Visual sedimentation.
We introduce Visual Sedimentation, a novel design metaphor for visualizing data streams directly inspired by the physical process of sedimentation. Visualizing data streams (e. g., Tweets, RSS, Emails) is challenging as incoming data arrive at unpredictable rates and have to remain readable. For data streams, clearly expressing chronological order while avoiding clutter, and keeping aging data visible, are important. The metaphor is drawn from the real-world sedimentation processes: objects fall due to gravity, and aggregate into strata over time. Inspired by this metaphor, data is visually depicted as falling objects using a force model to land on a surface, aggregating into strata over time. In this paper, we discuss how this metaphor addresses the specific challenge of smoothing the transition between incoming and aging data. We describe the metaphor's design space, a toolkit developed to facilitate its implementation, and example applications to a range of case studies. We then explore the generative capabilities of the design space through our toolkit. We finally illustrate creative extensions of the metaphor when applied to real streams of data.


The social context of smoking: A qualitative study comparing smokers of high versus low socioeconomic position.
The reductions in smoking prevalence in a number of industrialised countries are accompanied by a strong social gap and associated health inequality. Groups such as the World Health Organisation emphasise the importance of exploring potential causal factors for smoking such as socio-economic context & position. There has been little effort to compare the social context of smoking for smokers of high versus lower socio-economic position (SEP) to consider how tobacco control efforts might reduce smoking-related health inequality. Purposive sampling was used to recruit participants for eight focus groups. The groups were segregated by age, gender and SEP. Samples were selected from suburbs within the Sydney metropolitan area defined as either high or low SEP based on the Socio Economic Index for Areas. Emergent themes were analysed according to Poland's six dimensions of the social context of smoking. Differences according to SEP, age group and gender were explored. While there was commonality in social experiences for smokers across groups, some important aspects of the social context of smoking varied. Smokers of high SEP appeared to be aware of particular social pressures not to smoke on five of the six social context dimensions (power, body, identity, consumption and place). Not only were some of those pressures absent for low SEP participants, there were additional influences within the social context which were pro-smoking. In order to narrow the health inequality gap associated with smoking, it is important to take account of the more pro-smoking social context experienced by low SEP smokers. Suggestions are made regarding social marketing campaigns, support for quit assistance and approaches to the regulation of smoking which may assist in minimising smoking-related health inequality.


Pearls & Oy-sters: Genetic Epilepsy: An Important Cause of Neonatal Seizures in Infants With Complex Congenital Heart Disease.
Genetic epilepsies, such as KCNQ2 gene variants, though uncommon, are potential causes of neonatal seizures in infants with complex congenital heart disease (CHD). KCNQ2-related seizures commonly present as tonic posturing with autonomic changes and a distinctive amplitude-integrated EEG (aEEG) pattern with increase in amplitude immediately followed by background suppression. Seizures are typically refractory to commonly used antiepileptics in this age group and respond best to sodium channel blockers such as carbamazepine and fosphenytoin. We report the cases of two neonates with complex CHD who presented with seizures secondary to KCNQ2 gene variation and how early recognition of clinical and EEG features led to early treatment and improved seizure burden. When investigating the etiology of neonatal seizures in the perioperative complex cardiac infant, genetic etiologies, such as KCNQ2 variants should be considered, particularly in the absence of clinical exam and neuroimaging features consistent with brain injury. These two cases highlight the importance of a precision medicine approach utilizing clinical examination and seizure semiology, bedside aEEG monitoring, genetic testing, and targeted treatments to improve patient care and outcomes.


Disposition of (5H-dibenzo [a,d]cyclohepten-5-ylidene)acetic acid in laboratory animals.
The disposition of (5H-dibenzo[a,d]cyclohepten-5-ylidene)acetic acid (Wy-41,770), an anti-inflammatory agent, was investigated in rats, mice, rhesus monkeys, and dogs following single 12.5-mg/kg doses of 14C-labeled or unlabeled drug and in rodents receiving single 225-mg/kg doses of 14C-Wy-41,770. The drug was rapidly and well absorbed in all four animal species. Following an iv dose, plasma elimination half-lives of Wy-41,770 in monkeys and dogs were, respectively, 5.0 +/- 1.8 and 0.24 +/- 0.01 hr. Total body clearances (CL) of 1.8 +/- 0.2 ml/min/kg in monkeys and 7.7 +/- 1.1 ml/min/kg in dogs are low, indicating that, after an ig dose, little Wy-41,770 would be eliminated on first passage through the liver. The steady state volumes of distribution of 0.37 +/- 0.1 and 0.14 +/- 0.01 liters/kg, respectively, in monkeys and dogs are low, indicating limited extravascular distribution of Wy-41,770. Plasma half-lives of Wy-41,770 in rats and mice were, respectively, 10.8 and 8.4 hr. The longer half-life in rats compared to other animals is due to the extensive enterohepatic recycling of the drug in rats. The extensive cycling of the drug in rats may explain why ileocecal inflammation occurred in this species but not in mice and dogs following prolonged oral administration of high doses of Wy-41,770. Following a 12.5 mg/kg, ig dose, the rates of urinary excretion of radioactivity in monkeys, mice, and rats were, respectively, 73.4 +/- 10.7, 52.6 and 15.2% of the dose, whereas the fecal excretion was 9.1 +/- 3.7% in monkeys and 74.7% in rats.(ABSTRACT TRUNCATED AT 250 WORDS)


PI3 kinases in cancer: from oncogene artifact to leading cancer target.
At the time of its discovery in the 1980s, the lipid kinase activity found associated with certain viral oncoproteins, which we now know to originate from the class IA phosphatidylinositide 3-kinases (PI3Ks), was thought by many to be a purification artifact. Subsequent work identified these enzymes as key regulators of cell signaling pathways that control various cellular processes including proliferation, motility, survival, and apoptosis. It is now clear that the PI3K pathway is activated by genetic or epigenetic alterations in a large proportion of human tumors, and a search for small molecule inhibitors of PI3K activity is currently a major effort of the pharmaceutical industry. However, because of the importance of PI3Ks in normal physiology, the road to therapeutics might not be smooth and could require further dissection of PI3K signaling pathways. In particular, it may be important to distinguish among the roles of the various isoforms of class 1A PI3K in both normal physiology and tumorigenesis.


Optimizing an eHealth insomnia intervention for children with neurodevelopmental disorders: a Delphi study.
Insomnia, which is related to daytime deficits and is a common problem for children with neurodevelopmental disorders (NDDs), is often successfully treated with behavioral strategies. However, there are barriers to accessing these treatments, and there has been little research examining what these interventions need to be usable and effective. The goal of this study was to gain consensus from experts in the field on the key components of an eHealth, parent-implemented, intervention program aimed at improving sleep in children with attention-deficit/hyperactivity disorder, autism spectrum disorder, cerebral palsy, and fetal alcohol spectrum disorder. This was achieved using the Delphi method, which involves asking participants to respond to open-ended questions about a topic of interest and then, in iterative rounds, to rate the recommendations that were made by the group. In the current study, participants (27 responders in the first round, 21 in the second, and 18 in the third) rated a total of 131 recommendations. Of those 131 recommendations, 52 items had high importance and high consensus and were deemed to be priority items to consider for creating an eHealth, parent-delivered, behaviorally-based intervention for insomnia in children with NDD. Furthermore, 75% (n = 84) of the 112 recommendations from the first round were believed to be applicable across all 4 NDD groups, thus providing evidence of the potential for a transdiagnostic intervention.


Differential responses in ammonia excretion, sodium fluxes and gill permeability explain different sensitivities to acute high environmental ammonia in three freshwater teleosts.
We examined the acute physiological responses to high environmental ammonia (HEA), particularly the linkages between branchial ammonia fluxes and unidirectional Na(+) fluxes, as well as urea excretion, cortisol, and indicators of gill permeability in three freshwater teleosts differing in their sensitivities to ammonia; the highly sensitive salmonid Oncorhynchus mykiss (rainbow trout), the less sensitive cyprinid Cyprinus carpio (common carp) and the highly resistant cyprinid Carassius auratus (goldfish). Fish were acutely exposed to two sub-lethal ammonia concentrations (as NH(4)HCO(3)) at pH 7.9: 1 mM for a period of 12 h, identical for all species, and 5 mM for the cyprinids and 1.4 mM for the trout for 3 h. Elevation of plasma cortisol at both levels of HEA was apparent in all species. At 1 mM, ammonia excretion (J(amm)) was inhibited to a greater extent in trout than cyprinids and concurrently a significantly higher plasma ammonia level was evident in trout. However J(amm) was reversed in all species at 5 or 1.4 mM. Goldfish showed a significant increase in urea excretion rate (J(urea)) during HEA exposure. In carp and trout, neither level of HEA elevated J(urea) but urea production was increased as evidenced by a considerable elevation of plasma urea. At 1mM HEA, Na(+) imbalance became progressively more severe in trout and carp due to a stimulation of unidirectional Na(+) efflux (J(out)(Na)) without a concomitant increase in unidirectional Na(+) influx (J(in)(Na)). Additionally, a transient reduction of J(in)(Na) was evident in trout. Goldfish showed an opposite trend for J(out)(Na) with reduced efflux rates and a positive Na(+) balance during the first few hours of HEA. However, after 12 h of exposure, both J(in)(Na) and J(out)(Na) were also increased in both carp and goldfish, whereas only J(out)(Na) was increased in trout, leading to a net Na(+) loss. Na(+) homeostasis was entirely disrupted in all three species when subjected to the 5 or 1.4 mM ammonia for 3 h: J(in)(Na) was significantly inhibited while considerable activation of J(out)(Na) was observed. Diffusive water efflux rates and net K(+) loss rates across the gills were enhanced during HEA only in trout, indicating an increment in gill transcellular permeability. Transepithelial potential was increased in all the species during ammonia exposure, but to the least extent in goldfish. Overall, for several different physiological systems, trout were most disturbed, and goldfish were least disturbed by HEA, helping to explain the differential ammonia tolerance of the three species.


