Ecological Barriers to HIV Service Access among Young Men who have Sex with Men and High-Risk Young Women from Low-resourced Urban Communities.
Using an ecological perspective, we sought to elucidate the perceived barriers preventing HIV service access among two groups of U.S. youth (ages 12-24) disproportionately affected by HIV, men who have sex with men and high-risk women. We content analyzed interviews with 318 key informants to identify distinct service barriers. The 29 barriers informants named were organized into six categories (service-seeking demands, stigmas, knowledge and awareness, service quality, powerful opposition, and negative emotions). Findings suggest that barriers impacting access to HIV prevention, testing, and linkage-to-care services are remarkably similar and point to the need for comprehensive approaches to improving youth's access services that address both individual-level barriers and extra-individual barriers simultaneously. Findings can be used to guide future research, programming and interventions to reduce the disproportionate spread of HIV among US youth.


Occurrence of lacto series gangliosides 3'-isoLM1 and 3',6'-isoLD1 in human gliomas in vitro and in vivo.
Monoclonal antibodies (MAb; DMAb, monoclonal antibodies derived at Duke Medical Center) directed against the oncofetally expressed lactotetraosyl gangliosides 3'-isoLM1 (IV3NeuAc-LcOse4Cer) and 3',6'-isoLD1 (IV3NeuAc,III6NeuAc-LcOse4Cer) were produced and their reactivity spectra compared to that of the alpha-3'-isoLM1 MAb SL-50. The IgM MAb SL-50 defines the epitope NeuAc (or NeuGc)alpha 2-3Gal beta 1-3GlcNAc, the terminal sequence of both gangliosides. SL-50 requires an unsubstituted GlcNAc residue; IgM DMAb-14 will accept the alpha 2-6 linked sialic acid to GlcNAc found in 3',6'-isoLD1. Immunohistochemical localization of 3'-isoLM1 was performed on 31 biopsy specimens of human gliomas; 15 (48%) expressed 3'-isoLM1 as defined by binding of MAb SL-50. Staining of small anaplastic cells, giant cells, and the glial component of gliosarcomas was observed. Neoplastic gemistocytes, when present, showed particularly intense staining. The 3'-isoLM1 and 3',6'-isoLD1 distribution in cultured cell lines and derived xenografts of primary tumors of the human central nervous system and of embryonal or neuroectodermal tumor derivation was determined. Six of 29 cell lines expressed 3'-isoLM1: 2/16 gliomas, 3/3 teratomas, 1/1 pancreatic adenocarcinoma. No cell line expressed detectable 3',6'-isoLD1 by immunostain analysis of ganglioside extracts. The 3'-iso-LM1-positive cell lines expressed it in xenograft form; in five xenografts, the corresponding cell lines of which were 3'-isoLM1-negative, it was a proportion of the monosialoganglioside fraction. 3',6'-isoLD1 was detected in two xenografts, D-54 MG (glioma) and PA-1 (teratoma). The demonstration of 3'-isoLM1 in gliomas in in vivo forms and the relatively infrequent expression by derived cultured cells suggest that ganglioside expression is modified by environmental forces. Expression of 3'-isoLM1 and 3',6'-isoLD1 in fetal and neonatal brain, in intense reactive astrocytosis such as polyunsaturated fatty acid lipidosis, and in primary neoplasms of the central nervous system suggests their role in cell-cell attachment during development, migration, and neoplastic transformation.


The in-depth evaluation of suspected mitochondrial disease.
Mitochondrial disease confirmation and establishment of a specific molecular diagnosis requires extensive clinical and laboratory evaluation. Dual genome origins of mitochondrial disease, multi-organ system manifestations, and an ever increasing spectrum of recognized phenotypes represent the main diagnostic challenges. To overcome these obstacles, compiling information from a variety of diagnostic laboratory modalities can often provide sufficient evidence to establish an etiology. These include blood and tissue histochemical and analyte measurements, neuroimaging, provocative testing, enzymatic assays of tissue samples and cultured cells, as well as DNA analysis. As interpretation of results from these multifaceted investigations can become quite complex, the Diagnostic Committee of the Mitochondrial Medicine Society developed this review to provide an overview of currently available and emerging methodologies for the diagnosis of primary mitochondrial disease, with a focus on disorders characterized by impairment of oxidative phosphorylation. The aim of this work is to facilitate the diagnosis of mitochondrial disease by geneticists, neurologists, and other metabolic specialists who face the challenge of evaluating patients of all ages with suspected mitochondrial disease.


[Changing characteristic viscosity of DNA interacting with Cu2+ and Mn2+ ions].
The interaction of DNA with Cu2+ and Mn2+ ions in low ionic strength solutions (10(-3) M NaCl) has been studied by the viscosimetry method. The DNA characteristic viscosity [eta] decreases sharply at low ion concentrations (addition of 10(-5) M Cu2+ leads to [eta] reduction by a factor of 1.4) and attains certain saturation at high concentrations, the saturation magnitude slightly depending on the ion type. The reduction is much lower in solutions containing bivalent ions, in concentration 2 X 10(-2) M NaCl. The experimental data for bivalent and monovalent (Na+) ions have been compared. The results are discussed in terms of equilibrium ion-DNA binding and compared with the Fixman theory. It is discussed if ion binding constants can be determined by visosimetry. It is shown that the cause of the viscosity reduction with time observed by some authors may be the action of DNAases activated by metal ions.


Urticaria and anaphylaxis in a child after inhalation of lentil vapours: a case report and literature review.
Among legumes, lentils seem to be the most common legume implicated in pediatric allergic reactions in the Mediterranean area and India, and usually they start early in life, below 4 years of age. A 22 -month-old child was admitted to our Pediatric Department for anaphylaxis and urticaria. At the age of 9 months she presented a first episode of angioedema and laryngeal obstruction, due to a second assumption of lentils in her diet. At admission we performed routine analyses that were all in the normal range, except for the dosage of specific IgE, that revealed a positive result for lentils. Prick tests too were positive for lentils, while they were all negative for other main food allergens. The child also performed a prick by prick that gave the same positive result (with a wheal of 8 mm of diameter). The child had not previously eaten lentils and other legumes, but her pathological anamnesis highlighted that the allergic reaction appeared soon after the inhalation of cooking lentil vapours when the child entered the kitchen Therefore a diagnosis of lentils vapours allergy was made. Our case shows the peculiarity of a very early onset. In literature there are no data on episodes of anaphylaxis in so young children, considering that our child was already on lentils exclusion diet. Therefore a diet of exclusion does not absolutely preserve patients from allergic reactions, that can develop also after their cooking steams inhalation.


Clinical relevance of treatments for acute bipolar disorder: balancing therapeutic and adverse effects.
The US Food and Drug Administration (FDA) has approved 10 treatments for acute mania, but only 2 for acute bipolar depression. These agents differ from one another with respect to their efficacy and tolerability profiles, such that certain medications may be optimal for some patients but not others. Our aim was to compare the therapeutic and adverse effects of treatments for acute mania and acute bipolar depression to inform clinical decision making. Using data from large, randomized, double-blind, placebo-controlled acute mania and acute bipolar depression trials, we assessed number needed to treat (NNT) for response, number needed to harm (NNH) for sedation/weight gain, and likelihood to help or harm (LHH = NNH ÷ NNT) compared with placebo. For acute mania, lithium compared with other FDA-approved agents yielded substantively less sedation (NNH, 27 vs 5-17) yet broadly similar efficacy (NNT, 4 vs 4-8), and thus a more favorable efficacy:sedation likelihood (LHH, 6.8 vs 0.7-3.4). For acute bipolar depression, lamotrigine compared with FDA-approved treatments yielded substantively less sedation (NNH, 42 vs 6-12), weight gain (NNH, -34 vs 6-19), and efficacy (NNT, 12 vs 4-6), but still more favorable efficacy:sedation likelihood (LHH, 3.5) than quetiapine (LHH, 1.0) and efficacy:weight gain likelihood (LHH, -2.8) than the olanzapine plus fluoxetine combination (LHH, 1.5). For acute mania, lithium compared with other FDA-approved agents yielded less sedation yet similar efficacy, indicating utility for patients sensitive to sedation. For acute bipolar depression, lamotrigine compared with FDA-approved treatments yielded better tolerability but poorer efficacy, suggesting utility in patients sensitive to sedation/weight gain with milder episodes, whereas the FDA-approved treatments might have utility in patients with more severe episodes.


Retinal flat cells are a substrate that facilitates retinal neuron growth and fiber formation.
When embryonic chick neural retinas are dissociated into a suspension of single cells and plated in stationary cultures, "flat cells" spread out and form a monolayer to which the neuronal cells attach. It has been shown previously that the flat cells are related to the Müller cell population of the retina. The neuronal cells form aggregates interconnected by bundles of axon-like fibers. The authors have been able to isolate relatively pure flat cells by shaking off the neuronal aggregates after 5 or 6 days of culture. In order to determine if the flat cells have a unique relationship with the neuronal cells, freshly dissociated neural retina cells were added to monolayers of flat cells and their behavior compared to that on chick embryo mesodermal cells. It has been observed by phase contrast and scanning electron microscopy that the growth behavior of the retina cells on flat cells is significantly different from that on mesodermal cells. On flat cells, neuronal retina cells form flat patches in which new growing flat cells fuse with the monolayer, and neuronal cells attach as single cells or small clusters. Axon-like fibers are present several hours after plating, and by day 4 an extensive network of fibers connects single cells and clusters on the surface of the monolayer. When retina cells are plated onto mesodermal cells, the cells form aggregates which are organized along the long axis of the mesodermal cells. The flat cells provide a unique substrate for the differentiation and neurite extension of neuronal cells from embryonic chick retina.


Retrieval of old memories: the temporofrontal hypothesis.
Extensive neuropsychological testing is reported on two chronic patients with combined temporopolar and prefrontal damage, dominantly left-hemispheric, and, as control, one chronic patient with bi-hemispheric prefrontal damage. The principal finding is that combined temporofrontal damage, but not substantial prefrontal damage alone, results in marked retrograde memory deficits while leaving intelligence and new learning relatively unimpaired. Although their general world knowledge was good, the temporopolar patients demonstrated retrograde memory impairments on several tests of past events and faces of previously famous people. With respect to retrograde autobiographical memory, one of the temporopolar patients was severely impaired and the other was judged to be moderately impaired. The control patient appeared to be normal. These results, together with corresponding data from related single case and dynamic imaging studies, strongly support a crucial role of the temporofrontal junction area in the ecphory of old memories.


