Molecular detection of Theileria spp. and Babesia spp. in sheep and ixodid ticks from the northeast of Iran.
Theilerioses and babesioses are important diseases in Iranian sheep. The present study was undertaken to identify and classify/specify Theileria spp. and Babesia spp. in sheep and vector ticks. Investigation was carried out from 2009 to 2011 in the Khorasan Razavi Province, Iran. In total, 302 sheep originating from 60 different flocks were clinically examined and their blood collected. In addition, from the same flocks, ixodid ticks were sampled. Stained blood smears were microscopically examined for the presence of Theileria and Babesia organisms, and a semi-nested PCR was used for subsequent molecular specification. From the ticks, salivary glands and uterus were isolated and subsequently analyzed by semi-nested PCR. Piroplasm organisms were observed in 29% of the blood smears with low parasitemia, whereas 65% of the blood samples yielded positive PCR findings. The presence of Theileria ovis (55.6%), Theileria lestoquardi, and mixed infection with Theileria spp. and Babesia ovis were detected by semi-nested PCR in 0.3%, 5.6%, and 0.99%, respectively. In total, 429 ixodid ticks were collected from different areas of the province. The most prevalent ticks were Rhipicephalus turanicus (n = 376; 87.6% of the total), followed by Hyalomma marginatum turanicum (n = 30; 7.0%), Dermacentor raskemensis (n = 12; 2.8%), Hyalomma anatolicum anatolicum (n = 7; 1.6%), Dermacentor marginatus (n = 2; 0.5%), Rhipicephalus bursa (n = 1; 0.2%), and Haemaphysalis sp. (n = 1; 0.2%). Of the positive R. turanicus samples, 5 (5.7%) were infected with T. ovis and 2 (2.9%) with T. lestoquardi. Neither Babesia ovis nor Babesia motasi infection was detected in salivary glands or uterine samples of the ticks. The results also suggest that R. turanicus could be the vector responsible for transmission of the 2 Theileria species.


Recombinant human soluble thrombomodulin and mortality in sepsis-induced disseminated intravascular coagulation. A multicentre retrospective study.
Recombinant human soluble thrombomodulin (rhTM) is a novel class of anticoagulants for treating disseminated intravascular coagulation (DIC). Although rhTM is widely used in clinical settings throughout Japan, there is limited clinical evidence supporting the use of rhTM in patients with sepsis-induced DIC. Furthermore, rhTM is not approved for DIC treatment in other countries. This study aimed to clarify the survival benefits of rhTM administration in critically ill patients. Data from 3,195 consecutive adult patients who were admitted to 42 intensive care units for the treatment of severe sepsis or septic shock between January 2011 and December 2013 were retrospectively analysed, and 1,784 patients were diagnosed with DIC based on the scoring algorithm from the Japanese Association for Acute Medicine DIC (n = 645, rhTM group; n = 1,139, control group). Propensity score matching created 452 matched pairs, and logistic regression analysis revealed a significant association between rhTM administration and lower in-hospital all-cause mortality in the propensity score-matched groups (odds ratio, 0.757; 95 % confidence interval, 0.574-0.999, p = 0.049). Inverse probability of treatment weighted and quintile-stratified analyses also revealed significant associations between rhTM administration and lower in-hospital all-cause mortality. Survival time in the propensity score-matched rhTM group was significantly longer than that in the propensity score-matched control group (hazard ratio, 0.781; 95 % confidence interval, 0.624-0.977, p = 0.03). Bleeding complications were not more frequent in the rhTM groups. In conclusion, this study demonstrated that rhTM administration is associated with reduced in-hospital all-cause mortality among patients with sepsis-induced DIC.


Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice.
CREBBP is targeted by inactivating mutations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Here, we provide evidence from transgenic mouse models that Crebbp deletion results in deficits in B-cell development and can cooperate with Bcl2 overexpression to promote B-cell lymphoma. Through transcriptional and epigenetic profiling of these B cells, we found that Crebbp inactivation was associated with broad transcriptional alterations, but no changes in the patterns of histone acetylation at the proximal regulatory regions of these genes. However, B cells with Crebbp inactivation showed high expression of Myc and patterns of altered histone acetylation that were localized to intragenic regions, enriched for Myc DNA binding motifs, and showed Myc binding. Through the analysis of CREBBP mutations from a large cohort of primary human FL and DLBCL, we show a significant difference in the spectrum of CREBBP mutations in these 2 diseases, with higher frequencies of nonsense/frameshift mutations in DLBCL compared with FL. Together, our data therefore provide important links between Crebbp inactivation and Bcl2 dependence and show a role for Crebbp inactivation in the induction of Myc expression. We suggest this may parallel the role of CREBBP frameshift/nonsense mutations in DLBCL that result in loss of the protein, but may contrast the role of missense mutations in the lysine acetyltransferase domain that are more frequently observed in FL and yield an inactive protein.


Understanding the mechanisms of antitropical divergence in the seabird White-faced Storm-petrel (Procellariiformes: Pelagodroma marina) using a multilocus approach.
Analytical methods that apply coalescent theory to multilocus data have improved inferences of demographic parameters that are critical to understanding population divergence and speciation. In particular, at the early stages of speciation, it is important to implement models that accommodate conflicting gene trees, and benefit from the presence of shared polymorphisms. Here, we employ eleven nuclear loci and the mitochondrial control region to investigate the phylogeography and historical demography of the pelagic seabird White-faced Storm-petrel (Pelagodroma marina) by sampling subspecies across its antitropical distribution. Groups are all highly differentiated: global mitochondrial ΦST = 0.89 (P < 0.01) and global nuclear ΦST varies between 0.22 and 0.83 (all P < 0.01). The complete lineage sorting of the mitochondrial locus between hemispheres is corroborated by approximately half of the nuclear genealogies, suggesting a long-term antitropical divergence in isolation. Coalescent-based estimates of demographic parameters suggest that hemispheric divergence of P. marina occurred approximately 840 000 ya (95% HPD 582 000-1 170 000), in the absence of gene flow, and divergence within the Southern Hemisphere occurred 190 000 ya (95% HPD 96 000-600 000), both probably associated with the profound palaeo-oceanographic changes of the Pleistocene. A fledgling sampled in St Helena (tropical South Atlantic) suggests recent colonization from the Northern Hemisphere. Despite the great potential for long-distance dispersal, P. marina antitropical groups have been evolving as independent, allopatric lineages, and divergence is probably maintained by philopatry coupled with asynchronous reproductive phenology and local adaptation.


To notify or not to notify: decision aid for policy makers on whether to make an infectious disease mandatorily notifiable.
Mandatory notification can be a useful tool to support infectious disease prevention and control. Guidelines are needed to help policymakers decide whether mandatory notification of an infectious disease is appropriate. We developed a decision aid, based on a range of criteria previously used in the Netherlands or in other regions to help decide whether to make a disease notifiable. Criteria were categorised as being effective, feasible and necessary with regard to the relevance of mandatory notification. Expert panels piloted the decision aid. Here we illustrate its use for three diseases (Vibrio vulnificus infection, chronic Q fever and dengue fever) for which mandatory notification was requested. For dengue fever, the expert panel advised mandatory notification; for V. vulnificus infection and chronic Q fever, the expert panel concluded that mandatory notification was not (yet) justified. Use of the decision aid led to a structured, transparent decision making process and a thorough assessment of the advantages and disadvantages of mandatory notification of these diseases. It also helped identify knowledge gaps that required further research before a decision could be made. We therefore recommend use of this aid for public health policy making.


Biomarker-guided targeted and immunotherapies in malignant pleural mesothelioma.
Malignant pleural mesothelioma (MPM) is a lethal thoracic malignancy whose incidence is still increasing worldwide. MPM is characterized by frequent inactivation of tumor-suppressor genes (TSGs), e.g., the homozygous deletion of CDKN2A/2B and various genetic alterations that inactivate BAP1, NF2, LATS1/2, and TP53. The leading cause for the poor prognosis of patients with MPM is the lack of effective treatment options, with conventional chemotherapy being the standard of care in the clinic, which has remained unchanged for almost 20 years. Precision oncology, a burgeoning effort to provide precise cancer treatment tailored to unique molecular changes in individual patients, has made tremendous progress in the last decade in several cancers, but not in MPM. Recent studies indicate a high degree of tumor heterogeneity in MPM and the importance to optimize histological and molecular classifications for improved treatment. In this review, we provide an up-to-date overview of recent advances in MPM by focusing on new stratifications of tumor subgroups, specific vulnerabilities associated with functional loss of TSGs and other biomarkers, and potential clinical implications. The molecularly based subdivisions not only deepen our understanding of MPM pathobiology, but more importantly, they may raise unprecedented new hopes for personalized treatment of MPM patients with biomarker-guided targeted and immunotherapies.


Variability of physiological brain perfusion in healthy subjects - A systematic review of modifiers. Considerations for multi-center ASL studies.
Quantitative measurements of brain perfusion are influenced by perfusion-modifiers. Standardization of measurement conditions and correction for important modifiers is essential to improve accuracy and to facilitate the interpretation of perfusion-derived parameters. An extensive literature search was carried out for factors influencing quantitative measurements of perfusion in the human brain unrelated to medication use. A total of 58 perfusion modifiers were categorized into four groups. Several factors (e.g., caffeine, aging, and blood gases) were found to induce a considerable effect on brain perfusion that was consistent across different studies; for other factors, the modifying effect was found to be debatable, due to contradictory results or lack of evidence. Using the results of this review, we propose a standard operating procedure, based on practices already implemented in several research centers. Also, a theory of 'deep MRI physiotyping' is inferred from the combined knowledge of factors influencing brain perfusion as a strategy to reduce variance by taking both personal information and the presence or absence of perfusion modifiers into account. We hypothesize that this will allow to personalize the concept of normality, as well as to reach more rigorous and earlier diagnoses of brain disorders.