Municipal Officials' Participation in Built Environment Policy Development in the United States.
This study examined municipal officials' participation in built environment policy initiatives focused on land use design, transportation, and parks and recreation. Web-based cross-sectional survey. Eighty-three municipalities with 50,000 or more residents in eight states. Four hundred fifty-three elected and appointed municipal officials. Outcomes included self-reported participation in land use design, transportation, and parks and recreation policy to increase physical activity. Independent variables included respondent position; perceptions of importance, barriers, and beliefs regarding physical activity and community design and layout; and physical activity partnership participation. Multivariable logistic regression models. Compared to other positions, public health officials had lower participation in land use design (78.3% vs. 29.0%), transportation (78.1% vs. 42.1%), and parks and recreation (67.1% vs. 26.3%) policy. Perceived limited staff was negatively associated with participation in each policy initiative. Perceptions of the extent to which physical activity was considered in community design and physical activity partnership participation were positively associated with participation in each. Perceived lack of collaboration was associated with less land use design and transportation policy participation, and awareness that community design affects physical activity was associated with more participation. Perceived lack of political will was associated with less parks and recreation policy participation. Public health officials are underrepresented in built environment policy initiatives. Improving collaborations may improve municipal officials' policy participation.


The ASH1-RELATED3 SET-domain protein controls cell division competence of the meristem and the quiescent center of the Arabidopsis primary root.
The stem cell niche of the Arabidopsis (Arabidopsis thaliana) primary root apical meristem is composed of the quiescent (or organizing) center surrounded by stem (initial) cells for the different tissues. Initial cells generate a population of transit-amplifying cells that undergo a limited number of cell divisions before elongating and differentiating. It is unclear whether these divisions occur stochastically or in an orderly manner. Using the thymidine analog 5-ethynyl-2'-deoxyuridine to monitor DNA replication of cells of Arabidopsis root meristems, we identified a pattern of two, four, and eight neighboring cells with synchronized replication along the cortical, epidermal, and endodermal cell files, suggested to be daughters, granddaughters, and great-granddaughters of the direct progeny of each stem cell. Markers of mitosis and cytokinesis were not present in the region closest to the transition zone where the cells start to elongate, suggesting that great-granddaughter cells switch synchronously from the mitotic cell cycle to endoreduplication. Mutations in the stem cell niche-expressed ASH1-RELATED3 (ASHR3) gene, encoding a SET-domain protein conferring histone H3 lysine-36 methylation, disrupted this pattern of coordinated DNA replication and cell division and increased the cell division rate in the quiescent center. E2Fa/E2Fb transcription factors controlling the G1-to-S-phase transition regulate ASHR3 expression and bind to the ASHR3 promoter, substantiating a role for ASHR3 in cell division control. The reduced length of the root apical meristem and primary root of the mutant ashr3-1 indicate that synchronization of replication and cell divisions is required for normal root growth and development.


IL-33 signaling is essential to attenuate viral-induced encephalitis development by downregulating iNOS expression in the central nervous system.
Viral encephalitis is a common cause of lethal infections in humans, and several different viruses are documented to be responsible. Rocio virus is a flavivirus that causes a severe lethal encephalitis syndrome in humans and also mice, providing an interesting model to study the CNS compartmentalized immune response. Interleukin 33 (IL-33), a member of the IL-1 family, is an immunomodulatory cytokine that is highly expressed in the CNS. However, the role of IL-33 on viral encephalitis remains unclear. Therefore, we aimed to explore how the IL-33/ST2 axis regulates the local immune response during Rocio virus infection. Wild-type (WT), ST2 (ST2(-/-)), and nitric oxide synthase-deficient mice (iNOS(-/-)) and Stat6 (Stat6(-/-))-deficient mice were infected with different concentrations of the Rocio virus by intraperitoneal route, the cytokine mRNA level in CNS was analyzed by qPCR, and cellular immunophenotyping was performed on infected mice by the flow cytometry of isolated CNS mononuclear cells. We have shown that the mRNA expression of IL-33 and ST2 receptors is increased in the CNS of Rocio virus-infected WT mice and that ST2(-/-) mice showed increased susceptibility to infection. ST2 deficiency was correlated with increased tissue pathology, cellular infiltration, and tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ) mRNA levels and higher viral load in the CNS, compared with wild-type mice. The increased Th1 cytokine levels released in the CNS acted on infiltrating macrophages, as evidenced by flow cytometry characterization of cellular infiltrates, inducing the expression of iNOS, contributing to brain injury. Moreover, iNOS(-/-) mice were more resistant to Rocio virus encephalitis, presenting a lower clinical score and reduced mortality rate, despite the increased tissue pathology. We provide evidences of a specific role for IL-33 receptor signaling in nitric oxide induction through local IFN-γ modulation, suggesting that nitric oxide overproduction might have an important role in the progression of experimental viral encephalitis.


Pulsus alternans induced by inferior vena caval occlusion in man.
To assess the effect of rapid preload reduction on left ventricular performance in nonischemic cardiomyopathy, 11 patients were studied during inferior vena caval (IVC) balloon occlusion. Five developed sustained pulsus alternans. During pulsus alternans, the strong beats demonstrated systolic performance characteristics similar to baseline values, despite a drop in both left ventricular (LV) end-diastolic diameter (66 +/- 13 to 61 +/- 13 mm; p less than 0.05) and LV end-diastolic pressure (21 +/- 8 to 9 +/- 6 mmHg; p less than 0.05). In contrast, the weak beats demonstrated a reduction in peak systolic pressure (130 +/- 36 to 109 +/- 33 mmHg; p less than 0.02), fractional shortening (20% +/- 4% to 17% +/- 9%; p less than 0.05) and peak positive dP/dt (1,006 +/- 224 to 921 +/- 287 mmHg; p less than 0.05). Measures of diastolic performance (peak negative dP/dt, the time constant of LV relaxation, the length of diastasis, and LV end-diastolic stress) were not different between baseline beats and the strong beats; and only LV end-diastolic stress differed when baseline beats were compared to the weak beats. When the strong beats were compared to the weak beats during induced pulsus alternans, significant differences were observed in peak systolic pressure, peak positive dP/dt, and fractional shortening, but no differences in any measured diastolic parameter was observed. A slight difference was noted in the left ventricular end-diastolic diameters, with the weak beat consistently beginning at a slightly smaller diameter (61 +/- 13; mm vs 59 +/- 13; p less than 0.05). In summary, these data are consistent with an augmentation and deletion of intrinsic contractile forces in association with an alternation in preload on a beat-to-beat basis as best describing left ventricular performance during pulsus alternans.


Gramene database: a hub for comparative plant genomics.
The rich collection of known genetic information and the recent completion of rice genome sequencing project provided the cereal plant researchers a useful tool to investigate the roles of genes and genomic organization that contribute to numerous agronomic traits. Gramene ( http://www.gramene.org ) is a unique database where users are allowed to query and explore the power of genomic colinearity and comparative genomics for genetic and genomic studies on plant genomes. Gramene presents a wholesome perspective by assimilating data from a broad range of publicly available data sources for cereals like rice, sorghum, maize, wild rice, wheat, oats, barley, and other agronomically important crop plants such as poplar and grape, and the model plant Arabidopsis. As part of the process, it preserves the original data, but also reanalyzes for integration into several knowledge domains of maps, markers, genes, proteins, pathways, phenotypes, including Quantitative Trait Loci (QTL) and genetic diversity/natural variation. This allows researchers to use this information resource to decipher the known and predicted interactions between the components of biological systems, and how these interactions regulate plant development. Using examples from rice, this article describes how the database can be helpful to researchers representing an array of knowledge domains ranging from plant biology, plant breeding, molecular biology, genomics, biochemistry, genetics, bioinformatics, and phylogenomics.


Separable neural signatures of confidence during perceptual decisions.
Perceptual confidence is an evaluation of the validity of perceptual decisions. While there is behavioural evidence that confidence evaluation differs from perceptual decision-making, disentangling these two processes remains a challenge at the neural level. Here, we examined the electrical brain activity of human participants in a protracted perceptual decision-making task where observers tend to commit to perceptual decisions early whilst continuing to monitor sensory evidence for evaluating confidence. Premature decision commitments were revealed by patterns of spectral power overlying motor cortex, followed by an attenuation of the neural representation of perceptual decision evidence. A distinct neural representation was associated with the computation of confidence, with sources localised in the superior parietal and orbitofrontal cortices. In agreement with a dissociation between perception and confidence, these neural resources were recruited even after observers committed to their perceptual decisions, and thus delineate an integral neural circuit for evaluating perceptual decision confidence.


Vibrio cholerae VibF is required for vibriobactin synthesis and is a member of the family of nonribosomal peptide synthetases.
A 7.5-kbp fragment of chromosomal DNA downstream of the Vibrio cholerae vibriobactin outer membrane receptor, viuA, and the vibriobactin utilization gene, viuB, was recovered from a Sau3A lambda library of O395 chromosomal DNA. By analogy with the genetic organization of the Escherichia coli enterobactin gene cluster, in which the enterobactin biosynthetic and transport genes lie adjacent to the enterobactin outer membrane receptor, fepA, and the utilization gene, fes, the cloned DNA was examined for the ability to restore siderophore synthesis to E. coli ent mutants. Cross-feeding studies demonstrated that an E. coli entF mutant complemented with the cloned DNA regained the ability to synthesize enterobactin and to grow in low-iron medium. Sequence analysis of the cloned chromosomal DNA revealed an open reading frame downstream of viuB which encoded a deduced protein of greater than 2,158 amino acids, homologous to Yersinia sp. HMWP2, Vibrio anguillarum AngR, and E. coli EntF. A mutant with an in-frame deletion of this gene, named vibF, was created with classical V. cholerae strain O395 by in vivo marker exchange. In cross-feeding studies, this mutant was unable to synthesize ferric vibriobactin but was able to utilize exogenous siderophore. Complementation of the mutant with a cloned vibF fragment restored vibriobactin synthesis to normal. The expression of the vibF promoter was found to be negatively regulated by iron at the transcriptional level, under the control of the V. cholerae fur gene. Expression of vibF was not autoregulatory and neither affected nor was affected by the expression of irgA or viuA. The promoter of vibF was located by primer extension and was found to contain a dyad symmetric nucleotide sequence highly homologous to the E. coli Fur binding consensus sequence. A footprint of purified V. cholerae Fur on the vibF promoter, overlapping the Fur binding consensus sequence, was observed using DNase I footprinting. The protein product of vibF is homologous to the multifunctional nonribosomal protein synthetases and is necessary for the biosynthesis of vibriobactin.


