Rates, predictors, and consequences of remission from chronic migraine to episodic migraine.
This study has 3 objectives: 1) to estimate remission rates in a population-based sample of subjects with chronic migraine (CM); 2) to identify potential predictors of CM remission; and 3) to assess the influence of CM remission on headache-related disability. The American Migraine Prevalence and Prevention study is a prospective, population-based, mailed questionnaire survey, which included questions regarding headache frequency, symptomatology, demographics, comorbidities, health care utilization, and headache-related disability. Three years of longitudinal data were analyzed to determine rates of CM remission and assess predictors of remission using logistical regression models. The consequence of remission was measured by changes in disability, as measured by the Migraine Disability Assessment, over time. A total of 383 respondents had CM in 2005 and follow-up data in 2006 and 2007. Over 2 years, among those with CM at baseline, approximately 34% (n = 130) had persistent CM while 26% (n = 100) had remitted CM. In our final multivariate model, predictors of remission included baseline headache frequency (15-19 vs 25-31 headache days/month; odds ratio [OR] 0.29; 95% confidence interval [CI] 0.11 to 0.75) and absence of allodynia (OR 0.45; 95% CI 0.23 to 0.89). Preventive medication use was associated with lower remission rate (OR 0.41; 95% CI 0.23 to 0.75), but this effect lost significance when headache frequency was included. Over 2 years, those with persistent CM demonstrated increased disability while those with remitted CM demonstrated decreased disability. These findings have clinical practice implications, as it is important to consider that remission rates are variable. However, the benefit of remission goes beyond symptom reduction and may translate to marked decreases in headache-related disability.


Horseback riding in children with cerebral palsy: effect on gross motor function.
The effects of recreational horseback riding therapy (HBRT) on gross motor function in children with cerebral palsy (CP: spastic diplegia, spastic quadriplegia, and spastic hemiplegia) were determined in a blinded study using the Gross Motor Function Measure (GMFM). Seventeen participants (nine females, eight males; mean age 9 years 10 months, SE 10 months) served as their own control. Their mean Gross Motor Function Classification System score was 2.7 (SD 0.4; range 1 to 5). HBRT was 1 hour per week for three riding sessions of 6 weeks per session (18 weeks). GMFM was determined every 6 weeks: pre-riding control period, onset of HBRT, every 6 weeks during HBRT for 18 weeks, and 6 weeks following HBRT. GMFM did not change during pre-riding control period. GMFM Total Score (Dimensions A-E) increased 7.6% (p<0.04) after 18 weeks, returning to control level 6 weeks following HBRT. GMFM Dimension E (Walking, Running, and Jumping) increased 8.7% after 12 weeks (p<0.02), 8.5% after 18 weeks (p<0.03), and remained elevated at 1.8% 6 weeks following HBRT (p<0.03). This suggests that HBRT may improve gross motor function in children with CP, which may reduce the degree of motor disability. Larger studies are needed to investigate this further, especially in children. with more severe disabilities. Horseback riding should be considered for sports therapy in children with CP.


Prediction of smoking by multiplex bisulfite PCR with long amplicons considering allele-specific effects on DNA methylation.
Methylation of DNA is associated with a variety of biological processes. With whole-genome studies of DNA methylation, it became possible to determine a set of genomic sites where DNA methylation is associated with a specific phenotype. A method is needed that allows detailed follow-up studies of the sites, including taking into account genetic information. Bisulfite PCR is a natural choice for this kind of task, but multiplexing is one of the most important problems impeding its implementation. To address this task, we took advantage of a recently published method based on Pacbio sequencing of long bisulfite PCR products (single-molecule real-time bisulfite sequencing, SMRT-BS) and tested the validity of the improved methodology with a smoking phenotype. Herein, we describe the "panhandle" modification of the method, which permits a more robust PCR with multiple targets. We applied this technique to determine smoking by DNA methylation in 71 healthy people and 83 schizophrenia patients (n = 50 smokers and n = 104 non-smokers, Russians of the Moscow region). We used five targets known to be influenced by smoking (regions of genes AHRR, ALPPL2, IER3, GNG12, and GFI1). We discovered significant allele-specific methylation effects in the AHRR and IER3 regions and assessed how this information could be exploited to improve the prediction of smoking based on the collected DNA methylation data. We found no significant difference in the methylation profiles of selected targets in relation to schizophrenia suggesting that smoking affects methylation at the studied genomic sites in healthy people and schizophrenia patients in a similar way. We determined that SMRT-BS with "panhandle" modification performs well in the described setting. Additional information regarding methylation and allele-specific effects could improve the predictive accuracy of DNA methylation-based models, which could be valuable for both basic research and clinical applications.


Teaching open and reproducible scholarship: a critical review of the evidence base for current pedagogical methods and their outcomes.
In recent years, the scientific community has called for improvements in the credibility, robustness and reproducibility of research, characterized by increased interest and promotion of open and transparent research practices. While progress has been positive, there is a lack of consideration about how this approach can be embedded into undergraduate and postgraduate research training. Specifically, a critical overview of the literature which investigates how integrating open and reproducible science may influence student outcomes is needed. In this paper, we provide the first critical review of literature surrounding the integration of open and reproducible scholarship into teaching and learning and its associated outcomes in students. Our review highlighted how embedding open and reproducible scholarship appears to be associated with (i) students' scientific literacies (i.e. students' understanding of open research, consumption of science and the development of transferable skills); (ii) student engagement (i.e. motivation and engagement with learning, collaboration and engagement in open research) and (iii) students' attitudes towards science (i.e. trust in science and confidence in research findings). However, our review also identified a need for more robust and rigorous methods within pedagogical research, including more interventional and experimental evaluations of teaching practice. We discuss implications for teaching and learning scholarship.


Lack of AMPKalpha2 enhances pyruvate dehydrogenase activity during exercise.
5'-AMP-activated protein kinase (AMPK) was recently suggested to regulate pyruvate dehydrogenase (PDH) activity and thus pyruvate entry into the mitochondrion. We aimed to provide evidence for a direct link between AMPK and PDH in resting and metabolically challenged (exercised) skeletal muscle. Compared with rest, treadmill running increased AMPKalpha1 activity in alpha(2)KO mice (90%, P < 0.01) and increased AMPKalpha2 activity in wild-type (WT) mice (110%, P < 0.05), leading to increased AMPKalpha Thr(172) (WT: 40%, alpha(2)KO: 100%, P < 0.01) and ACCbeta Ser(227) phosphorylation (WT: 70%, alpha(2)KO: 210%, P < 0.01). Compared with rest, exercise significantly induced PDH-E(1)alpha site 1 (WT: 20%, alpha(2)KO: 62%, P < 0.01) and site 2 (only alpha(2)KO: 83%, P < 0.01) dephosphorylation and PDH(a) [ approximately 200% in both genotypes (P < 0.01)]. Compared with WT, PDH dephosphorylation and activation was markedly enhanced in the alpha(2)KO mice both at rest and during exercise. The increased PDH(a) activity during exercise was associated with elevated glycolytic flux, and muscles from the alpha(2)KO mice displayed marked lactate accumulation and deranged energy homeostasis. Whereas mitochondrial DNA content was normal, the expression of several mitochondrial proteins was significantly decreased in muscle of alpha(2)KO mice. In isolated resting EDL muscles, activation of AMPK signaling by AICAR did not change PDH-E(1)alpha phosphorylation in either genotype. PDH is activated in mouse skeletal muscle in response to exercise and is independent of AMPKalpha2 expression. During exercise, alpha(2)KO muscles display deranged energy homeostasis despite enhanced glycolytic flux and PDH(a) activity. This may be linked to decreased mitochondrial oxidative capacity.


In planta gene expression analysis of Xanthomonas oryzae pathovar oryzae, African strain MAI1.
Bacterial leaf blight causes significant yield losses in rice crops throughout Asia and Africa. Although both the Asian and African strains of the pathogen, Xanthomonas oryzae pv. oryzae (Xoo), induce similar symptoms, they are nevertheless genetically different, with the African strains being more closely related to the Asian X. oryzae pv. oryzicola (Xoc). Changes in gene expression of the African Xoo strain MAI1 in the susceptible rice cultivar Nipponbare were profiled, using an SSH Xoo DNA microarray. Microarray hybridization was performed comparing bacteria recovered from plant tissues at 1, 3, and 6 days after inoculation (dai) with bacteria grown in vitro. A total of 710 bacterial genes were found to be differentially expressed, with 407 up-regulated and 303 down-regulated. Expression profiling indicated that less than 20% of the 710 bacterial transcripts were induced in the first 24 h after inoculation, whereas 63% were differentially expressed at 6 dai. The 710 differentially expressed genes were one-end sequenced. 535 sequences were obtained from which 147 non-redundant sequences were identified. Differentially expressed genes were related to metabolism, secretion and transport, pathogen adherence to plant tissues, plant cell-wall degradation, IS elements, and virulence. In addition, various other genes encoding proteins with unknown function or showing no similarity to other proteins were also induced. The Xoo MAI1 non-redundant set of sequences was compared against several X. oryzae genomes, revealing a specific group of genes that was present only in MAI1. Numerous IS elements were also found to be differentially expressed. Quantitative real-time PCR confirmed 86% of the identified profile on a set of 14 genes selected according to the microarray analysis. This is the first report to compare the expression of Xoo genes in planta across different time points during infection. This work shows that as-yet-unidentified and potentially new virulence factors are appearing in an emerging African pathogen. It also confirms that African Xoo strains do differ from their Asian counterparts, even at the transcriptional level.


Polypyrimidine tract binding protein modulates efficiency of polyadenylation.
Polypyrimidine tract binding protein (PTB) is a major hnRNP protein with multiple roles in mRNA metabolism, including regulation of alternative splicing and internal ribosome entry site-driven translation. We show here that a fourfold overexpression of PTB results in a 75% reduction of mRNA levels produced from transfected gene constructs with different polyadenylation signals (pA signals). This effect is due to the reduced efficiency of mRNA 3' end cleavage, and in vitro analysis reveals that PTB competes with CstF for recognition of the pA signal's pyrimidine-rich downstream sequence element. This may be analogous to its role in alternative splicing, where PTB competes with U2AF for binding to pyrimidine-rich intronic sequences. The pA signal of the C2 complement gene unusually possesses a PTB-dependent upstream sequence, so that knockdown of PTB expression by RNA interference reduces C2 mRNA expression even though PTB overexpression still inhibits polyadenylation. Consequently, we show that PTB can act as a regulator of mRNA expression through both its negative and positive effects on mRNA 3' end processing.