An integrative and citizen science based approach to the rediscovery and redescription of the only known high-altitude endemic Pill Millipede, Glomeris aurita Koch (Diplopoda, Glomerida).
The pill millipede species Glomeris aurita Koch, 1847 remained of relative unknown origin and appearance until its recent rediscovery in samples from the Bergamasque Alps, northern Italy. In order to provide an integrative redescription and accurate identification of the high-altitude microendemic G. aurita, COI barcode sequences from three individuals coming from two different localities were obtained. These sequences are compared with those of the syntopic endemic G. oblongoguttata Verhoeff, 1894, the widespread black morph of G. romana Verhoeff, 1900, as well as several widespread species including G. marginata Villers, 1789, G. connexa Koch, 1847, and G. klugii Brandt, 1833, which have rare colour morphs that exhibit some similarity to G. aurita. To rule-out any identity confusion of G. aurita with other high-altitude or little-known Italian Glomeris, specimens of G. transalpina Koch, 1836, G. oropensis Verhoeff, 1934, and G. primordialis Verhoeff, 1932 were also added to the dataset. Altogether, 24 sequences were compared. Morphologically, the specimens of G. aurita were studied utilizing scanning electron microscopy as well as non-invasive micro-CT technology. The distribution of both Bergamasque endemics, G. aurita and G. oblongoguttata, could be mapped and compared utilizing samples from the Museo civico di Scienze Naturali di Bergamo, as well as photographic evidence from an Italian naturalist forum. G. aurita has a very short active period and is the first known pill millipede species restricted to mountain tops and cold places, possibly representing a Nunatak survivor.


A Wnt-bmp feedback circuit controls intertissue signaling dynamics in tooth organogenesis.
Many vertebrate organs form through the sequential and reciprocal exchange of signaling molecules between juxtaposed epithelial and mesenchymal tissues. We undertook a systems biology approach that combined the generation and analysis of large-scale spatiotemporal gene expression data with mouse genetic experiments to gain insight into the mechanisms that control epithelial-mesenchymal signaling interactions in the developing mouse molar tooth. We showed that the shift in instructive signaling potential from dental epithelium to dental mesenchyme was accompanied by temporally coordinated genome-wide changes in gene expression in both compartments. To identify the mechanism responsible, we developed a probabilistic technique that integrates regulatory evidence from gene expression data and from the literature to reconstruct a gene regulatory network for the epithelial and mesenchymal compartments in early tooth development. By integrating these epithelial and mesenchymal gene regulatory networks through the action of diffusible extracellular signaling molecules, we identified a key epithelial-mesenchymal intertissue Wnt-Bmp (bone morphogenetic protein) feedback circuit. We then validated this circuit in vivo with compound genetic mutations in mice that disrupted this circuit. Moreover, mathematical modeling demonstrated that the structure of the circuit accounted for the observed reciprocal signaling dynamics. Thus, we have identified a critical signaling circuit that controls the coordinated genome-wide expression changes and reciprocal signaling molecule dynamics that occur in interacting epithelial and mesenchymal compartments during organogenesis.


Heterogeneity in physicochemical properties explains differences in silver toxicity amelioration by natural organic matter to Daphnia magna.
Recently collected data have shown that natural organic matter (NOM) source is an important parameter influencing the toxicity of silver to the freshwater crustacean Daphnia magna. The present study attempted to correlate the physicochemical properties of 11 naturally isolated and commercially available NOM sources with their ameliorative effects. The protection offered by these samples was standardized to the protective effect of Aldrich humic acid using geochemical modeling approaches that accounted for associated changes in water chemistry and, consequently, silver speciation. The protective ability of NOM was not correlated with reactive sulfide or nitrogen content, which are considered to be strong silver-binding ligands. Color (specific absorbance coefficient) was positively correlated with protection but narrowly eluded statistical significance. The peak wavelength of emission fluorescence following excitation at 370 nm and the fluorescence index values of NOM samples were significantly correlated with protective effects, suggesting that aromatic carbon content may govern the ameliorative actions of NOM. Simple optical properties may therefore act as a suitable indicator for the ability of a given NOM to protect against waterborne silver toxicity to D. magna as long as changes in water chemistry and, thus, silver speciation, are considered.


Driving dimethyl carbonate synthesis from CO2 and methanol and production of acetylene simultaneously using CaC2.
The synthesis of dimethyl carbonate (DMC) from CO2 and methanol is a very interesting reaction, but is thermodynamically limited. In this work, CaC2 was used to consume the water produced in the reaction to shift the reaction equilibrium, and C2H2 was produced at the same time. This is the first work on the combination of driving a thermodynamically unfavorable reaction and producing C2H2 using CaC2.


Construction of a User-Led Resource for People Transitioning to Secondary Progressive Multiple Sclerosis: Results of an International Nominal Group Study.
Background: ManTra is a mixed-methods, co-production research project for developing an intervention (resource) for people with newly diagnosed secondary progressive multiple sclerosis (pwSPMS) in Italy and Germany. In previous project actions, six resources were outlined, meeting the needs prioritized by pwSPMS. Aims: This study aims to achieve multiple-stakeholder consensus on the most suitable resource and to refine the consensus resource. Methods: Two nominal group technique (NGT) meetings were held, one in Milan and one in Hamburg. Participants were pwSPMS (five in Italy/six in Germany), pwSPMS significant others (SOs, four/five), healthcare professionals (HPs, seven/four), and health service researchers/patient and citizen organizations representatives (HPCORs, five/five). Two of the four resources discussed in each meeting were the same in Italy and Germany: "Promoting the engagement of pwSPMS: a program for the patients and the HPs" and "Enriched physiotherapy program for pwSPMS." The other two were "A personalized care plan for pwSPMS" and "Roadmap for social and economic benefits" in Italy and "Metacognitive and everyday life training for pwSPMS" and "Psychological support for pwSPMS" in Germany. Each meeting consisted of two plenary sessions and a parallel group session (four stakeholder groups: pwSPMS, SOs, HPs, and HPCORs) in between. Meetings' narratives were analyzed thematically. Results: The two meetings were rich in participation and discussion. In Italy, the consensus resource was "A personalized care plan for pwSPMS." Refinements included enrichment with pwSPMS engagement, inclusion of additional HPs, improved definition of the MS nurse's role within the interdisciplinary panel, and community care integration. In Germany, the consensus resource was "Psychological support for pwSPMS." Refinements included reshaping this resource into a more comprehensive and adaptive rehabilitation intervention and training the psychologist in recognizing client's rehabilitative needs and enhancing his/her autonomy. Conclusions: The NGT eased multiple-stakeholder deliberation and resource fine-tuning in both countries.


[Unconditional to conditional rights: counterparts in Brazil's Family Allowance Program].
This paper analyzes the concepts and challenges of the counterpart contributions demanded by Brazil's Family Allowance Program, which requires mandatory school attendance for children and adolescents, and healthcare for children, pregnant women and breast-feeding mothers. These issues are prompting much discussion in Brazil and elsewhere in the world. This study charts theoretical aspects that underpin arguments for and against conditional cash transfer programs, through a review and systematization of the literature and a study of the related legislation. This analysis demonstrates that the opponents of counterpart obligations claim they breach unconditional rights to citizenship. Some supporters of these conditional transfers believe that a return is required for these benefits, while others see such requirements as a strategy for ensuring easier access to social welfare services, thereby breaking away from the cycle of poverty. Although latter view is present in Brazil's original Family Allowance Program, the manner in which supplementary legislation defines the application of the conditions is coercive and remote from the concept of social insertion.


Succinic semialdehyde dehydrogenase deficiency (SSADH) (4-hydroxybutyric aciduria, gamma-hydroxybutyric aciduria).
Succinic semialdehyde dehydrogenase deficiency is one of the disorders of GABA metabolism, so it is not surprising that seizures occur as one of the symptoms in affected patients. Other features that are described include delayed development, hypotonia, myopathy with ragged red fibres, abnormal behaviour, and ocular abnormalities. Neonatal problems include prematurity, respiratory difficulties, and hypoglycaemia. The responsible gene has been identified on the short arm of chromosome 6. There are many mutations, and there is poor genotype-phenotype correlation resulting in difficulties in diagnosis. The pathogenesis of the condition is discussed, especially the results of the disturbed GABA catabolism, and the production of the gamma-hydroxybutyric acid. The many properties of this substance suggest it may act as a neurotransmitter or neuromodulator in the brain. The diagnosis may be difficult as the clinical picture is not really suggestive, but the MRI examination can help if it shows abnormalities in the globus pallidus. It will be confirmed by finding an excess of 4-hydroxybutyric acid in the body fluids; and the methods of estimation are discussed. Prenatal diagnosis is possible using a combination of methods. Treatment possibilities are limited. Vigabatrin should be of value as it is an inhibitor of GABA transaminase, but results have been disappointing. Symptomatic treatment may well be needed for control of seizures, abnormal behaviour and other disorders; and special educational needs must be served.


[Crimean-Congo hemorrhagic fever in Senegal. Latest data on the ecology of the CCHF virus].
The authors finalize the knowledge on the ecology of the CCHF virus in Senegal, West Africa. They specify two new major data for the understanding of the viral ecology in West Africa. The recognition of a bird species, common and widely distributed in Senegal (Tockus erythrorhynchus, Coraciiformes, Bucerotidae), that replicates the virus and infects the immature stages of its current parasite Hyalomma marginatum rufipes in more than 90% of the cases, explains why the minimum infection rate of the adults of this species of tick is always very high. The implication of Rhipicephalus evertsi evertsi in the viral ecology and/or a high efficiency of the transovarial transmission of the virus in Hy. m. rufipes would help to explain the maintenance of the endemy in the sahelian area. In the sahelian zone, Hy. marginatum rufipes must play the leading part, together with Rh. e. evertsi if vector, for the maintenance of the endemy. Hy. truncatum, the adults of which can readily bite man, ensures the vectorial transmission to him. In the sudanian zone, Amblyomma variegatum must play the same part as the Hyalomma and Rh. e. evertsi (if vector), and is surely the main vector to man, giving perhaps rise to less virulent strains (non hemorrhagic ones).


Modulation of Aire regulates the expression of tissue-restricted antigens.
Intrathymic expression of tissue-restricted antigens (TRAs) has been viewed as the key element in the induction of central tolerance and recently, a central role for the autoimmune regulator (Aire) has been suggested in this process. The aim of this study was to establish whether down or up-regulation of Aire leads to alterations in TRA expression and whether this is limited to thymic epithelial cells. This study also characterized whether TRAs follow Aire expression during normal development, and whether thymic microenvironment plays a role in the expression of Aire and TRAs. We did several in vivo and in vitro experiments to manipulate Aire expression and measured expression of four TRAs (Trefoil factor-3, Insulin-2, Major urinary protein-1 and Salivary protein-1) by real-time RT-PCR. Aire had an allele dose-dependent effect on TRA expression in the thymuses of mice from two strains, C57BL/6J and Balb/c, but had no effect on TRA expression in the lymph nodes. In the thymus, Aire and TRAs were both localized in the medulla and were co-expressed during normal development and involution. In the primary stromal cells as well as thymic epithelial cell line, the adenoviral over-expression of Aire resulted in an increase in TRA expression. By manipulating in vitro organ-cultures we showed that thymic microenvironment plays a dominant role in Aire expression whereas TRAs follow the same pattern. The data underline a direct role for Aire in TRA expression and suggest that modulation of Aire has a potential to control central tolerance and autoimmunity.