Biosynthesis of callose and cellulose by detergent extracts of tobacco cell membranes and quantification of the polymers synthesized in vitro.
The conditions that favor the in vitro synthesis of cellulose from tobacco BY-2 cell extracts were determined. The procedure leading to the highest yield of cellulose consisted of incubating digitonin extracts of membranes from 11-day-old tobacco BY-2 cells in the presence of 1 mM UDP-glucose, 8 mM Ca(2+) and 8 mM Mg(2+). Under these conditions, up to nearly 40% of the polysaccharides synthesized in vitro corresponded to cellulose, the other polymer synthesized being callose. Transmission electron microscopy analysis revealed the occurrence of two types of structures in the synthetic reactions. The first type consisted of small aggregates with a diameter between 3 and 5 nm that associated to form fibrillar strings of a maximum length of 400 nm. These structures were sensitive to the acetic/nitric acid treatment of Updegraff and corresponded to callose. The second type of structures was resistant to the Updegraff reagent and corresponded to straight cellulose microfibrils of 2-3 nm in diameter and 200 nm to up to 5 microm in length. In vitro reactions performed on electron microscopy grids indicated that the minimal rate of microfibril elongation in vitro is 120 nm/min. Measurements of retardance by liquid crystal polarization microscopy as a function of time showed that small groups of microfibrils increased in retardance by up to 0.047 nm/min per pixel, confirming the formation of organized structures.


Power-weighted dispersion distribution function for characterizing nonlinear properties of long-haul optical transmission links.
Based on the first-order perturbation theory, we introduce the power-weighted dispersion distribution (PWDD) function to characterize nonlinear properties of fiber-optic transmission links. This technique offers a new perspective on dispersion management for pseudolinear transmission. A rectangular PWDD model is used to describe the formation of ghost pulses analytically in the time domain without relying on the assumption that the pulse shape is Gaussian.


Postpartum hormonal contraception in breastfeeding women.
To provide an overview of recent research and guidelines regarding contraception and breastfeeding. Recent studies assessed lactogenesis, breastfeeding rates, and milk supply concerns in patients starting postpartum hormonal contraception. One study showed a small but statistically significant increase in milk supply concerns between users and nonusers of postpartum hormonal contraception. Mean time to lactogenesis and breastfeeding rates were similar between patients with immediate and delayed insertion of the levonorgestrel (LNG) implant in one study and the LNG intrauterine device (IUD) in another study. Two studies assessed nursing knowledge and attitudes toward postpartum contraception in breastfeeding women, showing that postpartum nurses had incorrect knowledge of contraceptive safety in this patient population. Both studies demonstrated persistent erroneous beliefs that depot medroxyprogesterone acetate (DMPA) adversely affects breastfeeding. In postpartum patients intending to breastfeed, more than half intended to initiate contraception within 6 weeks postpartum and few indicated effect on breastfeeding as a factor in their decision. There are no significant differences in lactogenesis, breastfeeding, and infant growth parameters between immediate postpartum (IPP) and delayed insertion of LNG implants and IUDs. Labor and delivery and postpartum nurses have persistent erroneous beliefs that DMPA negatively affects breastfeeding. Patients desire to use contraception postpartum but prenatal counseling rates and practices are of variable content and quality.


Diagnosis of invasive aspergillosis in hematological malignancy patients: Performance of cytokines, Asp LFD, and Aspergillus PCR in same day blood and bronchoalveolar lavage samples.
Aspergillus spp. induce elevated levels of several cytokines. It remains unknown whether these cytokines hold value for clinical routine and enhance diagnostic performances of established and novel biomarkers/tests for invasive aspergillosis (IA). This cohort study included 106 prospectively enrolled (2014-2017) adult cases with underlying hematological malignancies and suspected pulmonary infection undergoing bronchoscopy. Serum samples were collected within 24 hours of bronchoalveolar lavage fluid (BALF) sampling. Both, serum and BALF samples were used to evaluate diagnostic performances of the Aspergillus-specific lateral-flow device test (LFD), Aspergillus PCR, β-D-glucan, and cytokines that have shown significant associations with IA before. Among 106 cases, 11 had probable IA, and 32 possible IA; 80% received mold-active antifungals at the time of sampling. Diagnostic tests and biomarkers showed better performance in BALF versus blood, with the exception of serum interleukin (IL)-8 which was the most reliable blood biomarker. Combinations of serum IL-8 with either BALF LFD (sensitivity 100%, specificity 94%) or BALF PCR (sensitivity 91%, specificity 97%) showed promise for differentiating probable IA from no IA. High serum IL-8 levels were highly specific, and when combined with either the BALF Aspergillus-specific LFD, or BALF Aspergillus PCR also highly sensitive for diagnosis of IA.


A polymorphism in the norepinephrine transporter gene alters promoter activity and is associated with attention-deficit hyperactivity disorder.
The norepinephrine transporter critically regulates both neurotransmission and homeostasis of norepinephrine in the nervous system. In this study, we report a previously uncharacterized and common A/T polymorphism at -3081 upstream of the transcription initiation site of the human norepinephrine transporter gene [solute carrier family 6, member 2 (SLC6A2)]. Using both homologous and heterologous promoter-reporter constructs, we found that the -3081(T) allele significantly decreases promoter function compared with the A allele. Interestingly, this T allele creates a new palindromic E2-box motif that interacts with Slug and Scratch, neural-expressed transcriptional repressors binding to the E2-box motif. We also found that both Slug and Scratch repress the SLC6A2 promoter activity only when it contains the T allele. Finally, we observed a significant association between the -3081(A/T) polymorphism and attention-deficit hyperactivity disorder (ADHD), suggesting that anomalous transcription factor-based repression of SLC6A2 may increase risk for the development of attention-deficit hyperactivity disorder and other neuropsychiatric diseases.


Modeling tumor predisposing FH mutations in yeast: effects on fumarase activity, growth phenotype and gene expression profile.
Heterozygous mutations in the fumarase (FH) gene cause the tumor predisposition syndrome hereditary leiomyomatosis and renal cell cancer (MIM 605839). While most families segregate a benign phenotype of multiple leiomyomas, others display a phenotype with early-onset renal cancer and leiomyosarcoma. Modifier genes may play a role in this, but an alternative explanation is simple genotype-phenotype association. FH mutations predisposing to cancer appear to be truncating or in fully conserved amino acids, suggesting that mutations severely affecting FH activity might predispose to malignancy. In the present study, we analyzed 2 conserved fumarase mutations in yeast. H153R has been described in 3 cancer predisposition families; whereas all 3 reported K187R families have displayed the benign phenotype. Examining H153R and K187R should clarify whether cancer-related FH mutations differ from their benign phenotype-associated counterparts. Yeast strains containing the 2 mutations, and knockout and wild type (WT) references, were created and the growth phenotypes studied on selected carbon sources to assess mitochondrial function. Additionally, Fum1 protein production and activity were measured, and the strains were subjected to transcriptional profiling. On nonfermentable lactate medium, the fumarase knockout strains did not grow, whereas the mutants showed no differences, as compared to WT yeast. Although both mutant strains produced fumarase, a considerable decrease in enzyme activity was seen in mutants with respect to WT. Transcription of the majority of Krebs cycle enzymes was downregulated in response to mutations in fumarase. In conclusion, both mutants displayed some, albeit greatly reduced, fumarase activity. This activity was sufficient to support normal growth on nonfermentable carbon source, unlike the deletion phenotype, demonstrating the significance of the residual activity. The findings support the hypothesis that modifier gene(s), rather than phenotype-genotype effects, display a major role in determining tumor phenotypes in families segregating FH mutations.


Pattern of p53 protein expression is predictive for survival in chemoradiotherapy-naive esophageal adenocarcinoma.
TP53 mutations are considered to be the driving factor in the initiation of esophageal adenocarcinoma (EAC). However, the impact of this gene and its encoded protein as a prognostic marker has not been definitely established yet. In total, 204 chemoradiotherapy (CRT)-naive patients with EAC were included for p53 protein expression evaluation by immunohistochemistry (IHC) on the resection specimens, categorized as overexpression, heterogeneous or loss of expression, and correlated with disease free survival (DFS) and overall survival (OS) using multivariable Cox regression analysis. In a subset representing all three IHC subgroups mutational status of selected candidate genes (n=33) and high throughput methylation profiling (n=16) was assessed. Compared to heterogeneous p53 expression, loss and overexpression were both independently predictive for adverse DFS and OS. TP53 mutational status significantly correlated with the IHC categories (p=0.035). Most of the EAC with loss- or overexpression harbored TP53 mutations (18/20, representing nonsense and missense mutations respectively). In contrast, 6/13 EAC with heterogeneous expression were TP53 wild type, of which two demonstrated MDM4 or MDM2 amplification. Combined genomic hypomethylation and high frequency of intra-chromosomal breaks was found in a selection of EAC without p53 overexpression. P53 expression pattern is prognostic for DFS and OS in this historical cohort of CRT-naive EAC. P53 IHC is an informative readout for TP53 mutational status in EAC with either loss- or overexpression, but not in case of a heterogeneous p53 pattern. Different EAC pathogenesis might exist, related to p53 and other candidate gene status, DNA hypomethylation and intrachromosomal breaks.


The effect of lung size mismatch on complications and resource utilization after bilateral lung transplantation.
Oversizing the lung allograft, as estimated by a donor-to-recipient predicted total lung capacity (pTLC) ratio > 1.0, was associated with improved long-term survival after lung transplantation (LTx) but could be associated with increased post-operative complications and higher resource utilization. The prospectively maintained LTx database at The Johns Hopkins Hospital was retrospectively reviewed for bilateral LTx patients in the post-Lung Allocation Score (LAS) era. Patients were grouped by pTLC ratio ≤ 1.0 (undersized) or > 1.0 (oversized). Post-operative complications and hospital charges were analyzed. The pTLC ratio was available for 70 patients: 31 were undersized and 39 oversized. Undersized patients had a higher LAS (40.4 vs 35.8, p = 0.009), were more often in the intensive care unit (ICU) pre-LTx (35% vs 10%, p = 0.01), and had a higher occurrence of primary graft dysfunction (PGD; 25% vs 5%, p = 0.013) and tracheostomy (32% vs 10%, p = 0.02), longer index hospitalizations (20 [interquartile range (IQR), 10-46] vs 16 [IQR, 12-25] days, p = 0.048), and higher index hospitalization charges ($176,247 [IQR, $137,646-$284,012] vs $158,492 [IQR, $136,250-$191,301], p = 0.04). After adjusting for LAS and pre-LTx ICU stay, a lower pTLC ratio remained associated with higher hospital charges (p = 0.049). Airway complications were more frequent and severe in undersized patients. Oversized allografts were not associated with an increase in post-LTx complications. However, LTx recipients of undersized allografts were more likely to experience PGD, tracheostomy, and had higher resource utilization. Higher acuity in the undersized group might explain these findings; however, multivariate models suggest an independent association between undersizing, PGD, and resource utilization.