Urinary renin, but not angiotensinogen or aldosterone, reflects the renal renin-angiotensin-aldosterone system activity and the efficacy of renin-angiotensin-aldosterone system blockade in the kidney.
To study which renin-angiotensin-aldosterone system (RAAS) component best reflects renal RAAS activity. We measured urinary and plasma renin, prorenin, angiotensinogen, aldosterone, albumin and creatinine in 101 diabetic and nondiabetic patients with or without hypertension. Plasma prorenin was elevated in diabetic patients. Urinary prorenin was undetectable. Urinary albumin and renin were higher in diabetic patients. Men had higher plasma renin/prorenin levels, and lower plasma angiotensinogen levels than women. Plasma creatinine and albumin were also higher in men. Urinary RAAS components showed no sexual dimorphism, whereas urinary creatinine and albumin were higher in men. Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers increased plasma renin and decreased plasma angiotensinogen, without altering plasma aldosterone. In contrast, in urine, these drugs decreased renin and aldosterone without affecting angiotensinogen. When analyzing all patients together, urinary angiotensinogen excretion closely mimicked that of albumin, whereas urinary angiotensinogen and albumin levels both were 0.05% or less of their concomitant plasma levels. This may reflect the identical glomerular filtration and tubular handling of both proteins, which have a comparable molecular weight. In contrast, urinary renin excretion did not correlate with urinary albumin excretion, and the urinary/plasma concentration ratio of renin was more than 200 times the ratio of albumin, despite its comparable molecular weight. Urinary aldosterone excretion closely followed urinary creatinine excretion. The increased urinary renin levels in diabetes and the decreased urinary renin levels following RAAS blockade, occurring independently of changes in plasma renin, reflect the activated renal RAAS in diabetes and the success of RAAS blockade in the kidney, respectively. Urinary renin, therefore, more closely reflects renal RAAS activity than urinary angiotensinogen or aldosterone.


Psychiatric and medical comorbidity and quality of life outcomes in childhood-onset epilepsy.
We compared associations of epilepsy remission status and severity as well as psychiatric and other comorbidities with child and parent-proxy reports of health-related quality of life (HRQoL) in adolescents previously diagnosed with epilepsy. In a prospective, community-based study of newly diagnosed childhood epilepsy, HRQoL of 277 children was assessed 8 to 9 years after diagnosis by using child and parent-proxy versions of the Child Health Questionnaire (CHQ). Multiple linear regression models adjusted for age and gender were used to compare associations of epilepsy remission and "complicated" epilepsy (secondary to an underlying neurologic insult or epileptic encephalopathy) status and psychiatric and other comorbidities with HRQoL. Mean age of epilepsy onset was 4.4 years (SD: 2.6). At the 9-year reassessment, children were, on average, 13.0 years old (SD: 2.6); 64% were seizure-free for 5 years, 31% were taking antiepileptic drugs, and 19% had a complicated epilepsy. Prevalence of comorbidities at follow-up were 26% psychiatric diagnosis; 39% neurodevelopmental spectrum disorder (NDSD); 24% chronic medical illness; and 15% migraine. In multivariable analysis, having a psychiatric disorder was broadly associated with child (6 of 11 scales) and parent-proxy (7 of 12 scales) HRQoL (P ≤ .0125). Five-year remission and complicated epilepsy status had few or no associations with HRQoL. Although parent-proxy HRQoL was strongly associated with NDSD (6 of 11 scales), child-reported HRQoL was not (2 of 11 scales). Psychiatric comorbidities are strongly associated with long-term HRQoL in childhood-onset epilepsy, which suggests that comprehensive epilepsy care must include screening and treatment for these conditions, even if seizures remit.


The IDEFICS validation study on field methods for assessing physical activity and body composition in children: design and data collection.
To describe the design, measurements and fieldwork of the IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) physical activity and body composition validation study, and to determine the potential and limitations of the data obtained. Multicentre validation study. A total of 98 children from four different European countries (age: 4-10 years). An 8-day measurement protocol was carried out in all children using a collaborative protocol. Reference methods were the doubly labelled water method for physical activity, and a three- and a four-compartment model for body composition. Investigated field methods were accelerometers, a physical activity questionnaire and various anthropometric measurements. For the validation of physical activity field methods, it was possible to gather data from 83 to 89 children, laying the basis for age- and sex-specific results. The validation of body composition field methods is possible in 64-80 children and allows sex-specific analyses but has only limited statistical power in the youngest age group (<6 years). The amount of activity energy expenditure (AEE) varied between centres, sexes and age groups, with boys and older children having higher estimates of AEE. After normalisation of AEE by body weight, most group-specific differences diminished, except for country-specific differences. The IDEFICS validation study will allow age- and sex-specific investigation of questions pertaining to the validity of several field methods of body composition and physical activity, using established reference methods in four different European countries. From the participant analyses it can be concluded that the compliance for the investigated field methods was higher than that for the reference methods used in this validation study.


Gestational B-vitamin supplementation alleviates PM2.5-induced autism-like behavior and hippocampal neurodevelopmental impairment in mice offspring.
Gestational exposure to PM2.5 is a worldwide environmental issue associated with long-lasting behavior abnormalities and neurodevelopmental impairments in the hippocampus of offspring. PM2.5 may induce hippocampus injury and lead to autism-like behavior such as social communication deficits and stereotyped repetitive behavior in children through neuroinflammation and neurodegeneration. Here, we investigated the preventive effect of B-vitamin on PM2.5-induced deleterious effects by focusing on anti-inflammation, antioxidant, synaptic remodeling and neurodevelopment. Pregnant mice were randomly divided into three groups including control group (mice subject to PBS only), model group (mice subject to both 30 μL PM2.5 of 3.456 μg/μL and 10 mL/(kg·d) PBS), and intervention group (mice subject to both 30 μL PM2.5 of 3.456 μg/μL and 10 mL/(kg·d) B-vitamin supplementation (folic acid, vitamin B6 and vitamin B12 with concentrations at 0.06, 1.14 and 0.02 mg/mL, respectively)). In the current study B-vitamin significantly alleviated neurobehavioral impairment reflected in reduced social communication disorders, stereotyped repetitive behavior, along with learning and spatial memory impairment in PM2.5-stimulated mice offspring. Next, B-vitamin corrected synaptic loss and reduced mitochondrial damage in hippocampus of mice offspring, demonstrated by normalized synapse quantity, synaptic cleft, postsynaptic density (PSD) thickness and length of synaptic active area. Furthermore, significantly down-regulated expression of pro-inflammatory cytokines including NF-κB, TNF-α and IL-1β, and lipid peroxidation were found. We observed elevated levels of oxidant-related genes (SOD, GSH and GSH-Px). Moreover, decreased cleaved caspase-3 and TUNEL-positive cells suggested inhibited PM2.5-induced apoptosis by B-vitamin. Furthermore, B-vitamin increased neurogenesis by increasing EdU-positive cells in the subgranular zone (SGZ) of offspring. Collectively, our results suggest that B-vitamin supplementation exerts preventive effect on autism-like behavior and neurodevelopmental impairment in hippocampus of mice offspring gestationally exposed to PM2.5, to which alleviated mitochondrial damage, increased anti-inflammatory and antioxidant capacity and synaptic efficiency, reduced neuronal apoptosis and improved hippocampal neurogenesis may contribute.


Characterization, cell-surface expression and ligand-binding properties of different truncated N-terminal extracellular domains of the ionotropic glutamate receptor subunit GluR1.
To identify the location of the first transmembrane segment of the GluR1 glutamate receptor subunit artificial stop codons have been introduced into the N-terminal domain at amino acid positions 442, 510, and 563, namely just before and spanning the proposed first two transmembrane regions. The resultant truncated N-terminal fragments of GluR1, termed NT1, NT2, and NT3 respectively were expressed in Cos-7 cells and their cellular distribution and cell-surface expression analysed using an N-terminal antibody to GluR1. All of the fragments were fully glycosylated and were found to be associated with cell membranes but none was secreted. Differential extraction of the cell membranes indicated that both NT1 and NT2 behave as peripheral membrane proteins. In contrast NT3, like the full subunit, has integral membrane protein properties. Furthermore only NT3 is expressed at the cell surface as determined by immunofluorescence and cell-surface biotinylation. Protease protection assays indicated that only NT3 had a cytoplasmic tail. Binding studies using the selective ligand [(3)H]alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate ([(3)H]AMPA) demonstrated that NT3 does not bind ligand. Together these results indicate that the first transmembrane domain of the GluR1 subunit lies between residues 509 and 562, that the N-terminal domain alone cannot form a functional ligand-binding site and that this domain can be targeted to the cell surface provided that it has a transmembrane-spanning region.


Neuropeptide Y modulates vasoconstriction in coronary microvessels in the beating canine heart.
The purpose of this study was to determine whether neuropeptide Y has a direct vasoconstrictor effect at low doses, mimicking the physiological plasma concentration on the specific site(s) of coronary arterial microvessels in in situ beating canine left ventricles. Coronary microvessels were directly observed by means of an intravital microscope and video system equipped with a floating objective. Epi-illuminated fluorescence coronary microangiography was performed in open-chest anesthetized dogs (n = 14) to examine the changes in internal diameter of epimyocardial arterial microvessels. Flow velocity of fluorescently labeled microshperes in capillaries was also measured (n = 6). To eliminate secondary effects of neuropeptide Y on coronary microvessels via autonomic nervous modulation, experiments were conducted under pharmacological blockade of the regional autonomic nervous system by intracoronary injection of propranolol, 50 micrograms/kg; phentolamine, 100 micrograms/kg; and atropine, 5 micrograms/kg. Aortic pressure and heart rate were kept constant during the experiments. Intracoronary infusion of three different doses of neuropeptide Y (1, 10, and 100 pmol/kg/min) for 5 minutes significantly constricted small microvessels (less than 100 microns in diameter) (-5.2 +/- 1.4%, -8.5 +/- 1.5%, and -14.0 +/- 1.7%; p less than 0.05 versus before neuropeptide Y at each dose), medium microvessels (100-200 microns in diameter) (-5.5 +/- 1.6%, -10.6 +/- 1.8%, and -16.8 +/- 2.1%, p less than 0.05 versus before neuropeptide Y at each dose), and large microvessels (greater than 200 microns in diameter) (-3.6 +/- 0.6%, -5.8 +/- 0.8%, and -10.0 +/- 1.1%; p less than 0.05 versus before neuropeptide Y at each dose) in a dose-dependent manner. Capillary flow velocity was reduced by 17.2 +/- 3.1% by an intracoronary dose of 100 pmol/kg/min of neuropeptide Y (p less than 0.05). The present study indicates that low doses of neuropeptide Y exert a homogeneous direct vasoconstrictor effect on various sizes of coronary arterial microvessels and reduce capillary flow velocity. These results suggest that neuropeptide Y may play a physiological role in modulating coronary microvascular tone.


