The First Co-Opted Endogenous Foamy Viruses and the Evolutionary History of Reptilian Foamy Viruses.
A recent study reported the discovery of an endogenous reptilian foamy virus (FV), termed ERV-Spuma-Spu, found in the genome of tuatara. Here, we report two novel reptilian foamy viruses also identified as endogenous FVs (EFVs) in the genomes of panther gecko (ERV-Spuma-Ppi) and Schlegel's Japanese gecko (ERV-Spuma-Gja). Their presence indicates that FVs are capable of infecting reptiles in addition to mammals, amphibians, and fish. Numerous copies of full length ERV-Spuma-Spu elements were found in the tuatara genome littered with in-frame stop codons and transposable elements, suggesting that they are indeed endogenous and are not functional. ERV-Spuma-Ppi and ERV-Spuma-Gja, on the other hand, consist solely of a foamy virus-like env gene. Examination of host flanking sequences revealed that they are orthologous, and despite being more than 96 million years old, their env reading frames are fully coding competent with evidence for strong purifying selection to maintain expression and for them likely being transcriptionally active. These make them the oldest EFVs discovered thus far and the first documented EFVs that may have been co-opted for potential cellular functions. Phylogenetic analyses revealed a complex virus-host co-evolutionary history and cross-species transmission routes of ancient FVs.


Cellular immunity in Q fever: modulation of responsiveness by a suppressor T cell-monocyte circuit.
Human infection with the rickettsia Coxiella burnetii presents as an acute flulike primary Q fever, as a subacute granulomatous hepatitis, or, rarely, as chronic endocarditis. We have previously described lymphocyte unresponsiveness to Coxiella antigen in patients with Q fever endocarditis. This unresponsiveness was antigen specific and was mediated in part by adherent suppressor cells. In this report we show that the adherent suppressor cells work via prostaglandin E2 (PGE2)4 production. Addition of the cyclooxygenase inhibitor indomethacin to cultures of PBMC from patients with endocarditis or chronic laboratory exposure resulted in consistent increases in Coxiella-specific lymphocyte proliferation. The degree of increase in proliferation induced by indomethacin correlated strongly with the amount of PGE2 produced in a 4-hr culture stimulated by Coxiella antigen, but it also correlated with the sensitivity to inhibition of mitogenesis by PGE2. The suppressor mechanism was antigen nonspecific, because induction of suppression in vitro by Coxiella antigen also suppressed Candida-induced proliferation when both antigens were present in the same culture. Addition of indomethacin to these antigen cocultures totally reversed the Coxiella-induced suppression, confirming the evidence above that the nonspecific effector mechanism of suppression was prostaglandin (PG)-mediated. Elicitation of suppression, however, was antigen specific and involved a T cell-monocyte suppressor circuit. Supernatants from Coxiella-stimulated immune T cells and from the suppressor subset (OKT8+-enriched) of those T cells, but not unstimulated immune cells, induced augmented PGE2 production by unrelated nonimmune PBMC. We conclude that the lymphocyte unresponsiveness characterizing patients with Q fever endocarditis is modulated in part by an antigen-specific T suppressor cell which secretes a lymphokine to stimulate PGE2 production by adherent cells.


Familial mental retardation: a continuing dilemma.
The heterogeneous nature of mental retardation, as well as certain common practices of workers in the area, has resulted in a variety of conceptual am biguities. Considerable order could be brought to the area if, instead of viewing all retardates as a homogeneous group arbitrarily defined by some I.Q. score, workers would clearly distinguish between the group of retardates known to suffer from some organic defect and the larger group of retardates referred to as familial retardates. It is the etiology of familial retardation that currently constitutes the greatest mystery. A number of authorities have emphasized the need for employing recent polygenic models of inheritance in an effort to understand the familial retardate. While appreciating the importance of environment in affecting the distribution determined by genetic inheritance, these workers have argued that familial retardates are not essentially different from individuals of greater intellect, but represent, rather, the lower portion of the intellectual curve which reflects normal intellectual variability. As emphasized by the two-group approach, retardates with known physiological or organic defect are viewed as presenting a quite different etiological problem. The familial retardate, on the other hand, is seen as a perfectly normal expression of the population gene pool, of slower and more limited intellectual development than the individual of average intellect. This view generates the proposition that retardates and normals at the same general cognitive level-that is, of the same mental age-are similar in respect to their cognitive functioning. However, such a proposition runs headlong into findings that retardates and normals of the same mental age often differ in performance. Such findings have bolstered what is currently the most popular theoretical approach to retarded functioning-namely, the view that all retardates suffer from some specific defect which inheres in mental retardation and thus makes the retardate immutably "different" from normals, even when the general level of intellectual development is controlled. While these defect or difference approaches, as exemplified in the work of Luria, Spitz, Ellis, and Lewin and Kounin, dominate the area of mental retardation, the indirect, and therefore equivocal, nature of the evidence of these workers has generated considerable controversy. In contrast to this approach, the general developmental position has emphasized systematic evaluation of the role of experiential, motivational, and personality factors. As a central thesis, this position asserts that performance on experimental and real-life tasks is never the single inexorable product of the retardate's cognitive structure but, rather, reflects a wide variety of relatively nonintellective factors which greatly influence the general adequacy of performance. Thus, many of the reported behavioral differences between normals and retardates of the same mental age are seen as products of motivational and experiential differences between these groups, rather than as the result of any inherent cognitive deficiency in the retardates. Factors thought to be of particular importance in the behavior of the retardate are social deprivation and the positive- and negative-reaction tendencies to which such deprivation gives rise; the high number of failure experiences and the particular approach to problem-solving which they generate; and atypical reinforcer hierarchies. There is little question that we are witnessing a productive, exciting, and perhaps inevitably chaotic period in the history of man's concern with the problem of mental retardation. Even the disagreements that presently exist must be considered rather healthy phenomena. These disagreements will unquestionably generate new knowledge which, in the hands of practitioners, may become the vehicle through which the performance of children, regardless of intellectual level, may be improved.


Consensus recommendations for a dynamic susceptibility contrast MRI protocol for use in high-grade gliomas.
Despite the widespread clinical use of dynamic susceptibility contrast (DSC) MRI, DSC-MRI methodology has not been standardized, hindering its utilization for response assessment in multicenter trials. Recently, the DSC-MRI Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition issued an updated consensus DSC-MRI protocol compatible with the standardized brain tumor imaging protocol (BTIP) for high-grade gliomas that is increasingly used in the clinical setting and is the default MRI protocol for the National Clinical Trials Network. After reviewing the basis for controversy over DSC-MRI protocols, this paper provides evidence-based best practices for clinical DSC-MRI as determined by the Committee, including pulse sequence (gradient echo vs spin echo), BTIP-compliant contrast agent dosing (preload and bolus), flip angle (FA), echo time (TE), and post-processing leakage correction. In summary, full-dose preload, full-dose bolus dosing using intermediate (60°) FA and field strength-dependent TE (40-50 ms at 1.5 T, 20-35 ms at 3 T) provides overall best accuracy and precision for cerebral blood volume estimates. When single-dose contrast agent usage is desired, no-preload, full-dose bolus dosing using low FA (30°) and field strength-dependent TE provides excellent performance, with reduced contrast agent usage and elimination of potential systematic errors introduced by variations in preload dose and incubation time.


Can a media campaign change health service use in a population with stroke symptoms? Examination of the first Irish stroke awareness campaign.
Mass media campaigns for stroke awareness encourage the public to recognise stroke symptoms and respond to stroke in a timely manner. However, there is little evidence to suggest that media messages can influence behaviour after stroke onset. The F.A.S.T. (Face Arm Speech Time) test is a common stroke recognition tool used in public education campaigns. To assess the impact of the F.A.S.T. campaign on health service use in Ireland, which has had no previous exposure to a F.A.S.T. media campaign. An interrupted time series design was used to detect behaviour change after the introduction of the first Irish F.A.S.T. campaign in presentations of patients with suspected stroke to two emergency departments (EDs), serving a population of about 580 000. There was a significant change in ED attendance of patients with reported stroke symptoms after the introduction of the F.A.S.T. campaign (β=0.84, 95% CI 0.43 to 1.24; p<0.001), although this was not sustained. ED presentation within 3.5 h was associated with emergency medical services activation (OR=3.1, p<0.001) and self-referral to the ED (OR=2.67, p<0.001). This first Irish F.A.S.T. campaign had an initial impact on ED attendance of patients with stroke symptoms. However, the campaign effects were not sustained in the long term. Results indicate that prehospital delay in accessing acute stroke services is a complex process with involvement of factors other than stroke knowledge and intention to call 911.


Brain-targeted solid lipid nanoparticles containing riluzole: preparation, characterization and biodistribution.
Developments within nanomedicine have revealed a great potential for drug delivery to the brain. In this study nanoparticulate systems as drug carriers for riluzole, with sufficiently high loading capacity and small particle size, were prepared to a reach therapeutic drug level in the brain. Solid lipid nanoparticles containing riluzole have great potential as drug-delivery systems for amyotrophic lateral sclerosis and were produced by using the warm oil-in-water microemulsion technique. The resulting systems obtained were approximately 88 nm in size and negatively charged. Drug-release profiles demonstrated that a drug release was dependent on medium pH. Biodistribution of riluzole blended into solid lipid nanoparticles was carried out after administration to rats and the results were compared with those obtained by riluzole aqueous dispersion administration. Rats were sacrificed at time intervals of 8, 16 and 30 h, and the riluzole concentration in the blood and organs such as the brain, liver, spleen, heart and kidney was determined. It was demonstrated that these solid lipid nanoparticles were able to successfully carry riluzole into the CNS. Moreover, a low drug biodistribution in organs such as the liver, spleen, heart, kidneys and lung was found when riluzole was administered as drug-loaded solid lipid nanoparticles. Riluzole-loaded solid lipid nanoparticles showed colloidal size and high drug loading, a greater efficacy than free riluzole in rats, a higher capability to carry the drug into the brain and a lower indiscriminate biodistribution.