Combination of essential oil of Melaleuca alternifolia and iodine in the treatment of molluscum contagiosum in children.
Molluscum contagiosum is a common childhood viral skin condition and is increasingly found as a sexually transmitted disease in adults. Current treatment options are invasive, requiring tissue destruction and attendant discomfort. Fifty-three children (mean age 6.3+5.1 years) with the diagnosis of molluscum contagiosum were treated with twice daily topical application of either essential oil of Melaleuca alternifolia (TTO), a combination of TTO and organically bound iodine (TTO-I), or iodine alone. At the end of 30 days, 48 children were available for follow up. A greater than 90% reduction in the number of lesions was observed in 16 of 19 children treated with TTO-I, while 1 of 16 and 3 of 18 children met the same criteria for improvement in the iodine and TTO groups (P<0.01, ANOVA) respectively by intention-to-treat analysis. No child discontinued treatment due to adverse events. The combination of essential oil of M. alternifolia with organically bound iodine offers a safe therapeutic alternative in the treatment of childhood molluscum. Clinical Trial Registry ACTRN12610000984099.


An optimized proportional-derivative controller for the human upper extremity with gravity.
When Functional Electrical Stimulation (FES) is used to restore movement in subjects with spinal cord injury (SCI), muscle stimulation patterns should be selected to generate accurate and efficient movements. Ideally, the controller for such a neuroprosthesis will have the simplest architecture possible, to facilitate translation into a clinical setting. In this study, we used the simulated annealing algorithm to optimize two proportional-derivative (PD) feedback controller gain sets for a 3-dimensional arm model that includes musculoskeletal dynamics and has 5 degrees of freedom and 22 muscles, performing goal-oriented reaching movements. Controller gains were optimized by minimizing a weighted sum of position errors, orientation errors, and muscle activations. After optimization, gain performance was evaluated on the basis of accuracy and efficiency of reaching movements, along with three other benchmark gain sets not optimized for our system, on a large set of dynamic reaching movements for which the controllers had not been optimized, to test ability to generalize. Robustness in the presence of weakened muscles was also tested. The two optimized gain sets were found to have very similar performance to each other on all metrics, and to exhibit significantly better accuracy, compared with the three standard gain sets. All gain sets investigated used physiologically acceptable amounts of muscular activation. It was concluded that optimization can yield significant improvements in controller performance while still maintaining muscular efficiency, and that optimization should be considered as a strategy for future neuroprosthesis controller design.


Nested association mapping reveals the genetic architecture of spike emergence and anthesis timing in intermediate wheatgrass.
Intermediate wheatgrass (Thinopyrum intermedium) is an outcrossing, cool season grass species currently undergoing direct domestication as a perennial grain crop. Though many traits are selection targets, understanding the genetic architecture of those important for local adaptation may accelerate the domestication process. Nested association mapping (NAM) has proven useful in dissecting the genetic control of agronomic traits many crop species, but its utility in primarily outcrossing, perennial species has yet to be demonstrated. Here, we introduce an intermediate wheatgrass NAM population developed by crossing ten phenotypically divergent donor parents to an adapted common parent in a reciprocal manner, yielding 1,168 F1 progeny from 10 families. Using genotyping by sequencing, we identified 8,003 SNP markers and developed a population-specific consensus genetic map with 3,144 markers across 21 linkage groups. Using both genomewide association mapping and linkage mapping combined across and within families, we characterized the genetic control of flowering time. In the analysis of two measures of maturity across four separate environments, we detected as many as 75 significant QTL, many of which correspond to the same regions in both analysis methods across 11 chromosomes. The results demonstrate a complex genetic control that is variable across years, locations, traits, and within families. The methods were effective at detecting previously identified QTL, as well as new QTL that align closely to the well-characterized flowering time orthologs from barley, including Ppd-H1 and Constans. Our results demonstrate the utility of the NAM population for understanding the genetic control of flowering time and its potential for application to other traits of interest.


Epigenetic Signatures at the RUNX2-P1 and Sp7 Gene Promoters Control Osteogenic Lineage Commitment of Umbilical Cord-Derived Mesenchymal Stem Cells.
Wharton's Jelly mesenchymal stem cells (WJ-MSCs) are an attractive potential source of multipotent stem cells for bone tissue replacement therapies. However, the molecular mechanisms involved in their osteogenic conversion are poorly understood. Particularly, epigenetic control operating at the promoter regions of the two master regulators of the osteogenic program, RUNX2/P57 and SP7 has not yet been described in WJ-MSCs. Via quantitative PCR profiling and chromatin immunoprecipitation (ChIP) studies, here we analyze the ability of WJ-MSCs to engage osteoblast lineage. In undifferentiated WJ-MSCs, RUNX2/P57 P1, and SP7 promoters are found deprived of significant levels of the histone post-translational marks that are normally associated with transcriptionally active genes (H3ac, H3K27ac, and H3K4me3). Moreover, the RUNX2 P1 promoter lacks two relevant histone repressive marks (H3K9me3 and H3K27me3). Importantly, RUNX2 P1 promoter is found highly enriched in the H3K4me1 mark, which has been shown recently to mediate gene repression of key regulatory genes. Upon induction of WJ-MSCs osteogenic differentiation, we found that RUNX2/P57, but not SP7 gene expression is strongly activated, in a process that is accompanied by enrichment of activating histone marks (H3K4me3, H3ac, and H3K27ac) at the P1 promoter region. Histone mark analysis showed that SP7 gene promoter is robustly enriched in epigenetic repressive marks that may explain its poor transcriptional response to osteoblast differentiating media. Together, these results point to critical regulatory steps during epigenetic control of WJ-MSCs osteogenic lineage commitment that are relevant for future applications in regenerative medicine. J. Cell. Physiol. 232: 2519-2527, 2017. © 2016 Wiley Periodicals, Inc.


Breast cancer screening in women with mental illness: comparative meta-analysis of mammography uptake.
There is a higher mortality rate due to cancer in people with mental illness and previous work suggests suboptimal medical care in this population. It remains unclear if this extends to breast cancer population screening. To conduct a systematic review and meta-analysis to establish if women with a mental health condition are less likely to receive mammography screening compared with those without mental ill health. Major electronic databases were searched from inception until February 2014. We calculated odds ratios (OR) with a random effects meta-analysis comparing mammography screening rates among women with and without a mental illness. Results were stratified according to primary diagnosis including any mental illness, mood disorders, depression, severe mental illness (SMI), distress and anxiety. We identified 24 publications reporting breast cancer screening practices in women with mental illness (n = 715,705). An additional 5 studies investigating screening for those with distress (n = 21,491) but no diagnosis of mental disorder were identified. The pooled meta-analysis showed significantly reduced rates of mammography screening in women with mental illness (OR = 0.71, 95% CI 0.66-0.77), mood disorders (OR = 0.83, 95% CI 0.76-0.90) and particularly SMI (OR = 0.54, 95% CI 0.45-0.65). No disparity was evident among women with distress alone. Rates of mammography screening are lower in women with mental illness, particularly women with SMI, and this is not explained by the presence of emotional distress. Disparities in medical care due to mental illness clearly extend into preventive population screening.


Coherent light scattering on nanofluids: computer simulation results.
If coherent light is incident on a suspension containing nanoparticles, they act as scattering centers and the result of the far-field interference is a "speckled" image. The scattering centers have a complex movement of both sedimentation and Brownian motion. Consequently the speckle image is not static but presents time fluctuations. A computer code to simulate the dynamics of the coherent light scattering on nanofluids was written, tested, and used to calculate the far-field intensity variation for nanofluids having different particle size. The results are discussed and an alternative experimental method for fast nanoparticle size assessing is suggested as a possible application.


Value is in the eye of the beholder: early visual cortex codes monetary value of objects during a diverted attention task.
A central concern in the study of learning and decision-making is the identification of neural signals associated with the values of choice alternatives. An important factor in understanding the neural correlates of value is the representation of the object itself, separate from the act of choosing. Is it the case that the representation of an object within visual areas will change if it is associated with a particular value? We used fMRI adaptation to measure the neural similarity of a set of novel objects before and after participants learned to associate monetary values with the objects. We used a range of both positive and negative values to allow us to distinguish effects of behavioral salience (i.e., large vs. small values) from effects of valence (i.e., positive vs. negative values). During the scanning session, participants made a perceptual judgment unrelated to value. Crucially, the similarity of the visual features of any pair of objects did not predict the similarity of their value, so we could distinguish adaptation effects due to each dimension of similarity. Within early visual areas, we found that value similarity modulated the neural response to the objects after training. These results show that an abstract dimension, in this case, monetary value, modulates neural response to an object in visual areas of the brain even when attention is diverted.


Usefulness of baseline statin therapy in non-obstructive coronary artery disease by coronary computed tomographic angiography: From the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) study.
The extent to which the presence and extent of subclinical atherosclerosis by coronary computed tomography angiography influences a potential mortality benefit of statin is unknown. We evaluated the relationship between statin therapy, mortality, and subclinical atherosclerosis. In the CONFIRM study, patients with normal or non-obstructive plaque (<50% diameter stenosis) for whom data on baseline statin use was available were included. Coronary artery calcium (CAC) was quantified using the Agatston score. The extent of non-obstructive coronary atherosclerosis was quantified using the segment involvement score (SIS). 8,016 patients were followed for a median of 2.5 years with analysis of all-cause mortality and major adverse cardiac events (MACE) including all-cause mortality, myocardial infarction, unstable angina, target vessel revascularization, and coronary artery disease-related hospitalization. 1.2% of patients experienced all-cause mortality. Patients not on baseline statin therapy had a stepwise increased risk of all-cause mortality by CAC (relative to CAC = 0; CAC 1-99: hazard ratio [HR] 1.65, CAC 100-299: HR 2.19, and CAC≥300: HR 2.98) or SIS (relative to SIS = 0; SIS 1: HR 1.62, SIS 2-3: 2.48 and SIS≥4: 2.95). Conversely, in patients on baseline statin therapy, there was no significant increase in mortality risk with increasing CAC (p value for interaction = 0.049) or SIS (p value for interaction = 0.007). The incidence of MACE was 2.1%. Similar to the all-cause mortality, the risk of MACE was increased with CAC or SIS strata in patient not on baseline statin therapy. However, this relation was not observed in patient on baseline statin therapy. In individuals with non-obstructive coronary artery disease, increased risk of adverse events occurs with increasing CAC or SIS who are not on baseline statin therapy. Statin therapy is associated with a mitigation of risk of cardiac events in the presence of increasing atherosclerosis, with no particular threshold of disease burden.