Effective treatment of experimental DU-145 prostate cancers with targeted cytotoxic somatostatin analog AN-238.
We evaluated the effectiveness of targeted cytotoxic analog of somatostatin (SST) AN-238, consisting of 2-pyrrolinodoxorubicin (AN-201) linked covalently to SST octapeptide carrier RC-121 in DU-145 human androgen-independent prostate cancers xenografted into nude mice. We also investigated the expression of mRNAs for SST receptor subtypes 2A and 5 (sst2A and sst5) in DU-145 tumors. After 8 weeks of treatment, AN-238 practically arrested the proliferation of DU-145 cancers. The tumor volume in nude mice that received 4 injections of AN-238 at the dose of 150 nmol/kg was 63.4+/-6.7 mm3, nearly 4 times smaller than that in controls which measured 249.1+/-36.3 mm3 (p<0.001). Treatment with AN-238 lowered tumor weight by 68% (p<0.01) compared with the control group and extended the tumor volume doubling time to 184.1+/-69.4 days, versus 32.1+/-6.6 days in controls (p<0.05). No toxicity-related deaths occurred during treatment with AN-238. Cytotoxic radical AN-201 administered alone or in an unconjugated mixture with carrier RC-121 inhibited the growth of DU-145 tumors only after the third and fourth injection and was toxic. The expression of mRNA for sst2A and sst5 was detected in all specimens of control DU-145 tumors and in tumors treated with AN-238. The present study demonstrates the high efficacy of SST-receptor-targeted chemotherapy in a model of human androgen-independent prostatic carcinoma.


Self-deflection and all-optical beam steering in CdZnTe.
We report on the experimental observation of very large self-deflection of optical beams, along with all-optical steering, and electro-optic beam deflection. We observe as many as 27 resolvable spots of deflection at 1-W/cm2 intensity. These deflections arise from enhanced photorefractive effects in CdZnTe:V, giving rise to optically induced index changes in excess of 0.08, which is to our knowledge the strongest nonlinearity ever reported for any bulk semiconductor.


All five host-range variants of Xanthomonas citri carry one pthA homolog with 17.5 repeats that determines pathogenicity on citrus, but none determine host-range variation.
Citrus canker disease is caused by five groups of Xanthomonas citri strains that are distinguished primarily by host range: three from Asia (A, A*, and A(w)) and two that form a phylogenetically distinct clade and originated in South America (B and C). Every X. citri strain carries multiple DNA fragments that hybridize with pthA, which is essential for the pathogenicity of wide-host-range X. citri group A strain 3213. DNA fragments that hybridized with pthA were cloned from a representative strain from all five groups. Each strain carried one and only one pthA homolog that functionally complemented a knockout mutation of pthA in 3213. Every complementing homolog was of identical size to pthA and carried 17.5 nearly identical, direct tandem repeats, including three new genes from narrow-host-range groups C (pthC), A(w) (pthAW), and A* (pthA*). Every noncomplementing paralog was of a different size; one of these was sequenced from group A* (pthA*-2) and was found to have an intact promoter and full-length reading frame but with 15.5 repeats. None of the complementing homologs nor any of the noncomplementing paralogs conferred avirulence to 3213 on grapefruit or suppressed avirulence of a group A* strain on grapefruit. A knockout mutation of pthC in a group C strain resulted in loss of pathogenicity on lime, but the strain was unaffected in ability to elicit an HR on grapefruit. This pthC- mutant was fully complemented by pthA, pthB, or pthC. Analysis of the predicted amino-acid sequences of all functional pthA homologs and nonfunctional paralogs indicated that the specific sequence of the 17th repeat may be essential for pathogenicity of X. citri on citrus.


Proteogenomic characterization of human colon and rectal cancer.
Extensive genomic characterization of human cancers presents the problem of inference from genomic abnormalities to cancer phenotypes. To address this problem, we analysed proteomes of colon and rectal tumours characterized previously by The Cancer Genome Atlas (TCGA) and perform integrated proteogenomic analyses. Somatic variants displayed reduced protein abundance compared to germline variants. Messenger RNA transcript abundance did not reliably predict protein abundance differences between tumours. Proteomics identified five proteomic subtypes in the TCGA cohort, two of which overlapped with the TCGA 'microsatellite instability/CpG island methylation phenotype' transcriptomic subtype, but had distinct mutation, methylation and protein expression patterns associated with different clinical outcomes. Although copy number alterations showed strong cis- and trans-effects on mRNA abundance, relatively few of these extend to the protein level. Thus, proteomics data enabled prioritization of candidate driver genes. The chromosome 20q amplicon was associated with the largest global changes at both mRNA and protein levels; proteomics data highlighted potential 20q candidates, including HNF4A (hepatocyte nuclear factor 4, alpha), TOMM34 (translocase of outer mitochondrial membrane 34) and SRC (SRC proto-oncogene, non-receptor tyrosine kinase). Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords a new paradigm for understanding cancer biology.


Reflectance sharing: predicting appearance from a sparse set of images of a known shape.
Three-dimensional appearance models consisting of spatially varying reflectance functions defined on a known shape can be used in analysis-by-synthesis approaches to a number of visual tasks. The construction of these models requires the measurement of reflectance, and the problem of recovering spatially varying reflectance from images of known shape has drawn considerable interest. To date, existing methods rely on either: (1) low-dimensional (e.g., parametric) reflectance models, or (2) large data sets involving thousands of images (or more) per object. Appearance models based on the former have limited accuracy and generality since they require the selection of a specific reflectance model a priori, and while approaches based on the latter may be suitable for certain applications, they are generally too costly and cumbersome to be used for image analysis. We present an alternative approach that seeks to combine the benefits of existing methods by enabling the estimation of a nonparametric spatially varying reflectance function from a small number of images. We frame the problem as scattered-data interpolation in a mixed spatial and angular domain, and we present a theory demonstrating that the angular accuracy of a recovered reflectance function can be increased in exchange for a decrease in its spatial resolution. We also present a practical solution to this interpolation problem using a new representation of reflectance based on radial basis functions. This representation is evaluated experimentally by testing its ability to predict appearance under novel view and lighting conditions. Our results suggest that since reflectance typically varies slowly from point to point over much of an object's surface, we can often obtain a nonparametric reflectance function from a sparse set of images. In fact, in some cases, we can obtain reasonable results in the limiting case of only a single input image.


Cataract surgery after deep anterior lamellar keratoplasty and penetrating keratoplasty in age- and disease-matched eyes.
To assess the efficacy and safety of cataract surgery after deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty (PKP). Tokyo Dental College Ichikawa General Hospital, Chiba, Japan. Retrospective case series. Age-matched and disease-matched eyes that had phacoemulsification and intraocular lens insertion after DALK or PKP were studied. Graft clarity was assessed at the final follow-up. The difference in the endothelial cell density (ECD), corrected distance visual acuity (CDVA), spherical equivalence, and refractive error between the expected values and values 1, 3, 6, and 12 months after cataract surgery were compared between the 2 groups. Indications for keratoplasty were corneal stromal scar (22 eyes), lattice dystrophy (2 eyes), keratoconus (2 eyes), and postherpetic keratitis (4 eyes). All 30 eyes in each group had successful cataract surgery after keratoplasty. Graft clarity rates were 90.0% and 80.0% in the DALK group and PKP group, respectively (P = .47). The decrease in ECD at 12 months was significantly greater in the PKP group than in the DALK group (8.7% [SD] ± 21.7% versus 26.3% ± 27.8%) (P = .043). The CDVA was significantly improved in both groups. At 1 month, the mean refractive error was -0.5 diopter (D) ± 2.4 (SD) in the DALK and -0.4 ± 1.9 D in the PKP groups and remained stable thereafter. Cataract surgery was successfully performed in eyes that had DALK or PKP, providing excellent visual and refractive outcomes. In cases of combined cataract and corneal pathology, and in the absence of endothelial involvement, DALK followed by cataract surgery might cause less endothelial damage.


Evolutionary conservation and selection of human disease gene orthologs in the rat and mouse genomes.
Model organisms have contributed substantially to our understanding of the etiology of human disease as well as having assisted with the development of new treatment modalities. The availability of the human, mouse and, most recently, the rat genome sequences now permit the comprehensive investigation of the rodent orthologs of genes associated with human disease. Here, we investigate whether human disease genes differ significantly from their rodent orthologs with respect to their overall levels of conservation and their rates of evolutionary change. Human disease genes are unevenly distributed among human chromosomes and are highly represented (99.5%) among human-rodent ortholog sets. Differences are revealed in evolutionary conservation and selection between different categories of human disease genes. Although selection appears not to have greatly discriminated between disease and non-disease genes, synonymous substitution rates are significantly higher for disease genes. In neurological and malformation syndrome disease systems, associated genes have evolved slowly whereas genes of the immune, hematological and pulmonary disease systems have changed more rapidly. Amino-acid substitutions associated with human inherited disease occur at sites that are more highly conserved than the average; nevertheless, 15 substituting amino acids associated with human disease were identified as wild-type amino acids in the rat. Rodent orthologs of human trinucleotide repeat-expansion disease genes were found to contain substantially fewer of such repeats. Six human genes that share the same characteristics as triplet repeat-expansion disease-associated genes were identified; although four of these genes are expressed in the brain, none is currently known to be associated with disease. Most human disease genes have been retained in rodent genomes. Synonymous nucleotide substitutions occur at a higher rate in disease genes, a finding that may reflect increased mutation rates in the chromosomal regions in which disease genes are found. Rodent orthologs associated with neurological function exhibit the greatest evolutionary conservation; this suggests that rodent models of human neurological disease are likely to most faithfully represent human disease processes. However, with regard to neurological triplet repeat expansion-associated human disease genes, the contraction, relative to human, of rodent trinucleotide repeats suggests that rodent loci may not achieve a 'critical repeat threshold' necessary to undergo spontaneous pathological repeat expansions. The identification of six genes in this study that have multiple characteristics associated with repeat expansion-disease genes raises the possibility that not all human loci capable of facilitating neurological disease by repeat expansion have as yet been identified.