Thermal conductivity and air-mediated losses in periodic porous silicon membranes at high temperatures.
Heat conduction in silicon can be effectively engineered by means of sub-micrometre porous thin free-standing membranes. Tunable thermal properties make these structures good candidates for integrated heat management units such as waste heat recovery, rectification or efficient heat dissipation. However, possible applications require detailed thermal characterisation at high temperatures which, up to now, has been an experimental challenge. In this work we use the contactless two-laser Raman thermometry to study heat dissipation in periodic porous membranes at high temperatures via lattice conduction and air-mediated losses. We find the reduction of the thermal conductivity and its temperature dependence closely correlated with the structure feature size. On the basis of two-phonon Raman spectra, we attribute this behaviour to diffuse (incoherent) phonon-boundary scattering. Furthermore, we investigate and quantify the heat dissipation via natural air-mediated cooling, which can be tuned by engineering the porosity.Nanostructuring of silicon allows acoustic phonon engineering, but the mechanism of related thermal transport in these structures is not fully understood. Here, the authors study the heat dissipation in silicon membranes with periodic nanoholes and show the importance of incoherent scattering.


Interactions of melatonin and its metabolites with the ABTS cation radical: extension of the radical scavenger cascade and formation of a novel class of oxidation products, C2-substituted 3-indolinones.
Melatonin had previously been shown to reduce up to four 2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid) cation radicals (ABTS*+) via a scavenger cascade ending with N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK). However, when melatonin is added to the reaction system in much lower quantities than ABTS*+, the number of radicals scavenged per melatonin molecule is considerably higher and can attain a value of ten. Under conditions allowing for such a stoichiometry, novel products have been detected which derive from AFMK (1). These were separated by repeated chromatography and the major compounds were characterized by spectroscopic methods, such as mass spectrometry (HPLC-MS, EI-MS and ESI-HRMS), 1H nuclear magnetic resonance (NMR) and 13C NMR, heteronuclear multiple bond connectivity (HMBC) correlations. The identified substances are formed by re-cyclization and represent 3-indolinones carrying the side chain at C2; the N-formyl group can be maintained, but deformylated analogs seem to be also generated, according to MS. The primary product from AFMK (1) is N-(1-formyl-5-methoxy-3-oxo-2,3-dihydro-1H-indol-2-ylidenemethyl)-acetamide (2), which is obtained after purification as E- and Z-isomers (2a, 2b); a secondary product has been identified as N-(1-formyl-2-hydroxy-5-methoxy-3-oxo-2,3-dihydro-1H-indol-2-ylmethyl)-acetamide (3). When H2O2 is added to the ABTS*+ reaction mixture in quantities not already leading to substantial reduction of this radical, compound 3 is isolated as the major product, whereas 2a and 2b are virtually absent. The substances formed differ from all previously known oxidation products which derive from melatonin and are, among these, the first 3-indolinones. Moreover, the aliphatic side chain at C2 is reminiscent of other substances which have been synthesized in the search for melatonin receptor ligands.


Meteorological influences on nitrogen dynamics of a coastal onsite wastewater treatment system.
On-site wastewater treatment systems (OWTS) can contribute nitrogen (N) to coastal waters. In coastal areas with shallow groundwater, OWTS are likely affected by meteorological events. However, the meteorological influences on temporal variability of N exports from OWTS are not well documented. Hydrogeological characterization and seasonal monitoring of wastewater and groundwater quality were conducted at a residence adjacent to the Pamlico River Estuary, North Carolina, during a 2-yr field study (October 2009-2011). Rainfall was elevated during the first study year, relative to the annual mean. In the second year, drought was followed by extreme precipitation from Hurricane Irene. Recent meteorological conditions influenced N speciation and concentrations in groundwater. Groundwater total dissolved nitrogen (TDN) beneath the OWTS drainfield was dominated by nitrate during the drought; during wetter periods, ammonium and organic N were common. Effective precipitation (precipitation [P] minus evapotranspiration [ET]) affected OWTS TDN exports because of its influence on groundwater recharge and discharge. Groundwater nitrate-N concentrations beneath the drainfield were typically higher than 10 mg/L when total biweekly precipitation was less than evapotranspiration (precipitation deficit: P < ET). Overall, groundwater TDN concentrations were elevated above background concentrations at distances >15 m downgradient of the drainfield. Although OWTS nitrate inputs caused elevated groundwater nitrate concentrations between the drainfield and the estuary, the majority of nitrate was attenuated via denitrification between the OWTS and 48 m to the estuary. However, DON originating from the OWTS was mobile and contributed to elevated TDN concentrations along the groundwater flowpath to the estuary.


HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury.
Acute lung injury (ALI) and the development of the multiple organ dysfunction syndrome (MODS) are major causes of death in trauma patients. Gut inflammation and loss of gut barrier function as a consequence of splanchnic ischemia-reperfusion (I/R) have been implicated as the initial triggering events that contribute to the development of the systemic inflammatory response, ALI, and MODS. Since hypoxia-inducible factor (HIF-1) is a key regulator of the physiological and pathophysiological response to hypoxia, we asked whether HIF-1 plays a proximal role in the induction of gut injury and subsequent lung injury. Utilizing partially HIF-1α-deficient mice in a global trauma hemorrhagic shock (T/HS) model, we found that HIF-1 activation was necessary for the development of gut injury and that the prevention of gut injury was associated with an abrogation of lung injury. Specifically, in vivo studies demonstrated that partial HIF-1α deficiency ameliorated T/HS-induced increases in intestinal permeability, bacterial translocation, and caspase-3 activation. Lastly, partial HIF-1α deficiency reduced TNF-α, IL-1β, cyclooxygenase-2, and inducible nitric oxide synthase levels in the ileal mucosa after T/HS whereas IL-1β mRNA levels were reduced in the lung after T/HS. This study indicates that prolonged intestinal HIF-1 activation is a proximal regulator of I/R-induced gut mucosal injury and gut-induced lung injury. Consequently, these results provide unique information on the initiating events in trauma-hemorrhagic shock-induced ALI and MODS as well as potential therapeutic insights.


Does Cannabis Use Influence Opioid Outcomes and Quality of Life Among Buprenorphine Maintained Patients? A Cross-sectional, Comparative Study.
Use of various psychoactive substances can influence outcomes of patients on opioid agonist treatment (OAT). While use of alcohol and cocaine has shown to adversely affect OAT results, associated cannabis use shows mixed results. This study aimed to assess the pattern of cannabis use among opioid-dependent patients maintained on buprenorphine. Additionally, the study compared the dose of buprenorphine, opioid-related craving and withdrawals, productivity, and also quality of life between those with and without recent (past 90-day) cannabis use. We collected data on demographic and drug use details in 100 randomly selected adult male patients attending a community drug treatment clinic, who were stabilized on buprenorphine for more than 3 months. Other measures included scores on World Health Organization (WHO)-Alcohol, Smoking and Substance Involvement Screening Tool and WHO-Quality of Life-Brief (WHOQOL-Bref) version. The average duration of maintenance treatment with buprenorphine was 96 months, with excellent compliance for buprenorphine (86.92 ± 9.58 days in 90 days). Thirty-five per cent had used cannabis in past 90 days, with lifetime use of cannabis in 77%. Participants using cannabis currently were on lower doses of buprenorphine (mean dose per day: 7.9 mg vs 8.9 mg; P = 0.04). Yet, there was no significant difference in the rates of opioid use or opioid withdrawals and craving between the 2 groups. Compliance to OAT, number of days of employment, daily earning, and WHOQOL-Bref scores in all domains were comparable between those with and without cannabis use. Duration of cannabis use, current use of alcohol, and dose of buprenorphine predicted current cannabis use in multivariable logistic regression analysis. Cannabis use does not negatively influence opioid outcomes among patients receiving buprenorphine maintenance treatment. There is no difference in productivity and quality of life between individuals maintained on buprenorphine with and without current cannabis use.


Fused in sarcoma (FUS) protein lacking nuclear localization signal (NLS) and major RNA binding motifs triggers proteinopathy and severe motor phenotype in transgenic mice.
Dysfunction of two structurally and functionally related proteins, FUS and TAR DNA-binding protein of 43 kDa (TDP-43), implicated in crucial steps of cellular RNA metabolism can cause amyotrophic lateral sclerosis (ALS) and certain other neurodegenerative diseases. The proteins are intrinsically aggregate-prone and form non-amyloid inclusions in the affected nervous tissues, but the role of these proteinaceous aggregates in disease onset and progression is still uncertain. To address this question, we designed a variant of FUS, FUS 1-359, which is predominantly cytoplasmic, highly aggregate-prone, and lacks a region responsible for RNA recognition and binding. Expression of FUS 1-359 in neurons of transgenic mice, at a level lower than that of endogenous FUS, triggers FUSopathy associated with severe damage of motor neurons and their axons, neuroinflammatory reaction, and eventual loss of selective motor neuron populations. These pathological changes cause abrupt development of a severe motor phenotype at the age of 2.5-4.5 months and death of affected animals within several days of onset. The pattern of pathology in transgenic FUS 1-359 mice recapitulates several key features of human ALS with the dynamics of the disease progression compressed in line with shorter mouse lifespan. Our data indicate that neuronal FUS aggregation is sufficient to cause ALS-like phenotype in transgenic mice.


High times, low sats: diffuse pulmonary infiltrates associated with chronic synthetic cannabinoid use.
In recent years, cases of severe adverse effects from recreational use of synthetic cannabinoids (SC) have established that these agents represent a novel toxicologic hazard. A 21-year-old male presenting as a vehicular trauma victim was noted with diffuse pulmonary infiltrates related to chronic inhalation of multiple synthetic cannabinoid-containing products. Chest imaging revealed bilateral, subacute lung infiltrates; histopathological analysis of bronchial and alveolar tissues revealed an inflammatory process. An extensive workup failed to identify infectious, malignant, autoimmune, or hematologic causes of the syndrome, and toxicological analysis of the blood and body fluids confirmed the presence of multiple synthetic cannabinoids and metabolites. The patient recovered after an 8-day ICU course, wherein he received antibiotics, steroids, and mechanical ventilation. This case contributes to the currently evolving knowledge about SC agents, adding a rarely described pulmonary complication to the growing list of adverse effects associated with these products.