Knee extensor muscle weakness and radiographic knee osteoarthritis progression.
Background and purpose - Knee extensor (KE) muscle weakness is a modifiable feature commonly observed in individuals with knee osteoarthritis (KOA) and constitutes a potential target for patient-specific interventions. Therefore, in this study, we explored whether KE weakness is associated with radiographic (medial and/or lateral) KOA progression and how this relationship differs depending on frontal plane knee alignment and sex. Patients and methods - We studied 3,075 knees (1,961 participants, 58% female) from the Osteoarthritis Initiative with radiographic Kellgren-Lawrence grade 1-3. Peak KE torque (Nm/kg) was assessed at baseline, and progression defined as fixed-location joint space width loss (≥ 0.7mm) in medial and lateral tibiofemoral compartments from baseline to 4-year follow-up. Knee-based generalized estimating equations, stratified by alignment (malaligned vs. neutral), estimated the relative risk (RR) of progression for those in the lowest (and middle) vs. highest KE torque group (split by tertiles). Secondary analyses explored whether this relationship was compartmental- or sex-specific. Results - Being in the lowest (or middle) compared with the highest torque group increased the risk of progression in neutrally aligned knees (relative risk [RR] 1.2 [95% CI 1.0-1.4]; and 1.2 [CI 1.0-1.4], respectively), but not after adjusting for age, sex, BMI, pain, and radiographic severity. In secondary analyses, women with neutral alignment in the lowest compared with the highest torque group had significantly increased risk of lateral compartment progression independent of age, BMI, disease severity, and pain (RR 1.3 [CI 1.0-1.8]). No association was observed between KE torque and KOA progression in men, irrespective of alignment. Interpretation - These results identify a potentially important clinical phenotype: KE weakness may be a more important risk factor for radiographic KOA progression in women without knee malalignment.


Atrial fibrillation: a comparison of methods to identify cases in general practice.
The importance of atrial fibrillation as a treatable risk factor for stroke is well established. Less is known about how to find previously unidentified cases within the community so that antithrombotic treatment can be offered to a wider group of at-risk patients. The aim of our study was to examine ways to improve the efficiency of practice-based screening for atrial fibrillation, including issues of time and financial cost. We used different combinations of pulse palpation and interpretation of 12-lead and bipolar electrocardiographs as carried out by practice nurses. The best strategy for the detection of atrial fibrillation in a practice population would appear to be to screen all eligible subjects by nurse pulse palpation, followed by 12-lead electrocardiograph readings in those who have a pulse suggestive of atrial fibrillation. The electrocardiograph interpretation can be undertaken effectively by a trained nurse.


SIV infection of rhesus macaques results in dysfunctional T- and B-cell responses to neo and recall Leishmania major vaccination.
HIV infection is characterized by immune system dysregulation, including depletion of CD4+ T cells, immune activation, and abnormal B- and T-cell responses. However, the immunologic mechanisms underlying lymphocytic dysfunctionality and whether it is restricted to immune responses against neo antigens, recall antigens, or both is unclear. Here, we immunized SIV-infected and uninfected rhesus macaques to induce immune responses against neo and recall antigens using a Leishmania major polyprotein (MML) vaccine given with poly-ICLC adjuvant. We found that vaccinated SIVuninfected animals induced high frequencies of polyfunctional MML-specific CD4+ T cells. However, in SIV-infected animals, CD4+ T-cell functionality decreased after both neo (P = .0025) and recall (P = .0080) MML vaccination. Furthermore, after SIV infection, the frequency of MML-specific antibody-secreting classic memory B cells was decreased compared with vaccinated, SIV-uninfected animals. Specifically, antibody-secreting classic memory B cells that produced IgA in response to either neo (P = .0221) or recall (P = .0356) MML vaccinations were decreased. Furthermore, we found that T-follicular helper cells, which are essential for priming B cells, are preferentially infected with SIV. These data indicate that SIV infection results in dysfunctional T-cell responses to neo and recall vaccinations, and direct SIV infection of T-follicular helper cells, both of which probably contribute to deficient B-cell responses and, presumably, susceptibility to certain opportunistic infections.


The hydrophobic internal region of bovine prion protein shares structural and functional properties with HIV type 1 fusion peptide.
The conserved fusion peptide at the N-terminus of HIV-1 envelope glycoprotein gp41 is involved in the virus-cell fusion reaction and in the cytopathic effects promoted by expression in single cells. The conserved bovine prion protein 121KHVAGAAAAGAVVGGLGGYMLGSAMSR147 transmembrane region (BPrP(tm)) contains a sequence rich in Gly residues [i.e., 130GAVVGGLGGYMLGSAMSR147 (BPrP(mi))] that shows homology with HIV-1 fusion peptide. As in the case of the latter peptide, analysis of the BPrP(mi) interfacial hydrophobicity confirms that this stretch bears an intrinsic tendency to partitioning from the aqueous phase into membranes. Experimental analyses of BPrP(mi)-lipid interactions suggest several similarities between this sequence and HIV-1 fusion peptide. Infrared spectroscopy reveals a conformational plasticity of the membrane-associated prion sequence comparable to that displayed by the viral sequence. The adoption of a mainly alpha-helical structure correlates with the formation of lytic pores. This helical structure can be converted into a beta-sheet conformation by addition of calcium, a process that is accompanied by vesicle membrane fusion. In contrast, transmembrane BPrP(tm) associates with membranes in a nonlytic, mainly helical structure but also containing some random coil. Upon addition of calcium, the random coils disappear while the helical conformation remains. In the absence of membranes both prion and HIV-1 sequences form amyloid-type fibers. It is proposed that during the pathological processes induced by secreted PrPSc and its proteolytic fragments, conformational polymorphism displayed by membrane-inserted BPrP(mi) may play a role at perturbing the general architecture of the membrane lipid bilayer and inducing protein-protein aggregation at membrane surfaces. These findings suggest the existence of common mechanisms underlying cytotoxicity by PrP and HIV-1 gp41.


Medicine administration errors in patients with dysphagia in secondary care: a multi-centre observational study.
The aim of this study was to describe the interventions used by nurses when administering oral medicines to patients with and without dysphagia, to quantify the appropriateness of these interventions and the medicine administration error rate. The administration of medicines to patients with dysphagia is complex and potentially more error prone because of the need to match the medication's formulation to the swallowing ability of the patient. Data was collected on the preparation and administration of oral medicines to patients with and without dysphagia, including those with enteral feeding tubes, using undisguised direct observation of 65 nurse-led medicine administration rounds on stroke and care-of-the-elderly wards at four acute general hospitals in East of England between 1 March and 30 June 2008. Of the 2129 medicine administrations observed, 817 involved an error, and of these 313 involved patients with dysphagia. Excluding time errors, the normalized frequency of medicine administration errors for patients with dysphagia was 21.1% compared with 5.9% for patients without. Using a mixed effects model and excluding time errors, there is a higher risk of errors for patients with dysphagia (excluding patients with enteral tubes) compared with those without (P < 0.001) and a further increase in risk of error for patients with enteral tubes compared with dysphagic patients without tubes (P < 0.001). The increased medicine administration error rate in patients with dysphagia requires healthcare professionals to take extra care when prescribing, dispensing and administering medicines to this group.


Does parallel item content on WOMAC's pain and function subscales limit its ability to detect change in functional status?
Although the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) is considered the leading outcome measure for patients with osteoarthritis of the lower extremity, recent work has challenged its factorial validity and the physical function subscale's ability to detect valid change when pain and function display different profiles of change. This study examined the etiology of the WOMAC's physical function subscale's limited ability to detect change in the presence of discordant changes for pain and function. We hypothesized that the duplication of some items on the WOMAC's pain and function subscales contributed to this shortcoming. Two eight-item physical function scales were abstracted from the WOMAC's 17-item physical function subscale: one contained activities and themes that were duplicated on the pain subscale (SIMILAR-8); the other version avoided overlapping activities (DISSIMILAR-8). Factorial validity of the shortened measures was assessed on 310 patients awaiting hip or knee arthroplasty. The shortened measures' abilities to detect change were examined on a sample of 104 patients following primary hip or knee arthroplasty. The WOMAC and three performance measures that included activity specific pain assessments--40 m walk test, stair test, and timed-up-and-go test--were administered preoperatively, within 16 days of hip or knee arthroplasty, and at an interval of greater than 20 days following the first post-surgical assessment. Standardized response means were used to quantify change. The SIMILAR-8 did not demonstrate factorial validity; however, the factorial structure of the DISSIMILAR-8 was supported. The time to complete the performance measures more than doubled between the preoperative and first postoperative assessments supporting the theory that lower extremity functional status diminished over this interval. The DISSIMILAR-8 detected this deterioration in functional status; however, no significant change was noted for the SIMILAR-8. The WOMAC pain scale demonstrated a slight reduction in pain and the performance specific pain measures did not reflect a change in pain. All measures showed substantial improvement over the second assessment interval. These findings support the hypothesis that activity overlap on the pain and function subscales plays a causal role in limiting the WOMAC physical function subscale's ability to detect change.


The complexity of managing COPD exacerbations: a grounded theory study of European general practice.
To understand the concerns and challenges faced by general practitioners (GPs) and respiratory physicians about primary care management of acute exacerbations in patients with chronic obstructive pulmonary disease (COPD). 21 focus group discussions (FGDs) were performed in seven countries with a Grounded Theory approach. Each country performed three rounds of FGDs. Primary and secondary care in Norway, Germany, Wales, Poland, Russia, The Netherlands, China (Hong Kong). 142 GPs and respiratory physicians were chosen to include urban and rural GPs as well as hospital-based and out patient-clinic respiratory physicians. Management of acute COPD exacerbations is dealt with within a scope of concerns. These concerns range from 'dealing with comorbidity' through 'having difficult patients' to 'confronting a hopeless disease'. The first concern displays medical uncertainty regarding diagnosis, medication and hospitalisation. These clinical processes become blurred by comorbidity and the social context of the patient. The second concern shows how patients receive the label 'difficult' exactly because they need complex attention, but even more because they are time consuming, do not take responsibility and are non-compliant. The third concern relates to the emotional reactions by the physicians when confronted with 'a hopeless disease' due to the fact that most of the patients do not improve and the treatment slows down the process at best. GPs and respiratory physicians balance these concerns with medical knowledge and practical, situational knowledge, trying to encompass the complexity of a medical condition. Knowing the patient is essential when dealing with comorbidities as well as with difficult relations in the consultations on exacerbations. This study suggests that it is crucial to improve the collaboration between primary and secondary care, in terms of, for example, shared consultations and defined work tasks, which may enhance shared knowledge of patients, medical decision-making and improved management planning.