Alterations in integrin receptor expression on chemically transformed human cells: specific enhancement of laminin and collagen receptor complexes.
The abilities of malignant tumor cells to bind and migrate through basement membranes are important steps in invasion and metastasis. Malignant tumor cells would therefore be expected to express receptors on their surfaces for basement membrane and stromal components, such as collagens, laminin, and fibronectin, although the pattern of expression of these receptors on the malignant cells may be different from that on their normal progenitors. We report here that chemically transformed tumorigenic human cells express an altered pattern of integrin receptors on their cell surfaces as compared with their untransformed nontumorigenic counterparts. Specifically, N-methyl-N'-nitro-N-nitrosoguanidine transformation of HOS cells into highly tumorigenic cells results in a significant specific increase in the expression of (in descending order of level of cell surface expression) the integrins alpha 6/beta 1, alpha 2/beta 1, and alpha 1/beta 1, which are receptors for laminin, collagens, and collagen type IV and laminin, respectively. The level of expression of two fibronectin receptor integrins, alpha 5/beta 1 and alpha 3/beta 1, are, however, unaltered, whereas the level of expression of vitronectin receptor integrin, alpha v/beta 3, is drastically reduced on the transformed cells. Consistent with the increased expression of laminin and collagen receptors and the decreased expression of vitronectin receptors on the transformed cells, these cells attached three- to fivefold more strongly to laminin and collagen but attached very poorly to vitronectin. The MNNG-HOS cells were also found to have a greater potential for invasion through reconstituted basement membrane, matrigel, the major components of which are laminin and type IV collagen. The invasion of both the HOS and MNNG-HOS cells was inhibited 45-50% by a polyclonal anti-fibronectin receptor antibody. However, although the invasion of HOS cells could be inhibited up to 75% by an anti-alpha 6 monoclonal antibody, a similar concentration of this antibody had no effect on the alpha 6-overproducing MNNG-HOS cells. A fivefold higher concentration of this antibody did result in partial inhibition of MNNG-HOS invasion. These data indicate a critical role for the alpha 6/beta 1 laminin receptor in the invasion of these cells through basement membranes and demonstrate that chemical transformation of nontumorigenic human cells to highly tumorigenic cells is associated with an altered pattern of integrin expression which may play a direct role in the increased capacity of these cells to bind and invade through basement membranes.


Perceptual expertise with Chinese characters predicts Chinese reading performance among Hong Kong Chinese children with developmental dyslexia.
This study explores the theoretical proposal that developmental dyslexia involves a failure to develop perceptual expertise with words despite adequate education. Among a group of Hong Kong Chinese children diagnosed with developmental dyslexia, we investigated the relationship between Chinese word reading and perceptual expertise with Chinese characters. In a perceptual fluency task, the time of visual exposure to Chinese characters was manipulated and limited such that the speed of discrimination of a short sequence of Chinese characters at an accuracy level of 80% was estimated. Pair-wise correlations showed that perceptual fluency for characters predicted speeded and non-speeded word reading performance. Exploratory hierarchical regressions showed that perceptual fluency for characters accounted for 5.3% and 9.6% variance in speeded and non-speeded reading respectively, in addition to age, non-verbal IQ, phonological awareness, morphological awareness, rapid automatized naming (RAN) and perceptual fluency for digits. The findings suggest that perceptual expertise with words plays an important role in Chinese reading performance in developmental dyslexia, and that perceptual training is a potential remediation direction.


Hurdles and potentials when implementing internet-delivered Acceptance and commitment therapy for chronic pain: a retrospective appraisal using the Quality implementation framework.
Internet-delivered psychological interventions can be regarded as evidence-based practices and have been implemented in psychiatric and somatic care at primary and specialist levels. However, challenges as low adherence and poor routinization, have arisen during attempts to implement internet-delivered interventions in chronic pain settings. Internet-delivered Acceptance and Commitment Therapy (IACT) has been found to be helpful for chronic pain patients and might aid in developing pain rehabilitation services. However, the integration of IACT into standard health care has not yet been described from an implementation science perspective. The aim of this hybrid 1 effectiveness-implementation study was to evaluate the process of implementing IACT in a pain rehabilitation setting, to guide future implementation initiatives. In this retrospective study we described actions taken during an implementation initiative, in which IACT was delivered as part of an interdisciplinary pain rehabilitation program (IPRP) at a specialist level clinic. All documents relevant to the study were reviewed and coded using the Quality Improvement Framework (QIF), focusing on adoption, appropriateness and sustainability. The QIF-analysis of implementation actions resulted in two categories: facilitators and challenges for implementation. Sustainability may be facilitated by sensitivity to the changing needs of a clinical setting and challenged by unfitting capacity building. Appropriateness might be challenged by an insufficient needs assessment and facilitated by aligning routines for communication with the clinic's existing infrastructure. Adoption may be facilitated by staff key champions and an ability to adapt to occurring hurdles. Possible influential factors, hypotheses and key process challenges are presented in a logic model to guide future initiatives. Sustainable implementation may depend on both the continuity of facilitating implementation actions and flexibility to the changing needs and interests of patients, caregivers and organization. We conclude that the use of theories, models and frameworks (TMF) as well as a logic model may ease design, planning and evaluation of an implementation process. Lastly, we suggest that IACT may be appropriate for IPRP when given before or after IPRP, focusing on psychiatric comorbidities.


Adaptor protein2 (AP2) orchestrates CXCR2-mediated cell migration.
The chemokine receptor CXCR2 is vital for inflammation, wound healing, angiogenesis, cancer progression and metastasis. Adaptor protein 2 (AP2), a clathrin binding heterotetrameric protein comprised of α, β2, μ2 and σ2 subunits, facilitates clathrin-mediated endocytosis. Mutation of the LLKIL motif in the CXCR2 carboxyl-terminal domain (CTD) results in loss of AP2 binding to the receptor and loss of ligand-mediated receptor internalization and chemotaxis. AP2 knockdown also results in diminished ligand-mediated CXCR2 internalization, polarization and chemotaxis. Using knockdown/rescue approaches with AP2-μ2 mutants, the binding domains were characterized in reference to CXCR2 internalization and chemotaxis. When in an open conformation, μ2 Patch 1 and Patch 2 domains bind tightly to membrane PIP2 phospholipids. When AP2-μ2, is replaced with μ2 mutated in Patch 1 and/or Patch 2 domains, ligand-mediated receptor binding and internalization are not lost. However, chemotaxis requires AP2-μ2 Patch 1, but not Patch 2. AP2-σ2 has been demonstrated to bind dileucine motifs to facilitate internalization. Expression of AP2-σ2 V88D and V98S dominant negative mutants resulted in loss of CXCR2 mediated chemotaxis. Thus, AP2 binding to both membrane phosphatidylinositol phospholipids and dileucine motifs is crucial for directional migration or chemotaxis. Moreover, AP2-mediated receptor internalization can be dissociated from AP2-mediated chemotaxis.


[Effect of alcohol abuse on the development and course of acute cerebral circulatory disorders].
A study of 544 patients with acute disorders of cerebral circulation demonstrated a correlation between the development of a stroke and the degree of alcohol abuse. In patients who abused alcoholic beverages acute disorders of cerebral circulation developed at a younger age, were much more acute and more frequently had a lethal outcome, especially if the stroke developed during acute alcoholic intoxication. The study also showed that in such cases hemorrhagical strokes were more common than ischemic.


Music Therapy for Preterm Infants and Their Parents: A Cluster-Randomized Controlled Trial Protocol.
Music therapy (MT) interventions and skin-to-skin care (SSC) both aim to address the varied needs of preterm infants, including sensory regulation and stress reduction, inclusion of parents in their infant's care, support of parents' emotional state, and enhancing the parent-infant attachment process. Few studies have investigated the combination of both modalities through randomized controlled trials. Evidence of longer-term effects is missing. This article presents a study protocol that will investigate the effects of combined family-centered MT intervention and SSC on preterm-infants' autonomic nervous system (ANS) stability, parental anxiety levels, and parent-infant attachment quality. 12 clusters with a total of 72 preterm infants, with their parents, will be randomized to one of two conditions: MT combined with SSC or SSC alone. Each parent-infant dyad will participate in 3 sessions (2 in the hospital and a 3-month follow-up). The primary outcome of preterm infants' ANS stability will be measured by the high frequency power of their heart rate variability. Secondary outcomes will be physiological measures and behavioral states in infants and anxiety and attachment levels of parents. This trial will provide important, evidence-based knowledge on the use of the "First Sounds: Rhythm, Breath, and Lullaby" model of MT in neonatal care, through an intervention that is in line with the Newborn Individualized Developmental Care and Assessment Program model for supportive developmental care of preterm infants and their parents. Ethical approval (no. 0283-15) was granted from the local Institutional Review Board in April 2017. This trial is registered in ClinicalTrials.gov, NCT03023267.


Poor awareness of risk factors for cancer in Irish adults: results of a large survey and review of the literature.
Knowledge of cancer risk factors is unknown in Ireland. An understanding of risk factors could help inform cancer prevention programs. A 48-question online survey was designed to gather data to assess levels of public knowledge about cancer risk factors. There were 748 participants (648 women, 100 men). Mean age was 37 years (range: 18-74 years). For the public, 81% were concerned about developing cancer; however, 20% believed that cancer is unavoidable if a family history exists, 27% believed that >50% of cancers are inherited, and 54% believed that 10%-20% of cancers are inherited; 20% were unaware that risk increases with age. The top five risk factors listed by respondents were smoking (87%), diet (76%), genetics (47%), alcohol (42%), and obesity (33%). Only 32% of the public were aware that obesity is a risk factor, and 33% did not think the location of fat was important. Moreover, 29% and 48% believed that risk could be increased by wearing a tight bra and by a blow to the breast, respectively. In addition, 85% and 86% believed that stress and that mobile phones, respectively, "strongly" increase risk; 12% believed that luck is important in avoiding cancer; 35% thought that "detox" diets could reduce risk; and 61% believed that organic food reduces risk. The majority were aware that physical activity of 30 minutes per day can reduce risk. A sizable portion of the population is misinformed about cancer risk. Most participants were aware of classic risk factors (e.g., smoking, diet); however, many overestimated risk attributable to genetics, environment, and stress and underestimated age, obesity, and sunlight. One in seven participants believed that lifetime risk of cancer is not modifiable.