Cross-linked actin networks (CLANs) are present in lamina cribrosa cells.
A study was undertaken to determine and compare the F-actin staining patterns in the cells of the lamina cribrosa (LC) of normal, dexamethasone (DEX)-treated and glaucomatous dissected tissue and cell cultures. About 30 dissected donor eyes and nine cell lines provided the human specimens; 25 eyes and 20 primary cell cultures provided the bovine material. Appropriate samples were exposed to 1×10⁻⁷ M DEX for up to 14 days. LC tissue and cells were stained with Phalloidin-Alexa 488 to identify F-actin, and all samples were examined by confocal or epifluorescent microscopy. Both in the LC tissue and LC cell cultures the dominant actin arrangement was bundles of stress fibres. However, cross-linked actin networks (CLANs) were identified in the tissue and in culture. These were markedly increased by steroid treatment and were particularly large and abundant in cultures from glaucoma donors. CLANs were not associated with optic nerve head astrocytes. The presence of abundant stress fibres in situ and in vitro highlights the biomechanical contribution of LC cells. However, the identification of CLANs in these cells shows that they are not exclusive to the trabecular meshwork, the only other place they have been found, and may have a role in glaucoma pathology.


Intermediate scattering function of an anisotropic Brownian circle swimmer.
Microswimmers exhibit noisy circular motion due to asymmetric propulsion mechanisms, their chiral body shape, or by hydrodynamic couplings in the vicinity of surfaces. Here, we employ the Brownian circle swimmer model and characterize theoretically the dynamics in terms of the directly measurable intermediate scattering function. We derive the associated Fokker-Planck equation for the conditional probabilities and provide an exact solution in terms of generalizations of the Mathieu functions. Different spatiotemporal regimes are identified reflecting the bare translational diffusion at large wavenumbers, the persistent circular motion at intermediate wavenumbers and an enhanced effective diffusion at small wavenumbers. In particular, the circular motion of the particle manifests itself in characteristic oscillations at a plateau of the intermediate scattering function for wavenumbers probing the radius.


Ketamine exerts neurotoxic effects on the offspring of pregnant rats via the Wnt/β-catenin pathway.
Ketamine is an anesthetic and analgesic drug widely used in clinical anesthesia. To ensure the safety of anesthesia, it is necessary to study its side effects. Pregnancy is a key period for the development and growth of offspring. During this period, the proliferation and differentiation of brain cells and the synaptic formation are easily affected by external stimuli. Therefore, the aim of this study was to evaluate the effect of ketamine. Ketamine anesthesia was administered to rats in the second trimester of pregnancy, and two behavioral tests were performed, including contextual and cued fear conditioning test (CFC) and Morris water maze (MWM). At the end of the behavioral test, Nissl and Golgi staining were used to detect the dendrite density of hippocampal neurons to reveal the effect of maternal ketamine anesthesia on the hippocampus of offspring. Key proteins and their downstream transcription factors in Wnt/β-catenin signaling pathway from the embryonic development to the adulthood were studied. Our results showed that rats receiving maternal ketamine suffered from nerve injury. The density of hippocampal nerves and dendritic spine changed. Some genes related to Wnt/β-catenin pathway and Tcf/Lef were downregulated. In conclusion, maternal anesthesia with ketamine in the second trimester of pregnancy can lead to cognitive memory impairment and neurotoxicity in the hippocampus of offspring through Wnt/ β-catenin signaling pathway.


Children with autism do not show sequence effects with auditory stimuli.
Categorization decisions that reflect constantly changing memory representations might be an important adaptive response to dynamic environments. We assessed One such influence from memory (i.e., sequence effects) on categorization decisions made by individuals with autism. A model of categorization (i.e., memory and contrast model, Stewart, Brown, & Chater, 2002) assumes that contextual influences in the form of sequence effects drive categorization performance in individuals with typical development. Difficulties with contextual processing in autism, described by the weak central coherence account (Frith, 1989; Frith & Happé, 1994) imply reduced sequence effects for this participant group. The experiment reported in this article tested this implication. High-functioning children and adolescents with autism (ages 10 to 15 years), matched on age and IQ with typically developing children, completed a test that measures sequence effects (i.e., category contrast effect task, Stewart et al., 2002) using auditory tones. Participants also completed a pitch discrimination task to measure any potential confound arising from possible enhanced discrimination sensitivity within the autism spectrum disorder group. The typically developing group alone demonstrated a category contrast effect. The data suggest that this finding cannot be attributed readily to participant group differences in discrimination sensitivity, perseveration, difficulties on the associated binary categorization task, or greater reliance on long-term memory. We discuss the broad methodological implication that comparison between autism spectrum disorder group and control group responses to sequential perceptual stimuli might be confounded by the influence of preceding trials. We also discuss implications for the weak central coherence account and models of typical cognition.


Potential of nanoparticles encapsulated drugs for possible inhibition of the antimicrobial resistance development.
The immune system is a dynamic network of cells and cytokines are the major mediators of immune responses which combat pathogens. Based on the cytokine production, effector T cells differentiate into subsets known as Th1, Th2, Th17, or Treg. This system serves as a barrier to intracellular pathogens, bacterial infections and stimulates the production of reactive oxygen species (ROS), reactive nitrogen intermediates, and nitric oxide, which diffuses across membranes and engulfs intracellular pathogens. Oxidative stress occurs when ROS, reactive nitrogen species (RNS) production, and antioxidant defences become imbalanced. Oxidative stress generated by infected cells produces a substantial amount of free radicals which enables the killing of intracellular pathogens. Intracellular pathogens are exposed to endogenous ROS as part of normal aerobic respiration, also exogenous ROS and RNS are generated by the host immune system in response to infection. Nanoparticles which are designed for drug delivery are capable of trapping the desired drug in the particles which protect the drug from enzymatic degradation in a biological system. The subcellular size of nanoparticles enables higher intracellular uptake of the drug which results in the reduction of the concentration of free drugs reducing their toxic effect. Research on the modulation of immune response and oxidative stress using nanoparticles used to encapsulate drugs has yet to be explored fully. In this review, we illustrate the immune activation and generation of oxidative stress properties which are mediated by nanoparticle encapsulated drug delivery systems which can make the therapy more effective in case of diseases caused by intracellular pathogens.


Efficient measurement error correction with spatially misaligned data.
Association studies in environmental statistics often involve exposure and outcome data that are misaligned in space. A common strategy is to employ a spatial model such as universal kriging to predict exposures at locations with outcome data and then estimate a regression parameter of interest using the predicted exposures. This results in measurement error because the predicted exposures do not correspond exactly to the true values. We characterize the measurement error by decomposing it into Berkson-like and classical-like components. One correction approach is the parametric bootstrap, which is effective but computationally intensive since it requires solving a nonlinear optimization problem for the exposure model parameters in each bootstrap sample. We propose a less computationally intensive alternative termed the "parameter bootstrap" that only requires solving one nonlinear optimization problem, and we also compare bootstrap methods to other recently proposed methods. We illustrate our methodology in simulations and with publicly available data from the Environmental Protection Agency.


Establishing Core Cardiovascular Outcome Measures for Trials in Hemodialysis: Report of an International Consensus Workshop.
Cardiovascular disease (CVD) affects more than two-thirds of patients receiving hemodialysis and is the leading cause of death in this population, yet CVD outcomes are infrequently and inconsistently reported in trials in patients receiving hemodialysis. As part of the Standardised Outcomes in Nephrology-Haemodialysis (SONG-HD) initiative, we convened a consensus workshop to discuss the potential use of myocardial infarction and sudden cardiac death as core outcome measures for CVD for use in all trials in people receiving hemodialysis. Eight patients or caregivers and 46 health professionals from 15 countries discussed selection and implementation of the proposed core outcome measures. Five main themes were identified: capturing specific relevance to the hemodialysis population (acknowledging prevalence, risk, severity, unique symptomology, and pathophysiology), the dilemmas in using composite outcomes, addressing challenges in outcome definitions (establishing a common definition and addressing uncertainty in the utility of biomarkers in hemodialysis), selecting a meaningful metric for decision making (to facilitate comparison across trials), and enabling and incentivizing implementation (by ensuring that cardiologists are involved in the development and integration of the outcome measure into registries, trial design, and reporting guidelines). Based on these themes, participants supported the use of myocardial infarction and sudden cardiac death as core outcome measures of CVD to be reported in all hemodialysis trials.


Selective determination of acidic pharmaceuticals in wastewater using molecularly imprinted solid-phase extraction.
The determination of acidic pharmaceuticals, such as non-steroidal anti-inflammatory drugs NSAIDs and clofibric acid (metabolite of clofibrate), at low ngL(-1) levels in wastewater requires highly selective and sensitive analytical procedures. The removal of matrix components during sample preparation results in significant benefits towards reducing the matrix effects during LC-MS analysis. Therefore this work describes a simple method to enrich and clean up NSAIDs and clofibric acid from sewage water using molecularly imprinted solid-phase extraction (MISPE). Final analysis was performed by liquid chromatography-tandem mass spectrometry. The performance of this method has been evaluated in fortified tap and sewage water in terms of recovery, precision, linearity, and method quantification limit. Recovery for all compounds ranged in all matrices between 84 and 116% with intra-day R.S.D. values below 11.5%. Matrix effect evaluation demonstrated that even complex sample matrixes, such as pond or sewage water did not showed significant ion suppression/enhancement compared to tap water. The performance of the method was further emphasized by the study of pond water, which receives treated water from a sewage treatment plant in south Sweden. Raw sewage and treated water were also tested. In those samples, all acidic pharmaceuticals were detected in concentration above method quantification limits ranging from 5.1 to 5153.0ngL(-1).


Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children.
The association between the use of antidepressants during gestation and the risk of autism spectrum disorder (ASD) in children is still controversial. The etiology of ASD remains unclear, although studies have implicated genetic predispositions, environmental risk factors, and maternal depression. To examine the risk of ASD in children associated with antidepressant use during pregnancy according to trimester of exposure and taking into account maternal depression. We conducted a register-based study of an ongoing population-based cohort, the Québec Pregnancy/Children Cohort, which includes data on all pregnancies and children in Québec from January 1, 1998, to December 31, 2009. A total of 145,456 singleton full-term infants born alive and whose mothers were covered by the Régie de l'assurance maladie du Québec drug plan for at least 12 months before and during pregnancy were included. Data analysis was conducted from October 1, 2014, to June 30, 2015. Antidepressant exposure during pregnancy was defined according to trimester and specific antidepressant classes. Children with ASD were defined as those with at least 1 diagnosis of ASD between date of birth and last date of follow-up. Cox proportional hazards regression models were used to estimate crude and adjusted hazard ratios with 95% CIs. During 904,035.50 person-years of follow-up, 1054 children (0.7%) were diagnosed with ASD; boys with ASD outnumbered girls by a ratio of about 4:1. The mean (SD) age of children at the end of follow-up was 6.24 (3.19) years. Adjusting for potential confounders, use of antidepressants during the second and/or third trimester was associated with the risk of ASD (31 exposed infants; adjusted hazard ratio, 1.87; 95% CI, 1.15-3.04). Use of selective serotonin reuptake inhibitors during the second and/or third trimester was significantly associated with an increased risk of ASD (22 exposed infants; adjusted hazard ratio, 2.17; 95% CI, 1.20-3.93). The risk was persistent even after taking into account maternal history of depression (29 exposed infants; adjusted hazard ratio, 1.75; 95% CI, 1.03-2.97). Use of antidepressants, specifically selective serotonin reuptake inhibitors, during the second and/or third trimester increases the risk of ASD in children, even after considering maternal depression. Further research is needed to specifically assess the risk of ASD associated with antidepressant types and dosages during pregnancy.


Meta-analysis of avian and small-mammal response to fire severity and fire surrogate treatments in U.S. fire-prone forests.
Management in fire-prone ecosystems relies widely upon application of prescribed fire and/or fire surrogate (e.g., forest thinning) treatments to maintain biodiversity and ecosystem function. Recently, published literature examining wildlife response to fire and fire management has increased rapidly. However, none of this literature has been synthesized quantitatively, precluding assessment of consistent patterns of wildlife response among treatment types. Using meta-analysis, we examined the scientific literature on vertebrate demographic responses to burn severity (low/moderate, high), fire surrogates (forest thinning), and fire and fire surrogate combined treatments in the most extensively studied fire-prone, forested biome (forests of the United States). Effect sizes (magnitude of response) and their 95% confidence limits (response consistency) were estimated for each species-by-treatment combination with two or more observations. We found 41 studies of 119 bird and 17 small-mammal species that examined short-term responses (< or =4 years) to thinning, low/moderate- and high-severity fire, and thinning plus prescribed fire; data on other taxa and at longer time scales were too sparse to permit quantitative assessment. At the stand scale (<50 ha), thinning and low/moderate-severity fire demonstrated similar response patterns in these forests. Combined thinning plus prescribed fire produced a higher percentage of positive responses. High-severity fire provoked stronger responses, with a majority of species possessing higher or lower effect sizes relative to fires of lower severity. In the short term and at fine spatial scales, fire surrogate forest-thinning treatments appear to effectively mimic low/moderate-severity fire, whereas low/moderate-severity fire is not a substitute for high-severity fire. The varied response of taxa to each of the four conditions considered makes it clear that the full range of fire-based disturbances (or their surrogates) is necessary to maintain a full complement of vertebrate species, including fire-sensitive taxa. This is especially true for high-severity fire, where positive responses from many avian taxa suggest that this disturbance (either as wildfire or prescribed fire) should be included in management plans where it is consistent with historic fire regimes and where maintenance of regional vertebrate biodiversity is a goal.


Automatic characterization of classic choroidal neovascularization by using AdaBoost for supervised learning.
To provide a computer-aided visualization tool for accurate diagnosis and quantification of choroidal neovascularization (CNV) on the basis of fluorescence leakage characteristics. All image frames of a fluorescein angiography (FA) sequence are first aligned and mapped to a global space. To automatically determine the severity of each pixel in the global space and hence the extent of CNV, the system matches the intensity variation of each set of spatially corresponding pixels across the sequence with the targeted leakage pattern, learned from a sampled population graded by a retina specialist. The learning strategy, known as the AdaBoost algorithm, has 12 classifiers for 12 features that summarize the variation in fluorescence intensity over time. Given a new sequence, the severity map image is generated using the contribution scores of the 12 classifiers. Initialized with points of low and high severity, regions of CNV are delineated using the random walk algorithm. A dataset of 33 FA sequences of classic CNV showed the average accuracy of CNV delineation to be 83.26%. In addition, the 30- to 60-second interval provided the most reliable information for differentiating CNV from the background. Using eight sequences of multiple visits of four patients for evaluation of the postphotodynamic therapy (PDT), the statistics derived from the segmented regions correlate closely with the clinical observed changes. The clinician can easily visualize the temporal characteristics of CNV fluorescence leakage using the severity map, which is a two-dimensional summary of a complete FA sequence. The computer-aided tool allows objective evaluation and computation of statistical data from the automatic delineation for surgical assessment.


Effects of a School-Based Social-Emotional and Character Development Program on Health Behaviors: A Matched-Pair, Cluster-Randomized Controlled Trial.
There is considerable research that suggests that school-based social-emotional programs can foster improved mental health and reduce problem behaviors for participating youth; in contrast, much less is known about the impact of these programs on physical health, even though some of these programs also include at least limited direct attention to promoting physical health behaviors. We examined the effects of one such program, Positive Action (PA), on physical health behaviors and body mass index (BMI), and tested for mediation of program effects through a measure of social-emotional and character development (SECD). Participating schools in the matched-pair, cluster-randomized trial were 14 low-performing K-8 Chicago Public Schools. We followed a cohort of students in each school from grades 3 to 8 (eight waves of data collection; 1170 total students). Student self-reports of health behaviors served as the basis for measures of healthy eating and exercise, unhealthy eating, personal hygiene, consistent bedtime, and SECD. We collected height and weight measurements at endpoint to calculate age- and gender-adjusted BMI z-scores. Longitudinal multilevel modeling analyses revealed evidence of favorable program effects on personal hygiene [effect size (ES) = 0.48], healthy eating and exercise (ES = 0.21), and unhealthy eating (ES = -0.19); in addition, BMI z-scores were lower among students in PA schools at endpoint (ES = -0.21). Program effects were not moderated by either gender or student mobility. Longitudinal structural equation modeling demonstrated mediation through SECD for healthy eating and exercise, unhealthy eating, and personal hygiene. Findings suggest that a SECD program without a primary focus on health behavior promotion can have a modest impact on outcomes in this domain during the childhood to adolescence transition.


Determination of inorganic fluoride in blood with a fluoride ion-selective electrode.
Inorganic fluoride in whole blood, serum, or plasma has been determined with a fluoride ion-selective electrode by adding the 0.5- to 2.0-mL sample to 20 mL of water containing a buffer and fluoride, 25 micrograms/L. The fluoride concentration in the sample is calculated from the resulting cell potential difference recorded after equilibrating for 10 min. This novel method has the advantages of simplicity, accuracy, and high precision, standard deviations for 5 to 7 replicate determinations of fluoride ranging from +/- 1.7 to +/- 2.4 micrograms/L. For whole blood from donors living in an area with fluorinated drinking water, the F- concentration was 20 to 60 micrograms/L.


Internet Alcohol Marketing Recall and Drinking in Underage Adolescents.
Evidence suggests that adolescents are exposed to alcohol marketing in digital media. We aimed to assess recall of Internet alcohol marketing and its association with underage drinking. New England adolescents age 12 to 17 years (N = 202) were recruited from a pediatric clinic. Subjects completed an online survey assessing: 1) general simple recall of Internet alcohol marketing and 2) image-prompted recall of specific Internet alcohol marketing channels (display ads, commercials, brand websites, and brand social media pages). Cross-sectional associations between recall (simple and image-prompted) and ever-drinking were each assessed in regression analysis adjusting for age, gender, race, parent education, ever-smoking, media use, sensation-seeking, peer/parent drinking, parent monitoring/responsiveness, and parent Internet monitoring. In this sample (Mage = 14.5 years; 55% female; 89% white; high parent education), 20% reported ever-drinking and 87% recalled Internet alcohol marketing. Of the latter, 67% recalled display ads, 67% Internet commercials, 5% websites, and 5% social media pages. In logistic regression, higher simple Internet alcohol advertising recall was independently associated with higher odds of ever-drinking for simple (adjusted odds ratio: 2.66 [1.04,6.83]) but not for image-prompted recall. Despite controlling for potential confounders, simple recall of Internet alcohol marketing was significantly associated with underage drinking whereas image-prompted recall was significant only in bivariate analysis, likely due to small sample and a more limited range of specific channels assessed than those accessed by adolescents. Further longitudinal studies using image-prompted recall and capturing a broader range of internet platforms could be used to better understand adolescent engagement with alcohol marketing and guide policy and prevention efforts.