Disposition index, glucose effectiveness, and conversion to type 2 diabetes: the Insulin Resistance Atherosclerosis Study (IRAS).
Disposition index (DI) and glucose effectiveness (S(G)) are risk factors for diabetes. However, the effect of DI and S(G) on future diabetes has not been examined in large epidemiological studies using direct measures. Insulin sensitivity index (S(I)), acute insulin response (AIR), and S(G) were measured in 826 participants (aged 40-69 years) in the Insulin Resistance Atherosclerosis Study (IRAS) by the frequently sampled intravenous glucose tolerance test. DI was expressed as S(I) x AIR. At the 5-year follow-up examination, 128 individuals (15.5%) had developed diabetes. The area under the receiver operating characteristic curve of a model with S(I) and AIR was similar to that of DI (0.767 vs. 0.774, P = 0.543). In a multivariate logistic regression model that included both DI and S(G), conversion to diabetes was predicted by both S(G) (odds ratio x 1 SD, 0.61 [0.47-0.80]) and DI (0.68 [0.54-0.85]) after adjusting for demographic variables, fasting and 2-h glucose concentrations, family history of diabetes, and measures of obesity. Age, sex, race/ethnicity, glucose tolerance status, obesity, and family history of diabetes did not have a significant modifying impact on the relation of S(G) and DI to incident diabetes. The predictive power of DI is comparable to that of its components, S(I) and AIR. S(G) and DI independently predict conversion to diabetes similarly across race/ethnic groups, varying states of glucose tolerance, family history of diabetes, and obesity.


Cholesteryl hemiazelate causes lysosome dysfunction impacting vascular smooth muscle cell homeostasis.
In atherosclerotic lesions, vascular smooth muscle cells (VSMCs) represent half of the foam cell population, which is characterized by an aberrant accumulation of undigested lipids within lysosomes. Loss of lysosome function impacts VSMC homeostasis and disease progression. Understanding the molecular mechanisms underlying lysosome dysfunction in these cells is, therefore, crucial. We identify cholesteryl hemiazelate (ChA), a stable oxidation end-product of cholesteryl-polyunsaturated fatty acid esters, as an inducer of lysosome malfunction in VSMCs. ChA-treated VSMCs acquire a foam-cell-like phenotype, characterized by enlarged lysosomes full of ChA and neutral lipids. The lysosomes are perinuclear and exhibit degradative capacity and cargo exit defects. Lysosome luminal pH is also altered. Even though the transcriptional response machinery and autophagy are not activated by ChA, the addition of recombinant lysosomal acid lipase (LAL) is able to rescue lysosome dysfunction. ChA significantly affects VSMC proliferation and migration, impacting atherosclerosis. In summary, this work shows that ChA is sufficient to induce lysosomal dysfunction in VSMCs, that, in ChA-treated VSMCs, neither lysosome biogenesis nor autophagy are triggered, and, finally, that recombinant LAL can be a therapeutic approach for lysosomal dysfunction.


Enhanced cognitive behaviour therapy for adolescents with anorexia nervosa: an alternative to family therapy?
A specific form of family therapy (family-based treatment) is the leading treatment for adolescents with anorexia nervosa. As this treatment has certain limitations, alternative approaches are needed. "Enhanced" cognitive behaviour therapy (CBT-E) is a potential candidate given its utility as a treatment for adults with eating disorder psychopathology. The aim of the present study was to establish, in a representative cohort of patients with marked anorexia nervosa, the immediate and longer term outcome following CBT-E. Forty-nine adolescent patients were recruited from consecutive referrals to a community-based eating disorder clinic. Each was offered 40 sessions of CBT-E over 40 weeks from a single therapist. Two-thirds completed the full treatment with no additional input. In these patients there was a substantial increase in weight together with a marked decrease in eating disorder psychopathology. Over the 60-week post-treatment follow-up period there was little change despite minimal subsequent treatment. These findings suggest that CBT-E may prove to be a cost-effective alternative to family-based treatment.


Effect of endothelin on outflow facility and accommodation in the monkey eye in vivo.
The effect of the vasoactive peptide, endothelin, on facility of outflow, accommodation, and pupil diameter was measured in the monkey eye in vivo. Endothelin increased the outflow facility 22-71% at approximate anterior chamber concentrations ranging from 10(-10)-10(-7) M. Endothelin-induced accommodation was modest but consistent and statistically significant ranging from 1.61 to a maximum of 2.43 diopters at 10(-9) M and 10(-7) M endothelin, respectively. No change in pupil diameter was noted with any of the administered doses. These data demonstrate an action of endothelin on outflow facility and, together with prior evidence indicating the presence of endothelin receptors on the ciliary muscle, suggest that, like cholinergic agonists, the observed effects of endothelin on outflow facility may be mediated, at least in part, through an action on the ciliary muscle.


Neural correlates of written emotion word processing: a review of recent electrophysiological and hemodynamic neuroimaging studies.
A growing body of literature investigating the neural correlates of emotion word processing has emerged in recent years. Written words have been shown to represent a suitable means to study emotion processing and most importantly to address the distinct and interactive contributions of the two dimensions of emotion: valence and arousal. The aim of the present review is to integrate findings from electrophysiological (ERP) and hemodynamic neuroimaging (fMRI) studies in order to provide a better understanding of emotion word processing. It provides an up-to-date review of recent ERP studies since the review by Kissler et al. (2006) as well as the first review of hemodynamic brain imaging studies in the field. A discussion of theoretical and methodological issues is also presented, along with suggestions for future research.


Age-related cognitive decline and associations with sex, education and apolipoprotein E genotype across ethnocultural groups and geographic regions: a collaborative cohort study.
The prevalence of dementia varies around the world, potentially contributed to by international differences in rates of age-related cognitive decline. Our primary goal was to investigate how rates of age-related decline in cognitive test performance varied among international cohort studies of cognitive aging. We also determined the extent to which sex, educational attainment, and apolipoprotein E ε4 allele (APOE*4) carrier status were associated with decline. We harmonized longitudinal data for 14 cohorts from 12 countries (Australia, Brazil, France, Greece, Hong Kong, Italy, Japan, Singapore, Spain, South Korea, United Kingdom, United States), for a total of 42,170 individuals aged 54-105 y (42% male), including 3.3% with dementia at baseline. The studies began between 1989 and 2011, with all but three ongoing, and each had 2-16 assessment waves (median = 3) and a follow-up duration of 2-15 y. We analyzed standardized Mini-Mental State Examination (MMSE) and memory, processing speed, language, and executive functioning test scores using linear mixed models, adjusted for sex and education, and meta-analytic techniques. Performance on all cognitive measures declined with age, with the most rapid rate of change pooled across cohorts a moderate -0.26 standard deviations per decade (SD/decade) (95% confidence interval [CI] [-0.35, -0.16], p < 0.001) for processing speed. Rates of decline accelerated slightly with age, with executive functioning showing the largest additional rate of decline with every further decade of age (-0.07 SD/decade, 95% CI [-0.10, -0.03], p = 0.002). There was a considerable degree of heterogeneity in the associations across cohorts, including a slightly faster decline (p = 0.021) on the MMSE for Asians (-0.20 SD/decade, 95% CI [-0.28, -0.12], p < 0.001) than for whites (-0.09 SD/decade, 95% CI [-0.16, -0.02], p = 0.009). Males declined on the MMSE at a slightly slower rate than females (difference = 0.023 SD/decade, 95% CI [0.011, 0.035], p < 0.001), and every additional year of education was associated with a rate of decline slightly slower for the MMSE (0.004 SD/decade less, 95% CI [0.002, 0.006], p = 0.001), but slightly faster for language (-0.007 SD/decade more, 95% CI [-0.011, -0.003], p = 0.001). APOE*4 carriers declined slightly more rapidly than non-carriers on most cognitive measures, with processing speed showing the greatest difference (-0.08 SD/decade, 95% CI [-0.15, -0.01], p = 0.019). The same overall pattern of results was found when analyses were repeated with baseline dementia cases excluded. We used only one test to represent cognitive domains, and though a prototypical one, we nevertheless urge caution in generalizing the results to domains rather than viewing them as test-specific associations. This study lacked cohorts from Africa, India, and mainland China. Cognitive performance declined with age, and more rapidly with increasing age, across samples from diverse ethnocultural groups and geographical regions. Associations varied across cohorts, suggesting that different rates of cognitive decline might contribute to the global variation in dementia prevalence. However, the many similarities and consistent associations with education and APOE genotype indicate a need to explore how international differences in associations with other risk factors such as genetics, cardiovascular health, and lifestyle are involved. Future studies should attempt to use multiple tests for each cognitive domain and feature populations from ethnocultural groups and geographical regions for which we lacked data.


Long-term effect of whole body vibration training on jump height: meta-analysis.
Whole body vibration (WBV) is widely promoted as a means of improving muscle strength, but the evidence of a performance benefit is unclear with some reporting improvements and others finding none. The objective of this study was to analyze the current evidence for the effectiveness of WBV on jump height. We included randomized controlled trials or matched design studies comparing the effect of WBV training on countermovement and squat jump (SJ) height, which were gathered from MEDLINE, Web of Knowledge, Sciencedirect, Proquest, Scopus, Google Scholar, and SPORTDiscus databases. The overall effect of WBV training (from the 15 studies included) compared with having no additional exercise on countermovement jump height yielded a positive standardized mean difference of 0.77 (95% confidence interval, 0.55-0.99). The effect of WBV training on SJ height was 0.68 (0.08-1.11). Vibration exercise consisting of a higher frequency (>30 Hz, 0.86, 0.62-1.10), higher amplitude (>3 mm, 0.84, 0.52-1.17), longer exposure duration (>10 minutes per session, 0.92, 0.48-1.36), longer training period (>12 weeks, 0.87, 0.56-1.19) and among nonathletes (0.96, 0.63-1.30) had greater benefit for jump height improvement than a lower frequency (≤ 30 Hz, 0.56, 0.13-0.99), lower amplitude (≤ 3 mm, 0.66, 0.35-0.98), shorter exposure duration (≤ 10 minutes per session, 0.68, 0.45-0.92), intermediate training period (4-12 weeks, 0.72, 0.35-1.09), shorter training period (<4 weeks, 0.58, -0.08 to -1.23) and in athletes (0.59, 0.31-0.88). The effect of WBV training compared with a standard cardiovascular-type exercise group from 4 studies was 0.63 (0.10-1.15). In conclusion, WBV training produces a moderate-to-large effect on jump height. Vibration training protocols with higher frequencies, higher amplitudes, longer exposures per session, and longer training periods are more likely to enhance muscle power.