Emergence of clonally related multidrug resistant Haemophilus influenzae with penicillin-binding protein 3-mediated resistance to extended-spectrum cephalosporins, Norway, 2006 to 2013.
Resistance to cephalosporins in Haemophilus influenzae is usually caused by characteristic alterations in penicillin-binding protein 3 (PBP3), encoded by the ftsI gene. Resistance to extended-spectrum cephalosporins is associated with high-level PBP3-mediated resistance (high-rPBP3), defined by the second stage S385T substitution in addition to a first stage substitution (R517H or N526K). The third stage L389F substitution is present in some high-rPBP3 strains. High-rPBP3 H. influenzae are considered rare outside Japan and Korea. In this study, 30 high-rPBP3 isolates from Norway, collected between 2006 and 2013, were examined by serotyping, multilocus sequence typing (MLST), ftsI sequencing, detection of beta-lactamase genes and minimum inhibitory concentration (MIC) determination. MICs were interpreted according to clinical breakpoints from the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Respiratory isolates predominated (proportion: 24/30). The 30 isolates included one serotype f isolate, while the remaining 29 lacked polysaccharide capsule genes. Resistance to extended-spectrum cephalosporins (cefixime, 29 isolates/30 isolates; cefepime, 28/30; cefotaxime, 26 /30; ceftaroline, 26/30; ceftriaxone, 14/30), beta-lactamase production (11/30) and co-resistance to non-beta-lactams (trimethoprim-sulfamethoxazole, 13/30; tetracycline, 4/30; chloramphenicol, 4/30; ciprofloxacin, 3/30) was frequent. The N526K substitution in PBP3 was present in 23 of 30 isolates; these included a blood isolate which represents the first invasive S385T + N526K isolate reported from Europe. The L389F substitution, present in 16 of 30 isolates, coincided with higher beta-lactam MICs. Non-susceptibility to meropenem was frequent in S385T + L389F + N526K isolates (8/12). All 11 beta-lactamase positive isolates were TEM-1. Five clonal groups of two to 10 isolates with identical MLST-ftsI allelic profiles were observed, including the first reported high-rPBP3 clone with TEM-1 beta-lactamase and co-resistance to ciprofloxacin, tetracycline, chloramphenicol and trimethoprim-sulfamethoxazole. Prior to this study, no multidrug resistant high-rPBP3 H. influenzae had been reported in Norway. Intensified surveillance of antimicrobial resistance is needed to guide empiric therapy.


Measuring hand preference: a comparison among different response formats using a selected sample.
Hand preference (HP) is a major behavioural variable for inferring individual differences in neurological organisation. Yet, despite the extensive use of HP measures for both research and clinical purposes, there is little research on the properties of the structural features of HP questionnaires, the most common method of HP measurement. We study here the effects of different response formats of HP questionnaires on participants' responses. A total of 200 volunteers (100 left-handers, 50 male; 100 right-handers, 50 male) completed two versions of a composite HP questionnaire containing the items of the Annett, Edinburgh, Healy, and Waterloo instruments, one with a binary response format and the other with a 5-point graded response format. The tendency towards extreme responses and the mapping between a graded either response and a binary left/right response were investigated. It was found that both patterns were significantly influenced by participant handedness, but not by sex. Finally, in terms of the overall ordering of participants by HP measures, considerable consistency was found across questionnaire content and response format.


Viral RNA induces type I interferon-dependent cytokine release and cell death in mesangial cells via melanoma-differentiation-associated gene-5: Implications for viral infection-associated glomerulonephritis.
Viral RNA can trigger interferon signaling in dendritic cells via the innate recognition receptors melanoma-differentiation-associated gene (MDA)-5 and retinod-inducible gene (RIG)-I in the cytosol or via Toll-like receptors (TLRs) in intracellular endosomes. We hypothesized that viral RNA would also activate glomerular mesangial cells to produce type I interferon (IFN) via TLR-dependent and TLR-independent pathways. To test this hypothesis, we examined Toll/Interleukin-1 receptor domain-containing adaptor-inducing interferon-beta (TRIF)-deficient mice, which lack a key adaptor for TLR3 signaling. In primary mesangial cells, poly I:C RNA-mediated IFN-beta induction was partially TRIF dependent; however, when poly I:C RNA was complexed with cationic lipids to enhance cytosolic uptake, mesangial cells produced large amounts of IFN-alpha and IFN-beta independent of TRIF. Mesangial cells expressed RIG-I and MDA-5 and their mitochondrial adaptor IFN-beta promoter stimulator-1 as well, and small interfering RNA studies revealed that MDA5 but not RIG-I was required for cytosolic poly I:C RNA signaling. In addition, mesangial cells produced Il-6 on stimulation with IFN-alpha and IFN-beta, suggesting an autocrine proinflammatory effect. Indeed, blockade of IFN-alphabeta or lack of the IFNA receptor reduced viral RNA-induced Il-6 production and apoptotic cell death in mesangial cells. Furthermore, viral RNA/cationic lipid complexes increased focal necrosis in murine nephrotoxic serum nephritis in association with increased renal mRNA expression of IFN-related genes. Thus, TLR-independent recognition of viral RNA is a potent inducer of type I interferon in mesangial cells, which can be an important mediator of virally induced glomerulonephritis.


Expression of metalloproteinases (MMP-1, MMP-2, and MMP-9) and their inhibitors (TIMP-1 and TIMP-2) in schistosomal portal fibrosis.
Focal extracellular matrix degradation morphologically identified in human portal pipestem fibrosis due to Schistosoma mansoni did not express immunohistochemical reactivity for metalloproteinases (MMP-1, MMP-2, and MMP-9) and their inhibitors (TIMP-1 and TIMP-2). However, when active schistosomal periovular granulomas were present, a strong reactivity for MMP-1, MMP-2, TIMP-1, and TIMP-2 was observed. No reactivity was ever observed for MMP-9. However, the positive pattern of immunohistochemical expression was not seen in old fibrotic periovular granulomas, which were sometimes situated in other areas of the same microscopic section. Positive staining for MMPs and TIMPs was observed at the same time in hepatocytes and within the apical portion of bile duct epithelium. These findings are consistent with the concept that matrix degradation in recent and old fibroses, in addition to differing at the ultrastructural level, also differs in immunohistochemical expression of metalloproteinases and their inhibitors.


Male mentally handicapped sex offenders.
Sex offences are overrepresented in the mentally handicapped, but information about the characteristics and offence behaviour of this group is limited. A retrospective case note survey was made of 47 male patients referred for antisocial sexual behaviour. Of 191 offences and/or incidents committed, 55.5% were heterosexual, 24% indecent exposure, 12.4% homosexual, 13.6% serious and 3.6% involved physical assault. Average age of the offenders was 23.9 years, with a mean IQ of 59.5, and there was a high prevalence of family psychopathology, psychiatric illness, minor physical disabilities, sexual experience, impaired relationship skills and sexual recidivism. Recidivists showed a low specificity for offence type and age and sex of victim. Categorical analysis differentiated a 'sex offences only' group from a 'sex plus other offences' group in the key areas of psychopathology, offence behaviour and outcome; this was supported by factor analysis. The finding of two subgroups of mentally handicapped male sex offenders has important implications for prevention, assessment and treatment.


No evidence of mitochondrial genetic variation for sperm competition within a population of Drosophila melanogaster.
Recent studies have advocated a role for mitochondrial DNA (mtDNA) in sperm competition. This is controversial because earlier theory and empirical work suggested that mitochondrial genetic variation for fitness is low. Yet, such studies dealt only with females and did not consider that variation that is neutral when expressed in females, might be non-neutral in males as, in most species, mtDNA is never selected in males. We measured male ability to compete for fertilizations, at young and late ages, across 25 cytoplasms expressed in three different nuclear genetic backgrounds, within a population of Drosophila melanogaster. We found no cytoplasmic (thus no mtDNA) genetic variation for either male offence or offensive sperm competitiveness. This contrasts with previous findings demonstrating cytoplasmic genetic variation for female fitness and female ageing across these same lines. Taken together, this suggests that mitochondrial genes do not contribute to variation in sperm competition at the within-population level.


Eco-evolutionary dynamics: fluctuations in population growth rate reduce effective population size in chinook salmon.
We empirically assess the relationship between population growth rate (lambda, a parameter central to ecology) and effective population size (N(e), a key parameter in evolutionary biology). Recent theoretical and numerical studies indicate that in semelparous species with variable age at maturity (such as Pacific salmon, many monocarpic plants, and various other species), differences in mean reproductive success among individuals reproducing in different years leads to variation in lambda, and this in turn can reduce N(e). However, this phenomenon has received little empirical evaluation. We examined time series of abundance data for 56 populations of chinook salmon (Onchorhynchus tshawytscha) from the northwestern United States and compared N(e) (calculated from demographic data) with the total number of spawners each generation (NT). Important results include: (1) The mean multigenerational ratio N(e)/N(T) was 0.64 (median = 0.67), indicating that annual variation in lambda reduces effective population size in chinook salmon by an average of approximately 35%. These reductions are independent of, and in addition to, factors that reduce N(e) within individual cohorts (uneven sex ratio and greater-than-random variance in reproductive success). (2) The coefficient of variation of lambda was the most important factor associated with reductions in N(e), explaining up to two-thirds of the variance in N(e)/N(T). (3) Within individual generations, N(e) was lower when there was a negative correlation between annual N(i) and lambda, i.e., when relatively few breeders produced relatively high numbers of offspring. Our results thus highlight an important and little-studied eco-evolutionary trade-off: density-dependent compensation has generally favorable ecological consequences (promoting stability and long-term viability) but incurs an evolutionary cost (reducing N(e) because a few individuals make a disproportionate genetic contribution). (4) For chinook salmon, N(eH) (an estimator based on the harmonic mean number of breeders per year) is generally a good proxy for true N(e) and requires much less data to calculate.


A potential proliferative gene, NUDT6, is down-regulated by green tea catechins at the posttranscriptional level.
The main aims of this study were to elucidate the effect of green tea catechins on Nudix-type motif 6 (NUDT6) suppression and to characterize NUDT6's biological activity. Our microarray data showed that the green tea component epicatechin-3-gallate suppressed NUDT6 expression, and this was confirmed by RT-PCR. Subsequently, the use of different catechins showed that the effect of epigallocatechin-3-gallate (EGCG) was stronger than that of other catechins. At the posttranscriptional level, EGCG decreased the RNA stability of NUDT6, indicating it as a potential mechanism of NUDT6 suppression. Further cloning of the 3' untranslated region of human NUDT6 mRNA resulted in reduced luciferase activity by EGCG treatment. This effect was at least, in part, mediated by the extracellular-signal-regulated kinase and p38MAPK pathways. Finally, increased cell proliferation and cell growth in soft agar were observed in NUDT6-overexpressing cells. These findings provide a novel mechanism for the suppression of the proliferative gene NUDT6 by green tea catechins in human colorectal cancer.