Activation of the FGFR1 signalling pathway by the Epstein-Barr virus-encoded LMP1 promotes aerobic glycolysis and transformation of human nasopharyngeal epithelial cells.
Non-keratinizing nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) infection. The EBV-encoded latent membrane protein 1 (LMP1) is believed to play an important role in NPC pathogenesis by virtue of its ability to activate multiple cell signalling pathways which collectively promote cell proliferation, transformation, angiogenesis, and invasiveness, as well as modulation of energy metabolism. In this study, we report that LMP1 increases cellular uptake of glucose and glutamine, enhances LDHA activity and lactate production, but reduces pyruvate kinase activity and pyruvate concentrations. LMP1 also increases the phosphorylation of PKM2, LDHA, and FGFR1, as well as the expression of PDHK1, FGFR1, c-Myc, and HIF-1α, regardless of oxygen availability. Collectively, these findings suggest that LMP1 promotes aerobic glycolysis. With respect to FGFR1 signalling, LMP1 not only increases FGFR1 expression, but also up-regulates FGF2, leading to constitutive activation of the FGFR1 signalling pathway. Furthermore, two inhibitors of FGFR1 (PD161570 and SU5402) attenuate LMP1-mediated aerobic glycolysis, cellular transformation (proliferation and anchorage-independent growth), cell migration, and invasion in nasopharyngeal epithelial cells, identifying FGFR1 signalling as a key pathway in LMP1-mediated growth transformation. Immunohistochemical staining revealed that high levels of phosphorylated FGFR1 are common in primary NPC specimens and that this correlated with the expression of LMP1. In addition, FGFR1 inhibitors suppress cell proliferation and anchorage-independent growth of NPC cells. Our current findings demonstrate that LMP1-mediated FGFR1 activation contributes to aerobic glycolysis and transformation of epithelial cells, thereby implicating FGF2/FGFR1 signalling activation in the EBV-driven pathogenesis of NPC.


Development of an rRNA-targeted oligonucleotide probe specific for the genus Acinetobacter and its application for in situ monitoring in activated sludge.
Enhanced biological phosphate removal in an anaerobic-aerobic activated sludge system has generally been ascribed to members of the genus Acinetobacter. A genus-specific 16S rRNA-targeted oligonucleotide probe was developed to investigate the role of Acinetobacter spp. in situ. Nonisotopic dot blot hybridization to 66 reference strains, including the seven described Acinetobacter spp., demonstrated the expected probe specificity. Fluorescent derivatives were used for in situ monitoring of Acinetobacter spp. in the anaerobic and aerobic compartments of a sewage treatment plant with enhanced biological phosphate removal. Microbial community structures were further analyzed with oligonucleotide probes specific for the alpha, beta, or gamma subclasses of the class Proteobacteria, for the Cytophaga-Flavobacterium cluster, for gram-positive bacteria with a high G + C DNA content, and for all bacteria. Total cell counts were determined by 4',6-diamidino-2-phenylindole staining. In both the anaerobic and the aerobic basins, the activated sludge samples were dominated by members of the class Proteobacteria belonging to the beta subclass and by gram-positive bacteria with a high G + C DNA content. Acinetobacter spp. constituted less than 10% of all bacteria. For both basins, the microbial community structures determined with molecular techniques were compared with the compositions of the heterotrophic saprophytic microbiota determined with agar plating techniques. Isolates on nutrient-rich medium were classified by whole-cell hybridization with rRNA-targeted probes and fatty acid analysis.(ABSTRACT TRUNCATED AT 250 WORDS)


Two regulatory domains flank the mouse H19 gene.
The mouse H19 gene was identified by virtue of its coordinate regulation with the mouse alpha-fetoprotein gene. Both genes are expressed in the fetal liver, gut, and visceral endoderm of the yolk sac and are repressed shortly after birth in the liver and gut. They are both under the control of two trans-acting loci: raf, which affects the adult basal levels of the two mRNAs, and Rif, which affects their inducibility during liver regeneration. One crucial difference between the two genes is the activation of the H19 gene in mesoderm derivatives, skeletal and cardiac muscle. As a strategy for explaining both the similarities and differences in their modes of expression, the regulatory domains responsible for the expression of the H19 gene in liver were identified by transiently introducing the gene into a human hepatoma cell line. Two regions necessary for high-level expression of the gene could be identified, a promoter-proximal domain immediately preceding the start of transcription and an enhancer domain which lies between 5 and 6.5 kilobases 3' of the polyadenylation site. The 3' domain consists of two separable enhancer elements, each of which exhibits the properties of tissue-specific enhancers. Nucleotide sequence comparisons between the two H19 and three alpha-fetoprotein enhancers revealed limited similarities which are candidates for binding of common regulatory factors. Sequences which lie 3' of the gene are also required for the expression of the H19 gene following differentiation of teratocarcinoma cells into visceral endoderm.


A Novel In Vivo Model to Study Impaired Tissue Regeneration Mediated by Cigarette Smoke.
Cigarette smoke is associated with several pathologies including chronic respiratory diseases and cancer. In addition, exposure to cigarette smoke is correlated with impaired wound healing, where a significant decrease in the regenerative capacity of smokers is well documented and broadly considered a negative risk factor after trauma or surgery. So far, some in vitro and in vivo models have been described to study how exposure to cigarette smoke diminishes the regenerative potential in different organisms. However, although useful, many of these models are difficult and expensive to implement and do not allow high-throughput screening approaches. In order to establish a reliable and accessible model, we have evaluated the effects of cigarette smoke extract (CSE) on zebrafish development and regeneration. In this work, zebrafish embryos and larvae were exposed to low doses of aqueous CSE showing severe developmental abnormalities in a dose-dependent manner. Furthermore, when adult zebrafish were subjected to caudal fin amputation, we observed a significant decrease in the regenerative capacity of animals exposed to CSE. The effect was exacerbated in male and aged fish compared to female or young organisms. The establishment of a zebrafish model to assess the consequences of cigarette smoke and its effects on animal physiology could provide a new tool to study the underlying mechanisms involved in impaired tissue regeneration, and aid the development of novel approaches to treat complications associated with cigarette smoke toxicity.


Non-human primates as a reservoir for rabies virus in Brazil.
Rabies virus (RABV) does not persist in the environment as it is a very fragile agent. The primary hosts are mammalian species in the orders Carnivora and Chiroptera. Since the late 1980s, RABV has been isolated from non-human primates, Callithrix jacchus (the white-tufted marmoset), in four coastal states (Rio Grande do Norte, Ceará, Piauí and Pernambuco) in north-eastern Brazil, where this species is indigenous. The original habitat of C. jacchus consisted of two Brazilian biomes, the Atlantic Forest and the Caatinga. However, these marmosets have since adapted to other ecosystems as a result of human activities. Between 1988 and 1989, RABV isolates were obtained from white-tufted marmosets in the state of Rio Grande do Norte, but antigenic and genetic identification studies were not conducted at that time. In the following years, three additional states reported cases (Ceará, Piauí and Pernambuco). In two of these states (Ceará and Piauí), human cases of rabies transmitted by marmosets were reported. According to Brazilian Health Ministry data, at least 19 human cases in which this species was the source of infection were registered in between 1990 and 2016. Recent findings in laboratory tests of 12 rabid samples from humans and marmosets and the regional transmission among these animals for over 20 years, together with the gradual increase in the affected geographic area, support the concept of the emergence of a new RABV reservoir. Regional tourism, the wild animal trade and the cultural practice of maintaining these animals as pets, particularly in coastal regions, appear to be major risk factors for the increase in human cases. Additional epidemiological and ecological studies are required to better understand local disease dynamics and to identify ideal opportunities for prevention and control of this fatal infection.


A uniformly valid approximation algorithm for nonlinear ordinary singular perturbation problems with boundary layer solutions.
This paper is concerned with two-point boundary value problems for singularly perturbed nonlinear ordinary differential equations. The case when the solution only has one boundary layer is examined. An efficient method so called Successive Complementary Expansion Method (SCEM) is used to obtain uniformly valid approximations to this kind of solutions. Four test problems are considered to check the efficiency and accuracy of the proposed method. The numerical results are found in good agreement with exact and existing solutions in literature. The results confirm that SCEM has a superiority over other existing methods in terms of easy-applicability and effectiveness.


Sunset science. I. The mock mirage.
A previously unrecognized phenomenon, which we call the mock mirage, produces inverted images of the Sun and Moon near the horizon when the observer looks downward through a thermal inversion. No ducting is involved; the rays can be concave toward the Earth throughout their length, with a radius of curvature larger than the radius of the Earth. Quite mild inversions produce surprisingly large effects, which increase with the height of the observer. Although the phenomenon has frequently been photographed, published pictures have been misinterpreted. Finally, we distinguish between features that are due to waves on inversion layers and the larger features that are due to the inversions themselves.


A Comparison of Residency Applications and Match Performance in 3-Year vs 4-Year Family Medicine Training Programs.
The optimal length of residency training in family medicine is under debate. This study compared applicant type, number of applicants, match positions filled, matched applicant type, and ranks to fill between 3-year (3YR) and 4-year (4YR) residencies. The Length of Training Pilot (LOTP) is a case-control study comparing 3YR (seven residencies) and 4YR (six residencies) training models. We collected applicant and match data from LOTP programs from 2012 to 2018 and compared data between 3YR and 4YR programs. National data provided descriptive comparisons. An annual resident survey captured resident perspectives on training program selection. Summary statistics and corresponding t-tests and χ2 tests of independence were performed to assess differences between groups. We used a linear mixed model to account for repeated measures over time within programs. There were no differences in the mean number of US MD, US DO, and international medical graduate applicants between 3YR and 4YR programs. Both the 3YR and 4YR programs had a substantially higher number of US MD and DO applicants compared to national averages. The percentages of positions filled in the match and positions filled by US MDs, DOs and IMGs were not different between groups. The percentage of residents in 4YR programs who think training in family medicine requires a fourth year varied significantly during the study period, from 35% to 25% (P<.001). The predominant reasons for pursuing training in a 4YR program was a desire for more flexibility in training and a desire to learn additional skills beyond clinical skills. The applicant pool and match performance of the residencies in the LOTP was not affected by length of training. Questions yet to be addressed include length of training's impact on medical knowledge, scope of practice, and clinical preparedness.