Color vision in the peripheral retina. II. Hue and saturation.
Hue and saturation of spectral lights were measured (direct scaling) in the fovea and at 45 degrees in the periphery; all lights were of equal photopic retinal illuminance (1200 trolands). At each retinal location both large and small targets were used. As shown by previous studies, small peripheral targets appear desaturated and of uncertain hue, except long wavelengths which appear red. However, if target size is increased, saturation increases and a full range of hues is seen; the hue functions for large peripheral targets are comparable to foveal ones for very small targets. From a modified form of color matching, it was concluded that the color deficiency in the periphery is more tritanlike than deutanlike; this is strengthened by the observation, that, for small peripheral targets, hues are generally apportioned between two hue categories and the change from one to the other is at about 580 nm.


HMGB proteins are required for sexual development in Aspergillus nidulans.
Aspergillus nidulans has three high mobility group box (HMGB) proteins, HmbA, HmbB and HmbC that are chromatin-associated architectural proteins involved in DNA-related functions. By creating and studying deletion strains in both veA+ and veA1 background, we have characterized the role of HmbA, HmbB and HmbC in sexual development. Expression of the mating-type MAT1-1 and MAT1-2 coding genes were found to be extremely down-regulated in all three mutants on day 4 of sexual development, which results in deficient ascospore production and/or ascospore viability in the mutants. In addition, we found that HmbA and HmbB play also a role in sensing of and response to environmental signals, while HmbC functionally interacts with VeA, a key regulator of the coordination of asexual and sexual development, as well as of secondary metabolism.


Telephone follow-up for patients with amyotrophic lateral sclerosis.
The relentless evolution of amyotrophic lateral sclerosis (ALS), a severe neurodegenerative disorder of the upper and lower motoneurons, leads to an increasing level of disability. Most patients, during the course of the disease, become unable to attend the tertiary clinical care center and are thus prevented from enrolling in clinical trials or benefiting from specialized care and management. The main objective of this study was to verify whether the ALS functional rating scale (ALSFRS) could be reliably administered by telephone to patients, when unable to attend the ALS clinic, or to their caregivers. ALSFRS is a validated instrument that assesses the functional status and the disease progression in ALS. We first administered the functional rating scale directly in the clinic to 30 patients, with definite or probable ALS, and to their respective caregivers, and found a very high agreement between the two groups for the total score and the majority of the rating items. Next, we showed, in both patients and caregivers, a high degree of correlation between the total score of the ALSFRS measured by telephone and that reported in the clinic. This indicates that ALSFRS is a reliable instrument for monitoring the disease progression in homebound patients, even when the person contacted by telephone is the caregiver. We also performed a telephone clinic, based on an unstructured interview, with 16 ALS patients at an advanced stage of the disease and unable to attend the ALS clinic. On some occasions, the person interviewed was the caregiver. The symptoms most frequently reported were a worsening of muscle strength, swallowing and breathing problems, constipation, and inability to clear lung secretions. Several patients asked for assistive and adaptive equipment. All patients and caregivers found the telephone clinic very useful and considered it a good complement to the management and care programme.


Induction of Pseudomonas syringae pv. tomato DC3000 MexAB-OprM multidrug efflux pump by flavonoids is mediated by the repressor PmeR.
In this study, we have analyzed the expression of the Pseudomonas syringae pv. tomato DC3000 mexAB-oprM efflux pump operon and of the regulatory gene pmeR, and we have investigated the role of the PmeR protein on transcription from both promoters. We demonstrate that mexAB-oprM and pmeR are expressed in vivo at a relatively high and moderate basal level, respectively, which, in both cases, increases in the presence of different flavonoids and other compounds, such as butyl and methylparaben. We show that PmeR is the local repressor of the mexAB-oprM promoter and is able to regulate its own expression. The mechanism for this regulation includes binding to a pseudopalindromic operator site which overlaps both mexAB-oprM and pmeR promoters. We have also proven that flavonoids are able to interact with PmeR and induce a conformational change that interferes with the DNA binding ability of PmeR, thereby modulating mexAB-oprM and pmeR expression. Finally, we demonstrate by in vivo experiments that the PmeR/MexAB-OprM system contributes to the colonization of tomato plants. These results provide new insight into a transcriptional regulator and a transport system that play essential roles in the ability of P. syringae pv. tomato DC3000 to resist the action of flavonoids produced by the host.


YTHDC1-modified m6A methylation of hsa_circ_0102678 promotes keratinocyte inflammation induced by Cutibacterium acnes biofilm through regulating miR-146a/TRAF6 and IRAK1 axis.
CircRNAs are closely related to many human diseases, however, their role in acne remains unclear. This study aimed to determine the role of hsa-circ_0102678 in regulating inflammation of acne. Firstly, microarray analysis was performed to study the expression of circRNAs in acne. Subsequently, RNase R digestion assay and FISH assay were utilized to confirm the characteristics of hsa-circ_0102678. Finally, qRT-PCR, Western blotting analysis, Immunoprecipitation, Luciferase reporter assay, circRNA probe pull-down assay, Biotin-labeled miRNA pull-down assay, RNA immunoprecipitation (RIP) assay and m6A dot blot assay were utilized to reveal the functional roles of hsa-circ_0102678 on inflammation induced by C. acnes biofilm in human primary keratinocytes. Our investigations showed that the expression of hsa-circ_0102678 was significantly decreased in acne tissues and hsa-circ_0102678 was a type of circRNAs, which was mainly localized in the cytoplasm of primary human keratinocytes. Moreover, hsa-circ_0102678 remarkably affected the expression of IL-8, IL-6, and TNF-α, which induced by C. acnes biofilm. Importantly, mechanistic studies indicated that the YTHDC1 could bind directly to hsa-circ_0102678 and promote the export of N6-methyladenosine modified hsa-circ_0102678 to the cytoplasm. Besides, hsa-circ_0102678 could bind to miR-146a and sponge miR-146a to promote the expression of IRAK1 and TRAF6. Our findings revealed a previously unknown process by which hsa_circ_0102678 promoted keratinocyte inflammation induced by C. acnes biofilm via regulating miR-146a/TRAF6 and IRAK1 axis.


Predictive Value and Interrater Reliability of Radiographic Factors in Neurofibromatosis Patients With Dystrophic Scoliosis.
Scoliosis in patients with neurofibromatosis type I (NF1) can manifest as dystrophic or nondystrophic curves. Dystrophic scoliosis is rapidly progressive, rendering treatment challenging. Radiographic characteristics have been reported to predict dystrophic scoliosis, but their reliability and predictive value have not been well described. The purpose of this study is to assess the interobserver reliability for eight radiographic characteristics of dystrophic scoliosis and to evaluate the sensitivity and specificity of these characteristics relative to the gold standard of a definitive clinical diagnosis. Spine radiographs of 122 NF1 patients from multiple institutions were graded by five spine surgeons as dystrophic or nondystrophic, based on eight radiographic characteristics of dystrophic modulation: rib penciling, vertebral rotation, scalloping, wedging, spindling of transverse processes, short sharp angular curve, widened interpedicular distance, and atypical location. The curves were classified by each submitting institution as dystrophic or nondystrophic based on clinical outcome. Interobserver reliability analysis was performed using Fleiss kappa. For the 122 cases, the interrater agreement among the five readers for the diagnosis of dystrophic scoliosis was good at 0.61. The agreement for individual radiographic characteristic ranged from 0.62 for wedging to 0.14 (poor) for scalloping. Surgeons underestimated the number of dystrophic curves, rating from 45% to 67% of the curve patterns as dystrophic, compared to the gold standard, which revealed 68% of the curves to be dystrophic. On multivariate analysis, rib penciling, vertebral rotation, vertebral wedging, and atypical location were significantly associated with true dystrophic status (odds ratios of 2.4, 3.0, 2.4, and 3.0, respectively). Overall dystrophic diagnosis can be assessed by radiographic characteristics. Better understanding of the predictive value of specific radiographic features may assist in early diagnosis of patients with dystrophic NF and assist surgeons in identifying dystrophic curve patterns and instituting prompt, appropriate treatment. Level III.


Chicken consumption and use of acid-suppressing medications as risk factors for Campylobacter enteritis, England.
In a case-control study of Campylobacter spp. risk factors in England during 2005-2006, we identified recent consumption of commercially prepared chicken as an important risk factor. The risk for illness associated with recent chicken consumption was much lower for persons who regularly ate chicken than in those who did not, which suggests that partial immunologic protection may follow regular chicken preparation or consumption. Chicken-related risk factors accounted for 41% of cases; acid-suppressing medication, for 10%; self-reported past Campylobacter enteritis, 2%; and recent acquisition of a pet dog, 1%. Understanding the risks associated with chicken from different sources will benefit strategies to reduce Campylobacter infections. Better characterization of immune correlates for Campylobacter infection is necessary to assess the relative importance of immunity and behavioral factors in determining risk.