Completing the 3-dimensional picture.
Orthodontics has a commitment to precision and accuracy similar in concept to physical engineering. Both work in a 3-dimensional (3D) world--the engineer designing and modeling physical products, and the orthodontist diagnosing and treating patients. To achieve the best possible results, both fields have readily adopted and successfully implemented highly advanced mathematical techniques and sophisticated protocols. Today, a notable difference between the 2 fields relates to the data input and analysis/modeling tools that are now available. Technology advances in the past 5 years have started to erode these barriers to safely make human 3D data input as precise and easy to obtain as physical 3D object input. Many are familiar with the advances in 3D computed tomography, specifically cone-beam technology; this article focuses on a sister imaging technology called 3D surface imaging. These 3D systems enable extraoral imaging protocols to be equally precise in providing highly accurate 3D facial surface images for diagnosis, analysis, treatment monitoring, simulation, and outcome evaluation.


Current trends in the treatment of hepatocellular carcinoma with transarterial embolization: a cross-sectional survey of techniques.
Despite being accepted as a mainstay of treatment for hepatocellular carcinoma (HCC), technical aspects of transarterial chemoembolization (TACE) continue to vary by reporting author, leading to heterogeneity in the literature and making meaningful comparisons between treatments difficult. The goal of this survey was to report international chemoembolization practices for the treatment of HCC in an effort to understand current treatment strategies as a first step towards technique standardization. An anonymous 18-question online survey, evaluating technical aspects of their TACE practice, was distributed via email to practicing members of the five largest interventional radiology societies in Chinese and English. A total of 1160 responses were obtained from 62 countries. Responses were categorized according to region of practice and analyzed using Fisher's exact test and chi-square test with Bonferroni correction as needed. There were significant statistical differences between regions for nearly all questions. Doxorubicin was more commonly used among respondents from North America, Europe, and South Korea than Japan and China (p = 0.0001). For single and multiple HCCs, drug-eluting bead TACE was most popular in North America and Europe (p = 0.0001), while conventional TACE was most popular in Japan, Korea, and China (p = 0.0001). CT was the most commonly used modality for follow-up among all respondents, although MR was used more commonly in North America and in academic centers (p = 0.0001). This survey provides comprehensive information on and confirms the heterogeneous nature of current practice patterns in regard to TA(C)E for HCC. • There is a lack of information regarding current practice patterns in the area of technical considerations when performing transarterial chemoembolization. • Type of transarterial chemoembolization utilized to treat hepatocellular carcinoma varies widely across geographical area. • Chemotherapeutic agents and embolic agents used to perform transarterial chemoembolization for the treatment of hepatocellular carcinoma vary widely across geographical areas.


Innovative solutions for iliotibial band syndrome.
Though recognizing the sharp, burning lateral knee pain of iliotibial band syndrome isn't difficult, treating the condition can be a challenge because underlying myofascial restrictions can significantly contribute to the patient's pain and disability. The physical exam should include a thorough evaluation to identify tender trigger points as well as tenderness and possible swelling at the distal iliotibial band. After acute symptoms are alleviated with activity restriction and modalities, problematic trigger points can be managed with massage therapy or other treatments. A stepwise stretching and strengthening program can expedite patients' return to running.


Critical appraisal process: step-by-step.
We present information describing how to search to identify those reports that provide insight into the answer to the query. We have presented a reasonable approach to searching, with our end-point being the identification of published articles which appear to answer our queries. The decision as to whether these articles are applicable to the patient under discussion is determined by our clinical knowledge and the specifics of the patient's medical concerns. This process is recognized as critical analysis. Our structure for optimal searching includes use of the PICO model, formulating a focused clinical question, and defining key search terms. Using these principles, we have addressed an example important controversy in the practice of clinical medicine; in other words, the effectiveness of screening for prostate cancer and whether it alters the natural history of this illness.


Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6.
Up to 30% of patients with acute myeloid leukemia have constitutively activating internal tandem duplications (ITDs) of the FLT3 receptor tyrosine kinase. Such mutations are associated with a poor prognosis and a high propensity to relapse after remission. FLT3 inhibitors are being developed as targeted therapy for FLT3-ITD(+) acute myeloid leukemia; however, their use is complicated by rapid development of resistance, which illustrates the need for additional therapeutic targets. We show that the US Food and Drug Administration-approved CDK4/6 kinase inhibitor palbociclib induces apoptosis of FLT3-ITD leukemic cells. The effect is specific for FLT3-mutant cells and is ascribed to the transcriptional activity of CDK6: CDK6 but not its functional homolog CDK4 is found at the promoters of the FLT3 and PIM1 genes, another important leukemogenic driver. There CDK6 regulates transcription in a kinase-dependent manner. Of potential clinical relevance, combined treatment with palbociclib and FLT3 inhibitors results in synergistic cytotoxicity. Simultaneously targeting two critical signaling nodes in leukemogenesis could represent a therapeutic breakthrough, leading to complete remission and overcoming resistance to FLT3 inhibitors.


Dysregulated Lipid Metabolism Precedes Onset of Psychosis.
A key clinical challenge in the management of individuals at clinical high risk for psychosis (CHR) is that it is difficult to predict their future clinical outcomes. Here, we investigated if the levels of circulating molecular lipids are related to adverse clinical outcomes in this group. Serum lipidomic analysis was performed in 263 CHR individuals and 51 healthy control subjects, who were then clinically monitored for up to 5 years. Machine learning was used to identify lipid profiles that discriminated between CHR and control subjects, and between subgroups of CHR subjects with distinct clinical outcomes. At baseline, compared with control subjects, CHR subjects (independent of outcome) had higher levels of triacylglycerols with a low acyl carbon number and a double bond count, as well as higher levels of lipids in general. CHR subjects who subsequently developed psychosis (n = 50) were distinguished from those that did not (n = 213) on the basis of lipid profile at baseline using a model with an area under the receiver operating curve of 0.81 (95% confidence interval = 0.69-0.93). CHR subjects who became psychotic had lower levels of ether phospholipids than CHR individuals who did not (p < .01). Collectively, these data suggest that lipidomic abnormalities predate the onset of psychosis and that blood lipidomic measures may be useful in predicting which CHR individuals are most likely to develop psychosis.


Factors Affecting Infection and Disease Development on Olive Leaves Inoculated with Fusicladium oleagineum.
Infection and development of olive scab disease, caused by Fusicladium oleagineum, were evaluated on detached leaves and potted plants of the susceptible cultivar Picual in growth chambers and a shadehouse. An inoculum dose of 1 × 105 conidia per ml was selected from a range of densities tested, and it was used for all experiments. Infection occurred from 5 to 25°C, and disease severity was the greatest at ~20°C for wetness durations of 12 to 24 h and at ~15°C for longer durations. Based on a generalized form of the Analytis Beta model, the optimum temperature and minimum wetness duration for infection were 15.5°C and 11.9 h. Dry periods ≤78 h immediately after inoculation did not reduce disease incidence but did reduce disease severity. Disease severity was negatively correlated with leaf age. Disease incubation period was positively correlated with leaf age, with a minimum incubation period of 28 days in the youngest leaves. Inoculated plants that were incubated in a growth chamber or in a shadehouse had the same level of infection, but disease severity was lower in plants incubated in the growth chamber because many infections remained latent for 6 months after inoculation. The data in this study will be useful for the development of a forecasting system for olive scab epidemics.


Engineering biosynthesis of high-value compounds in photosynthetic organisms.
The photosynthetic, autotrophic lifestyle of plants and algae position them as ideal platform organisms for sustainable production of biomolecules. However, their use in industrial biotechnology is limited in comparison to heterotrophic organisms, such as bacteria and yeast. This usage gap is in part due to the challenges in generating genetically modified plants and algae and in part due to the difficulty in the development of synthetic biology tools for manipulating gene expression in these systems. Plant and algal metabolism, pre-installed with multiple biosynthetic modules for precursor compounds, bypasses the requirement to install these pathways in conventional production organisms, and creates new opportunities for the industrial production of complex molecules. This review provides a broad overview of the successes, challenges and future prospects for genetic engineering in plants and algae for enhanced or de novo production of biomolecules. The toolbox of technologies and strategies that have been used to engineer metabolism are discussed, and the potential use of engineered plants for industrial manufacturing of large quantities of high-value compounds is explored. This review also discusses the routes that have been taken to modify the profiles of primary metabolites for increasing the nutritional quality of foods as well as the production of specialized metabolites, cosmetics, pharmaceuticals and industrial chemicals. As the universe of high-value biosynthetic pathways continues to expand, and the tools to engineer these pathways continue to develop, it is likely plants and algae will become increasingly valuable for the biomanufacturing of high-value compounds.


Bayesian estimation of the receiver operating characteristic curve for a diagnostic test with a limit of detection in the absence of a gold standard.
The receiver operating characteristic (ROC) curve is commonly used for evaluating the discriminatory ability of a biomarker. Measurements for a diagnostic test may be subject to an analytic limit of detection leading to immeasurable or unreportable test results. Ignoring the scores that are beyond the limit of detection of a test leads to a biased assessment of its discriminatory ability, as reflected by indices such as the associated area under the curve (AUC). We propose a Bayesian approach for the estimation of the ROC curve and its AUC for a test with a limit of detection in the absence of gold standard based on assumptions of normally and gamma-distributed data. The methods are evaluated in simulation studies, and a truncated gamma model with a point mass is used to evaluate quantitative real-time polymerase chain reaction data for bovine Johne's disease (paratuberculosis). Simulations indicated that estimates of diagnostic accuracy and AUC were good even for relatively small sample sizes (n=200). Exceptions were when there was a high per cent of unquantifiable results (60 per cent) or when AUC was < or =0.6, which indicated a marked overlap between the outcomes in infected and non-infected populations.