Infection with Batrachochytrium dendrobatidis lowers heat tolerance of tadpole hosts and cannot be cleared by brief exposure to CTmax.
Climate change and infectious disease by the chytrid fungus Batrachochytrium dendrobatidis (Bd) are major drivers of amphibian extinctions, but the potential interactions of these two factors are not fully understood. Temperature is known to influence (1) the infectivity, pathogenicity and virulence of Bd; (2) host-parasite dynamics, especially when both hosts and parasites are ectothermic organisms exhibiting thermal sensitivities that may or may not differ; and (3) amphibian vulnerability to extinction depending on their heat tolerance, which may decrease with infection. Thus, in a global warming scenario, with rising temperatures and more frequent and extreme weather events, amphibians infected by Bd could be expected to be more vulnerable if temperatures approach their critical thermal maximum (CTmax). However, it is also possible that predicted high temperatures could clear the Bd infection, thus enhancing amphibian survival. We tested these hypotheses by measuring CTmax values of Bd-infected and Bd-free aquatic tadpoles and terrestrial toadlets/juveniles of the common midwife toad (Alytes obstetricans) and examining whether exposure of A. obstetricans individuals to peak temperatures reaching their CTmax clears them from Bd infection. We show that (1) Bd has a wide thermal tolerance range; (2) Bd is capable of altering the thermal physiology of A. obstetricans, which is stage-dependent, lowering CTmax in tadpoles but not in toadlets; and (3) Bd infection is not cleared after exposure of tadpoles or toadlets to CTmax. Living under climatic change with rising temperatures, the effect of Bd infection might tip the balance and lead some already threatened amphibian communities towards extinction.


CobD, a novel enzyme with L-threonine-O-3-phosphate decarboxylase activity, is responsible for the synthesis of (R)-1-amino-2-propanol O-2-phosphate, a proposed new intermediate in cobalamin biosynthesis in Salmonella typhimurium LT2.
The cobD gene of Salmonella typhimurium LT2 has been cloned, sequenced, and overexpressed. The overexpressed protein had a molecular mass of approximately 40 kDa, in agreement with the mass predicted by the deduced amino acid sequence (40.8 kDa). Computer analysis of the deduced amino acid sequence of CobD identified a consensus pyridoxal phosphate-binding motif. The role of CobD in cobalamin biosynthesis in this bacterium has been established. CobD was shown to decarboxylate L-threonine O-3-phosphate to yield (R)-1-amino-2-propanol O-2-phosphate. We propose that the latter is a substrate in the reaction catalyzed by the CbiB enzyme proposed to be responsible for the conversion of adenosylcobyric acid to adenosylcobinamide and that the product of the reaction is adenosylcobinamide phosphate, not adenosylcobinamide as previously thought. The implications of these findings are discussed in light of the demonstrated kinase activity of the CobU enzyme (O'Toole, G. A., and Escalante-Semerena, J. C. (1995) J. Biol. Chem. 270, 23560-23569) responsible for the conversion of adenosylcobinamide to adenosylcobinamide phosphate. These findings shed light on the strategy used by this bacterium for the assimilation of exogenous unphosphorylated cobinamide from its environment. To our knowledge, CobD is the first enzyme reported to have L-threonine-O-3-phosphate decarboxylase activity, and computer analysis of its amino acid sequence suggests that it may be a member of a new class of pyridoxal phosphate-dependent decarboxylases.


[Effect of cholinergic substances on the spontaneous activity of lower respiratory tract neurons].
Acetylcholine and low concentrations of nicotine were shown to increase firing rate, to induce grouping of spikes of spontaneously active cells and to activate "silent" neurons. High concentrations of nicotine exert a biphasic (excitatory-inhibitory) effect. Atropine just alters and benzohexonium suppresses the spontaneous unit activity. Changes in the unit activity seem to stem from an interaction of cholinergic substances with the nicotine and muscarine cholinoreceptors. Neurons with a mixed type activity were found to receive inhibitory cholinergic projections.


The haplolethal region at the 16F gene cluster of Drosophila melanogaster: structure and function.
Extensive aneuploid analyses had shown the existence of a few haplolethal (HL) regions and one triplolethal region in the genome of Drosophila melanogaster. Since then, only two haplolethals, 22F1-2 and 16F, have been directly linked to identified genes, dpp and wupA, respectively. However, with the possible exception of dpp, the actual bases for this dosage sensitivity remain unknown. We have generated and characterized dominant-lethal mutations and chromosomal rearrangements in 16F and studied them in relation to the genes in the region. This region extends along 100 kb and includes at least 14 genes. The normal HL function depends on the integrity of a critical 4-kb window of mostly noncoding sequences within the wupA transcription unit that encodes the muscle protein troponin I (TNI). All dominant lethals are breakpoints within that window, which prevent the functional expression of TNI and other adjacent genes in the proximal direction. However, independent mutations in these genes result in recessive lethal phenotypes only. We propose that the HL at 16F represents a long-range cis regulatory region that acts upon a number of functionally related genes whose combined haploidy would yield the dominant-lethal effect.


Interferon induction by polynucleotides: structure-function relationship.
In view of recent developments, the structural determinants of the interferon inducing activity of polynucleotides have been (re)evaluated. To induce interferon, the polynucleotide should be sufficiently large and double-stranded, although not necessarily double-stranded over its whole length. It should be sufficiently stable to both thermal denaturation and hydrolysis by nucleases. It should also contain a particular steric conformation. This conformation is most regularly ensured by the presence of 2'-hydroxyl in the ribose moieties and intact purine-pyrimidine base pairs in the interior of the double helix. Other biologic activities of polynucleotides, such as anti-complement activity and inhibition of reverse transcriptase (RNA-directed DNA polymerase) activity, depend on structural requirements which are rather antagonistic to those governing the interferon response.


Out-of-Field Doses Produced by a Proton Scanning Beam Inside Pediatric Anthropomorphic Phantoms and Their Comparison With Different Photon Modalities.
Since 2010, EURADOS Working Group 9 (Radiation Dosimetry in Radiotherapy) has been involved in the investigation of secondary and scattered radiation doses in X-ray and proton therapy, especially in the case of pediatric patients. The main goal of this paper is to analyze and compare out-of-field neutron and non-neutron organ doses inside 5- and 10-year-old pediatric anthropomorphic phantoms for the treatment of a 5-cm-diameter brain tumor. Proton irradiations were carried out at the Cyclotron Centre Bronowice in IFJ PAN Krakow Poland using a pencil beam scanning technique (PBS) at a gantry with a dedicated scanning nozzle (IBA Proton Therapy System, Proteus 235). Thermoluminescent and radiophotoluminescent dosimeters were used for non-neutron dose measurements while secondary neutrons were measured with track-etched detectors. Out-of-field doses measured using intensity-modulated proton therapy (IMPT) were compared with previous measurements performed within a WG9 for three different photon radiotherapy techniques: 1) intensity-modulated radiation therapy (IMRT), 2) three-dimensional conformal radiation therapy (3D CDRT) performed on a Varian Clinac 2300 linear accelerator (LINAC) in the Centre of Oncology, Krakow, Poland, and 3) Gamma Knife surgery performed on the Leksell Gamma Knife (GK) at the University Hospital Centre Zagreb, Croatia. Phantoms and detectors used in experiments as well as the target location were the same for both photon and proton modalities. The total organ dose equivalent expressed as the sum of neutron and non-neutron components in IMPT was found to be significantly lower (two to three orders of magnitude) in comparison with the different photon radiotherapy techniques for the same delivered tumor dose. For IMPT, neutron doses are lower than non-neutron doses close to the target but become larger than non-neutron doses further away from the target. Results of WG9 studies have provided out-of-field dose levels required for an extensive set of radiotherapy techniques, including proton therapy, and involving a complete description of organ doses of pediatric patients. Such studies are needed for validating mathematical models and Monte Carlo simulation tools for out-of-field dosimetry which is essential for dedicated epidemiological studies which evaluate the risk of second cancers and other late effects for pediatric patients treated with radiotherapy.


Effect of a test and control program for Johne's disease in Victorian beef herds 1992-2002.
To report on progress in Johne's disease (JD) control in infected beef herds participating in the Victorian Johne's disease test and control program (TCP). Clinical histories and JD testing data recorded by the Department of Primary Industries were analysed for 18 beef herds participating in the TCP. The herds were required to conduct annual whole herd tests with an absorbed ELISA, cull reactors and control the grazing of young cattle to minimise infection. Testing of over 11,000 animals identified 68 reactors giving an average prevalence of reactors at the first whole-herd test round (T1) of 0.77%. There had been 20 clinical cases detected in the 7 years before the TCP started and two cases detected in the 10 years after TCP started. Most reactors and all clinical cases were born before the TCP started. Of 34 reactors necropsied, 25 (74%) were confirmed to have JD by histology or culture of tissues. The modal age of reactors and clinical cases was 5 and 6 years respectively. Six herds completed the program by achieving three successive negative whole herd tests, four herds dropped out and eight continued to test. There were 18 reactors detected at T1 and 33 reactors that were negative at T1 but detected at subsequent tests. The TCP was associated with a marked decline in clinical cases. The similar age distributions of clinical cases and reactors probably meant that testing detected animals for which clinical disease was imminent. Whether the measures used in the TCP were adequate to control the disease in beef herds could not be determined because of the long incubation period of the disease. The relatively high proportion of the reactors investigated that were confirmed as infected provided confidence that the test was continuing to operate at a high specificity. If all unconfirmed reactors were presumed to be uninfected, the minimum specificity of the ELISA was 99.83%. The sensitivity of the ELISA appeared to be very low because of the large number of reactors that were negative at T1 but positive at later tests.