Reconstruction of organ dose for external radiotherapy patients in retrospective epidemiologic studies.
Organ dose estimation for retrospective epidemiological studies of late effects in radiotherapy patients involves two challenges: radiological images to represent patient anatomy are not usually available for patient cohorts who were treated years ago, and efficient dose reconstruction methods for large-scale patient cohorts are not well established. In the current study, we developed methods to reconstruct organ doses for radiotherapy patients by using a series of computational human phantoms coupled with a commercial treatment planning system (TPS) and a radiotherapy-dedicated Monte Carlo transport code, and performed illustrative dose calculations. First, we developed methods to convert the anatomy and organ contours of the pediatric and adult hybrid computational phantom series to Digital Imaging and Communications in Medicine (DICOM)-image and DICOM-structure files, respectively. The resulting DICOM files were imported to a commercial TPS for simulating radiotherapy and dose calculation for in-field organs. The conversion process was validated by comparing electron densities relative to water and organ volumes between the hybrid phantoms and the DICOM files imported in TPS, which showed agreements within 0.1 and 2%, respectively. Second, we developed a procedure to transfer DICOM-RT files generated from the TPS directly to a Monte Carlo transport code, x-ray Voxel Monte Carlo (XVMC) for more accurate dose calculations. Third, to illustrate the performance of the established methods, we simulated a whole brain treatment for the 10 year-old male phantom and a prostate treatment for the adult male phantom. Radiation doses to selected organs were calculated using the TPS and XVMC, and compared to each other. Organ average doses from the two methods matched within 7%, whereas maximum and minimum point doses differed up to 45%. The dosimetry methods and procedures established in this study will be useful for the reconstruction of organ dose to support retrospective epidemiological studies of late effects in radiotherapy patients.


Moon: possible nature of the body that produced the imbrian basin, from the composition of apollo 14 samples.
Soils from the Apollo 14 site contain nearly three times as much meteoritic material as soils from the Apollo 11, Apollo 12, and Luna 16 sites. Part of this material consists of the ubiquitous micrometeorite component, of primitive (carbonaceous-chondrite-like) composition. The remainder, seen most conspicuously in coarse glass and norite fragments, has a decidedly fractionated composition, with volatile elements less than one-tenth as abundant as siderophiles. This material seems to be debris of the Cyprus-sized planetesimal that produced the Imbrian basin. Compositionally this planetesimal has no exact counterpart among known meteorite classes, though group IVA irons come close. It also resembles the initial composition of the earth as postulated by the two-component model. Apparently the Imbrian planetesimal was an Earth satellite swept up by the moon during tidal recession or capture, or an asteroid deflected by Mars into terrestrial space.


Three-layered atmospheric structure in accretion disks around stellar-mass black holes
Modeling of the x-ray spectra of the Galactic superluminal jet sources GRS 1915+105 and GRO J1655-40 reveals a three-layered atmospheric structure in the inner region of their accretion disks. Above the cold and optically thick disk with a temperature of 0.2 to 0.5 kiloelectron volts, there is a warm layer with a temperature of 1.0 to 1.5 kiloelectron volts and an optical depth around 10. Sometimes there is also a much hotter, optically thin corona above the warm layer, with a temperature of 100 kiloelectron volts or higher and an optical depth around unity. The structural similarity between the accretion disks and the solar atmosphere suggests that similar physical processes may be operating in these different systems.


Prediction of low back pain with two expert systems.
Low back pain (LBP) is one of the common problems encountered in medical applications. This paper proposes two expert systems (artificial neural network and adaptive neuro-fuzzy inference system) for the assessment of the LBP level objectively. The skin resistance and visual analog scale (VAS) values have been accepted as the input variables for the developed systems. The results showed that the expert systems behave very similar to real data and that use of the expert systems can be used to successfully diagnose the back pain intensity. The suggested systems were found to be advantageous approaches in addition to existing unbiased approaches. So far as the authors are aware, this is the first attempt of using the two expert systems achieving very good performance in a real application. In light of some of the limitations of this study, we also identify and discuss several areas that need continued investigation.


Genetic origins of lactase persistence and the spread of pastoralism in Africa.
In humans, the ability to digest lactose, the sugar in milk, declines after weaning because of decreasing levels of the enzyme lactase-phlorizin hydrolase, encoded by LCT. However, some individuals maintain high enzyme amounts and are able to digest lactose into adulthood (i.e., they have the lactase-persistence [LP] trait). It is thought that selection has played a major role in maintaining this genetically determined phenotypic trait in different human populations that practice pastoralism. To identify variants associated with the LP trait and to study its evolutionary history in Africa, we sequenced MCM6 introns 9 and 13 and ~2 kb of the LCT promoter region in 819 individuals from 63 African populations and in 154 non-Africans from nine populations. We also genotyped four microsatellites in an ~198 kb region in a subset of 252 individuals to reconstruct the origin and spread of LP-associated variants in Africa. Additionally, we examined the association between LP and genetic variability at candidate regulatory regions in 513 individuals from eastern Africa. Our analyses confirmed the association between the LP trait and three common variants in intron 13 (C-14010, G-13907, and G-13915). Furthermore, we identified two additional LP-associated SNPs in intron 13 and the promoter region (G-12962 and T-956, respectively). Using neutrality tests based on the allele frequency spectrum and long-range linkage disequilibrium, we detected strong signatures of recent positive selection in eastern African populations and the Fulani from central Africa. In addition, haplotype analysis supported an eastern African origin of the C-14010 LP-associated mutation in southern Africa.


Lithium inhibits carcinoid cell growth in vitro.
Carcinoids are slow growing neuroendocrine tumors that often cause debilitating symptoms due to excessive secretion of hormones such as serotonin. Surgery is the only potentially curative treatment, but many patients have unresectable metastatic disease. Lithium is a non- competitive inhibitor of GSK-3 with an established safety profile. The objective of this study was to investigate the effects of lithium on carcinoid cell growth in vitro. Lithium treatment caused a dose-dependent reduction in carcinoid cancer cell (BON and H727) growth. Western blot analysis revealed increased expression of cleaved poly (ADP-ribose) polymerase (PARP), indicating the induction of apoptosis. Lithium treatment also suppressed cellular levels of serotonin and chromogranin A. In summary, lithium inactivates GSK-3, induces apoptosis, and suppresses carcinoid cancer cell growth in vitro. The drug has been used clinically since the 19(th) century to treat a variety of diseases including bipolar disorder, and its safety profile is well documented. Therefore, based on these findings, we have undertaken a clinical trial of lithium chloride in the treatment of patients with unresectable carcinoid cancer.


Serine/threonine phosphatase 1 modulates the subnuclear distribution of pre-mRNA splicing factors.
HeLa cell nuclei were permeabilized and reconstituted with nuclear extract to identify soluble nuclear factors which play a role in the organization of pre-mRNA splicing factors in the mammalian cell nucleus. Permeabilized nuclei reconstituted with nuclear extract were active in transcription and DNA replication and nuclear speckles containing pre-mRNA splicing factors were maintained over several hours independent of soluble nuclear components. The characteristic rounding up of nuclear speckles in response to inhibition of RNA polymerase II seen in vivo was reproduced in permeabilized cells and was strictly dependent on a catalytic activity present in the nuclear extract. By inhibitor titration experiments and sensitivity to inhibitor 2, this activity was identified as a member of the serine/threonine protein phosphatase 1 family (PP1). Interference with PP1 activity affected the distribution of pre-mRNA splicing factors in transcriptionally active, permeabilized cells, and excess PP1 activity caused increased dephosphorylation of SR proteins in nuclear speckles. These data show that the dynamic reorganization of the mammalian cell nucleus can be studied in permeabilized cells and that PP1 is involved in the rounding up of speckles as well as the overall organization of pre-mRNA splicing factors in the mammalian cell nucleus.


Structural evaluation of an alternative Protein A biomimetic ligand for antibody purification.
Affinity chromatography is one of the most common techniques employed at the industrial-scale for antibody purification. In particular, the purification of human immunoglobulin G (hIgG) has gained relevance with the immobilization of its natural binding counterpart-Staphylococcus aureus Protein A (SpA) or with the recent development of biomimetic affinity ligands, namely triazine-based ligands. These ligands have been developed in order to overcome economic and leaching issues associated to SpA. The most recent triazine-based ligand-TPN-BM, came up as an analogue of 2-(3-amino-phenol)-6-(4-amino-1-naphthol)-4-chloro-sym-triazine ligand also known as ligand 22/8 with improved physico-chemical properties and a greener synthetic route. This work intends to evaluate the potential of TPN-BM as an alternative affinity ligand towards antibody recognition and binding, namely IgG, at an atomic level, since it has already been tested, after immobilization onto chitosan-based monoliths and demonstrated interesting affinity behaviour for this purpose. Herein, combining automated molecular docking and molecular dynamics simulations it was predicted that TPN-BM has high propensity to bind IgG through the same binding site found in the crystallographic structure of SpA_IgG complex, as well as theoretically predicted for ligand 22/8_IgG complex. Furthermore, it was found that TPN-BM established preferential interactions with aromatic residues at the Fab domain (Trp 50, Tyr 53, Tyr 98 and Trp 100), while in the Fc domain the main interactions are based on hydrogen bonds with pH sensitive residues at operational regime for binding and elution like histidines (His 460, His 464, His 466). Moreover, the pH dependence of TPN-BM_IgG complex formation was more evident for the Fc domain, where at pH 3 the protonation state and consequently the charge alteration of histidine residues located at the IgG binding site induced ligand detachment which explains the optimal elution condition at this pH observed experimentally.


Data quality and factor analysis of the Danish version of the Relationship Scale Questionnaire.
The Relationship Scale Questionnaire (RSQ) is a widely-used measure of adult attachment, but whether the results obtained by the RSQ fit the attachment construct has only been examined to a limited extent. The objectives of this study were to investigate the psychometric properties of the Danish translation of the RSQ and to test whether the results are consistent with the hypothesized model of attachment. The study included two samples: 602 general practitioners and 611 cancer patients. The two samples were analyzed separately. Data quality was assessed by mean, median and missing values for each item, floor and ceiling effects, average inter-item correlations and Cronbach's α for each subscale. Test-retest was assessed by intra-class correlations among 76 general practitioners. A confirmatory factor analysis was conducted to establish evidence of the four proposed subscales. Due to an inadequate fit of the model, data was randomly split into two equally sized subsamples and an exploratory factor analysis was conducted for all 30 items in the first subsample comprised of 286 cancer patients and 285 general practitioners. The EFA yielded a three-factor structure which was validated through a confirmatory factor analyses in a second subsample comprised of 278 cancer patients and 289 general practitioners. The data quality of the RSQ was generally good, except low internal consistency and low to moderate test-retest reliability. The four subscales of the RSQ were not confirmed by the confirmatory factor analysis. An exploratory factor analysis suggested a three-factor solution for both general practitioners and patients, which accounted for 61.1% of the variance among general practitioners and 62.5% among patients. The new three-factor solution was verified in a confirmatory factor analyses. The proposed four-factor model of the RSQ could not be confirmed in this study. Similar challenges have been found by other studies validating the RSQ. An alternative three-factor structure was found for the RSQ.