Communication between family carers and health professionals about end-of-life care for older people in the acute hospital setting: a qualitative study.
This paper focuses on communication between hospital staff and family carers of patients dying on acute hospital wards, with an emphasis on the family carers' perspective. The age at which people in the UK die is increasing and many continue to die in the acute hospital setting. Concerns have been expressed about poor quality end of life care in hospitals, in particular regarding communication between staff and relatives. This research aimed to understand the factors and processes which affect the quality of care provided to frail older people who are dying in hospital and their family carers. The study used mixed qualitative methods, involving non-participant observation, semi-structured interviews and a review of case notes. Four acute wards in an English University teaching hospital formed the setting: an admissions unit, two health care of older people wards and a specialist medical and mental health unit for older people. Thirty-two members of staff took part in interviews, five members of the palliative care team participated in a focus group and 13 bereaved family carers were interviewed. In all, 245 hours of observation were carried out including all days of the week and all hours of the day. Forty-two individual patient cases were constructed where the patient had died on the wards during the course of the study. Thirty three cases included direct observations of patient care. Interviews were completed with 12 bereaved family carers of ten patient cases. Carers' experience of the end of life care of their relative was enhanced when mutual understanding was achieved with healthcare professionals. However, some carers reported communication to be ineffective. They felt unsure about what was happening with their relative and were distressed by the experience of their relative's end of life care. Establishing a concordant relationship, based on negotiated understanding of shared perspectives, can help to improve communication between healthcare professionals and family carers of their patients.


Endo-microscopy beyond the Abbe and Nyquist limits.
For several centuries, far-field optical microscopy has remained a key instrument in many scientific disciplines, including physical, chemical, and biomedical research. Nonetheless, far-field imaging has many limitations: the spatial resolution is controlled by the diffraction of light, and the imaging speed follows the Nyquist-Shannon sampling theorem. The recent development of super-resolution techniques has pushed the limits of spatial resolution. However, these methods typically require complicated setups and long acquisition times and are still not applicable to deep-tissue bioimaging. Here, we report imaging through an ultra-thin fibre probe with a spatial resolution beyond the Abbe limit and a temporal resolution beyond the Nyquist limit simultaneously in a simple and compact setup. We use the random nature of mode coupling in a multimode fibre, the sparsity constraint and compressive sensing reconstruction. The new approach of super-resolution endo-microscopy does not use any specific properties of the fluorescent label, such as depletion or stochastic activation of the molecular fluorescent state, and therefore can be used for label-free imaging. We demonstrate a spatial resolution more than 2 times better than the diffraction limit and an imaging speed 20 times faster than the Nyquist limit. The proposed approach can significantly expand the realm of the application of nanoscopy for bioimaging.


Extrapolation of in vitro structural alerts for mutagenicity to the in vivo endpoint.
As part of the hazard and risk assessment of chemicals in man, it is important to assess the ability of a chemical to induce mutations in vivo. Because of the commonalities in the molecular initiating event, mutagenicity in vitro can correlate well to the in vivo endpoint for certain compound classes; however, the difficulty lies in identifying when this correlation holds true. In silico alerts for in vitro mutagenicity may therefore be used as the basis for alerts for mutagenicity in vivo where an expert assessment is carried out to establish the relevance of the correlation. Taking this into account, a data set of publicly available transgenic rodent gene mutation assay data, provided by the National Institute of Health Sciences of Japan, was processed in the expert system Derek Nexus against the in vitro mutagenicity endpoint. The resulting predictivity was expertly reviewed to assess the validity of the observed correlations in activity and mechanism of action between the two endpoints to identify suitable in vitro alerts for extension to the in vivo endpoint. In total, 20 alerts were extended to predict in vivo mutagenicity, which has significantly improved the coverage of this endpoint in Derek Nexus against the data set provided. Updating the Derek Nexus knowledge base in this way led to an increase in sensitivity for this data set against this endpoint from 9% to 66% while maintaining a good specificity of 89%.


SOURSOP: A Python package for the analysis of simulations of intrinsically disordered proteins.
Conformational heterogeneity is a defining hallmark of intrinsically disordered proteins and protein regions (IDRs). The functions of IDRs and the emergent cellular phenotypes they control are associated with sequence-specific conformational ensembles. Simulations of conformational ensembles that are based on atomistic and coarse-grained models are routinely used to uncover the sequence-specific interactions that may contribute to IDR functions. These simulations are performed either independently or in conjunction with data from experiments. Functionally relevant features of IDRs can span a range of length scales. Extracting these features requires analysis routines that quantify a range of properties. Here, we describe a new analysis suite SOURSOP, an object-oriented and open-source toolkit designed for the analysis of simulated conformational ensembles of IDRs. SOURSOP implements several analysis routines motivated by principles in polymer physics, offering a unique collection of simple-to-use functions to characterize IDR ensembles. As an extendable framework, SOURSOP supports the development and implementation of new analysis routines that can be easily packaged and shared.


Massive Retinal Gliosis in an Infant Microphthalmic Globe: A Case Report.
BACKGROUND Massive retinal gliosis (MRG) is a rare benign intraocular tumor that results from the proliferation of well-differentiated glial cells in response to long-standing pathological processes, including glaucoma, trauma, chronic inflammation, vascular disorders, and congenital anomalies. This lesion is considered to be nonneoplastic and occurs ≥10 years after the predisposing insult. It usually affects children and can mimic other conditions, including uveal melanomas, vasoproliferative tumors of the retina, astrocytic hamartomas, and retinal hemangioblastomas. CASE REPORT We present a case of infant MRG with severe left eye microphthalmia. An 11-month-old boy was presented by his parents in the Oculoplastic Unit of a teaching university hospital with bilateral incomplete cryptophthalmos and small globes. An enucleation of the left globe was carried out to stimulate orbital bone growth and to improve the cosmetic outcome. The histopathological examination revealed a microphthalmic globe with sclerocornea and disorganized intraocular anterior segment structures. The retina was dysplastic with proliferating spindle-shaped glial cells showing fibrillar eosinophilic cytoplasm and filled most of the vitreous cavity. The glial origin of the cells was confirmed by the immunohistochemical markers (glial fibrillary acidic protein and synaptophysin), supporting the diagnosis of MRG. The optic nerve was markedly hypoplastic. CONCLUSIONS MRG is a rare intraocular tumor that is clinically difficult to diagnose. A definite diagnosis can be made only on the basis of a histopathological examination and immunohistochemical markers.


Effect of aerobic exercise on echocardiographic epicardial adipose tissue thickness in overweight individuals.
Epicardial adipose tissue thickness (EATT) measured by echocardiography is a reliable indicator of visceral adipose tissue in the body and metabolic syndrome. The objective of this work was to study the effect of 12-week aerobic exercise training on echocardiographic epicardial adipose tissue thickness (EEATT), body composition and other metabolic parameters in asymptomatic overweight adults. A total of 170 overweight and mild obese individuals were randomly allocated to 12-week aerobic exercise program (intervention group) or no supervised exercise (control group). The body fat percentage and visceral fat levels were measured by bioelectric impedance analyzer, and blood tests were conducted to measure lipids, fasting blood sugar (FBS) and high-sensitivity C-reactive protein (Hs-CRP). The participants also underwent transthoracic echocardiography to measure EATT. All the outcomes were measured after 12 weeks. Repeated measures were analyzed using ANOVA and Mann-Whitney U-test were used to analyze the data. EEATT values significantly reduced by -16.24% (3.12±1.18 to 2.70±1.04, p<0.05) following 12 weeks of aerobic exercise along with a reduction in weight by 2.96% (80.66±12.12 to 78.27±12.31, p<0.05), body mass index by 3.11% (29.20±2.71 to 28.29±2.81, p<0.05) and waist circumference by 2.29% (94.82±7.23 to 92.64±7.33, p<0.05) and improved Hs-CRP values. The 12-week aerobic exercise was found to be effective in reducing EEATT in overweight and mild obese individuals. There was significant improvement in body composition, blood lipids, FBS, Hs-CRP and exercise capacity in intervention group compared to control group.


Hypothalamic-pituitary-adrenal axis responses to stress in subjects with 3,4-methylenedioxy-methamphetamine ('ecstasy') use history: correlation with dopamine receptor sensitivity.
Fifteen 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') users who did not have other drug dependencies or prolonged alcohol abuse and 15 control subjects were studied. All the subjects were exposed to the same psychosocial stressor (Stroop Color-Word Interference Task, public speaking and mental arithmetic in front of an audience) 3 weeks after MDMA discontinuation. Plasma concentrations of adrenocorticotropic hormone (ACTH) and cortisol were measured immediately before the tests began and at their end, 30 min later. Growth hormone (GH) responses to the dopaminergic agonist bromocriptine and psychometric measures (Tridimensional Personality Questionnaire, Minnesota Multiphasic Personality Inventory, Buss-Durkee Hostility Inventory) were also obtained 4 weeks after MDMA discontinuation for the same subjects. ACTH and cortisol basal levels were significantly higher in ecstasy users than in control subjects. In contrast, ACTH and cortisol responses to stress were significantly blunted in MDMA users. The sensitivity of dopamine D2 receptors, reflected by GH responses to bromocriptine challenge, was reduced in MDMA users compared with controls. The responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis (ACTH and cortisol delta peaks) correlated directly with GH areas under curves in response to bromocriptine, and inversely with psychometric measures of aggressiveness and novelty seeking. No correlation was found between hormonal measures and the extent of MDMA exposure. Reduced D2 receptor sensitivity, HPA basal hyperactivation and reduced responsiveness to stress may represent a complex neuroendocrine dysfunction associated with MDMA use. The present findings do not exclude the possibility that dopamine dysfunction partly predated MDMA exposure.


ProNodal acts via FGFR3 to govern duration of Shh expression in the prechordal mesoderm.
The secreted glycoprotein sonic hedgehog (Shh) is expressed in the prechordal mesoderm, where it plays a crucial role in induction and patterning of the ventral forebrain. Currently little is known about how Shh is regulated in prechordal tissue. Here we show that in the embryonic chick, Shh is expressed transiently in prechordal mesoderm, and is governed by unprocessed Nodal. Exposure of prechordal mesoderm microcultures to Nodal-conditioned medium, the Nodal inhibitor CerS, or to an ALK4/5/7 inhibitor reveals that Nodal is required to maintain both Shh and Gsc expression, but whereas Gsc is largely maintained through canonical signalling, Nodal signals through a non-canonical route to maintain Shh. Further, Shh expression can be maintained by a recombinant Nodal cleavage mutant, proNodal, but not by purified mature Nodal. A number of lines of evidence suggest that proNodal acts via FGFR3. ProNodal and FGFR3 co-immunoprecipitate and proNodal increases FGFR3 tyrosine phosphorylation. In microcultures, soluble FGFR3 abolishes Shh without affecting Gsc expression. Further, prechordal mesoderm cells in which Fgfr3 expression is reduced by Fgfr3 siRNA fail to bind to proNodal. Finally, targeted electroporation of Fgfr3 siRNA to prechordal mesoderm in vivo results in premature Shh downregulation without affecting Gsc. We report an inverse correlation between proNodal-FGFR3 signalling and pSmad1/5/8, and show that proNodal-FGFR3 signalling antagonises BMP-mediated pSmad1/5/8 signalling, which is poised to downregulate Shh. Our studies suggest that proNodal/FGFR3 signalling governs Shh duration by repressing canonical BMP signalling, and that local BMPs rapidly silence Shh once endogenous Nodal-FGFR3 signalling is downregulated.