Subtle alterations of the native zinc finger structures have dramatic effects on the nucleic acid chaperone activity of human immunodeficiency virus type 1 nucleocapsid protein.
The nucleocapsid protein (NC) of human immunodeficiency virus type 1 has two zinc fingers, each containing the invariant CCHC zinc-binding motif; however, the surrounding amino acid context is not identical in the two fingers. Recently, we demonstrated that zinc coordination is required when NC unfolds complex secondary structures in RNA and DNA minus- and plus-strand transfer intermediates; this property of NC reflects its nucleic acid chaperone activity. Here we have analyzed the chaperone activities of mutants having substitutions of alternative zinc-coordinating residues, i.e., CCHH or CCCC, for the wild-type CCHC motif. We also investigated the activities of mutants that retain the CCHC motifs but have mutations that exchange or duplicate the zinc fingers (mutants 1-1, 2-1, and 2-2); these changes affect amino acid context. Our results indicate that in general, for optimal activity in an assay that measures stimulation of minus-strand transfer and inhibition of nonspecific self-priming, the CCHC motif in the zinc fingers cannot be replaced by CCHH or CCCC and the amino acid context of the fingers must be conserved. Context changes also reduce the ability of NC to facilitate primer removal in plus-strand transfer. In addition, we found that the first finger is a more crucial determinant of nucleic acid chaperone activity than the second finger. Interestingly, comparison of the in vitro results with earlier in vivo replication data raises the possibility that NC may adopt multiple conformations that are responsible for different NC functions during virus replication.


Noxa: Role in Cancer Pathogenesis and Treatment.
The B-cell lymphoma 2 (Bcl-2) family proteins play an important role in regulating apoptosis, or programmed cell death, in response to several extracellular and intracellular signals. These proteins are either pro-apoptotic or anti-apoptotic. The pro-apoptotic Noxa is a Bcl-2 family protein that belongs to a subclass of BH3-only proteins. Noxa induces apoptosis via p53-dependent and/or p53-independent mechanisms. While Noxa may play a limited role in apoptosis, it is a crucial player that interacts with several proteins in the apoptosis pathway, highlighting its importance in the pathogenesis and treatment of certain cancers. In this review, we will elucidate the mechanisms by which Noxa regulates apoptosis and review the roles of chemotherapeutic drugs in relation to Noxa.


[Pruritometer 1: Portable measuring system for quantifying scratching as an objective measure of cholestatic pruritus].
Objective assessment of subjective symptoms such as pruritus always presents problems, which can often be resolved only indirectly. The objectification of pruritus was necessitated by a study on the efficacy of a serotonin antagonist used as treatment of cholestatic pruritus. In the present paper, a portable measuring system for the indirect objective assessment of pruritus via the quantification of scratching is described. A piezoelectric scratch-vibration sensor for attachment to the middle finger of the patient's dominant hand was developed. A sensor interface detects the scratching signals and generates pulses that are then summed in an adapted sports watch. The entire system-Pruritometer 1- is worn by the patient like a wrist watch, and is characterized by ease of handling. Acceptance by the patient is reported to be good. A statistically good correlation between measured (Pruritometer) and visually counted scratches was demonstrated. Pruritometer 2, which will enable scratch frequency and intensity distribution over time to be determined, is presently being developed.


Inhibition Mediated by Glycinergic and GABAergic Receptors on Excitatory Neurons in Mouse Superficial Dorsal Horn Is Location-Specific but Modified by Inflammation.
The superficial dorsal horn is the synaptic termination site for many peripheral sensory fibers of the somatosensory system. A wide range of sensory modalities are represented by these fibers, including pain, itch, and temperature. Because the involvement of local inhibition in the dorsal horn, specifically that mediated by the inhibitory amino acids GABA and glycine, is so important in signal processing, we investigated regional inhibitory control of excitatory interneurons under control conditions and peripheral inflammation-induced mechanical allodynia. We found that excitatory interneurons and projection neurons in lamina I and IIo are dominantly inhibited by GABA while those in lamina IIi and III are dominantly inhibited by glycine. This was true of identified neuronal subpopulations: neurokinin 1 receptor-expressing (NK1R+) neurons in lamina I were GABA-dominant while protein kinase C gamma-expressing (PKCγ+) neurons at the lamina IIi-III border were glycine-dominant. We found this pattern of synaptic inhibition to be consistent with the distribution of GABAergic and glycinergic neurons identified by immunohistochemistry. Following complete Freund's adjuvant injection into mouse hindpaw, the frequency of spontaneous excitatory synaptic activity increased and inhibitory synaptic activity decreased. Surprisingly, these changes were accompanied by an increase in GABA dominance in lamina IIi. Because this shift in inhibitory dominance was not accompanied by a change in the number of inhibitory synapses or the overall postsynaptic expression of glycine receptor α1 subunits, we propose that the dominance shift is due to glycine receptor modulation and the depressed function of glycine receptors is partially compensated by GABAergic inhibition.SIGNIFICANCE STATEMENT Pain associated with inflammation is a sensation we would all like to minimize. Persistent inflammation leads to cellular and molecular changes in the spinal cord dorsal horn, including diminished inhibition, which may be responsible for enhance excitability. Investigating inhibition in the dorsal horn following peripheral inflammation is essential for development of improved ways to control the associated pain. In this study, we have elucidated regional differences in inhibition of excitatory interneurons in mouse dorsal horn. We have also discovered that the dominating inhibitory neurotransmission within specific regions of dorsal horn switches following peripheral inflammation and the accompanying hypersensitivity to thermal and mechanical stimuli. Our novel findings contribute to a more complete understanding of inflammatory pain.


Aspects of black-fly control and entomology in the New World in relation to the Simulium problem in Nigeria.
A general account is given of insecticidal control of black-flies in North and Central America, and the problems are contrasted with those arising in the control of Simulium damnosum Theo. in Nigeria. Some recent biological observations on Canadian black-flies are described, and it is emphasized that these have materially contributed to successful control. It is pointed out that S. damnosum control is being practised in the absence of much fundamental biological knowledge of this pest. Entomological aspects of onchocerciasis in Mexico and Guatemala are discussed, and compared with S. damnosum and its relationship to onchocerciasis in Nigeria.


Acute arboviral infections in Guinea, West Africa, 2006.
Acute febrile illnesses comprise the majority of the human disease burden in sub-Saharan Africa. We hypothesized that arboviruses comprised a considerable proportion of undiagnosed febrile illnesses in Guinea and sought to determine the frequency of arboviral disease in two hospitals there. Using a standard case definition, 47 suspected cases were detected in approximately 4 months. Immunoglobulin M antibody capture enzyme-linked immunosorbent assays and plaque-reduction neutralization assays revealed that 63% (30/47) of patients were infected with arboviruses, including 11 West Nile, 2 yellow fever, 1 dengue, 8 chikungunya, and 5 Tahyna infections. Except for yellow fever, these are the first reported cases of human disease from these viruses in Guinea and the first reported cases of symptomatic Tahyna infection in Africa. These results strongly suggest that arboviruses circulate and are common causes of disease in Guinea. Improving surveillance and laboratory capacity for arbovirus diagnoses will be integral to understanding the burden posed by these agents in the region.


Use of a reference source in probability imaging.
We describe the relations between the statistics of the speckled image I(x) that is produced by an astronomical object at the focus of a telescope and the statistics of the point-source speckle pattern S(x) that is obtained under comparable conditions of turbulence. We show that the characteristic function (CF) of I(x) can be written as a central slice of a higher-order CF of S(x); as a consequence, probability density functions (PDF's) of I(x) and S(x) are related to one another by means of projections. An illustration, consisting of one-dimensional scans obtained with the European Southern Observatory's slit-scanning infrared specklograph, is made for real data. It is shown how the onefold and twofold PDF's of a double star can be synthesized from the twofold and the threefold PDF's of the reference source.


Acute myelogenous leukemia in patients receiving chlorambucil as long-term adjuvant chemotherapy for stage II breast cancer.
Thirteen consecutive stage II breast cancer patients were treated with long-term adjuvant chemotherapy using chlorambucil. At least three of these patients developed acute myelogenous leukemia (AML). All three patients (and possibly a fourth) who developed AML were postmenopausal, received continuous chlorambucil for greater than or equal to 4 years, had acute red cell anemia at the time of treatment, and had a wbc count in the range of 2700-7700/mm3. After the chlorambucil was discontinued, the wbc count began to slowly rise and the patient developed clinical AML. In all three patients, the diagnosis of AML was established by pathologists on the basis of bone marrow biopsy, aspirate, and peripheral smears. Each of these was subsequently reviewed by the hematologist who treated the patients for AML. Patients who have breast cancer (or any other solid tumor malignancy) are at risk to develop a second malignancy. However, an increasing number of reports are appearing suggesting more than just a casual relationship between leukemia and the use of alkylating agents. This may be related to the dose and duration of therapy with these agents.


Validation of New Methods of Using Simulated Whole-Body Movements as Implicit Indicators of Sound and Odor Preferences.
Would you get close to a stinky perfume bottle or to a loudspeaker producing noise? In this paper, we present two procedures that allowed us to assess the ability of auditory and olfactory cues to elicit automatic approach/avoidance reactions toward their sources. The procedures resulted from an adaptation of the Visual Approach/Avoidance by the Self Task (VAAST; Rougier et al., 2018), a task having the peculiarity of simulating approach/avoidance reactions by using visual feedback coming from the whole-body movements. In the auditory VAAST (Experiment 1), participants were instructed to move forward or backward from a loudspeaker that produced spoken words differentiated by their level of distortion and thus by their hedonic value. In the olfactory VAAST (Experiment 2), participants were asked to move forward or backward from a perfume bottle that delivered pleasant and unpleasant odors. We expected, consistent with the approach/avoidance compatibility effect, shorter latencies for approaching positive stimuli and avoiding negative stimuli. In both experiments, we found an effect of the quality of the emotional stimulus on forward actions of participants, with undistorted words and pleasant odors inducing faster forward movements compared with that for distorted words and unpleasant odors. Notably, our results further suggest that the VAAST can successfully be used with implicit instructions, i.e., without requiring participants to explicitly process the valence of the emotional stimulus (in Experiment 1) or even the emotional stimulus itself (in Experiment 2). The sensitivity of our procedures is analyzed and its potential in cross-modal and (contextualized) consumer research discussed.