Antitumor activity of epigenetic immunomodulation combined with CTLA-4 blockade in syngeneic mouse models.
The multifaceted immunomodulatory activity of DNA hypomethylating agents improves immunogenicity and immune recognition of neoplastic cells; thus, we predicted they could be utilized to design new immunotherapeutic combinations in cancer. Testing this hypothesis, the antitumor efficacy of the DNA hypomethylating agent 5-aza-2'-deoxycytidine (5-AZA-CdR) combined with the anti-CTLA-4 monoclonal antibody (mAb) 9H10 in syngeneic transplantable murine models was investigated. Murine mammary carcinoma TS/A or mesothelioma AB1 cells were injected in BALB/c, athymic nude, and SCID/Beige mice that were treated with 5-AZA-CdR, mAb 9H10, or their combination. Tumor volumes were captured at different time-points; molecular and immunohistochemical assays investigated changes in neoplastic and normal tissues. A significant antitumor effect of 5-AZA-CdR combined with mAb 9H10 was found: compared to controls, a 77% (p < 0.01), 54% (p < 0.01) and 33% (p = 0.2) decrease in TS/A tumor growth was induced by 5-AZA-CdR combined with mAb 9H10, 5-AZA-CdR or mAb 9H10, respectively. These antitumor activities were confirmed utilizing the AB1 model. 5-AZA-CdR-based regimens induced a promoter-demethylation-sustained tumor expression of cancer testis antigens. MHC class I expression was up-regulated by 5-AZA-CdR. Antitumor efficacy of 5-AZA-CdR in athymic nude and SCID/Beige mice was not increased by mAb 9H10. In BALB/c mice, combined treatment induced the highest tumor infiltration by CD3+ lymphocytes, which included both CD8+ and CD4+ T cells; no such infiltrates were observed in normal tissues. This significant immune-related antitumor activity of 5-AZA-CdR combined with CTLA-4 blockade, demonstrated in highly aggressive mouse tumor models, provides a strong scientific rationale to implement epigenetically-based immunotherapies in cancer patients.


Genome-wide association analysis of Mexican bread wheat landraces for resistance to yellow and stem rust.
Deploying under-utilized landraces in wheat breeding has been advocated to accelerate genetic gains in current era of genomics assisted breeding. Mexican bread wheat landraces (Creole wheats) represent an important resource for the discovery of novel alleles including disease resistance. A core set of 1,098 Mexican landraces was subjected to multi-location testing for rust diseases in India, Mexico and Kenya. The landrace core set showed a continuous variation for yellow (YR) and stem rust (SR) disease severity. Principal component analysis differentiated Mexican landraces into three groups based on their respective collection sites. Linkage disequilibrium (LD) decay varied from 10 to 32 Mb across chromosomes with an averge of 23Mb across whole genome. Genome-wide association analysis revealed marker-trait associations for YR resistance in India and Mexico as well as for SR resistance in Kenya. In addition, significant additive-additive interaction effects were observed for both YR and SR resistance including genomic regions on chromosomes 1BL and 3BS, which co-locate with pleiotropic genes Yr29/Lr46/Sr58/Pm39/Ltn2 and Sr2/Yr30/Lr27, respectively. Study reports novel genomic associations for YR (chromosomes 1AL, 2BS, and 3BL) and SR (chromosomes 2AL, 4DS, and 5DS). The novel findings in Creole wheat landraces can be efficiently utilized for the wheat genetic improvement.


Rapid detection of methicillin resistance in Staphylococcus aureus isolates by the MRSA-screen latex agglutination test.
The slide agglutination test MRSA-Screen (Denka Seiken Co., Niigata, Japan) was compared with the mecA PCR ("gold standard") for the detection of methicillin resistance in Staphylococcus aureus. The MRSA-Screen test detected the penicillin-binding protein 2a (PBP2a) antigen in 87 of 90 genetically diverse methicillin-resistant S. aureus (MRSA) stock culture strains, leading to a sensitivity of 97%. The three discrepant MRSA strains displayed positive results only after induction of the mecA gene by exposure to methicillin. Both mecA PCR and MRSA-Screen displayed negative results among the methicillin-susceptible S. aureus strains (n = 106), as well as for Micrococcus spp. (n = 10), members of the family Enterobacteriaceae (n = 10), Streptococcus pneumoniae (n = 10), and Enterococcus spp. (n = 10) (specificity = 100%). Producing the same PBP2a antigen, all 10 methicillin-resistant Staphylococcus epidermidis strains score positived in both the latex test and the mecA PCR. Consequently, the MRSA-Screen test should be applied only after identification of the MRSA strain to the species level to rule out coagulase-negative staphylococci. In conclusion, due to excellent specificity and sensitivity the MRSA-Screen latex test has the potential to be successfully used for routine applications in the microbiology laboratory.


Heat Maps of Hypertension, Diabetes Mellitus, and Smoking in the Continental United States.
Geographic variations in cardiovascular mortality are substantial, but descriptions of geographic variations in major cardiovascular risk factors have relied on data aggregated to counties. Herein, we provide the first description of geographic variation in the prevalence of hypertension, diabetes mellitus, and smoking within and across US counties. We conducted a cross-sectional analysis of baseline risk factor measurements and latitude/longitude of participant residence collected from 2003 to 2007 in the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Of the 30 239 participants, all risk factor measurements and location data were available for 28 887 (96%). The mean (±SD) age of these participants was 64.8(±9.4) years; 41% were black; 55% were female; 59% were hypertensive; 22% were diabetic; and 15% were current smokers. In logistic regression models stratified by race, the median(range) predicted prevalence of the risk factors were as follows: for hypertension, 49% (45%-58%) among whites and 72% (68%-78%) among blacks; for diabetes mellitus, 14% (10%-20%) among whites and 31% (28%-41%) among blacks; and for current smoking, 12% (7%-16%) among whites and 18% (11%-22%) among blacks. Hypertension was most prevalent in the central Southeast among whites, but in the west Southeast among blacks. Diabetes mellitus was most prevalent in the west and central Southeast among whites but in south Florida among blacks. Current smoking was most prevalent in the west Southeast and Midwest among whites and in the north among blacks. Geographic disparities in prevalent hypertension, diabetes mellitus, and smoking exist within states and within counties in the continental United States, and the patterns differ by race.


InterPro--an integrated documentation resource for protein families, domains and functional sites.
InterPro is a new integrated documentation resource for protein families, domains and functional sites, developed initially as a means of rationalising the complementary efforts of the PROSITE, PRINTS, Pfam and ProDom database projects. Merged annotations from PRINTS, PROSITE and Pfam form the InterPro core. Each combined InterPro entry includes functional descriptions and literature references, and links are made back to the relevant parent database(s), allowing users to see at a glance whether a particular family or domain has associated patterns, profiles, fingerprints, etc. Merged and individual entries (i.e. those that have no counterpart in the companion resources) are assigned unique accession numbers. Release 1.2 of InterPro (June 2000) contains over 3000 entries, representing families, domains, repeats and sites of post-translational modification (PTMs) encoded by 6581 different regular expressions, profiles, fingerprints and Hidden Markov Models (HMMs). Each InterPro entry lists all the matches against SWISS-PROT and TrEMBL (more than 1000000 hits from 264333 different proteins out of 384572 in SWISS-PROT and TrEMBL).


Quantification of lung fibrosis and emphysema in mice using automated micro-computed tomography.
In vivo high-resolution micro-computed tomography allows for longitudinal image-based measurements in animal models of lung disease. The combination of repetitive high resolution imaging with fully automated quantitative image analysis in mouse models of lung fibrosis lung benefits preclinical research. This study aimed to develop and validate such an automated micro-computed tomography analysis algorithm for quantification of aerated lung volume in mice; an indicator of pulmonary fibrosis and emphysema severity. Mice received an intratracheal instillation of bleomycin (n = 8), elastase (0.25 U elastase n = 9, 0.5 U elastase n = 8) or saline control (n = 6 for fibrosis, n = 5 for emphysema). A subset of mice was scanned without intervention, to evaluate potential radiation-induced toxicity (n = 4). Some bleomycin-instilled mice were treated with imatinib for proof of concept (n = 8). Mice were scanned weekly, until four weeks after induction, when they underwent pulmonary function testing, lung histology and collagen quantification. Aerated lung volumes were calculated with our automated algorithm. Our automated image-based aerated lung volume quantification method is reproducible with low intra-subject variability. Bleomycin-treated mice had significantly lower scan-derived aerated lung volumes, compared to controls. Aerated lung volume correlated with the histopathological fibrosis score and total lung collagen content. Inversely, a dose-dependent increase in lung volume was observed in elastase-treated mice. Serial scanning of individual mice is feasible and visualized dynamic disease progression. No radiation-induced toxicity was observed. Three-dimensional images provided critical topographical information. We report on a high resolution in vivo micro-computed tomography image analysis algorithm that runs fully automated and allows quantification of aerated lung volume in mice. This method is reproducible with low inherent measurement variability. We show that it is a reliable quantitative tool to investigate experimental lung fibrosis and emphysema in mice. Its non-invasive nature has the unique benefit to allow dynamic 4D evaluation of disease processes and therapeutic interventions.


Walking along the serendipitous path of discovery.
Deciphering of the molecular mechanism of the "unfolded protein response" (UPR) provides a wonderful example of how serendipity can shape scientific discovery. Secretory and membrane proteins begin their journey to the cell surface in the endoplasmic reticulum (ER). Before leaving the organelle, proteins are quality-controlled, and only properly folded proteins are transported onwards. The UPR detects an insufficiency in the protein-folding capacity in the ER and in the ways of a finely tuned homeostat adjusts organelle abundance according to need. If the protein-folding defect in the ER cannot be corrected, the UPR switches from a cell-protective to a cell-destructive mode and activates apoptosis in metazoan cells. Such life or death decisions position the UPR in the center of numerous pathologies, including viral infection, protein-folding diseases, diabetes, and cancer. The UPR proved to be a rich field for serendipitous discovery because the molecular machines that transmit information about insufficient protein folding and activate appropriate gene expression programs function in unusual, unprecedented ways. A key regulatory switch in the UPR, for example, is a cytoplasmic, nonconventional mRNA spicing reaction, initiated by a bifunctional transmembrane kinase/endoribonuclease.


The role of bacterial biofilms and surface components in plant-bacterial associations.
The role of bacterial surface components in combination with bacterial functional signals in the process of biofilm formation has been increasingly studied in recent years. Plants support a diverse array of bacteria on or in their roots, transport vessels, stems, and leaves. These plant-associated bacteria have important effects on plant health and productivity. Biofilm formation on plants is associated with symbiotic and pathogenic responses, but how plants regulate such associations is unclear. Certain bacteria in biofilm matrices have been found to induce plant growth and to protect plants from phytopathogens (a process termed biocontrol), whereas others are involved in pathogenesis. In this review, we systematically describe the various components and mechanisms involved in bacterial biofilm formation and attachment to plant surfaces and the relationships of these mechanisms to bacterial activity and survival.