New paradigms and tools in drug design for pain and addiction.
New modalities providing safe and effective treatment of pain, especially prolonged pathological pain, have not appeared despite much effort. In this mini-review/overview we suggest that new paradigms of drug design are required to counter the underlying changes that occur in the nervous system that may elicit chronic pain states. We illustrate this approach with the example of designing, in a single ligand, molecules that have agonist activity at mu and delta opioid receptors and antagonist activities at cholecystokinin (CCK) receptors. Our findings thus far provide evidence in support of this new approach to drug design. We also report on a new biophysical method, plasmon waveguide resonance (PWR) spectroscopy, which can provide new insights into information transduction in G-protein coupled receptors (GPCRs) as illustrated by the delta opioid receptor.


Generation of Heterogeneous Drug Gradients Across Cancer Populations on a Microfluidic Evolution Accelerator for Real-Time Observation.
Conventional cell culture remains the most frequently used preclinical model, despite its proven limited ability to predict clinical results in cancer. Microfluidic cancer-on-chip models have been proposed to bridge the gap between the oversimplified conventional 2D cultures and more complicated animal models, which have limited ability to produce reliable and reproducible quantitative results. Here, we present a microfluidic cancer-on-chip model that reproduces key components of a complex tumor microenvironment in a comprehensive manner, yet is simple enough to provide robust quantitative descriptions of cancer dynamics. This microfluidic cancer-on-chip model, the "Evolution Accelerator," breaks down a large population of cancer cells into an interconnected array of tumor microenvironments while generating a heterogeneous chemotherapeutic stress landscape. The progression and the evolutionary dynamics of cancer in response to drug gradient can be monitored for weeks in real time, and numerous downstream experiments can be performed complementary to the time-lapse images taken through the course of the experiments.


Complete genome sequence of the Sulfodiicoccus acidiphilus strain HS-1T, the first crenarchaeon that lacks polB3, isolated from an acidic hot spring in Ohwaku-dani, Hakone, Japan.
Sulfodiicoccus acidiphilus HS-1T is the type species of the genus Sulfodiicoccus, a thermoacidophilic archaeon belonging to the order Sulfolobales (class Thermoprotei; phylum Crenarchaeota). While S. acidiphilus HS-1T shares many common physiological and phenotypic features with other Sulfolobales species, the similarities in their 16S rRNA gene sequences are less than 89%. In order to know the genomic features of S. acidiphilus HS-1T in the order Sulfolobales, we determined and characterized the genome of this strain. The circular genome of S. acidiphilus HS-1T is comprised of 2353,189 bp with a G+C content of 51.15 mol%. A total of 2459 genes were predicted, including 2411 protein coding and 48 RNA genes. The notable genomic features of S. acidiphilus HS-1T in Sulfolobales species are the absence of genes for polB3 and the autotrophic carbon fixation pathway, and the distribution pattern of essential genes and sequences related to genomic replication initiation. These insights contribute to an understanding of archaeal genomic diversity and evolution.


Cost-effectiveness analysis for determining optimal cut-off of immunochemical faecal occult blood test for population-based colorectal cancer screening (KCIS 16).
We aimed to determine the optimal cut-off of the immunochemical faecal occult blood test (iFOBT) by using cost-effectiveness analysis. A total of 22,672 subjects aged 50 years or older were invited to have an uptake of iFOBT. We collected data from screen-detected cases for the cut-off above 100 ng/mL and obtained interval cancers from a nationwide cancer registry for a cut-off below 100 ng/mL. We found a total of 65 colorectal cancer (CRC) cases, including 43 detected by screen and 22 diagnosed between screens (interval cases). The optimal cut-off was first determined by receiver operating characteristics (ROC) curve analysis. Formal economic evaluation was further applied to identifying the optimal cut-off by assessing the minimum incremental cost-effectiveness ratio (ICER), an indicator for cost per life year gained (effectiveness), given a series of cut-offs of iFOBT, ranging from 30 to 200 ng/mL compared with no screening. ROC curve analysis found the optimal cut-off of iFOBT to be 100 ng/mL at which the sensitivity, false-positive and odds of being affected given a positive result were 81.5% (70.2%-89.2%), 5.7% (5.4%-6.0%) and 1.24 (1.19-1.32), respectively. The area under ROC curve was 0.87 (0.81-0.93). In economic appraisal, the screening programme irrespective of any cut-off dominated (less cost and more effectiveness) over the control group. The optimal cut-off (the lowest ICER) was 110 ng/mL at which an average of 0.054 life year was gained and that of 950 ($US) was saved. We used cost-effectiveness to identify 110 ng/mL as the optimal cut-off of iFOBT in a Taiwanese population-based screening for CRC. Our model provides a useful approach for health policy-makers in designing population-based screening for CRC to determine the optimal cut-off of iFOBT when cost and effectiveness need to be taken into account.


Munc18: a presynaptic transmitter release site N type (CaV2.2) calcium channel interacting protein.
Munc18 is a presynaptic protein that is essential for transmitter release. Recent studies have indicated that this protein is involved in secretory vesicle docking but its binding partners in this role remain a mystery. We demonstrate using the isolated calyx-type presynaptic terminal of the chick ciliary ganglion that staining for Munc18 colocalizes and covaries with that for transmitter release site N type calcium channels (CaV2.2), consistent with elements of a common release site complex. Biochemical analysis demonstrated that the protein coprecipitates with CaV2.2 from lysates of rat or chick brain, including its synaptic, long-splice variant; presynaptic terminal surface membrane proteins, and a cell line coexpressing Munc18 and CaV2.2. Munc18 bound with high affinity to the CaV2.2 II-III intracellular loop, low affinity to the I-II loop but not to other channel intracellular regions. Over-expression of Munc18 in dorsal root ganglion neurons did not affect CaV2.2 current amplitude or fast kinetics but siRNA-knockdown resulted in a negative shift in the steady state inactivation curve, an effect attributed to an indirect action via syntaxin 1. Recombinant Munc18 also coprecipitated strongly with the v-SNARE synaptotagmin, but only weakly with other SNAREs. Thus, the calcium channel may serve as a surface membrane platform anchoring a Munc18-containing bridge to synaptotagmin and the synaptic vesicle.


Performance of atraumatic restorative treatment (ART) depending on operator-experience.
Oral health care is not of major interest in developing countries because of lack of infrastructure and professional manpower. Therefore, atraumatic restorative treatment (ART) was introduced by the World Health Organization to be performed by dental auxiliary personnel. The aim of this study was to evaluate the performance of ART depending on operator-experience in The Republic of The Gambia. One hundred twenty-eight newly inserted restorations were followed up for 12 months using the clinical ART index in a prospective and blinded study design. The patients were randomly assigned to operators. The clinical performance was compared among three groups: trainees, experienced Community Oral Health Workers (COHW), and professional dentists. The difference in success rates was calculated at a 95 percent confidence interval. There was a statistically significant difference between trainees and dentists in performing leakage/gap-free one-surface restorations (P < 0.05). No significant differences were found between the two groups of auxiliaries (trainees versus experienced COHWs, P > 0.05). Finally, both groups--experienced COHWs and dentists--performed restorations not showing statistically significant differences (P > 0.05). For The Republic of The Gambia--especially for areas with underdeveloped medical infrastructure--training and assignment to perform ART can be recommended for auxiliary dental staff of Community Oral Health Workers.


AISAIC: a software suite for accurate identification of significant aberrations in cancers.
Accurate identification of significant aberrations in cancers (AISAIC) is a systematic effort to discover potential cancer-driving genes such as oncogenes and tumor suppressors. Two major confounding factors against this goal are the normal cell contamination and random background aberrations in tumor samples. We describe a Java AISAIC package that provides comprehensive analytic functions and graphic user interface for integrating two statistically principled in silico approaches to address the aforementioned challenges in DNA copy number analyses. In addition, the package provides a command-line interface for users with scripting and programming needs to incorporate or extend AISAIC to their customized analysis pipelines. This open-source multiplatform software offers several attractive features: (i) it implements a user friendly complete pipeline from processing raw data to reporting analytic results; (ii) it detects deletion types directly from copy number signals using a Bayes hypothesis test; (iii) it estimates the fraction of normal contamination for each sample; (iv) it produces unbiased null distribution of random background alterations by iterative aberration-exclusive permutations; and (v) it identifies significant consensus regions and the percentage of homozygous/hemizygous deletions across multiple samples. AISAIC also provides users with a parallel computing option to leverage ubiquitous multicore machines. AISAIC is available as a Java application, with a user's guide and source code, at https://code.google.com/p/aisaic/.


Porcine model of proliferative vitreoretinopathy with platelets.
To develop an experimental model of proliferative vitreoretinopathy (PVR) in the pig, and determine the efficacy of platelet-derived growth factor (PDGF) compared with different platelet plasma concentrates in its development. Animals were divided into four groups of 12 pigs each. Group 1, 2, and 3 underwent four 3-mm-long retinotomies, a partial mechanical vitrectomy, and six transconjunctival retinal cryoapplications and were injected intravitreally with, respectively, 0.2 ml of platelet rich plasma, 0.2 ml of a solution containing 200 ng of porcine PDGF, and 0.2 ml of platelet concentrated plasma. Group 4 received only an intravitreal injection of 0.2 ml of porcine PDGF. In Group 1, retinal detachments (RDs) developed in six eyes (50%) (two eyes, total RDs; four, extensive RDs). In Group 2, focal RDs developed in six eyes (50%). In Group 3, 11 eyes (92%) developed Rds (six eyes, total RDs; three, extensive RDs, two, focal RDs). Group 4, did not develop lesions. Statistically significant differences were found between Group 3 and the other groups. Group 2 RDs were associated with the presence of vitreoretinal membranes but there were no signs of PVR. In Groups 1 and 3, signs of anterior PVR, posterior PVR, and retinal holes with rolled edges were observed. We have developed a model of PVR in the pig, the retina of which more closely resembles that of humans. Platelet plasma more effectively contributed to the development of an experimental model of porcine PVR than 200 ng of PDGF. The efficacy depends on the platelet concentration of the plasma. These results suggest that other growth factors and plasma components may interact synergistically with PDGF in the pathogenesis of PVR.


