-11-2013
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Platforms which can display cell membrane ligands and receptors as a microarray library of probes for screening against a target are essential tools in drug discovery, biomarker identification, and pathogen detection. Membrane receptors and ligands require their native bilayer environment to retain their selectivity and binding affinity, and this complicates displaying them in a microarray platform. In this study, a design is developed in which the probes are first incorporated in supported lipid bilayers formed around micron-sized particles (lipobeads), and the microbeads themselves are then arrayed on a surface by hydrodynamic capture in a microfluidic obstacle course of traps. The traps are "V" shaped open enclosures, which are arranged in a wide channel of a microfluidic device, and capture the lipobeads (slightly smaller than the channel height) as they are streamed through the course. Screening assays are undertaken directly in the device after assembly, by streaming a fluorescently labeled target through the device and detecting the bead fluorescence. Conditions are first established for which the supported bilayers on the bead surface remain intact during the capture and assay steps, using fluorescent tags in the bilayer to infer bilayer integrity. Numerical calculations of the hydrodynamic drag coefficient on the entrapped beads are presented in conjunction with the stability experiments to develop criteria for the bilayer stability as a function of the screening assay perfusion rate. Simulations of the flow streamlines are also presented to quantify the trapping efficiency of the obstacle course. Screening assays are illustrated, assaying fluorescently labeled NeutrAvidin with biotin, and labeled cholera toxin with its ganglioside binding ligand, GM1. Sequential capturing of sets of lipobeads (one at a time, and with each set bearing a different probe), followed by indexing the bead positions after each set is entrapped, allows for the construction of an indexed array of multiple probes without the need for particle encoding and is illustrated using the NeutrAvidin-biotin pair. Finally, the lipobead platform is used for quantitatively measuring the kinetic rate constants for the binding of a probe (biotin) to a target (NeutrAvidin).
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Health outcomes of HIV-exposed uninfected African infants.
AIDS
PUBLISHED: 05-31-2013
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To evaluate severe (grade 3/4) morbidity and mortality in HIV-exposed, uninfected infants.
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