Computational analysis suggests that lyssavirus glycoprotein gene plays a minor role in viral adaptation.
The Lyssavirus glycoprotein (G) is a membrane protein responsible for virus entry and protective immune responses. To explore possible roles of the glycoprotein in host shift or adaptation of Lyssavirus, we retrieved 53 full-length glycoprotein gene sequences from NCBI GenBank. The sequences were from different host isolates over a period of 70 years in 21 countries. Computational analyses detected 1 recombinant (AY987478, a dog isolate of CHAND03, genotype 1 in India) with incongruent phylogenetic support. No recombination was detected when AY98748 was excluded in the analyses. We applied different selection models to identify selection pressure on the glycoprotein gene. One codon at amino acid residual 483 was found to be under weak positive selection with marginal probability of 95% by using the maximum likelihood method. We found no significant evidence of positive selection on any site of the glycoprotein gene when the putative recombinant AY987478 was excluded. The computational analyses suggest that the G gene has been under purifying selection and that the evolution of the G gene may not play a significant role in Lyssavirus adaptation.


Hydrodynamics of cellular cortical flows and the formation of contractile rings.
We propose a mechanism for the formation of contractile rings and the apparition of a flow in the cortical layer of cells undergoing cytokinesis at the end of cell division or during the healing of a wound in the cortex of Xenopus eggs. We generalize the hydrodynamic active gel theory along the lines of thin shell theory of continuum elasticity to describe the cell cortex. As in liquid crystal physics, the flow couples to the orientation of the actin filaments. The cortical flow is driven by an increased density of myosin motors in the cortex, and orients the filaments to form the ring.


A network inference method for large-scale unsupervised identification of novel drug-drug interactions.
Characterizing interactions between drugs is important to avoid potentially harmful combinations, to reduce off-target effects of treatments and to fight antibiotic resistant pathogens, among others. Here we present a network inference algorithm to predict uncharacterized drug-drug interactions. Our algorithm takes, as its only input, sets of previously reported interactions, and does not require any pharmacological or biochemical information about the drugs, their targets or their mechanisms of action. Because the models we use are abstract, our approach can deal with adverse interactions, synergistic/antagonistic/suppressing interactions, or any other type of drug interaction. We show that our method is able to accurately predict interactions, both in exhaustive pairwise interaction data between small sets of drugs, and in large-scale databases. We also demonstrate that our algorithm can be used efficiently to discover interactions of new drugs as part of the drug discovery process.


Recurrent loss of heterozygosity in 1p36 associated with TNFRSF14 mutations in IRF4 translocation negative pediatric follicular lymphomas.
Pediatric follicular lymphoma is a rare disease that differs genetically and clinically from its adult counterpart. With the exception of pediatric follicular lymphoma with IRF4-translocation, the genetic events associated with these lymphomas have not yet been defined. We applied array-comparative genomic hybridization and molecular inversion probe assay analyses to formalin-fixed paraffin-embedded tissues from 18 patients aged 18 years and under with IRF4 translocation negative follicular lymphoma. All evaluable cases lacked t(14;18). Only 6 of 16 evaluable cases displayed chromosomal imbalances with gains or amplifications of 6pter-p24.3 (including IRF4) and deletion and copy number neutral-loss of heterozygosity in 1p36 (including TNFRSF14) being most frequent. Sequencing of TNFRSF14 located in the minimal region of loss in 1p36.32 showed nine mutations in 7 cases from our series. Two subsets of pediatric follicular lymphoma were delineated according to the presence of molecular alterations, one with genomic aberrations associated with higher grade and/or diffuse large B-cell lymphoma component and more widespread disease, and another one lacking genetic alterations associated with more limited disease.


Is a history of depressive symptoms associated with an increased risk of infertility in women?
Researchers have reported an association between self-reported antidepressant use and increased risk of ovulatory infertility but could not control for confounding by the drug indication. We evaluated the role of depressive symptoms in the development of infertility. We recontacted a population-based sample of Pawtucket Heart Health Program (PHHP) health survey respondents to perform this case-control study. Self-reported infertility was defined as an inability to conceive after 12 months of unprotected intercourse. Controls were women who reported at least one pregnancy. The index age for infertile women was the age at which they first experienced fertility problems, and for the fertile women it was the age of their first pregnancy. History of depressive symptoms was based on self-report before the index age. Women with a history of depressive symptoms were nearly twice as likely to report infertility relative to women without a history of depressive symptoms before the index age after controlling for potential confounders (90% confidence interval: 0.9-3.2). Our data suggest that depressive symptoms as well as the drugs used to treat these conditions may play an important role in the pathogenesis of infertility. The association between depressive symptoms and infertility should be explored further.


Caffeine dependence syndrome. Evidence from case histories and experimental evaluations.
The extent to which daily caffeine use is associated with a substance dependence syndrome similar to that associated with other psychoactive drugs is unknown. The purpose of this study was to assess volunteers who reported problems with their use of caffeine for evidence suggesting a diagnosis of caffeine dependence based on the generic criteria for substance dependence from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Case-series evaluations. An academic research center. Self-identified adults who believed they were psychologically or physically dependent on caffeine. Diagnoses made by a psychiatrist using a structured clinical interview that included a section on caffeine dependence based on genetic criteria for DSM-IV substance dependence. Double-blind caffeine-withdrawal evaluation. Ninety-nine subjects were screened for the study, and 16 were identified as having a diagnosis of caffeine dependence. Median daily caffeine intake was 357 mg, and 19% of subjects consumed less than the national (US) daily average of caffeine. Criteria used for making diagnoses (and rates of their prevalence) were as follows: withdrawal (94%), use continued despite knowledge of a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by caffeine use (94%), persistent desire or unsuccessful efforts to cut down or control use (81%), and tolerance (75%). Eleven subjects underwent the double-blind caffeine-withdrawal evaluation portion of the study, and nine (82%) of the 11 showed objective evidence of caffeine withdrawal, including eight of 11 with functional impairment. These results, together with other experimental evidence, suggest that caffeine exhibits the features of a typical psychoactive substance of dependence. It is valuable to recognize caffeine dependence as a clinical syndrome, since some people feel compelled to continue caffeine use despite desires and recommendations to the contrary.


Mind your heart to bear the weight: Cardiac interoception predicts action-related visual perception when wearing a heavy backpack.
Visual perception can be modulated by the physiological potential for action. For instance, it was famously shown that a geographical slant appears steeper when wearing a heavy backpack than not wearing any. However, those results are not always replicated. In the present exploratory study, we test the hypothesis that the backpack weight's effect on perception relies on the ability of the cognitive system to integrate the physiological constraint's change rather than the change itself. Young adults (n = 54) wore an electrocardiogram monitor and completed a computerised task in which photographs of real geographical slants were displayed on a screen while wearing a heavy versus light backpack. The activity of the vagus nerve, as an index of physiological adaptability, was recorded as a proxy of the physiological state during the task. The participants also completed an interoception task assessing one's ability to detect his or her own heartbeat as the index of integration ability of the cognitive system. While Bayesian analyses revealed no difference in angle estimation between carrying a heavy versus light backpack, the results indicated that interoception predicted less accurate angle estimation only when wearing a heavy backpack. In contrast, there was anecdotal evidence that vagal activity changes predicted visual perception. Interoception might thus play a crucial role in the interplay between the physiological potential for action and action-related visual perception.


Treating intracranial dural arteriovenous fistulas with gamma knife radiosurgery: A single-center experience.
We evaluated the effectiveness and safety of gamma knife radiosurgery (GKRS) for the treatment of intracranial dural arteriovenous fistulas (dural AVFs) over the past 10 years. The records of 21 patients diagnosed with dural AVFs between 2004 and 2014 and treated with GKRS were reviewed retrospectively. Complete obliteration (CO) was defined as total symptom relief plus confirmation through magnetic resonance imaging or conventional angiography. The median follow-up was 70.5 months (range 3-136 months). Five patients underwent embolization (2 after GKRS). One patient underwent GKRS twice. The CO rate was 47%, and partial to CO rate was 88%. The complete symptom resolution rate was 77%, and all patients achieved partial to complete symptom resolution. The CO rates for Borden Type I and Type II/III dural AVFs were 66.7% and 25% (P = 0.153), respectively, and complete symptom-free rates were 76.9% and 75.0% (P = 1.000%), respectively. The median duration between initial GKRS and complete symptom resolution was 14.3 months. The median treatment to image-free durations for Borden Type I and Type II/III dural AVFs were 25.9 and 60.4 months (P = 0.028), respectively, and treatment to symptom-free durations were 10.6 and 36.7 months (P = 0.103), respectively. One patient had a recurrent hemorrhage. Two patients experienced brain edema after stereotactic radiosurgery and one patient experienced cystic formation after GKRS. The morbidity rate was 19% (four patients) and there was no mortality. Treatment with GKRS for dural AVFs offers a favorable rate of obliteration. Patients with dural AVFs that are refractory or not amenable to endovascular or surgical therapy may be safely and effectively treated using GKRS.


Analysis of the transcriptome of adult Dictyocaulus filaria and comparison with Dictyocaulus viviparus, with a focus on molecules involved in host-parasite interactions.
Parasitic nematodes cause diseases of major economic importance in animals. Key representatives are species of Dictyocaulus (=lungworms), which cause bronchitis (=dictyocaulosis, commonly known as "husk") and have a major adverse impact on the health of livestock. In spite of their economic importance, very little is known about the immunomolecular biology of these parasites. Here, we conducted a comprehensive investigation of the adult transcriptome of Dictyocaulus filaria of small ruminants and compared it with that of Dictyocaulus viviparus of bovids. We then identified a subset of highly transcribed molecules inferred to be linked to host-parasite interactions, including cathepsin B peptidases, fatty-acid and/or retinol-binding proteins, β-galactoside-binding galectins, secreted protein 6 precursors, macrophage migration inhibitory factors, glutathione peroxidases, a transthyretin-like protein and a type 2-like cystatin. We then studied homologues of D. filaria type 2-like cystatin encoded in D. viviparus and 24 other nematodes representing seven distinct taxonomic orders, with a particular focus on their proposed role in immunomodulation and/or metabolism. Taken together, the present study provides new insights into nematode-host interactions. The findings lay the foundation for future experimental studies and could have implications for designing new interventions against lungworms and other parasitic nematodes. The future characterisation of the genomes of Dictyocaulus spp. should underpin these endeavours.