Looking good but doing harm? Perceptions of short-term medical missions in Nicaragua.
In this paper, we present findings from a qualitative study that gathered Nicaraguans' perceptions of short-term foreign medical missions, towards deepening the understanding of what Nicaraguans value or find limited in the work of such foreign missions operating in their country. Fifty-two interviews were conducted with patients, relatives of patients, Nicaraguan physicians and nurses who partnered with or observed missions at work, 'beneficiary' community leaders, and individuals who were unable or unwilling to access mission-provided healthcare. Factors underlying participants' positive and more critical accounts of foreign primary and surgical missions are described and analysed. Empirical investigation on how, whether or not, or on what bases short-term medical missions (STMs) have been perceived as beneficial, harmful, or otherwise by those on the receiving end of these efforts is limited. This study aims to contribute to the evidence base for reflecting on the ethical performance of trans-national STMs.


Evaluation of nosocomial infections following cardiovascular surgery.
To evaluate nosocomial infections (NI) following cardiovascular surgery (CVS), and to share the first seven-year experience of the infection control commission in a private medical center. Active prospective and laboratory based surveillance program of the hospital from January 1999 to December 2005 was used and all patients who were found to have NIs after CVS during their stay or readmission were included. A total of 14,502 cardiovascular operations were performed and 416 (2.9%) patients had 494 NIs. The most prevalent infections were surgical site infections (42%) and urinary tract infections (22%). The most frequently isolated microorganisms were coagulase-negative staphylococci (19%), Escherichia coli (16%) and Staphylococcus aureus (16%). A total of 99 patients (24%) died. The mortality rates were high in patients with blood-stream infections (58%) and lower respiratory tract infections (37%). The 2003 was the year with the lowest NI rate when compared to 2000, 2001, 2002, 2004, and 2005 (p< 0.005). This study allowed an evaluation of NIs, including incidence and distribution, following CVS. While carrying on the studies to prevent NIs that are responsible for serious morbidity and mortality, risk factors also need to be identified in order to take preventive measures, other than the ones present.


Widespread expression of an extended peptide sequence of GATA-6 during murine embryogenesis and non-equivalence of RNA and protein expression domains.
The transcription factor GATA-6 is known to be a critical determinant of early vertebrate development. We have shown previously that mammalian GATA-6 genes have the potential to encode two protein isoforms, resulting from alternative, in-frame, initiator methionine codons. We have generated GATA-6 antibodies, including one specific to the longer form of GATA-6, and by immunohistochemical analysis we demonstrate here that the longer protein, which is the more potent transcriptional transactivator, is widely expressed in vivo. In accordance with previous RNA expression studies, GATA-6 protein was found to be abundant within regions of the gut and pulmonary systems, in addition to the heart myocardium. We also report novel GATA-6 expression within sites of chondrogenesis derived from cranial neural crest and sclerotomes. Surprisingly however, levels of GATA-6 protein were substantially reduced within the endocardial cushions and outflow tract of the heart. These are regions which express the highest levels of GATA-6 RNA within the heart.


Structure-activity studies of homologues of short chain neurotoxins from Elapid snake venoms.
Three neurotoxin homologues (CM10 and CM12 from Naja haje annulifera and S5C10 from Dendroaspis jamesoni kaimosae) and two short neurotoxins (CM14 from Naja haje annulifera and erabutoxin b from Laticauda semifasciata) were examined by circular dichroism (c.d.) and tested for neuromuscular activity on chick biventer cervicis nerve-muscle preparations. All three homologues had acetylcholine receptor blocking activity, as they abolished responses to indirect stimulation, acetylcholine and carbachol but had no effect on responses to direct muscle stimulation. CM10 was only about 5 times less potent than the short neurotoxin CM14; S5C10 and CM12 were respectively 30 and 300 times less active. The block induced by the three homologues, but not by the neurotoxins, was readily reversed by washing. CM10 and CM12 had virtually identical c.d. spectra which were closely similar to those of the neurotoxins. The spectrum of S5C10 indicated changes in the environment of tyrosine-25 and in the position of tryptophan-29. These alterations could distort the 3-dimensional arrangement of the residues postulated to form the receptor binding site. The results with CM10 and CM12 highlight a role for the first loop (residues 6-16) in the binding of neurotoxins to acetylcholine receptors, in addition to the previously postulated reactive site.


Transmission of hepatitis C virus among intravenous drug users in the Uppsala region of Sweden.
Epidemiology and transmission patterns of hepatitis C virus (HCV) are important subjects as we enter a new era of treatment with directly acting antivirals (DAAs). The highest prevalence of HCV in developed countries is found among intravenous drug users (IDUs), where unsafe needle sharing practices provide the main route of infection. Efforts to prohibit the continuous spread of HCV among these groups have been initiated by the community services and health care providers. Our goal was to understand how HCV was transmitted among IDUs within a limited population group. We provide a retrospective study (2005-2007) of the HCV transmission patterns in a population of IDUs in the Uppsala region of Sweden. Eighty-two serum samples were collected from IDUs in Uppsala County. Our reverse transcription nested polymerase chain reaction (RT-nested PCR) and sequencing method enabled a comprehensive genetic analysis for a broad spectrum of genotypes of two relatively conserved regions, NS5B and NS3, that encodes for the viral polymerase and protease, respectively. HCV RNA in serum samples was amplified and sequenced with in-house primers. Sequence similarities between individuals and subgroups were analyzed with maximum likelihood (ML) phylogenetic trees. Published HCV reference sequences from other geographic regions and countries were also included for clarity. Phylogenetic analysis was possible for 59 NS5B (72%) and 29 NS3 (35%) sequences from Uppsala patients. Additionally, we also included 15 NS3 sequences from Örebro patients, making a total of 44 NS3 sequences for the analysis. By analyzing the NS3 sequences, two transmission sets were found between the IDUs (>98% sequence identity), with one set consisting of two individuals and another set consisting of three individuals. In addition, the phylogenetic analysis done with our serum samples displayed clusters that distinguished them from the reference sequences. Our method seems to enable us to trace the HCV transmission between IDUs. Furthermore, the method is fairly independent of the time of infection because the method uses relatively conserved HCV sequence regions (i.e. NS5B and NS3).


Colds and influenza: a review of diagnosis and conventional, botanical, and nutritional considerations.
The common cold is the leading cause of doctor visits in the United States and annually results in 189 million lost school days. In the course of one year the U.S. population contracts approximately 1 billion colds. Influenza infection is still a leading cause of morbidity and mortality, accounting for 20-25 million doctor visits and 36,000 deaths per year in the United States. Conventional therapies for colds and flu focus primarily on temporary symptom relief and include over-the-counter antipyretics, anti-inflammatories, and decongestants. Treatment for influenza also includes prescription antiviral agents and vaccines for prevention. This article reviews the common cold and influenza viruses, presents the conventional treatment options, and highlights select botanicals (Echinacea spp., Sambucus nigra, larch arabinogalactan, Astragalus membranaceous, Baptisia tinctoria, Allium sativa, Panax quinquefolium, Eleutherococcus senticosus, Andrographis paniculata, olive leaf extract, and Isatis tinctoria) and nutritional considerations (vitamins A and C, zinc, high lactoferrin whey protein, N-acetylcysteine, and DHEA) that may help in the prevention and treatment of these conditions.


Partial do-not-resuscitate orders: A hazard to patient safety and clinical outcomes?
Patients and families commonly discuss end-of-life decisions with clinicians to create a treatment plan based on patient wishes. In some instances, respect for patient autonomy in making choices may create the potential for patient harm. Medical treatments are often performed in groupings in order to work effectively. When such combinations are separated as a result of patient or surrogate choices, critical elements of life- saving care may be omitted, and the patient may receive nonbeneficial or harmful treatment. A partial do-not-resuscitate order may serve as an example. The limited literature available regarding partial do-not-resuscitate order(s) suggests the practice is clinically and ethically problematic. Not much is known about the prevalence of these orders, but some clinicians believe they are a growing phenomenon. Medical and bioethics organizations have produced guidelines and recommendations on the use of full do-not-resuscitate order(s) with little mention of partial do-not-resuscitate order(s). Partial do-not-resuscitate order(s) are designed based on the patient's anticipated need for resuscitation and are intended to manage dying in a tolerable manner based on what the decision maker believes is "best." Through an analysis of the medical literature, we propose that a partial do-not-resuscitate order contradicts this "best" management intention because it is impossible for the decision maker, or care providers, to anticipate all possible prearrest and arrest situations. We propose that a partial do-not-resuscitate order highlights larger problems: 1) a misunderstanding of the meaning and scope of a do-not-resuscitate order and 2) a need for discussions around goals of care. Discouraging partial do-not-resuscitate(s) order may help promote more accurate and comprehensive advance care planning.


Efficacy and safety of intravenous iron therapy as an alternative/adjunct to allogeneic blood transfusion.
Anaemia is a common condition among patients admitted to hospital medicosurgical departments, as well as in critically ill patients. Anaemia is more frequently due to absolute iron deficiency (e.g. chronic blood loss) or functional iron deficiency (e.g. chronic inflammatory states), with other causes being less frequent. In addition, preoperative anaemia is one of the major predictive factors for perioperative blood transfusion. In surgical patients, postoperative anaemia is mainly caused by perioperative blood loss, and it might be aggravated by inflammation-induced inhibition of erythropoietin and functional iron deficiency (a condition that cannot be corrected by the administration of oral iron). All these mechanisms may be involved in the anaemia of the critically ill. Intravenous iron administration seems to be safe, as very few severe side-effects were observed, and may result in hastened recovery from anaemia and lower transfusion requirements. However, it is noteworthy that many of the recommendations given for intravenous iron treatment are not supported by a high level of evidence and this must be borne in mind when making decisions regarding its application to a particular patient. Nonetheless, this also indicates the need for further large, randomized controlled trials on the safety and efficacy of intravenous iron for the treatment of anaemia in different clinical settings.