Many-Body Effects Determine the Local Hydration Structure of Cs+ in Solution.
A systematic analysis of the hydration structure of Cs+ ions in solution is derived from simulations carried out using a series of molecular models built upon a hierarchy of approximate representations of many-body effects in ion-water interactions. It is found that a pairwise-additive model, commonly used in biomolecular simulations, provides poor agreement with experimental X-ray spectra, indicating an incorrect description of the underlying hydration structure. Although the agreement with experiment improves in simulations with a polarizable model, the predicted hydration structure is found to lack the correct sequence of water shells. Progressive inclusion of explicit many-body effects in the representation of Cs+-water interactions as well as accounting for nuclear quantum effects is shown to be necessary for quantitatively reproducing the experimental X-ray spectra. Besides emphasizing the importance of many-body effects, these results suggest that molecular models rigorously derived from many-body expansions hold promise for realistic simulations of aqueous solutions.


Mercury reduces avian reproductive success and imposes selection: an experimental study with adult- or lifetime-exposure in zebra finch.
Mercury is a global pollutant that biomagnifies in food webs, placing wildlife at risk of reduced reproductive fitness and survival. Songbirds are the most diverse branch of the avian evolutionary tree; many are suffering persistent and serious population declines and we know that songbirds are frequently exposed to mercury pollution. Our objective was to determine the effects of environmentally relevant doses of mercury on reproductive success of songbirds exposed throughout their lives or only as adults. The two modes of exposure simulated philopatric species versus dispersive species, and are particularly relevant because of the heightened mercury-sensitivity of developing nervous systems. We performed a dosing study with dietary methylmercury in a model songbird species, the zebra finch (Taeniopygia guttata), at doses from 0.3 - 2.4 parts per million. Birds were exposed to mercury either as adults only or throughout their lives. All doses of mercury reduced reproductive success, with the lowest dose reducing the number of independent offspring produced in one year by 16% and the highest dose, representing approximately half the lethal dose for this species, causing a 50% reduction. While mercury did not affect clutch size or survivorship, it had the most consistent effect on the proportion of chicks that fledged from the nest, regardless of mode of exposure. Among birds exposed as adults, mercury caused a steep increase in the latency to re-nest after loss of a clutch. Birds exposed for their entire lifetimes, which were necessarily the offspring of dosed parents, had up to 50% lower reproductive success than adult-exposed birds at low doses of methylmercury, but increased reproductive success at high doses, suggesting selection for mercury tolerance at the highest level of exposure. Our results indicate that mercury levels in prey items at contaminated sites pose a significant threat to populations of songbirds through reduced reproductive success.


Intake of milk, but not total dairy, yogurt, or cheese, is negatively associated with the clustering of cardiometabolic risk factors in adolescents.
Epidemiologic studies have reported an inverse association between dairy product consumption and cardiometabolic risk factors in adults, but this relation is relatively unexplored in adolescents. We hypothesized that a higher dairy product intake is associated with lower cardiometabolic risk factor clustering in adolescents. To test this hypothesis, a cross-sectional study was conducted with 494 adolescents aged 15 to 18 years from the Azorean Archipelago, Portugal. We measured fasting glucose, insulin, total cholesterol, high-density lipoprotein cholesterol, triglycerides, systolic blood pressure, body fat, and cardiorespiratory fitness. We also calculated homeostatic model assessment and total cholesterol/high-density lipoprotein cholesterol ratio. For each one of these variables, a z score was computed using age and sex. A cardiometabolic risk score (CMRS) was constructed by summing up the z scores of all individual risk factors. High risk was considered to exist when an individual had at least 1 SD from this score. Diet was evaluated using a food frequency questionnaire, and the intake of total dairy (included milk, yogurt, and cheese), milk, yogurt, and cheese was categorized as low (equal to or below the median of the total sample) or "appropriate" (above the median of the total sample).The association between dairy product intake and CMRS was evaluated using separate logistic regression, and the results were adjusted for confounders. Adolescents with high milk intake had lower CMRS, compared with those with low intake (10.6% vs 18.1%, P = .018). Adolescents with appropriate milk intake were less likely to have high CMRS than those with low milk intake (odds ratio, 0.531; 95% confidence interval, 0.302-0.931). No association was found between CMRS and total dairy, yogurt, and cheese intake. Only milk intake seems to be inversely related to CMRS in adolescents.


[Reduced risk of diabetes and cardiovascular disease after bariatric surgery].
The worldwide incidence of obesity, defined as a BMI ≥ 30 kg/m2, has more than doubled during the past four decades. Bariatric/metabolic surgery provides the largest and most sustainable degree of weight loss. This review briefly summarises the emerging randomised evidence of the superiority of these procedures over conventional treatment, in achieving glycaemic control and inducing remission in patients with type 2 diabetes as well as the observational evidence suggesting improvements in the long-term risks of cardiovascular outcomes and mortality.


'Keeping your brain active': the activities of people aged 50-65 years.
The paper aims to construct a baseline of knowledge about current activities, attitudes and motivations of a sample of people aged 50-65 years in relation to 'keeping one's brain active', with a particular focus on activities suggested in the literature and in popular parlance to have positive effects. An online survey of people aged 50-65 years concerning their activities and motivations in relation to 'keeping one's brain active' was conducted with a sample of people employed in Scotland and in two online discussion forums. The survey ascertained respondents' background demographic data, data on health and lifestyle factors, activities they engaged in and reasons for engagement, including any concerns about dementia and experience of dementia. The achieved sample of 402 responses was representative of the general population on most counts, although the sample included more better-educated people and more smokers. Dementia prevention was a motivating factor for 21% of the respondents. More women and more of those living alone reported this motivation. It was linked with experience of dementia and future fears of developing the condition. New 'brain-training' technologies were used by younger people in higher socio-economic groups, and dementia prevention was cited as a motivation. The findings indicate that dementia prevention motivates activities perceived to keep the brain active, despite there being a virtual absence of scientific evidence showing that the desired effects will follow. Given the existence of evidence suggesting that other activities, particularly physical exercise, may be more important and the possibility that stress itself may promote the development of dementia, further research is urgently needed.


The Temporal Relationship Between Faulty Gambling Cognitions and Gambling Severity in Young Adults.
Disordered gambling in young adults is hypothesized as being related to mistaken gambling-related cognitions. Few studies have examined the temporal order of this relationship using longitudinal data. The purpose of this study is to understand the directionality of the relationship between gambling cognitions and gambling severity in a longitudinal sample of young adults. Young adults (N = 578), initially aged 18-21 years, completed the Manitoba Longitudinal Survey of Young Adults at two time points approximately 2-3 years apart. Measures of beliefs about randomness related to gambling and gambling severity, as measured by the Problem Gambling Severity Index, were utilized. A cross-sectional relationship between gambling severity and gambling-related cognitions was observed with greater gambling severity being associated with increased endorsement of mistaken cognitions. Evidence for a bidirectional longitudinal relationship was observed with faulty gambling cognitions leading to later problematic gambling behaviors and vice versa when examining a total beliefs scale. When examining specific beliefs about randomness, initial gambling group membership predicted later endorsement of certain beliefs about randomness while initial belief ratings did not impact later gambling group membership. The results of this study suggest a bidirectional relationship between gambling severity and erroneous gambling-related cognitions. However, when examining specific beliefs about randomness, evidence was found for problem gambling behaviors leading to erroneous gambling beliefs. These findings suggest that prevention efforts targeting cognitions may not be as effective in impacting those not yet demonstrating disordered gambling behaviors.


Comparative effectiveness of autologous blood-derived products, shock-wave therapy and corticosteroids for treatment of plantar fasciitis: a network meta-analysis.
To compare the efficacy of autologous blood-derived products (ABPs), CSs and shock-wave (SW) therapy in the treatment of plantar fasciitis. Electronic databases were searched for studies that compared ABPs, CSs and SW therapy for the treatment of plantar fasciitis, published up to June 2014. The primary and secondary outcomes were reduction in visual analogue scale (VAS) score at 3 and 6 months and odds ratio of treatment success, respectively. Groups were compared by traditional pair-wise meta-analysis and by network meta-analysis. Seven randomized controlled trials and three quasi-experimental studies that included 604 patients were enrolled. Pair-wise meta-analysis indicated a trend favouring ABPs over CSs regarding VAS reduction at 3 months; this benefit was significant in a subgroup analysis of platelet-rich plasma (PRP) vs CSs. There were no significant between-group differences in VAS reduction at 6 months and in treatment success. Network meta-analysis showed that ABPs had the highest probability of being the best treatment at 3 months, but ABPs were slightly inferior to SW for VAS reduction at 6 months. Although SW therapy had the highest likelihood of treatment success, the between-group differences in probabilities were less remarkable than those for pain reduction at 3 and 6 months. ABPs, followed by CSs, were best in providing relief from pain at 3 months. SW therapy and ABPs had similar probabilities of providing pain relief at 6 months, and were better than CSs at that time. Subgroup analysis indicated that an ABP regimen consisting of platelet-rich plasma improves treatment efficacy.


The diagnosis of cor triatriatum sinistrum in children: a continuing dilemma.
Cor triatriatum (CT) is a rare congenital cardiac anomaly. The salient clinical, roentgenographic, electrocardiographic, echocardiographic, and hemodynamic findings are presented in two asymptomatic children and one with nonspecific dyspnea on exertion. Two male children had a classical form of cor triatriatum with normal physical and inconsequential roentgenographic and electrocardiographic findings. One of the male patients had surgery for a large atrial septal defect ostium secundum (ASD 2 degrees) and pulmonary hypertension in infancy. The female patient had CT with a communicating accessory chamber to right atrium and a rare patent foramen ovale. Her clinical findings confirmed an atrial level shunt. All patients had excision of the fibromuscular membrane from the right and left atrial transseptal approach with excellent results and with no recurrence during 2 to 4 year follow-up. We report the dilemma encountered in the clinical diagnosis of CT in children and the pivotal role played by echocardiography in the diagnosis of this anomaly.