Effects of monoclonal antibodies to the alpha and beta chains of the human lymphocyte function-associated (H-LFA-1) antigen on T lymphocyte functions.
The ability of two antibodies, one specific for the alpha chain, p180, and the other for the beta chain, p95, of the human lymphocyte function-associated (LFA-1) antigens, to inhibit T cell function was measured. Both antibodies inhibited T cell-mediated lysis of virus-infected target cells and of K562 cells. Only the anti-beta chain antibody inhibited natural killer cell lysis of K562. The antibodies inhibited cytotoxic T lymphocyte cell (CTL) lysis of HLA-mismatched target cells in the presence of concanavalin A at 6.25-12.5 micrograms/ml, but at higher doses of Con A no inhibition was seen. When the lytic process was divided into calcium-independent (adherence) and -dependent (lysis) steps the antibodies were found to block at the initial step of conjugate formation. The effects of these antibodies on T cell proliferative responses showed that responses to antigens, alloantigens, mitogens and anti-CD3 (UCHT1) antibody were greatly inhibited. All of these responses are adherent cell dependent and proliferation of adherent cell-depleted mononuclear cells to Sepharose-coupled UCHT1 was not inhibited by anti-LFA-1 antibodies. Proliferation to paired anti-CD2 (T11) antibodies was also only weakly inhibited. Release of interferon-gamma by CTL on contact with target cells was also inhibited by anti-LFA antibody. These results are evidence that the LFA antigen is necessary for a nonspecific interaction with antigen-presenting cells that is essential for activation of T cells through the CD3-T cell receptor complex.


Air breathing in Magadi tilapia Alcolapia grahami, under normoxic and hyperoxic conditions, and the association with sunlight and reactive oxygen species.
Observations of the Magadi tilapia Alcolapia grahami in hot, highly alkaline Lake Magadi revealed that they air breathe not only during hypoxia, as described previously, but also during normoxia and hyperoxia. Air breathing under these latter conditions occurred within distinct groupings of fish (pods) and involved only a small proportion of the population. Air breathing properties (duration and frequency) were quantified from video footage. Air breathing within the population followed a diel pattern with the maximum extent of pod formation occurring in early afternoon. High levels of reactive oxygen species (ROS) in the water may be an irritant that encourages the air-breathing behaviour. The diel pattern of air breathing in the field and in experiments followed the diel pattern of ROS concentrations in the water which are amongst the highest reported in the literature (maximum daytime values of 2.53 – 8.10 μM H₂O₂). Interlamellar cell masses (ILCM) occurred between the gill lamellae of fish from the lagoon with highest ROS and highest oxygen levels, while fish from a normoxic lagoon with one third the ROS had little or no ILCM. This is the first record of air breathing in a facultative air-breathing fish in hyperoxic conditions and the first record of an ILCM in a cichlid species.


Drugs for treating urinary schistosomiasis.
Urinary schistosomiasis is caused by an intravascular infection with parasitic Schistosoma haematobium worms. The adult worms typically migrate to the venous plexus of the human bladder and excrete eggs which the infected person passes in their urine. Chronic infection can cause substantial morbidity and long-term complications as the eggs become trapped in human tissues causing inflammation and fibrosis. We summarised evidence of drugs active against the infection. This is new edition of a review first published in 1997. To evaluate the efficacy and safety of drugs for treating urinary schistosomiasis. We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, CENTRAL, EMBASE and LILACS and reference lists of articles up to 23 May 2014. Randomized controlled trials (RCTs) of antischistosomal drugs and drug combinations compared to placebo, no intervention, or each other. Two researchers independently screened the records, extracted the data and assessed risk of bias. The primary efficacy outcomes were parasitological failure (defined as the continued presence of S. haematobium eggs in the urine at time points greater than one month after treatment), and percent reduction of egg counts from baseline. We presented dichotomous data as risk ratios (RR), and continuous data as mean difference (MD), alongside their 95% confidence intervals (CIs). Where appropriate we combined trials in meta analyses or tables. We assessed the quality of evidence using the GRADE approach. We included 30 RCTs enrolling 8165 participants in this review. Twenty-four trials were conducted in children in sub-Saharan Africa, and 21 trials were over 20 years old. Many studies were assessed as being at unclear risk of bias due to inadequate descriptions of study methods. PraziquantelOn average, a single 40 mg/kg dose of praziquantel reduced the proportion of people still excreting eggs in their urine by around 60% compared to placebo at one to two months after treatment (treatment failure: RR 0.42, 95% CI 0.29 to 0.59, 864 participants, seven trials, high quality evidence). The proportion of people cured with praziquantel varied substantially between trials, from 22.5% to 83.3%, but was higher than 60% in five of the seven trials. At one to two months following praziquantel treatment at 40 mg/kg, the mean number of schistosome eggs in the urine was reduced by over 95% in five out of six trials (678 participants, six trials, high quality evidence).Splitting praziquantel 40 mg/kg into two doses over 12 hours probably has no benefits over a single dose, and in a single trial of 220 participants the split dose caused more vomiting (RR 0.5, 95% CI 0.29 to 0.86) and dizziness (RR 0.39, 95% CI 0.16 to 0.94). MetrifonateA single dose of metrifonate 10 mg/kg reduced egg excretion (210 participants, one trial, at eight months), but was only marginally better than placebo at achieving cure at one month (RR 0.83, 95% CI 0.74 to 0.94, 142 participants, one trial). In a single trial comparing one, two and three doses, the absolute number of participants cured improved from 47% after one dose to 81% after three doses (93 participants, one trial, low quality evidence).Two small trials compared 40 mg/kg single dose praziquantel with two or three doses of 10 mg/kg metrifonate and found no clear evidence of differences in cure (metrifonate 2 x 10 mg/kg at one month: RR 1.03, 95% CI 0.8 to 1.34, 72 participants, one trial; metrifonate 3 x 10 mg/kg at three months: RR 0.33, 95% CI 0.07 to 1.57, 100 participants, one trial. In one trial both drugs performed badly and in one trial both performed well. Other drugsThree trials have evaluated the antimalarial artesunate; with inconsistent results. Substantial antischistosomal effects were only seen in one of the three trials, which was at unclear risk of bias due to poor reporting of the trial methods. Similarly, another anti-malarial mefloquine has been evaluated in two small trials with inconsistent effects.Adverse events were described as mild for all evaluated drugs, but adverse event monitoring and reporting was generally of low quality. Praziquantel 40 mg/kg is the most studied drug for treating urinary schistosomiasis, and has the strongest evidence base.Potential strategies to improve future treatments for schistosomiasis include the combination of praziquantel with metrifonate, or with antimalarial drugs with antischistosomal properties such as artesunate and mefloquine. Evaluation of these combinations requires rigorous, adequately powered trials using standardized outcome measures.


Muscle dependency of corticomuscular coherence in upper and lower limb muscles and training-related alterations in ballet dancers and weightlifters.
It has been well documented that the 15- to 35-Hz oscillatory activity of the sensorimotor cortex shows coherence with the muscle activity during weak to moderate steady contraction. To investigate the muscle dependency of the corticomuscular coherence and its training-related alterations, we quantified the coherence between electroencephalogram (EEG) from the sensorimotor cortex and rectified electromyogram (EMG) from five upper limb (first dorsal interosseous, flexor carpi radialis, extensor carpi radialis, biceps brachii, triceps brachii) and four lower limb muscles (soleus, tibialis anterior, biceps femoris, rectus femoris), while maintaining a constant force level at 30% of maximal voluntary contraction of each muscle, in 24 untrained, 12 skill-trained (ballet dancers), and 10 strength-trained (weightlifters) individuals. Data from untrained subjects demonstrated the muscle dependency of corticomuscular coherence. The magnitude of the EEG-EMG coherence was significantly greater in the distally located lower limb muscles, such as the soleus and tibialis anterior, than in the upper or other lower limb muscles in untrained subjects (P < 0.05). These results imply that oscillatory coupling between the sensorimotor cortex and spinal motoneurons during steady contraction differs among muscles, according to the functional role of each muscle. In addition, the ballet dancers and weightlifters showed smaller EEG-EMG coherences than the untrained subjects, especially in the lower limb muscles (P < 0.05). These results indicate that oscillatory interaction between the sensorimotor cortex and spinal motoneurons can be changed by long-term specialized use of the muscles and that this neural adaptation may lead to finer control of muscle force during steady contraction.


Informal carers in Sweden - striving for partnership.
Informal carers have an important role in society through their care and support of their long-term ill relatives. Providing informal care is challenging and can lead to caregiver burden; moreover, many support needs of the carers are not met, leading to confusion, disappointment and frustration. We conducted an interview study to clarify the meaning of support given and received by informal carers to relatives with chronic obstructive pulmonary disease or chronic heart failure. We purposively selected and recruited informants via participants in another study, thereby conducting interviews over the phone from June 2016 to May 2017. In total, we conducted 14 interviews with 12 informants. All interviews were transcribed verbatim and the content was analysed using a phenomenological hermeneutical approach. Our comprehensive understanding of the meaning of support for these carers is twofold: it is a self-evident struggle for the good life of their relatives and that they want to be carers in partnership. The healthcare system must recognize the efforts of carers and include them in the strategic planning and operational stages of care and treatment for people with long-term illness.