Management of long segment anterior urethral stricture (≥ 8cm) using buccal mucosal (BM) graft and penile skin (PS) flap: outcome and predictors of failure.
To evaluate the surgical outcome and predictors of failure of substitution urethroplasty using either dorsal onlay buccal mucosal (BM) graft or ventral onlay penile skin flap (PS) for anterior urethral stricture ≥ 8cm. Between March 2010 and January 2016, 50 patients with anterior urethral stricture ≥ 8 cm were treated at our hospital. The surgical outcome and success rate were assessed. The predictors of failure were analyzed using multivariate analysis. Failure was considered when subsequent urethrotomy or urethroplasty were needed. Dorsal onlay BM graft was carried out in 24 patients, while PS urethroplasty in 26 patients. There was no significant difference between both groups regarding patients demographics, stricture characteristics or follow-up period. One case in the BM group was lost during follow- up. Stricture recurrence was detected in 7 (30.4%) patients out of BM group while in 6 (23.1%) patients out of PS group (p value= 0.5). No significant differences between both groups regarding overall early and late complications were observed. Occurrence of early complications and the stricture length were the only predictors of failure in univariate analysis, while in multivariate analysis the occurrence of early complications was only significant. On short-term follow-up, both dorsal onlay BM graft and ventral onlay PS flap urethroplasty have similar success rates. However, BM graft has a potential advantage to reduce operative time and is also technically easier. The surgeon should avoid early local complications as they represent a higher risk for failure.


Genetic Determinants for Enzymatic Digestion of Lignocellulosic Biomass Are Independent of Those for Lignin Abundance in a Maize Recombinant Inbred Population.
Biotechnological approaches to reduce or modify lignin in biomass crops are predicated on the assumption that it is the principal determinant of the recalcitrance of biomass to enzymatic digestion for biofuels production. We defined quantitative trait loci (QTL) in the Intermated B73 × Mo17 recombinant inbred maize (Zea mays) population using pyrolysis molecular-beam mass spectrometry to establish stem lignin content and an enzymatic hydrolysis assay to measure glucose and xylose yield. Among five multiyear QTL for lignin abundance, two for 4-vinylphenol abundance, and four for glucose and/or xylose yield, not a single QTL for aromatic abundance and sugar yield was shared. A genome-wide association study for lignin abundance and sugar yield of the 282-member maize association panel provided candidate genes in the 11 QTL of the B73 and Mo17 parents but showed that many other alleles impacting these traits exist among this broader pool of maize genetic diversity. B73 and Mo17 genotypes exhibited large differences in gene expression in developing stem tissues independent of allelic variation. Combining these complementary genetic approaches provides a narrowed list of candidate genes. A cluster of SCARECROW-LIKE9 and SCARECROW-LIKE14 transcription factor genes provides exceptionally strong candidate genes emerging from the genome-wide association study. In addition to these and genes associated with cell wall metabolism, candidates include several other transcription factors associated with vascularization and fiber formation and components of cellular signaling pathways. These results provide new insights and strategies beyond the modification of lignin to enhance yields of biofuels from genetically modified biomass.


Negative regulation of STAT92E by an N-terminally truncated STAT protein derived from an alternative promoter site.
Previously unrecognized mRNAs originating from a dual promoter at the stat92E locus are described. One of these encodes a truncated protein, DeltaNSTAT92E, that lacks the N-terminal 133 amino acids. Antibodies detect both the full-length and truncated molecules early in embryogenesis (1-5 h), and mRNA detection by specific RT-PCR reactions accords with the protein distribution. Given that the N termini of mammalian STATs are known to have positive functions in transcriptional activation, we explored the role of DeltaNSTAT92E early in embryogenesis. By increasing the DeltaNSTAT92E-to-STAT92E ratio in overexpression and RNAi experiments, we observe phenotypes compatible with suppression of wild-type STAT92E activity. We therefore conclude that the short form of STAT92E is a naturally occurring dominant-negative product that can be added to the growing list of negative regulators of STAT activity.


Thymus-dependent network responses to a monoclonal cross-reactive antiidiotypic antibody.
BALB/c mice were inoculated i.p. with a cross-reactive anti-Idiotypic mAb (designated FD5-1) in the absence of Ag or adjuvants. Injection with unmodified FD5-1 resulted in the induction of serum antibodies reactive with both FD5-1 (Ab3) and the hapten DNP (Ab1'). Endpoint titers of the Ab3 response showed an increase in serum IgM, which was dose-responsive to both the number of injections and the amount of FD5-1 antibody injected. The serum IgM Ab3 response was found to be thymus dependent and idiotypically specific for FD5-1. Athymic mice injected with FD5-1 were unable to produce a serum IgM Ab3 response, whereas their euthymic littermates produced strong Ab3 responses. Serum Ab3 responses and Ab1' were detectable only in the IgM isotype; no specific IgG responses were observed. Indeed, IgG recognized by FD5-1 appeared to be suppressed by FD5-1. Injection of mice with FD5-1 modulated serum IgM responses to DNP, (4-hydroxy-3-nitrophenyl)acetyl (NP), 4-ethoxymethylene-2-phenyloxazol-5-one (OX), phosphorylcholine (PC), and alpha 1,3-dextran (DEX) in a thymus-dependent manner. FD5-1 injection induced IgM responses against DNP, (4-hydroxy-3-nitrophenyl)acetyl (NP), 4-ethoxymethylene-2-phenyloxazol-5-one, and DEX but decreased IgM binding to PC. No detectable Ab1' responses to any of the aforementioned molecules were found when the same sera were probed for IgG. The specificity of serum Ab1' from FD5-1-injected mice was evaluated by antigenic inhibition. Binding of serum Ab1' to DNP-BSA was inhibitable by DNP-lysine, whereas equivalent concentrations of lysine alone had no inhibitory effect. The antigenic specificity of IgM from normal serum binding to PC-BSA was demonstrated by inhibition with free PC, and the binding of Ab1' from FD5-1-injected mice to DEX-coated plates was shown to be inhibitable by DEX. We have described in vivo network perturbation in adult BALB/c mice injected with anti-Id antibody in the absence of Ag or adjuvants. Our findings show that injection of the cross-reactive anti-Id FD5-1 can induce thymus-dependent Ag-specific responses. In two systems where FD5-1 functions as an anti-anti-anti-Id antibody (PC and DEX), thymus-dependent responses were also observed. FD5-1 injection suppressed antibodies binding to PC, whereas DEX-specific responses were induced.


Framing ethical issues associated with the UK COVID-19 contact tracing app: exceptionalising and narrowing the public ethics debate.
This paper explores ethical debates associated with the UK COVID-19 contact tracing app that occurred in the public news media and broader public policy, and in doing so, takes ethics debate as an object for sociological study. The research question was: how did UK national newspaper news articles and grey literature frame the ethical issues about the app, and how did stakeholders associated with the development and/or governance of the app reflect on this? We examined the predominance of different ethical issues in news articles and grey literature, and triangulated this using stakeholder interview data. Findings illustrate how news articles exceptionalised ethical debate around the app compared to the way they portrayed ethical issues relating to 'manual' contact tracing. They also narrowed the debate around specific privacy concerns. This was reflected in the grey literature, and interviewees perceived this to have emerged from a 'privacy lobby'. We discuss the findings, and argue that this limited public ethics narrative masked broader ethical issues.


A Silenced vanA Gene Cluster on a Transferable Plasmid Caused an Outbreak of Vancomycin-Variable Enterococci.
We report an outbreak of vancomycin-variable vanA(+) enterococci (VVE) able to escape phenotypic detection by current guidelines and demonstrate the molecular mechanisms for in vivo switching into vancomycin resistance and horizontal spread of the vanA cluster. Forty-eight vanA(+) Enterococcus faecium isolates and one Enterococcus faecalis isolate were analyzed for clonality with pulsed-field gel electrophoresis (PFGE), and their vanA gene cluster compositions were assessed by PCR and whole-genome sequencing of six isolates. The susceptible VVE strains were cultivated in brain heart infusion broth containing vancomycin at 8 μg/ml for in vitro development of resistant VVE. The transcription profiles of susceptible VVE and their resistant revertants were assessed using quantitative reverse transcription-PCR. Plasmid content was analyzed with S1 nuclease PFGE and hybridizations. Conjugative transfer of vanA was assessed by filter mating. The only genetic difference between the vanA clusters of susceptible and resistant VVE was an ISL3-family element upstream of vanHAX, which silenced vanHAX gene transcription in susceptible VVE. Furthermore, the VVE had an insertion of IS1542 between orf2 and vanR that attenuated the expression of vanHAX Growth of susceptible VVE occurred after 24 to 72 h of exposure to vancomycin due to excision of the ISL3-family element. The vanA gene cluster was located on a transferable broad-host-range plasmid also detected in outbreak isolates with different pulsotypes, including one E. faecalis isolate. Horizontally transferable silenced vanA able to escape detection and revert into resistance during vancomycin therapy represents a new challenge in the clinic. Genotypic testing of invasive vancomycin-susceptible enterococci by vanA-PCR is advised.


An Increased Risk of Osteoporosis during Acquired Immunodeficiency Syndrome.
Osteoporosis is characterized by decreased bone mineral density and mechanistic imbalances of bone tissue that may result in reduced skeletal strength and an enhanced susceptibility to fractures. Osteoporosis in its most common form affects the elderly (both sexes) and all racial groups of human beings. Multiple environmental risk factors like acquired immune deficiency syndrome (AIDS) are believed to be one of the causes of osteoporosis. Recently a high incidence of osteoporosis has been observed in human immunodeficiency virus (HIV) infected individuals. The etiology of this occurrence in HIV infections is controversial. This problem seems to be more frequent in patients receiving potent antiretroviral therapy. In AIDS, the main suggested risk factors for the development of osteoporosis are use of protease inhibitors, longer duration of HIV infection, lower body weight before antiretroviral therapy, high viral load. Variations in serum parameters like osteocalcin, c-telopeptide, levels of elements like Calcium, Magnesium, Phosphorus, concentration of vitamin-D metabolites, lactate levels, bicarbonate concentrations, amount of alkaline phosphatase are demonstrated in the course of development of osteoporosis. OPG/RANKL/RANK system is final mediator of bone remodeling. Bone mineral density (BMD) test is of added value to assess the risk of osteoporosis in patients infected with AIDS. The biochemical markers also aid in this assessment. Clinical management mostly follows the lines of treatment of osteoporosis and osteopenia.