Prenatal development of cranial base in normal Korean fetuses.
The cranial base is not only an end result of complex segmental growth of rostral end of axial skeleton but also has a tremendous impact on the development of the brain and facial structure. However, little is known about the method for the systematic analysis of the shape of the cranial base in the developing human fetus. We used roentgenograms of the cranial base and eviscerated bones for the assessment of the development of the cranial bony complex. The cranial base was removed from 64 normal human fetuses after 18-40 weeks of gestation. Roentgenograms were taken perpendicular to the cranial base. Major anatomical landmarks are defined as follows: the center of pituitary fossa of sphenoid bone (point S), the growth center of zygomatic bone, the anterior point of nasal septum, otic cartilage, and anterior and posterior growth centers of maxilla. The anterior cranial base angle, the middle cranial base angle, the posterior cranial base angle, the maxillary trapezoid area, the horizontal middle face area, and the occipital cranial base triangle area are defined from the landmarks, and the growth of each parameter was analyzed by gestational age. The proportional growth of the anterior, middle, and posterior cranial fossae could be assessed by the angles around the center of the pituitary fossa (point S) and by the anterior, middle, and posterior cranial base angles. The anterior cranial base angle was relatively constant during the fetal period at 107.4-112.5 degrees, whereas the middle cranial base angle gradually increased, and the posterior cranial base angle decreased. With increasing gestational age, the horizontal middle face area increased rapidly, in contrast to those of the maxillary trapezoid area, occipital cranial base triangle area, or foramen magnum area. The important keys in the structural development of the normal human cranial base are anterior, middle, and posterior cranial base angles. We could define the developmental pattern of human cranial base, which in turn provides a model of a standard growth pattern applicable to the study of the different malformations in the craniofacial structure.


Risk of incisional recurrence after midface and anterior skull base surgery in sinonasal malignancies.
We sought to determine the risk of tumor incisional recurrence in patients receiving surgery and postoperative radiation therapy for locally advanced sinonasal malignancies. Medical records for 70 patients newly diagnosed with nonmetastatic American Joint Committee on Cancer stage II to stage IV sinonasal malignancies between 1991 and 2003 were retrospectively reviewed. Patient demographics and tumor variables were recorded. All patients underwent upfront surgical resection with postoperative three-dimensional conformal proton beam radiotherapy. Recurrence and survival-related outcomes were recorded. Two patients with squamous cell carcinoma had pathologically confirmed tumor recurrence at the incision site. The actuarial risk of incisional recurrence for the entire group at 1 year was 3%. One of the two patients had a maxillary sinus tumor and developed isolated skin recurrence along the transfacial incision. The other patient with an ethmoid sinus tumor developed isolated dural recurrence along the craniotomy incision. Both patients underwent multiple courses of salvage surgery and radiation therapy. One was successfully salvaged locally but developed distant metastases and the other died of local recurrence. Tumor seeding following transfacial and craniotomy surgery can occur, especially for squamous cell carcinoma. Sound oncological surgical technique, even when utilizing these difficult surgical approaches, is important to minimize incisional recurrence.


Increased Vocalization of Rats in Response to Ultrasonic Playback as a Sign of Hypervigilance Following Fear Conditioning.
We investigated the effects of prior stress on rats' responses to 50-kHz (appetitive) and 22-kHz (aversive) ultrasonic playback. Rats were treated with 0, 1, 6 or 10 shocks (1 s, 1.0 mA each) and were exposed to playbacks the following day. Previous findings were confirmed: (i) rats moved faster during 50-kHz playback and slowed down after 22-kHz playback; (ii) they all approached the speaker, which was more pronounced during and following 50-kHz playback than 22-kHz playback; (iii) 50-kHz playback caused heart rate (HR) increase; 22-kHz playback caused HR decrease; (iv) the rats vocalized more often during and following 50-kHz playback than 22-kHz playback. The previous shock affected the rats such that singly-shocked rats showed lower HR throughout the experiment and a smaller HR response to 50-kHz playback compared to controls and other shocked groups. Interestingly, all pre-shocked rats showed higher locomotor activity during 50-kHz playback and a more significant decrease in activity following 22-kHz playback; they vocalized more often, their ultrasonic vocalizations (USV) were longer and at a higher frequency than those of the control animals. These last two observations could point to hypervigilance, a symptom of post-traumatic stress disorder (PTSD) in human patients. Increased vocalization may be a valuable measure of hypervigilance used for PTSD modeling.


Patterns of illness among individuals reporting high and low stress.
This paper reports the results of a prospective study of 428 adults, which was designed to explore the relationship between social stress and health. Individuals in the study were grouped into cohorts based on the number of stressful events experienced in a 12 month period, and the differences in the quantity and quality of health measures among the cohorts in the same time period explored. Individuals under stress experienced considerably more illness (assessed by symptoms reported on health diary and physician visits) than those not under stress. However the quality of these illness episodes were similar in both groups, as measured by the distribution of problems in organ system/body region and diagnostic categories. A second analysis, examining a subgroup of individuals who went from periods of low to high stress came to similar conclusions. The results suggest that the onset of stressful events is associated with a deterioration of health of a general nature, not associated with particular diseases of body systems.


The J domain of papovaviral large tumor antigen is required for synergistic interaction with the POU-domain protein Tst-1/Oct6/SCIP.
Large T antigens from polyomaviruses are multifunctional proteins with roles in transcriptional regulation, viral DNA replication, and cellular transformation. They have been shown to enhance the activity of various cellular transcription factors. In the case of the POU protein Tst-1/Oct6/SCIP, this enhancement involves a direct physical interaction between the POU domain of the transcription factor and the amino-terminal region of large T antigen. Here we have analyzed the structural requirements for synergistic interaction between the two proteins in greater detail. Tst-1/Oct6/SCIP and the related POU protein Brn-1 were both capable of direct physical interaction with large T antigen. Nevertheless, only Tst-1/Oct6/SCIP functioned synergistically with large T antigen. This differential behavior was due to differences in the amino-terminal regions of the proteins, as evident from chimeras between Tst-1/Oct6/SCIP and Brn-1. Synergy was specifically observed for constructs containing the amino-terminal region of Tst-1/Oct6/SCIP. Large T antigen, on the other hand, functioned synergistically with Tst-1/Oct6/SCIP only when the integrity of its J-domain-containing amino terminus was maintained. Mutations that disrupted the J domain concomitantly abolished the ability to enhance the function of Tst-1/Oct6/SCIP. The J domain of T antigen was also responsible for the physical interaction with Tst-1/Oct6/SCIP and could be replaced in this property by other J domains. Intriguingly, a heterologous J domain from a human DnaJ protein partially substituted for the amino terminus of T antigen even with regard to the synergistic enhancement of Tst-1/Oct6/SCIP function. Given the general role of J domains, we propose chaperone activity as the underlying mechanism for synergy between Tst-1/Oct6/SCIP and large T antigens.


A review of paroxysmal sympathetic hyperactivity after acquired brain injury.
Severe excessive autonomic overactivity occurs in a subgroup of people surviving acquired brain injury, the majority of whom show paroxysmal sympathetic and motor overactivity. Delayed recognition of paroxysmal sympathetic hyperactivity (PSH) after brain injury may increase morbidity and long-term disability. Despite its significant clinical impact, the scientific literature on this syndrome is confusing; there is no consensus on nomenclature, etiological information for diagnoses preceding the condition is poorly understood, and the evidence base underpinning our knowledge of the pathophysiology and management strategies is largely anecdotal. This systematic literature review identified 2 separate categories of paroxysmal autonomic overactivity, 1 characterized by relatively pure sympathetic overactivity and another group of disorders with mixed parasympathetic/sympathetic features. The PSH group comprised 349 reported cases, with 79.4% resulting from traumatic brain injury (TBI), 9.7% from hypoxia, and 5.4% from cerebrovascular accident. Although TBI is the dominant causative etiology, there was some suggestion that the true incidence of the condition is highest following cerebral hypoxia. In total, 31 different terms were identified for the condition. Although the most common term in the literature was dysautonomia, the consistency of sympathetic clinical features suggests that a more specific term should be used. The findings of this review suggest that PSH be adopted as a more clinically relevant and appropriate term. The review highlights major problems regarding conceptual definitions, diagnostic criteria, and nomenclature. Consensus on these issues is recommended as an essential basis for further research in the area.


Rate-induced tipping in complex high-dimensional ecological networks.
In an ecosystem, environmental changes as a result of natural and human processes can cause some key parameters of the system to change with time. Depending on how fast such a parameter changes, a tipping point can occur. Existing works on rate-induced tipping, or R-tipping, offered a theoretical way to study this phenomenon but from a local dynamical point of view, revealing, e.g., the existence of a critical rate for some specific initial condition above which a tipping point will occur. As ecosystems are subject to constant disturbances and can drift away from their equilibrium point, it is necessary to study R-tipping from a global perspective in terms of the initial conditions in the entire relevant phase space region. In particular, we introduce the notion of the probability of R-tipping defined for initial conditions taken from the whole relevant phase space. Using a number of real-world, complex mutualistic networks as a paradigm, we find a scaling law between this probability and the rate of parameter change and provide a geometric theory to explain the law. The real-world implication is that even a slow parameter change can lead to a system collapse with catastrophic consequences. In fact, to mitigate the environmental changes by merely slowing down the parameter drift may not always be effective: Only when the rate of parameter change is reduced to practically zero would the tipping be avoided. Our global dynamics approach offers a more complete and physically meaningful way to understand the important phenomenon of R-tipping.


Novel SPECT Technologies and Approaches in Cardiac Imaging.
Recent novel approaches in myocardial perfusion single photon emission CT (SPECT) have been facilitated by new dedicated high-efficiency hardware with solid-state detectors and optimized collimators. New protocols include very low-dose (1 mSv) stress-only, two-position imaging to mitigate attenuation artifacts, and simultaneous dual-isotope imaging. Attenuation correction can be performed by specialized low-dose systems or by previously obtained CT coronary calcium scans. Hybrid protocols using CT angiography have been proposed. Image quality improvements have been demonstrated by novel reconstructions and motion correction. Fast SPECT acquisition facilitates dynamic flow and early function measurements. Image processing algorithms have become automated with virtually unsupervised extraction of quantitative imaging variables. This automation facilitates integration with clinical variables derived by machine learning to predict patient outcome or diagnosis. In this review, we describe new imaging protocols made possible by the new hardware developments. We also discuss several novel software approaches for the quantification and interpretation of myocardial perfusion SPECT scans.