The state of food systems worldwide in the countdown to 2030.
This Analysis presents a recently developed food system indicator framework and holistic monitoring architecture to track food system transformation towards global development, health and sustainability goals. Five themes are considered: (1) diets, nutrition and health; (2) environment, natural resources and production; (3) livelihoods, poverty and equity; (4) governance; and (5) resilience. Each theme is divided into three to five indicator domains, and indicators were selected to reflect each domain through a consultative process. In total, 50 indicators were selected, with at least one indicator available for every domain. Harmonized data of these 50 indicators provide a baseline assessment of the world's food systems. We show that every country can claim positive outcomes in some parts of food systems, but none are among the highest ranked across all domains. Furthermore, some indicators are independent of national income, and each highlights a specific aspiration for healthy, sustainable and just food systems. The Food Systems Countdown Initiative will track food systems annually to 2030, amending the framework as new indicators or better data emerge.


Adjunctive vasodilator therapy in the treatment of murine ischemia.
Potent vasoconstrictors such as angiotensin II and vasopressin have been implicated as mediators of persistent vasoconstriction after reversible superior mesenteric artery (SMA) occlusion. Neither captopril (CAP), an angiotensin-converting enzyme (ACE) inhibitor, nor papaverine (PAP), a vasodilator, has proven effective in reversing this vasoconstriction when employed singly. The present study examined the combined effect of these agents in reducing mortality in a murine model of acute mesenteric ischemia. The SMAs of 106 adult male Sprague-Dawley rats were totally occluded for 85 minutes. Test agents were given intravenously at reperfusion over a 90-minute period. Survival rates were assessed at 48 hours. CAP was given as a single bolus (0.3 mg/kg) and PAP (0.5 mg/kg/h) as an infusion. Aortic and SMA blood flows were measured pretreatment and posttreatment in a separate group of 19 animals treated with CAP and PAP as single agents. chi 2 analysis and analysis of variance were used to test differences with p < or = 0.05 accepted as significant. PAP alone as an adjunct resulted in a significant increase in 48-hour survival (57% versus 19%, p < or = 0.005). PAP in combination with CAP produced the best outcome in this model (87% versus 19%, p < or = 0.005). Aortic blood flow decreased, whereas SMA blood flow increased after treatment both with CAP and with PAP, but not significantly. The combination of an intravenously administered vasodilator with either glucagon or an ACE inhibitor was the most effective adjunctive therapy in this mesenteric ischemia model. There was no evidence that an inotropic effect, rather than SMA vasodilation, was the responsible mechanism of action.


Protocol for a prospective, controlled, cross-sectional, diagnostic accuracy study to evaluate the specificity and sensitivity of ambulatory monitoring systems in the prompt detection of hypoxia and during movement.
Automated continuous ambulatory monitoring may provide an alternative to intermittent manual vital signs monitoring. This has the potential to improve frequency of measurements, timely escalation of care and patient safety. However, a major barrier to the implementation of these wearable devices in the ward environment is their uncertain reliability, efficiency and data fidelity. The purpose of this study is to test performance of selected devices in a simulated clinical setting including during movement and low levels of peripheral oxygen saturation. This is a single centre, prospective, controlled, cross-sectional, diagnostic accuracy study to determine the specificity and sensitivity of currently available ambulatory vital signs monitoring equipment in the detection of hypoxia and the effect of movement on data acquisition. We will recruit up to 45 healthy volunteers who will attend a single study visit; starting with a movement phase and followed by the hypoxia exposure phase where we will gradually decrease saturation levels down to 80%. We will simultaneously test one chest patch, one wrist worn only and three wrist worn with finger probe devices against 'clinical standard 'and 'gold standard' references. We will measure peripheral oxygen saturations, pulse rate, heart rate and respiratory rate continuously and arterial blood gases intermittently throughout the study. This study has received ethical approval by the East of Scotland Research Ethics Service REC 2 (19/ES/0008). The results will be broadly distributed through conference presentations and peer-reviewed publications. ISRCTN61535692 registered on 10/06/2019.


Hospital admission for acute stroke: who, for how long, and to what effect?
Data from 976 patients registered in a community survey as suffering an acute stroke have been analysed to discover what factors are associated with admission to hospital, how long patients spend in hospital, and whether there are any specific benefits attributable to hospital admission. Six hundred and twenty-five patients were admitted on account of their index stroke. These patients were compared with the 249 who remained at home throughout the first six months after the stroke--the remaining patients were admitted for other reasons or had their stroke in hospital. Two major factors related to an increased chance of admission: having a more severe disability and not having a carer. The same factors were associated with a longer length of stay for those who returned home within six months. Nevertheless 26% of patients managed at home were severely disabled when first seen within seven days. Patients admitted had a median stay of seven days if they died, 19 days if they returned home, and 149 days if they needed alternative long-term accommodation. Patients from the study population of 215 000 people occupied an average of 11.4 beds/100 000 over the first six months after their stroke. After making allowance for the increased severity of disability seen in those admitted to hospital, no differences in functional, social or emotional outcome were found for either place of care.


Efficacy and safety of Curcuma domestica extracts compared with ibuprofen in patients with knee osteoarthritis: a multicenter study.
To determine the efficacy and safety of Curcuma domestica extracts in pain reduction and functional improvement. 367 primary knee osteoarthritis patients with a pain score of 5 or higher were randomized to receive ibuprofen 1,200 mg/day or C. domestica extracts 1,500 mg/day for 4 weeks. The main outcomes were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total, WOMAC pain, WOMAC stiffness, and WOMAC function scores. Adverse events (AEs) were also recorded. 185 and 182 patients were randomly assigned into C. domestica extracts and ibuprofen groups, respectively. The baseline characteristics were no different between groups. The mean of all WOMAC scores at weeks 0, 2, and 4 showed significant improvement when compared with the baseline in both groups. After using the noninferiority test, the mean difference (95% confidence interval) of WOMAC total, WOMAC pain, and WOMAC function scores at week 4 adjusted by values at week 0 of C. domestica extracts were noninferior to those for the ibuprofen group (P=0.010, P=0.018, and P=0.010, respectively), except for the WOMAC stiffness subscale, which showed a trend toward significance (P=0.060). The number of patients who developed AEs was no different between groups. However, the number of events of abdominal pain/discomfort was significantly higher in the ibuprofen group than that in the C. domestica extracts group (P=0.046). Most subjects (96%-97%) were satisfied with the treatment, and two-thirds rated themselves as improved in a global assessment. C. domestica extracts are as effective as ibuprofen for the treatment of knee osteoarthritis. The side effect profile was similar but with fewer gastrointestinal AE reports in the C. domestica extracts group.


Wavelet-based SAR image despeckling and information extraction, using particle filter.
This paper proposes a new-wavelet-based synthetic aperture radar (SAR) image despeckling algorithm using the sequential Monte Carlo method. A model-based Bayesian approach is proposed. This paper presents two methods for SAR image despeckling. The first method, called WGGPF, models a prior with Generalized Gaussian (GG) probability density function (pdf) and the second method, called WGMPF, models prior with a Generalized Gaussian Markov random field (GGMRF). The likelihood pdf is modeled using a Gaussian pdf. The GGMRF model is used because it enables texture parameter estimation. The prior is modeled using GG pdf, when texture parameters are not needed. A particle filter is used for drawing particles from the prior for different shape parameters of GG pdf. When the GGMRF prior is used, the particles are drawn from prior in order to estimate noise-free wavelet coefficients and for those coefficients the texture parameter is changed in order to obtain the best textural parameters. The texture parameters are changed for a predefined set of shape parameters of GGMRF. The particles with the highest weights represents the final noise-free estimate with corresponding textural parameters. The despeckling algorithms are compared with the state-of-the-art methods using synthetic and real SAR data. The experimental results show that the proposed despeckling algorithms efficiently remove noise and proposed methods are comparable with the state-of-the-art methods regarding objective measurements. The proposed WGMPF preserves textures of the real, high-resolution SAR images well.


A hemoglobin-based multifunctional therapeutic: polynitroxylated pegylated hemoglobin.
Polynitroxylated pegylated hemoglobin (PNPH) as a multifunctional therapeutic takes advantage of the ability of hemoglobin (Hb) to transport oxygen, the antioxidative stress activities from the redox coupling of nitroxide and heme iron, and the hypercolloid properties of pegylation. The published preclinical data demonstrating that PNPH acts as a neurovascular protective multifunctional therapeutic in an animal model simulating prehospital resuscitation of traumatic brain injury (TBI) with hemorrhagic shock (HS) are reviewed. Preliminary results on the potential utility of PNPH for neurovascular protection in thrombolytic stroke therapy and for correction of vascular dysfunction through transfusion in sickle-cell disease (SCD) are also discussed. We hypothesize that with PNPH, Hb has more than been tamed--it has become a therapeutic and not just a nontoxic extracellular oxygen carrier--and that successful PNPH development as a multifunctional therapeutic that protects the neurovasculature and reduces oxidative stress may represent a paradigm shift in transfusion and critical care medicine, which may meet a number of unmet medical needs resulting from oxidative stress and inadequate blood flow, such as HS, TBI, SCD, and stroke.


MiR-126 and miR-126* regulate shear-resistant firm leukocyte adhesion to human brain endothelium.
Leukocyte adhesion to brain endothelial cells, the blood-brain barrier main component, is a critical step in the pathogenesis of neuroinflammatory diseases such as multiple sclerosis (MS). Leukocyte adhesion is mediated mainly by selectins, cell adhesion molecules and chemokines induced by pro-inflammatory cytokines such as TNFα and IFNγ, but the regulation of this process is not fully clear. This study investigated the regulation of firm leukocyte adhesion to human brain endothelium by two different brain endothelial microRNAs (miRs), miR-126 and miR-126*, that are downregulated by TNFα and IFNγ in a human brain endothelial cell line, hCMEC/D3. Using a leukocyte adhesion in vitro assay under shear forces mimicking blood flow, we observed that reduction of endothelial miR-126 and miR-126* enhanced firm monocyte and T cell adhesion to hCMEC/D3 cells, whereas their increased expression partially prevented THP1, Jurkat and primary MS patient-derived PBMC firm adhesion. Furthermore, we observed that miR-126* and miR-126 downregulation increased E-selectin and VCAM1, respectively, while miR-126 overexpression reduced VCAM1 and CCL2 expression by hCMEC/D3 cells, suggesting that these miRs regulate leukocyte adhesion by modulating the expression of adhesion-associated endothelial mRNA targets. Hence, human brain endothelial miR-126 and miR-126* could be used as a therapeutic tool to reduce leukocyte adhesion and thus reduce neuroinflammation.