Semantic retrieval of spoken words with an obliterated initial phoneme in a sentence context.
Perception of a phoneme may occur even when the speech sound is missing (e.g., when an extraneous noise replaces the sound). This phenomenon, called phonemic restoration, has been observed to depend on the type of distortion. It requires a replacing sound that provides acoustic input to the auditory system, since the restoration has not been found when a speech sound was replaced by silence. We examined the brain activation underlying speech processing when the word's initial phoneme was completely replaced by a silent gap. Event-related potentials (ERPs) and reaction times (RTs) were measured as indicators of semantic processing of sentence final words. Slower voice onset times during repetition of the manipulated words as compared to normal words indicated increased difficulty in retrieving their meaning. The N400, which is related to the increased demands of the semantic integration of words, was elicited by less expected words as compared to highly expected ones. For manipulated words, the N400 was elicited at the same latency than for normal words, with respect to the onset of the remaining word fragment. The amplitude of the N400 was not increased, nor did it last longer, thereby indicating successful retrieval of the word's meaning based on the semantic context and remaining phonetic information. Thus, semantic retrieval does not seem to require the word's initial phoneme to be present in a sentence context. The results suggest that both context-driven expectancy (top-down) and stimulus-driven processes (bottom-up) are utilized in word processing and contribute to the overall N400 response.


Non-virally engineered human adipose mesenchymal stem cells produce BMP4, target brain tumors, and extend survival.
There is a need for enabling non-viral nanobiotechnology to allow safe and effective gene therapy and cell therapy, which can be utilized to treat devastating diseases such as brain cancer. Human adipose-derived mesenchymal stem cells (hAMSCs) display high anti-glioma tropism and represent a promising delivery vehicle for targeted brain tumor therapy. In this study, we demonstrate that non-viral, biodegradable polymeric nanoparticles (NPs) can be used to engineer hAMSCs with higher efficacy (75% of cells) than leading commercially available reagents and high cell viability. To accomplish this, we engineered a poly(beta-amino ester) (PBAE) polymer structure to transfect hAMSCs with significantly higher efficacy than Lipofectamine™ 2000. We then assessed the ability of NP-engineered hAMSCs to deliver bone morphogenetic protein 4 (BMP4), which has been shown to have a novel therapeutic effect by targeting human brain tumor initiating cells (BTIC), a source of cancer recurrence, in a human primary malignant glioma model. We demonstrated that hAMSCs genetically engineered with polymeric nanoparticles containing BMP4 plasmid DNA (BMP4/NP-hAMSCs) secrete BMP4 growth factor while maintaining their multipotency and preserving their migration and invasion capacities. We also showed that this approach can overcome a central challenge for brain therapeutics, overcoming the blood brain barrier, by demonstrating that NP-engineered hAMSCs can migrate to the brain and penetrate the brain tumor after both intranasal and systemic intravenous administration. Critically, athymic rats bearing human primary BTIC-derived tumors and treated intranasally with BMP4/NP-hAMSCs showed significantly improved survival compared to those treated with control GFP/NP-hAMCSs. This study demonstrates that synthetic polymeric nanoparticles are a safe and effective approach for stem cell-based cancer-targeting therapies.


A case of fulminant type 1 diabetes associated with acute renal failure.
A 56-year-old man suffered from severe diabetic ketoacidosis which was complicated by acute renal failure and rhabdomyolysis. Before admission the patient had had flu-like symptoms for 5 days and had developed polyuria and polydipsia. The clinical examination on admission showed his plasma glucose level was 80.65 mmol/L while the HbA1c was 7.4%. His amylase concentration was high without any signs of pancreatitis. The islet-associated autoantibodies (GAD antibody, islet cell antibody) were absent. These data were compatible with the diagnosis of fulminant type 1 diabetes. A continuous intravenous insulin infusion therapy was given during the acute phase to control hyperglycemia and ketoacidosis. This patient remained dependent on continuous veno-venous hemofiltration (CVVHF) for 5 days, followed by regular kidney dialysis for three times, before his renal function was finally recovered. To conclude, this is a rare case of abrupt onset fulminant type 1 diabetes with the onset of acute renal failure. Hence, early detection, quick diagnosis and immediate treatment are very important. In particular, prompt CVVHF and kidney dialysis are required and useful for rescuing the renal function.


Stage B prostate adenocarcinoma. Flow cytometric nuclear DNA ploidy analysis.
Over a 16-year period (1966 to 1981), 349 patients underwent radical retropubic prostatectomy for pathologic stage B adenocarcinoma of the prostate. Nuclear DNA content was measured by flow cytometry on available archival material of 283 patients. Two hundred sixty-one patients (92%) had high-quality histograms. The ploidy distribution was as follows: DNA diploid, 177 (68%); DNA tetraploid, 74 (28%); and DNA aneuploid, 10 (4%). The average follow-up was 9.4 years. At the time of follow-up, 53 patients (20%) within the study group had developed tumor progression: 22 local, 23 systemic, and 8 both. The ploidy distribution of the population that developed tumor progression was 27 DNA diploid (51%), 16 DNA tetraploid (30%), and 10 DNA aneuploid (19%). This ploidy distribution is significantly different from that found for the nonprogression group with stage B disease. Overall, 31% of patients with DNA nondiploid tumors had tumors that progressed compared with 15% of patients with DNA diploid tumors. All (100%) DNA aneuploid tumors progressed. The DNA ploidy distribution of all pathologic stage B prostate cancers differs significantly from that found in more advanced stages (C and D1) previously reported for the same time interval. However, the ploidy distribution of stage B tumors that progressed closely resembles that of the stage C and D1 tumors. These results further support the working hypothesis that nuclear DNA content has marked prognostic significance for patients with adenocarcinoma of the prostate. It seems to us that analysis of ploidy by flow or static cytometry will become an essential tool for treating patients with localized prostate cancer.


Uncovering hidden in vivo resonances using editing based on localized TOCSY.
A novel single-shot spectral editing technique for in vivo proton NMR is proposed to recover resonances of low-concentration metabolites obscured by very strong resonances. With this new method, editing is performed by transferring transverse magnetization to J-coupled spins from selected coupling partners using a homonuclear Hartmann-Hahn polarization transfer with adiabatic pulses. The current implementation uses 1D-TOCSY with single-voxel localization based on LASER to recover the H1 proton of beta-glucose at 4.63 ppm from under water and the lactate methyl resonances from beneath a strong lipid signal. The method can be extended to further spin systems where conventional editing methods are difficult to perform.


Suitability of written supplemental materials available on the Internet for nonprescription medications.
The suitability, readability, and cultural appropriateness of written supplemental materials available on the Internet for nonprescription medications were examined. We videotaped 48 hours of television programming, recording a total of 152 advertisements highlighting 37 unique nonprescription medications. The supplemental materials corresponding to each advertised medication were downloaded and printed in their entirety from each product-specific Web site. These materials were assessed using the Suitability Assessment of Materials (SAM) instrument. Total SAM scores were grouped as follows: not suitable (0-39%), adequate (40-69%), and superior (70-100%). The Fry readability formula was used to determine the reading grade level for the materials assessed with the SAM instrument. The mean +/- S.D. SAM score of all materials was 54.9% +/- 0.1% (range, 38-76%). Materials for the majority of drugs (86.5%, n = 32) were rated adequate. Materials for four drugs (10.8%) were rated superior, and the material for one drug was not suitable. While the total SAM scores were adequate for most of the materials evaluated, the majority of materials scored particularly poorly for their reading level (the materials for 81.1% of drugs were not suitable). The materials for 40.9% of drugs used uncommon words. Evaluation of the suitability, readability, and cultural appropriateness of written supplemental materials for nonprescription medications available on manufacturer-sponsored Web sites and intended for consumers or patients revealed that SAM scores were adequate for most of the materials; however, many scored poorly in the areas of reading level and used uncommon words.


Lobar lung transplantation from deceased donors: A systematic review.
To systematically review reports on deceased-donor-lobar lung transplantation (ddLLTx) and uniformly describe size matching using the donor-to-recipient predicted-total lung-capacity (pTLC) ratio. We set out to systematically review reports on ddLLTx and uniformly describe size matching using the donor-to-recipient pTLC ratio and to summarize reported one-year survival data of ddLLTx and conventional-LTx. We searched in PubMed, CINAHL via EBSCO, Cochrane Database of Systematic Reviews via Wiley (CDSR), Database of Abstracts of Reviews of Effects via Wiley (DARE), Cochrane Central Register of Controlled Trials via Wiley (CENTRAL), Scopus (which includes EMBASE abstracts), and Web of Science for original reports on ddLLTx. Nine observational cohort studies reporting on 301 ddLLTx met our inclusion criteria for systematic review of size matching, and eight for describing one-year-survival. The ddLLTx-group was often characterized by high acuity; however there was heterogeneity in transplant indications and pre-operative characteristics between studies. Data to calculate the pTLC ratio was available for 242 ddLLTx (80%). The mean pTLCratio before lobar resection was 1.25 ± 0.3 and the transplanted pTLCratio after lobar resection was 0.76 ± 0.2. One-year survival in the ddLLTx-group ranged from 50%-100%, compared to 72%-88% in the conventional-LTx group. In the largest study ddLLTx (n = 138) was associated with a lower one-year-survival compared to conventional-LTx (n = 539) (65.1% vs 84.1%, P < 0.001). Further investigations of optimal donor-to-recipient size matching parameters for ddLLTx could improve outcomes of this important surgical option.


Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients.
Recent studies have suggested that CD4(+)CD25(+) regulatory T cells (Treg) are increased and linked to compromised immune responses in patients with hepatocellular carcinoma (HCC). This study attempted to further characterize CD4(+)CD25(+) forkhead/winged helix transcription factor (FoxP3)(+) Treg in blood, tumor, and nontumor liver tissues of HCC patients, and to understand how the Treg affects immune responses and contributes to disease progression. A total of 123 HCC patients with chronic hepatitis B virus (HBV) infection, 21 HBV-related liver cirrhosis (LC) patients, and 47 normal controls were enrolled randomly. Flow cytometric, immunohistochemical, and immunosuppressive assays were used for analyses of properties of Treg. Multivariate analysis of prognostic factors for overall survival was performed using the Cox proportional hazards model. Circulating CD4(+)CD25(+)FoxP3(+) Treg frequency was increased significantly and correlated with disease progression in HCC patients. An abundant accumulation of Treg concurrent with significantly reduced infiltration of CD8(+) T cells was found in tumor regions compared with nontumor regions. Expression of granzyme A, granzyme B, and perforin was decreased dramatically in tumor-infiltrating CD8(+) T cells. Furthermore, Treg of HCC patients inhibited proliferation, activation, degranulation, and production of granzyme A, granzyme B, and perforin of CD8(+) T cells induced by anti-CD3/CD28 antibodies. Importantly, an increased quantity of circulating Treg was associated with high mortality and reduced survival time of HCC patients. Increased CD4(+)CD25(+)FoxP3(+) Treg may impair the effector function of CD8(+) T cells, promote disease progression, and represent both a potential prognostic marker and a therapeutic target for HBV-related HCC individuals.