Scattering amplitudes and static atomic correction factors for the composition-sensitive 002 reflection in sphalerite ternary III-V and II-VI semiconductors.
Modified atomic scattering amplitudes (MASAs), taking into account the redistribution of charge due to bonds, and the respective correction factors considering the effect of static atomic displacements were computed for the chemically sensitive 002 reflection for ternary III-V and II-VI semiconductors. MASAs were derived from computations within the density functional theory formalism. Binary eight-atom unit cells were strained according to each strain state s (thin, intermediate, thick and fully relaxed electron microscopic specimen) and each concentration (x = 0, …, 1 in 0.01 steps), where the lattice parameters for composition x in strain state s were calculated using continuum elasticity theory. The concentration dependence was derived by computing MASAs for each of these binary cells. Correction factors for static atomic displacements were computed from relaxed atom positions by generating 50 × 50 × 50 supercells using the lattice parameter of the eight-atom unit cells. Atoms were randomly distributed according to the required composition. Polynomials were fitted to the composition dependence of the MASAs and the correction factors for the different strain states. Fit parameters are given in the paper.


Hyperlactatemia during cardiopulmonary bypass: risk factors and impact on surgical results with a focus on the long-term outcome.
Lactate, a product of anaerobic metabolism, is a biomarker and indicator for tissue hypoperfusion and oxygen debt. An elevated blood lactate level has been associated with poor outcome in many clinical conditions, including cardiac surgery. Nevertheless, debate exists regarding which blood lactate concentration is most indicative of poor outcomes. We evaluate the impact of hyperlactatemia, defined as a peak arterial blood concentration ⩾2.0 mmol/L during cardiopulmonary bypass, on surgical results with a focus on long-term outcome. We reviewed 1,099 consecutive adult patients who underwent cardiac surgery on pump. The patients were divided into two groups based on the presence or not of hyperlactatemia. Pre- and intraoperative risk factors for hyperlactatemia were identified, and the postoperative outcome of patients with or without hyperlactatemia was compared. Hyperlactatemia was present in 372 patients (33.8%). Factors independently associated with hyperlactatemia were urgent/emergency procedure, cardiopulmonary bypass duration and aortic cross-clamp time. Patients with hyperlactatemia had significantly higher rate of prolonged mechanical ventilation time, in-hospital stay and requirement of inotropes and intra-aortic balloon pump support (p < 0.001). Operative (30-day) mortality was higher in the group of patients with hyperlactatemia (7.8% vs. 1.1%; p < 0.001). Kaplan-Meier curve showed worse long-term survival (mean follow-up: 4.02 ± 1.58 years) in patients with hyperlactatemia. Hyperlactatemia during cardiopulmonary bypass has a significant association with postoperative morbidity and mortality. Correction of risk factors for hyperlactatemia, together with prompt detection and correction of this condition, may control complications and improve outcome.


Autonomously-triggered microfluidic cooling using thermo-responsive hydrogels.
We present autonomously-triggered on-chip microfluidic cooling devices that utilize thermo-responsive hydrogels to adapt to local environmental temperatures. An external rotating magnetic stirrer couples with an in situ fabricated nickel impeller in these centrifugal-based microfluidic cooling devices to recirculate cooler water. Temperature-responsive hydrogels, which exhibit volumetric expansion and contraction, are integrated at the axle of the impeller. In this design, the hydrogels behave similar to an automotive clutch, to autonomously control the impeller's rotation as a function of the local environmental temperature. Therefore, the hydrogels act as both sensors and actuators and help take away the necessity for additional temperature sensing, feedback, and/or control units here. Cooling devices capable of on-chip thermal management at multiple predetermined onset operation points are realized by changes to the composition of hydrogel to alter its lowest critical solution temperature (LCST). Furthermore, the effect of magnetic stirrer frequency on the fluid cooling and flowrates for different two-blade nickel impeller designs are presented.


Correction of sample absorption of radioactivity.
In the method presented here for the correction of sample absorption of C(14) activity, the only requirement is the availability of any C(14)-labeled compound of sufficiently high specific activity to permit addition, in negligible mass, of a number of counts equal to or greater than that in unknown samples and with solubility characteristics that exclude preferential layering during drying of samples. The principle may be applied to liquid scintillation counting. Absorption curves are dispensed with, and the weights of the assayed samples need not be determined.


Nicotinic aspects of the discriminative stimulus effects of arecoline.
Despite the evidence that the muscarinic agonist arecoline is a drug of abuse throughout Southeast Asia, its stimulus characteristics have not been well studied. The goal of this work was to understand more about the mediation of discriminative stimulus effects of arecoline. Arecoline (1.0 mg/kg s.c.) was trained as a discriminative stimulus in a group of eight rats. The ability of various cholinergic agonists and antagonists to mimic or antagonize the discriminative stimulus effects of arecoline and to modify its rate-suppressing effects was evaluated. A muscarinic antagonist, but neither of two nicotinic antagonists, was able to modify the discriminative stimulus effects of arecoline, suggesting a predominant muscarinic basis of arecoline's discriminative stimulus effects in this assay. However, both nicotine itself and two nicotine agonists with selective affinity for the α4β2* receptor (ispronicline and metanicotine) produced full arecoline-like discriminative stimulus effects in these rats. The discriminative stimulus effects of the selective nicotine agonists were blocked by both the general nicotine antagonist mecamylamine and by the selective α4β2* antagonist, dihydro-beta-erythroidine (DHβE). Surprisingly, only DHβE antagonized the rate-suppressing effects of the selective nicotine agonists. These data indicate a selective α4β2* nicotine receptor component to the behavioral effects of arecoline. Although the nicotinic aspects of arecoline's behavior effects could suggest that abuse of arecoline-containing material (e.g. betel nut chewing) is mediated through nicotinic rather than muscarinic actions, further research, specifically on the reinforcing effects of arecoline, is necessary before this conclusion can be supported.


Evaluation of marine bacteroidetes-specific primers for microbial diversity and dynamics studies.
Assumptions on the matching specificity of group-specific bacterial primers may bias the interpretation of environmental microbial studies. As available sequence data continue growing, the performance of primers and probes needs to be reevaluated. Here, we present an evaluation of several commonly used and one newly designed Bacteroidetes-specific primer (CF418). First, we revised the in silico primer coverage and specificity with the current SILVA and RDP databases. We found minor differences with previous studies, which could be explained by the chosen databases, taxonomies, and matching criteria. We selected eight commonly used Bacteroidetes primers and tested them with a collection of assorted marine bacterial isolates. We also used the denaturing gradient gel electrophoresis (DGGE) approach in environmental samples to evaluate their ability to yield clear and diverse band patterns corresponding to Bacteroidetes phylotypes. Among the primers tested, CF968R did not provide satisfactory results in DGGE, although it exhibited the highest in silico coverage for Flavobacteria. Primers CFB560 and CFB555 presented undesirable features, such as requiring nested protocols or presence of degeneracies. Finally, the new primer CF418 and primer CF319a were used to explore the Bacteroidetes dynamics throughout a 1-year cycle in Mediterranean coastal waters (Blanes Bay Microbial Observatory). Both primers provided clear and diverse banding patterns, but the low specificity of CF319a was evidenced by 83.3 % of the bands sequenced corresponding to nontarget taxa. The satisfactory DGGE banding patterns and the wide diversity of sequences retrieved from DGGE bands with primer CF418 prove it to be a valuable alternative for the study of Bacteroidetes communities, recovering a wide range of phylotypes within the group.


Cardiopulmonary Resuscitation in Adults and Children With Mechanical Circulatory Support: A Scientific Statement From the American Heart Association.
Cardiac arrest in patients on mechanical support is a new phenomenon brought about by the increased use of this therapy in patients with end-stage heart failure. This American Heart Association scientific statement highlights the recognition and treatment of cardiovascular collapse or cardiopulmonary arrest in an adult or pediatric patient who has a ventricular assist device or total artificial heart. Specific, expert consensus recommendations are provided for the role of external chest compressions in such patients.


Intra-Operative Bioprinting of Hard, Soft, and Hard/Soft Composite Tissues for Craniomaxillofacial Reconstruction.
Reconstruction of complex craniomaxillofacial (CMF) defects is challenging due to the highly organized layering of multiple tissue types. Such compartmentalization necessitates the precise and effective use of cells and other biologics to recapitulate the native tissue anatomy. In this study, intra-operative bioprinting (IOB) of different CMF tissues, including bone, skin, and composite (hard/soft) tissues, is demonstrated directly on rats in a surgical setting. A novel extrudable osteogenic hard tissue ink is introduced, which induced substantial bone regeneration, with ≈80% bone coverage area of calvarial defects in 6 weeks. Using droplet-based bioprinting, the soft tissue ink accelerated the reconstruction of full-thickness skin defects and facilitated up to 60% wound closure in 6 days. Most importantly, the use of a hybrid IOB approach is unveiled to reconstitute hard/soft composite tissues in a stratified arrangement with controlled spatial bioink deposition conforming the shape of a new composite defect model, which resulted in ≈80% skin wound closure in 10 days and 50% bone coverage area at Week 6. The presented approach will be absolutely unique in the clinical realm of CMF defects and will have a significant impact on translating bioprinting technologies into the clinic in the future.


The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy.
Mast cells (MCs) are critical components of the innate immune system and important for host defense, allergy, autoimmunity, tissue regeneration and tumor progression. Dysregulated MC development leads to systemic mastocytosis (SM), a clinically variable but often devastating family of hematologic disorders. Here we report that induced expression of Lin28, a heterochronic gene and pluripotency factor implicated in driving a fetal hematopoietic program, caused MC accumulation in adult mice in target organs such as the skin and peritoneal cavity. In vitro assays revealed a skewing of myeloid commitment in LIN28B-expressing hematopoietic progenitors, with increased levels of LIN28B in common myeloid and basophil-MC progenitors altering gene expression patterns to favor cell fate choices that enhanced MC specification. In addition, LIN28B-induced MCs appeared phenotypically and functionally immature, and in vitro assays suggested a slowing of MC terminal differentiation in the context of LIN28B upregulation. Finally, interrogation of human MC leukemia samples revealed upregulation of LIN28B in abnormal MCs from patients with SM. This work identifies Lin28 as a novel regulator of innate immune function and a new protein of interest in MC disease.