Upper Face: Clinical Anatomy and Regional Approaches with Injectable Fillers.
The use of facial fillers has been rapidly increased as the range of injectable products and indications continues to expand. Complications may arise from improper placement or technique. This article highlights the importance of anatomic knowledge when using injectable fillers in the face. A detailed review of the clinical anatomy of the upper face is performed. Regional approaches are described using the applied anatomy to efficiently and safely augment the different subunits of the upper face. Key aspects of safe and successful injection of fillers in the upper face include a thorough knowledge of the location of fat compartments and neurovascular structures. Awareness of these structures enables the practitioner to maximize injections, while avoiding damage to important nerves and vessels. A detailed knowledge of the anatomy and properties of the product is paramount to maximize the efficacy while minimizing the risk of complications.


Tolerability and safety of ropinirole versus other dopamine agonists and levodopa in the treatment of Parkinson's disease: meta-analysis of randomized controlled trials.
Dopamine agonists have a well established role in the treatment of Parkinson's disease. The choice of a particular dopamine agonist requires assessing the benefit-risk balance of each available medication. The present study evaluated the tolerability and safety of ropinirole against those of other dopamine agonists (bromocriptine, cabergoline, pramipexole, rotigotine, pergolide) and placebo in monotherapy and adjuvant therapy with levodopa in the treatment of Parkinson's disease, as reported in the peer reviewed medical literature. A systematic review of the medical literature was carried out for relevant English language articles in the MEDLINE database and Cochrane Library from January 1975 to November 2008. The searches were limited to either double-blind clinical trials or randomized clinical trials that included both patients with early Parkinson's disease receiving dopamine agonist monotherapy, and patients at a later stage on combined treatment with levodopa. The Cochrane Collaboration guidelines were followed and the following data were extracted from each study: identifier (title and bibliographical reference), classification of the quality of the evidence (Jadad criteria), type and design of the study, number of patients, patient demographics (average age, sex), Parkinson's disease stage (Hoehn and Yahr Scale), treatment (monotherapy or adjuvant to levodopa), drugs used (including dosage and duration), study objective (safety or tolerability), method of evaluation of results, randomization and blinding, and description of all the adverse events in all treatment groups. A meta-analysis was performed, calculating relative risks (RRs) and confidence intervals for the 12 most relevant adverse events. On the basis of incidence and clinical importance criteria, the final selection of 12 adverse events was made by consensus between the investigators. Forty randomized clinical trials were included. Direct comparison of ropinirole with bromocriptine showed a lower RR of constipation for ropinirole (0.55 [95% CI 0.35, 0.89]), while the direct comparison with levodopa showed a lower RR of dyskinesia for ropinirole (0.25 [95% CI 0.09, 0.71]); no significant differences for either dyskinesia or constipation were found when a direct comparison of ropinirole and rotigotine was made. For nausea, ropinirole, pergolide and rotigotine versus placebo all demonstrated similar RRs (2.25 [95% CI 1.85, 2.74]; 2.28 [95% CI 1.54, 3.37]; and 2.08 [95% CI 1.30, 3.34], respectively). On indirect comparison of ropinirole with pramipexole, ropinirole showed a higher RR for nausea (2.25 [95% CI 1.85, 2.74] vs 1.48 [95% CI 1.24, 1.76]), dizziness (1.87 [95% CI 1.48, 2.37] vs 1.20 [95% CI 1.01, 1.43]), somnolence (2.45 [95% CI 1.30, 4.61] vs 1.68 [95% CI 1.25, 2.25]), and dyskinesia (2.71 [95% CI 1.74, 4.21] vs 2.27 [95% CI 1.58, 3.27]). Pramipexole (3.36 [95% CI 2.41, 4.68], pergolide (4.80 [95% CI 2.24, 10.29]), ropinirole (2.84 [95% CI 1.34, 5.99]), and rotigotine (4.02 [95% CI 1.23, 13.11]) all had a higher RR of hallucinations compared with placebo. Pramipexole also showed a higher RR of confusion (2.64 [95% CI 1.18, 5.91]) and constipation (2.23 [95% CI 1.53, 3.25]) compared with placebo. In all the included studies, dopamine agonists, including ropinirole, exhibited a higher incidence of adverse events than placebo. Ropinirole showed an adverse event profile similar to other dopamine agonists. Consideration of the clinical characteristics of each patient and the differences in the incidence of adverse events related to each dopamine agonist, may help to optimize the dopamine agonist therapy.


The Influence of Environmental Air Pollution on Ventricular Arrhythmias: A Scoping Review.
Exposure to air pollution is a recognised risk factor for cardiovascular disease and has been associated with supraventricular arrhythmias. The effect of air pollution on ventricular arrhythmias is less clear. This scoping review assessed the effects of particulate and gaseous air pollutants on the incidence of ventricular arrhythmias. MEDLINE and EMBASE databases were searched for studies assessing the effects of air pollutants on ventricular tachycardia and ventricular fibrillation. These pollutants were particulate matter (PM) 2.5, PM10, Nitrogen Dioxide (NO2), Carbon Monoxide (CO), Sulphur Dioxide (SO2), and Ozone (O3). This review identified 27 studies: nine in individuals with implantable cardioverter defibrillators, five in those with ischaemic heart disease, and 13 in the general population. Those with ischaemic heart disease appear to have the strongest association with ventricular arrhythmias in both gaseous and particulate pollution, with all three studies assessing the effects of PM2.5 demonstrating some association with ventricular arrythmia. Results in the general and ICD population were less consistent. Individuals with ischaemic heart disease may be at an increased risk of ventricular arrhythmias following exposure to air pollution.


A neuromodulatory role for the human amygdala in processing emotional facial expressions.
Localized amygdalar lesions in humans produce deficits in the recognition of fearful facial expressions. We used functional neuroimaging to test two hypotheses: (i) that the amygdala and some of its functionally connected structures mediate specific neural responses to fearful expressions; (ii) that the early visual processing of emotional faces can be influenced by amygdalar activity. Normal subjects were scanned using PET while they performed a gender discrimination task involving static grey-scale images of faces expressing varying degrees of fear or happiness. In support of the first hypothesis, enhanced activity in the left amygdala, left pulvinar, left anterior insula and bilateral anterior cingulate gyri was observed during the processing of fearful faces. Evidence consistent with the second hypothesis was obtained by a demonstration that amygdalar responses predict expression-specific neural activity in extrastriate cortex.


Coordinated movements prevent jamming in an Emperor penguin huddle.
For Emperor penguins (Aptenodytes forsteri), huddling is the key to survival during the Antarctic winter. Penguins in a huddle are packed so tightly that individual movements become impossible, reminiscent of a jamming transition in compacted colloids. It is crucial, however, that the huddle structure is continuously reorganized to give each penguin a chance to spend sufficient time inside the huddle, compared with time spent on the periphery. Here we show that Emperor penguins move collectively in a highly coordinated manner to ensure mobility while at the same time keeping the huddle packed. Every 30-60 seconds, all penguins make small steps that travel as a wave through the entire huddle. Over time, these small movements lead to large-scale reorganization of the huddle. Our data show that the dynamics of penguin huddling is governed by intermittency and approach to kinetic arrest in striking analogy with inert non-equilibrium systems, including soft glasses and colloids.


Aminoacylation at the Atomic Level in Class IIa Aminoacyl-tRNA Synthetases.
Abstract The crystal structures of histidyl- (HisRS) and threonyl-tRNA synthetase (ThrRS) from E. coli and glycyl-tRNA synthetase (GlyRS) from T. thermophilus, all homodimeric class IIa enzymes, were determined in enzyme-substrate and enzyme-product states corresponding to the two steps of aminoacylation. HisRS was complexed with the histidine analog histidinol plus ATP and with histidyl-adenylate, while GlyRS was complexed with ATP and with glycyl-adenylate; these complexes represent the enzyme-substrate and enzyme-product states of the first step of aminoacylation, i.e. the amino acid activation. In both enzymes the ligands occupy the substrate-binding pocket of the N-terminal active site domain, which contains the classical class II aminoacyl-tRNA synthetase fold. HisRS interacts in the same fashion with the histidine, adenosine and α-phosphate moieties of the substrates and intermediate, and GlyRS interacts in the same way with the adenosine and α-phosphate moieties in both states. In addition to the amino acid recognition, there is one key mechanistic difference between the two enzymes: HisRS uses an arginine whereas GlyRS employs a magnesium ion to catalyze the activation of the amino acid. ThrRS was complexed with its cognate tRNA and ATP, which represents the enzyme-substrate state of the second step of aminoacylation, i.e. the transfer of the amino acid to the 3'-terminal ribose of the tRNA. All three enzymes utilize class II conserved residues to interact with the adenosine-phosphate. ThrRS binds tRNA(Thr) so that the acceptor stem enters the active site pocket above the adenylate, with the 3'-terminal OH positioned to pick up the amino acid, and the anticodon loop interacts with the C-terminal domain whose fold is shared by all three enzymes. We can thus extend the principles of tRNA binding to the other two enzymes.


Quantitative trait loci for upper thermal tolerance in outbred strains of rainbow trout (Oncorhynchus mykiss).
The expression of three putative QTL for upper thermal tolerance (UTT) was examined in two strains of outbred rainbow trout unselected for this trait using simple-sequence repeat (SSR; microsatellite) markers associated with UTT in backcrosses of lines selected on this trait. Two-way diallel lots in the third generation of an outbred pedigree were exposed to an acute thermal challenge. QTL detection was performed separately by each second-generation parent within each diallel lot, incorporating the effects of full sib families and correlated traits. Inheritance of different alleles at the SSR Ssa20.19NUIG from the sire 93-32-1 was strongly associated with the thermal tolerance of his half sib progeny, explaining 7.5% of their phenotypic variance in this trait. A hierarchical linear model incorporating allelic inheritance from all four grandsires of the experimental diallels (in addition to family specific and covariate trait effects) was also used to detect associations between the SSR and thermal tolerance in their third-generation grandprogeny. Ssa20.19NUIG was strongly associated with thermal tolerance in the grandprogeny of the grandsire G(0)SVM2. The generally stronger marker-trait associations found in male parents may be partially due to reduced chromosomal recombination rates in male salmonids compared to females. These results indicate the effects of a QTL on a fitness-related trait in unselected populations of rainbow trout.


Excitation of surface-plasmon polaritons by use of a zeroth-order Bessel beam.
We report an experimental result that shows the excitation of surface plasmon polaritons by use of a zeroth-order Bessel beam. From the viewpoint of energy efficiency, the zeroth order Bessel beam is ideal for the local excitation of surface plasmon polaritons on a metal film. We introduce an optical setup using an axicon element in order to carry out the excitation.