Methods and timing of curricular integration in U.S. dental education in preparation for the Integrated National Board Dental Examination.
To characterize methods, timing, faculty training, and barriers pertaining to curricular integration in preparation for the Integrated National Board Dental Examination (INBDE) at U.S. dental schools METHODS: Academic deans at 67 U.S. dental schools were emailed an online survey consisting of questions on the time frame and methods of curricular integration, faculty training, and barriers to curricular integration RESULTS: Approximately 86% of schools have implemented (∼39%) or will implement (∼61%) changes in curriculum in preparation for the INBDE. Curricular integration was completed in 3-4 years in most schools, with those schools with larger class sizes taking longer. While 56% of respondents reported avoiding a complete curricular overhaul, 79% reported course sequencing changes, adding, subtracting, or combining courses, and making some changes in existing courses. Curriculum committees had the most input in curricular changes, while individual instructors had the least influence. Sixty seven percent of respondents reported faculty being trained to teach in an integrated curriculum. Problem/case-based learning and clinical case presentations are being used more for incorporation of biomedical sciences in clinical curriculum; use of clinical examples was the most used mechanism to integrate clinical information in biomedical sciences curriculum. Eighty two percent of respondents indicated that lack of faculty time to prepare courses as the primary barrier for implementing an integrated curriculum. Our results show that most U.S. dental schools are implementing integrated teaching models to prepare their students for the INBDE. However, lack of faculty time and training need to be addressed for more successful curricular integration.


Corticomotoneuronal function and hyperexcitability in acquired neuromyotonia.
Acquired neuromyotonia encompasses a group of inflammatory disorders characterized by symptoms reflecting peripheral nerve hyperexcitability, which may be clinically confused in the early stages with amyotrophic lateral sclerosis. Despite a clear peripheral nerve focus, it remains unclear whether the ectopic activity in acquired neuromyotonia receives a central contribution. To clarify whether cortical hyperexcitability contributes to development of clinical features of acquired neuromyotonia, the present study investigated whether threshold tracking transcranial magnetic stimulation could detect cortical hyperexcitability in acquired neuromyotonia, and whether this technique could differentiate acquired neuromyotonia from amyotrophic lateral sclerosis. Cortical excitability studies were undertaken in 18 patients with acquired neuromyotonia and 104 patients with amyotrophic lateral sclerosis, with results compared to 62 normal controls. Short-interval intracortical inhibition in patients with acquired neuromyotonia was significantly different when compared to patients with amyotrophic lateral sclerosis (averaged short interval intracortical inhibition acquired neuromyotonia 11.3 +/- 1.9%; amyotrophic lateral sclerosis 2.6 +/- 0.9%, P < 0.001). In addition, the motor evoked potential amplitudes (acquired neuromyotonia 21.0 +/- 3.1%; amyotrophic lateral sclerosis 38.1 +/- 2.2%, P < 0.0001), intracortical facilitation (acquired neuromyotonia -0.9 +/- 1.3%; amyotrophic lateral sclerosis -2.3 +/- 0.6%, P < 0.0001), resting motor thresholds (acquired neuromyotonia 62.2 +/- 1.6%; amyotrophic lateral sclerosis 57.2 +/- 0.9%, P < 0.05) and cortical silent period durations (acquired neuromyotonia 212.8 +/- 6.9 ms; amyotrophic lateral sclerosis 181.1 +/- 4.3 ms, P < 0.0001) were significantly different between patients with acquired neuromyotonia and amyotrophic lateral sclerosis. Threshold tracking transcranial magnetic stimulation established corticomotoneuronal integrity in acquired neuromyotonia, arguing against a contribution of central processes to the development of nerve hyperexcitability in acquired neuromyotonia.


The impact of dyslipidaemia on cardiovascular mortality in individuals without a prior history of diabetes in the DECODE Study.
To evaluate the impact of dyslipidaemia on cardiovascular disease (CVD) mortality in relation to fasting (FPG) and 2-h (2hPG) plasma glucose levels in individuals without a prior history of diabetes. Data from 14 European population-based prospective studies of 9132 men and 8631 women aged 25-89 years were jointly analysed. A total of 871 CVD deaths occurred during the average 10 years of follow-up. Subjects were classified into normoglycaemia, isolated fasting hyperglycaemia (IFH, FPG> or =6.10 mmol/l and 2hPG<7.80 mmol/l), isolated post-load hyperglycaemia (IPH, FPG<6.10 mmol/l and 2hPG> or =7.80 mmol/l) and combined fasting and post-load hyperglycaemia (CH, FPG> or =6.10 mmol/l and 2hPG> or =7.80 mmol/l). Multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD mortality were estimated using Cox proportional hazard analysis. Multivariate-adjusted HRs (95% CIs) for high-density lipoprotein cholesterol (HDL-C) were 0.84 (0.75-0.94), 0.66 (0.48-0.92), 1.03 (0.84-1.27) and 0.67 (0.51-0.89) in individuals with normoglycaemia, IFH, IPH and CH, respectively. For total cholesterol (TC) to HDL-C ratio they were 1.14 (1.03-1.27), 1.44 (1.13-1.84), 0.94 (0.77-1.15) and 1.26 (1.05-1.50), respectively. HRs for TC and triglycerides (TG) were not significant in most of the glucose categories except for TG in those with CH [HR 1.12 (1.00-1.27)]. Low HDL-C and high TC/HDL-C increase CVD mortality in either diabetic or non-diabetic individuals defined based on the fasting glucose criteria, but not the 2-h criteria. TG is a significant CVD risk predictor only in the presence of combined hyperglycaemia or diabetes. The difference between fasting and post-load hyperglycaemia with regard to the lipid-CVD relation may suggest a different pathophysiology underlying these two prediabetic states.


A literature review of indirect costs associated with stroke.
Stroke is a leading cause of mortality and long-term disability. However, the indirect costs of stroke, such as productivity loss and costs of informal care, have not been well studied. To better understand this, we conducted a literature review of the indirect costs of stroke. A literature search using PubMed, MEDLINE, and EconLit, with the key words stroke, cerebrovascular disease, subarachnoid hemorrhage, intracerebral hemorrhage, cost-of-illness, productivity loss, indirect cost, economic burden, and informal caregiving was conducted. We identified original research articles published during 1990-2012 in English-language peer-reviewed journals. We summarized indirect costs by study type, cost categories, and study settings. We found 31 original research articles that investigated the indirect cost of stroke. Six of these investigated indirect costs only; the other 25 studies were cost-of-illness studies that included indirect costs as a component. Of the 31 articles, 6 examined indirect costs in the United States, with 2 of these focused solely on indirect costs. Because of diverse methods, kinds of data, and definitions of cost used in the studies, the literature indicated a very wide range internationally in the proportion of the total cost of stroke that is represented by indirect costs (from 3% to 71%). Most of the literature indicates that indirect costs account for a significant portion of the economic burden of stroke, and there is a pressing need to develop proper approaches to analyze these costs and to make better use of relevant data sources for such studies or establish new ones.


Arcicella rigui sp. nov., isolated from water of a wetland, and emended descriptions of the genus Arcicella, Arcicella aquatica, Arcicella rosea and Arcicella aurantiaca.
A bacterial strain, designated NSW-5(T), was isolated from a water sample taken from Niao-Song Wetland Park in Taiwan and characterized using a polyphasic taxonomic approach. Cells of strain NSW-5(T) were strictly aerobic, Gram-stain-negative, non-motile and polymorphic, being straight, vibrioid, curved and spiral-shaped rods surrounded by a thick capsule and forming light pink-coloured colonies. Some rings consisting of several cells were present. Growth occurred at 10-40 °C (optimum, 25 °C), with 0-3.0 % NaCl (optimum, 0 %) and at pH 6.0-8.0 (optimum, pH 7.0). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain NSW-5(T) belonged to the genus Arcicella with sequence similarities of 98.6, 98.0 and 97.3 % with Arcicella aquatica NO-502(T), Arcicella rosea TW5(T) and Arcicella aurantiaca TNR-18(T), respectively. The predominant cellular fatty acids were summed feature 3 (C(16 : 1)ω7c and/or C(16 : 1)ω6c; 20.8 %), C(16 : 0) (14.6 %), iso-C(15 : 0) (13.8 %), C(16 : 1)ω5c (12.5 %) and C(18 : 0) (11.4 %), and the only respiratory quinone was MK-7. The polar lipid profile consisted of phosphatidylethanolamine and several uncharacterized glycolipids, aminolipids, phospholipids and aminophospholipids. The DNA G+C content of strain NSW-5(T) was 44.1 mol%. The DNA-DNA relatedness of strain NSW-5(T) with respect to recognized species of the genus Arcicella was less than 70 %. On the basis of phylogenetic inference and phenotypic data, strain NSW-5(T) should be classified as a representative of a novel species, for which the name Arcicella rigui sp. nov. is proposed. The type strain is NSW-5(T) (= KCTC 23307(T) = BCRC 80260(T)). Emended descriptions of the genus Arcicella and of Arcicella aquatica, Arcicella rosea and Arcicella aurantiaca are also proposed.


What Doesn't Kill You Doesn't Make You Stronger: The Long-Term Consequences of Nonfatal Injury for Older Adults.
The majority of research efforts centering on injury among older adults focus on fall-related injuries and short-term consequences of injury. Little is known about the long-term consequences of all-cause nonfatal injuries, including minor injuries. Using a recent, large, and nationally representative sample of the U.S. non-institutionalized civilian population, the current study examines whether older adults who sustained a nonfatal injury (serious and minor) have higher risk of long-term morbidity and mortality outcomes compared with noninjured seniors. Linked National Health Interview Survey-Medical Expenditure Panel Survey (NHIS-MEPS) data were used to fit logistic and 2-part models to estimate associations between injury incidence and later injury, hospitalization incidence, and length of hospital stay during the 2.5 years following the NHIS interview among 16,109 older adults. Data from the linked National Health Interview Survey-National Death Index (NHIS-NDI) files were used to estimate a Cox proportional hazards model to examine the association between injury incidence and mortality for up to 11 years after the initial interview among 79,504 older adults. Relative to no injury, serious nonfatal injury was significantly associated with increased risk of another injury, hospitalization, and mortality. Minor injuries were significantly related to higher risk of later injury and mortality. Because even minor injuries are strongly associated with increased risks of later injury and mortality, preventing injury among seniors may be an effective way to improve quality of life and reduce declines in functional capacity.