Omics and therapy - a basis for precision medicine.
A founding premise of the human genome project was that knowledge of the spectrum of abnormalities that comprise cancers and other human diseases would lead to improved disease management by identifying molecular abnormalities that could guide disease detection and diagnosis, suggest new therapeutic strategies and be developed as markers to predict response to therapy. This project led to elucidation of a reference normal human genome sequence and normal polymorphisms therein against which sequences from diseased tissues can be compared to enable identification of causal abnormalities. It also stimulated development of an array of computational tools for genomic analysis and catalyzed public and private sector development of revolutionary tools for genome analysis that transformed analysis of whole genomes from an enterprise that required international teams and hundreds of millions of dollars to a process that can be carried out in core facilities for only a few thousand dollars per sample. Indeed, the $1000 genome is nearly upon us. Applications of these technologies to human cancers in international cancer genome projects are now revealing the spectra of abnormalities that comprise thousands of individual cancers. Analyses of these data are leading to the promised improvements in disease management. We review several aspects of cancer genomics with emphasis on aspects that are relevant to improving cancer therapy.


Ecological validity of cost-effectiveness models of universal HPV vaccination: A systematic literature review.
The protective (herd) effect of the selective vaccination of pubertal girls against human papillomavirus (HPV) implies a high probability that one of the two partners involved in intercourse is immunised, hence preventing the other from this sexually transmitted infection. The dynamic transmission models used to inform immunisation policy should include consideration of sexual behaviours and population mixing in order to demonstrate an ecological validity, whereby the scenarios modelled remain faithful to the real-life social and cultural context. The primary aim of this review is to test the ecological validity of the universal HPV vaccination cost-effectiveness modelling available in the published literature. The research protocol related to this systematic review has been registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42016034145). Eight published economic evaluations were reviewed. None of the studies showed due consideration of the complexities of human sexual behaviour and the impact this may have on the transmission of HPV. Our findings indicate that all the included models might be affected by a different degree of ecological bias, which implies an inability to reflect the natural demographic and behavioural trends in their outcomes and, consequently, to accurately inform public healthcare policy. In particular, ecological bias have the effect to over-estimate the preference-based outcomes of selective immunisation. A relatively small (15-20%) over-estimation of quality-adjusted life years (QALYs) gained with selective immunisation programmes could induce a significant error in the estimate of cost-effectiveness of universal immunisation, by inflating its incremental cost effectiveness ratio (ICER) beyond the acceptability threshold. The results modelled here demonstrate the limitations of the cost-effectiveness studies for HPV vaccination, and highlight the concern that public healthcare policy might have been built upon incomplete studies.


Myosin 5b loss of function leads to defects in polarized signaling: implication for microvillus inclusion disease pathogenesis and treatment.
Microvillus inclusion disease (MVID) is an autosomal recessive condition resulting in intractable secretory diarrhea in newborns due to loss-of-function mutations in myosin Vb (Myo5b). Previous work suggested that the apical recycling endosomal (ARE) compartment is the primary location for phosphoinositide-dependent protein kinase 1 (PDK1) signaling. Because the ARE is disrupted in MVID, we tested the hypothesis that polarized signaling is affected by Myo5b dysfunction. Subcellular distribution of PDK1 was analyzed in human enterocytes from MVID/control patients by immunocytochemistry. Using Myo5b knockdown (kd) in Caco-2BBe cells, we studied phosphorylated kinases downstream of PDK1, electrophysiological parameters, and net water flux. PDK1 was aberrantly localized in human MVID enterocytes and Myo5b-deficient Caco-2BBe cells. Two PDK1 target kinases were differentially affected: phosphorylated atypical protein kinase C (aPKC) increased fivefold and phosohoprotein kinase B slightly decreased compared with control. PDK1 redistributed to a soluble (cytosolic) fraction and copurified with basolateral endosomes in Myo5b kd. Myo5b kd cells showed a decrease in net water absorption that could be reverted with PDK1 inhibitors. We conclude that, in addition to altered apical expression of ion transporters, depolarization of PDK1 in MVID enterocytes may lead to aberrant activation of downstream kinases such as aPKC. The findings in this work suggest that PDK1-dependent signaling may provide a therapeutic target for treating MVID.


Formation and Effects of Upstream DNA-RNA Base Pairing in Telomerase.
Telomere elongation by telomerase consists of two types of translocation: duplex translocation during each repeat synthesis and template translocation at the end of repeat synthesis. Our replica exchange molecular dynamics simulations show that in addition to the Watson-Crick interactions in the active site, templating RNA can also form base pairs with the upstream regions of DNA, mostly with the second upstream DNA repeat with respect to the 3'-end. At the end of the repeat synthesis, dG10-P442 and dG11-N446 hydrogen bonds form. Then, active-site base pairs dissociate one by one, and the RNA bases reanneal with the complementary base on the upstream DNA repeat. For each dissociating base pair a new one forms, thus conserving the number of base pairs during template translocation.


MiR-15a/b promote adipogenesis in porcine pre-adipocyte via repressing FoxO1.
Diabetes and many other metabolism syndromes are closely related to obesity. To reveal the underlying mechanism of fat deposition, an increasing number of studies are focusing on the functions of miRNAs during adipocytes development. Previous studies have proved that miR-15a/b play important roles in multiple physiological processes; however, their functions during adipogenesis remain unclear. To reveal this, we detected the expression profiles of miR-15a/b during adipogenesis in porcine pre-adipocyte, and found that their expression levels increased in the early stage of adipocyte differentiation and dropped after day 4. Moreover, over-expression of miR-15a/b in porcine pre-adipocytes promoted adipocyte differentiation and lipid accumulation. Target genes of miR-15a/b were predicted and examined, which revealed that Forkhead box protein O1 (FoxO1) is the target gene of miR-15a/b. The inhibition of FoxO1 expression level caused by miR-15a/b over-expression had a positive effect on adipogenesis. Thus, we conclude that miR-15a/b promote adipogenesis in porcine pre-adipocyte via repressing FoxO1.


Effects of withdrawal from long-term diphenylhydantoin treatment on audiogenic and maximal electroshock-induced seizures in rats.
Rats withdrawal from long-term diphenylhydantoin treatment (DPH) were tested for their sensibility to convulsant stimuli. Animals were more sensitive to convulsions elicited by maximal electroshock and sound, respectively, at 48 and 72 h after drug removal. These results suggest that long-term DPH treatment might develop a central nervous system supersensitivity state.


Avian psychology and communication.
The evolution of animal communication is a complex issue and one that attracts much research and debate. 'Receiver psychology' has been highlighted as a potential selective force, and we review how avian psychological processes and biases can influence the evolution and design of signals as well as the progress that has been made in testing these ideas in behavioural studies. Interestingly, although birds are a focal group for experimental psychologists and behavioural ecologists alike, the integration of theoretical ideas from psychology into studies of communication has been relatively slow. However, recent operant experiments are starting to address how birds perceive and respond to complex natural signals in an attempt to answer evolutionary problems in communication. This review outlines how a psychological approach to understanding communication is useful, and we hope that it stimulates further research addressing the role of psychological mechanisms in signal evolution.


[Diagnostic and therapeutic puncture sonography of the prostate].
Endosonography of the prostate in combination with ultrasonically guided biopsy is indicated to detect subclinical cancer and to determine local tumour extent. It is easy to puncture any area of interest in the prostate under accurate ultrasound guidance. The percutaneous, transperineal and ultrasonically guided 125iodine implantation enables, as an alternative procedure to radical surgery, good local tumour control in prostatic carcinoma. Ultrasonically guided puncture technique and implantation procedure are described and preliminary clinical results are presented.


Drug-resistant dihydrofolate reductases: generation, expression and therapeutic application.
Although methotrexate (MTX) and other antifolates are effective antitumor chemotherapeutic agents, their utility is limited by toxicity for normal hematopoietic and gastrointestinal tissues. Gene transfer and expression of variant dihydrofolate reductase (DHFR) which confers resistance to MTX could protect these tissues from MTX toxicity. Drug-resistant DHFR variants have been cloned from a number of sources and have also been generated by in vitro mutagenesis. A procedure is described which we used for saturation mutagenesis of the murine DHFR coding sequence at codon positions 22 and 31, resulting in a number of mutant DHFR genes encoding enzyme exhibiting a favorable combination of drug resistance with retention of catalytic activity. To evaluate the in vivo effectiveness of variant DHFR expression, we established several lines of FVB/N transgenic mice which expressed drug-resistant DHFR activity and which exhibited varying degrees of increased resistance to MTX administration. Transplantation of bone marrow from drug-resistant DHFR transgenic animals into normal, irradiated recipients conferred resistance to MTX at surprisingly high levels, indicating that drug-resistant DHFR expression in hematopoietic cells also protects gastrointestinal tissues from MTX toxicity. These studies have thus provided encouraging results with respect to the potential of drug-resistant DHFR gene transfer for improved use of MTX as an antitumor agent and for its use as an in vivo selective agent.


Recent Application of Advanced MR Imaging to Predict Pseudoprogression in High-grade Glioma Patients.
Pseudoprogression is regarded as a subacute form of treatment-related change with a reported incidence of 20-30%, occurring predominantly within the first three months after the completion of concurrent chemoradiotherapy (CCRT) in glioblastoma multiforme (GBM) patients. Occurrence of progressive lesions on conventional contrast-enhanced MR imaging may also accompany clinical deterioration, posing considerable diagnostic challenges to clinicians and radiologists. False interpretation of treatment-related change as true progression may lead to the cessation of effective first-line therapy (i.e., adjuvant temozolomide) and unnecessary surgery. Increasing awareness of the diagnostic challenge of the phenomenon has underscored the need for better imaging techniques that may aid in differentiating the treatment-related change from true progression. In this review, we discuss the recent applications of advanced MR imaging such as diffusion-weighted and perfusion-weighted imaging in the evaluation of treatment response in high-grade glioma patients and highlight their potential role in differentiating pseudoprogression from true progression.