Mechanical strength of the side-to-side versus Pulvertaft weave tendon repair.
The side-to-side (SS) tendon suture technique was designed to function as a repair that permits immediate postoperative activation and mobilization of a transferred muscle. This study was designed to test the strength and stiffness of the SS technique against a variation of the Pulvertaft (PT) repair technique. Flexor digitorum superficialis (FDS) and flexor digitorum profundus (FDP) tendons were harvested from 4 fresh cadavers and used as a model system. Seven SS and 6 PT repairs were performed, using the FDS as the donor and the FDP as the recipient tendon. For SS repairs, the FDS was woven through one incision in the FDP and was joined with 4 cross-stitch running sutures down both sides and one double-loop suture at each tendon free end. For PT repairs, the FDS was woven through 3 incisions in the FDP and joined with a double-loop suture at both ends of the overlap and 4 evenly spaced mattress sutures between the ends. Tendon repairs were placed in a tensile testing machine, preconditioned, and tested to failure. There were no statistically significant differences in cross-sectional area (p = .99) or initial length (p = .93) between SS and PT repairs. Therefore, all comparisons between methods were made using measures of loads and deformations, rather than stresses and strains. All failures occurred in the repair region, rather than at the clamps. However, failure mechanisms were different between the 2 techniques-PT repairs failed by the suture knots either slipping or pulling through the tendon material, followed by the FDS tendon pulling through the FDP tendon; SS repairs failed by shearing of fibers within the FDS. Load at first failure, ultimate load, and repair stiffness were all significantly different between SS and PT techniques; in all cases, the mean value for SS was higher than for PT. The SS repair using a cross-stitch suture technique was significantly stronger and stiffer than the PT repair using a mattress suture technique. This suggests that using SS repairs could enable patients to load the repair soon after surgery. Ultimately, this should reduce the risk of developing adhesions and result in improved functional outcome and fewer complications in the acute postoperative period. Future work will address the specific mechanisms (eg, suture-throw technique and tendon-weave technique) that underlie the improved strength and stiffness of the SS repair.


Association of Neck Range of Motion and Skin Caliper Measures on Dysphagia Outcomes in Head and Neck Cancer and Effects of Neck Stretches and Swallowing Exercises.
To date, there is a paucity of information in the literature regarding the association between cervical range of motion (CROM) and skin caliper measures (SCM) and swallowing outcomes in post-RT individuals with head and neck cancer. Also lacking in the literature are reports of the effect of swallowing exercises and neck stretches on changes in CROM and SCM and their associations with swallowing outcomes. The aim of this study was to assess the associations between CROM and SCM before initiation of a neck stretching and swallowing exercise program and to determine if 12 weeks of twice daily practice changes in CROM and SCM were associated with changes in swallowing outcomes in a cohort of 119 head and neck cancer survivors. Primary results revealed that at baseline, greater right and left CROM were associated with lower penetration aspiration scale (PAS) scores (r = - 0.321, p = < 0.001; r = - 0.203, p = 0.026, respectively). Improved skin pliability revealed lower PAS scores (r = - 0.210, p = 0.022). After 12 weeks, there were no significant correlations between changes in CROM and SCM and PAS scores. Changes in left CROM and CROM extension had positive associations with the Head and Neck Cancer Inventory eating score (r = 0.210, p = 0.026; r = 0.245, p = 0.009, respectively). Findings appear to indicate that any improvement was not associated with changes in swallowing outcomes. Head and neck cancer survivors may perceive improved diet and swallowing skills through exercise, with respect to improved CROM extension.


The long noncoding RNA HOXA11 antisense induces tumor progression and stemness maintenance in cervical cancer.
Recent research has focused on the impact of long noncoding RNA (lncRNA) in cervical carcinogenesis. However, whether HOXA11 antisense (HOXA11-AS) is involved in cervical cancer remains to be elucidated. In the present study, we examined HOXA11-AS expression levels in cervical cancer patients and determined the relationships between HOXA11-AS expression and clinicopathological factors. We also investigated the bio-functional consequences of HOXA11-AS overexpression both in vitro and in vivo. HOXA11-AS expression was significantly greater in tissues from patients with cervical cancer than in control patients (P<0.001). Multivariate analysis showed that high HOXA11-AS was an independent prognosticator of overall survival (Hazard ratio=2.450, P=0.032). HOXA11-AS overexpression enhanced cell proliferation, migration, and tumor invasion in vitro, whereas HOXA11-AS knockdown inhibited these biologic aggressive features. These adverse changes were accompanied by characteristics of epithelial-mesenchymal transition (EMT). In vivo xenograft experiments using the siHOXA11-AS-transfected HeLa cells revealed that HOXA11-AS strongly induced tumor growth. Furthermore, we found that HOXA11-AS knockdown decreased cancer stemness and triggered the EMT program. In conclusion, HOXA11-AS overexpression correlated with poor survival in patients with cervical cancer. Thus, HOXA11-AS may be a pivotal target for exploring novel cervical cancer therapeutics.


PET imaging of tumours with a 64Cu labeled macrobicyclic cage amine ligand tethered to Tyr3-octreotate.
The use of copper radioisotopes in cancer diagnosis and radionuclide therapy is possible using chelators that are capable of binding Cu(II) with sufficient stability in vivo to provide high tumour-to-background contrast. Here we report the design and synthesis of a new bifunctional chelator, 5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid (MeCOSar), that forms copper complexes of exceptional stability by virtue of a cage amine (sarcophagine) ligand and a new conjugate referred to as SarTATE, obtained by the conjugation of MeCOSar to the tumour-targeting peptide Tyr(3)-octreotate. Radiolabeling of SarTATE with (64)Cu(II), a radioisotope suitable for positron emission tomography (PET), was fast (~20 min), easily performed at room temperature and consistently resulted in high radiochemical purity (>99%). In vitro and in vivo evaluation of (64)CuSarTATE demonstrated its high selectivity for tumour cells expressing somatostatin receptor 2 (sstr2). Biodistribution and PET imaging comparisons were made between (64)CuSarTATE and (64)Cu-labeled DOTA-Tyr(3)-octreotate ((64)CuDOTATATE). Both radiopharmaceuticals showed excellent uptake in sstr2-positive tumours at 2 h post-injection. While tumour uptake of (64)CuDOTATATE decreased significantly at 24 h, (64)CuSarTATE activity was retained, improving contrast at later time points. (64)CuSarTATE accumulated less than (64)CuDOTATATE in the non-target organs, liver and lungs. The uptake of (64)CuSarTATE in the kidneys was high at 2 h but showed significant clearance by 24 h. The new chemistry and pre-clinical evaluation presented here demonstrates that MeCOSar is a promising bifunctional chelator for Tyr(3)-octreotate that could be applied to a combined imaging and therapeutic regimen using a combination of (64)Cu- and (67)CuSarTATE complexes, owing to improved tumour-to-non-target organ ratios compared to (64)CuDOTATATE at longer time points.


Far-infrared tangential interferometer/polarimeter design and installation for NSTX-U.
The Far-infrared Tangential Interferometer/Polarimeter (FIReTIP) system has been refurbished and is being reinstalled on the National Spherical Torus Experiment-Upgrade (NSTX-U) to supply real-time line-integrated core electron density measurements for use in the NSTX-U plasma control system (PCS) to facilitate real-time density feedback control of the NSTX-U plasma. Inclusion of a visible light heterodyne interferometer in the FIReTIP system allows for real-time vibration compensation due to movement of an internally mounted retroreflector and the FIReTIP front-end optics. Real-time signal correction is achieved through use of a National Instruments CompactRIO field-programmable gate array.


Investigation of the predictive validity of laser-EPs in normal, UVB-inflamed and capsaicin-irritated skin with four analgesic compounds in healthy volunteers.
The aim of the present study was to assess the predictivity of laser-(radiant-heat)-evoked potentials (LEPs) from the vertex electroencephalogram, using an algesimetric procedure, testing the anti-nociceptive/anti-hyperalgesic effects of single oral doses of four marketed analgesics (of different compound classes) vs. placebo, in healthy volunteers with three skin types. This was a randomized, placebo-controlled, single-blind, five-way-crossover trial. Twenty-five healthy male/female Caucasians were included (receiving celecoxib 200 mg, pregabalin 150 mg, duloxetine 60 mg, lacosamide 100 mg or placebo) in a Williams design, with CO2 laser-induced painful stimuli to normal, ultraviolet (UV) B-inflamed and capsaicin-irritated skin. LEPs and visual analogue scale ratings were taken at baseline and hourly for 6 h postdose from all three skin types. In normal skin, the averaged postdose LEP peak-to-peak-(PtP)-amplitudes were reduced by pregabalin (-2.68 μV; 95% confidence interval (CI) -4.16, 1.19) and duloxetine (-1.73 μV; 95% CI -3.21, -0.26) but not by lacosamide and celecoxib vs. placebo. On UVB-irradiated skin, reflecting inflammatory pain, celecoxib induced a pronounced reduction in LEP PtP amplitudes vs. placebo (-6.2 μV; 95% CI -7.88, -4.51), with a smaller reduction by duloxetine (-4.54 μV; 95% CI -6.21, -2.87) and pregabalin (-3.72 μV; 95% CI -5.40, -2.04), whereas lacosamide was inactive. LEP PtP amplitudes on capsaicin-irritated skin, reflecting peripheral/spinal sensitization, as in neuropathic pain, were reduced by pregabalin (-3.78 μV; 95% CI -5.31, -2.25) and duloxetine (-2.32 μV; 95% CI -3.82, -0.82) but not by celecoxib or lacosamide vs. placebo, which was in agreement with known clinical profiles. Overall, PtP amplitude reductions were in agreement with subjective ratings. LEP algesimetry is sensitive to analgesics with different modes of action and may enable the effects of novel analgesics to be assessed during early clinical development.