Unique mutational profile associated with a loss of TDG expression in the rectal cancer of a patient with a constitutional PMS2 deficiency.
Cells with DNA repair defects have increased genomic instability and are more likely to acquire secondary mutations that bring about cellular transformation. We describe the frequency and spectrum of somatic mutations involving several tumor suppressor genes in the rectal carcinoma of a 13-year-old girl harboring biallelic, germline mutations in the DNA mismatch repair gene PMS2. Apart from microsatellite instability, the tumor DNA contained a number of C:G→T:A or G:C→A:T transitions in CpG dinucleotides, which often result through spontaneous deamination of cytosine or 5-methylcytosine. Four DNA glycosylases, UNG2, SMUG1, MBD4 and TDG, are involved in the repair of these deamination events. We identified a heterozygous missense mutation in TDG, which was associated with TDG protein loss in the tumor. The CpGs mutated in this patient's tumor are generally methylated in normal colonic mucosa. Thus, it is highly likely that loss of TDG contributed to the supermutator phenotype and that most of the point mutations were caused by deamination of 5-methylcytosine to thymine, which remained uncorrected owing to the TDG deficiency. This case provides the first in vivo evidence of the key role of TDG in protecting the human genome against the deleterious effects of 5-methylcytosine deamination.


Osteopontin: Versatile modulator of liver diseases.
Osteopontin (OPN) is a multifunctional protein, involved in pathological conditions including inflammation, immunity, angiogenesis, fibrosis and cancer progression in various tissues. Hepatic inflammation and fibrosis induced by feeding with a diet deficient in methionine and choline (MCD diet) were markedly attenuated in OPN knockout mice when compared with wild-type mice in the model of non-alcoholic steatohepatitis (NASH). Hepatic cholangiocytes, myofibroblastic stellate cells and natural killer T cells were suggested to secret OPN in mice fed an MCD diet. Plasma and hepatic OPN levels were significantly higher in patients with NASH with advanced fibrosis than in those with early fibrosis. Hepatic OPN mRNA level was correlated with hepatic neutrophil infiltration and fibrosis in patients with alcoholic liver diseases. In those with hepatocellular carcinoma (HCC), OPN levels in plasma and HCC were prognostic factors after liver resection or transplantation. Downregulation of OPN inhibited tumor growth and lung metastasis in nude mice implanted with HCC cells. The single nucleotide polymorphism in the promoter region of the OPN gene was shown to be associated with activity of hepatitis in chronic hepatitis C patients, prognosis in patients with HCC, and growth and lung metastasis of HCC xenografts in nude mice. OPN was reported to be a downstream effecter of Hedgehog pathway, which modulates hepatic fibrosis and carcinogenesis. This review focuses on the roles of OPN in hepatic inflammation, fibrosis and cancer progression. Further elucidation of cellular interactions and molecular mechanisms associated with OPN actions may contribute to development of novel strategies for treatment of the liver diseases.


Cytoplasmic lattices are not linked to mouse 2-cell embryos developmental arrest.
Cytoplasmic lattices are important regulators of oocyte maturation. They store components of the protein synthesis machinery including ribosomes and, among others, they are involved in the regulation of microtubule dynamics in both mouse and human. Cytoplasmic lattices undergo dramatic reorganizations at crucial stages of oocyte maturation, where they are abundantly present in the cytoplasm of developmentally competent oocytes named SN (Surrounded Nucleolus) while they are rare in the cytoplasm of 2-cell stage-arresting NSN (Not Surrounded Nucleolus) oocytes, suggestive of a requirement of cytoplasmic lattices for development past the 2-cell stage. Here, to elucidate this requirement, 2-cell mouse embryos derived from SN and NSN oocytes were analyzed by transmission electron microscopy. Contrary to what had been proposed hitherto, cytoplasmic lattices are present in 2-cell embryos derived not only from SN, but also from NSN oocytes, irrespective of the embryo production system (intra cytoplasmic sperm injection, parthenogenesis). Hence our conclusion that cytoplasmic lattices do not count among the factor(s) responsible for the embryo arrest at this crucial stage of development.


Observation of inverse Compton emission from a long γ-ray burst.
Long-duration γ-ray bursts (GRBs) originate from ultra-relativistic jets launched from the collapsing cores of dying massive stars. They are characterized by an initial phase of bright and highly variable radiation in the kiloelectronvolt-to-megaelectronvolt band, which is probably produced within the jet and lasts from milliseconds to minutes, known as the prompt emission1,2. Subsequently, the interaction of the jet with the surrounding medium generates shock waves that are responsible for the afterglow emission, which lasts from days to months and occurs over a broad energy range from the radio to the gigaelectronvolt bands1-6. The afterglow emission is generally well explained as synchrotron radiation emitted by electrons accelerated by the external shock7-9. Recently, intense long-lasting emission between 0.2 and 1 teraelectronvolts was observed from GRB 190114C10,11. Here we report multi-frequency observations of GRB 190114C, and study the evolution in time of the GRB emission across 17 orders of magnitude in energy, from 5 × 10-6 to 1012 electronvolts. We find that the broadband spectral energy distribution is double-peaked, with the teraelectronvolt emission constituting a distinct spectral component with power comparable to the synchrotron component. This component is associated with the afterglow and is satisfactorily explained by inverse Compton up-scattering of synchrotron photons by high-energy electrons. We find that the conditions required to account for the observed teraelectronvolt component are typical for GRBs, supporting the possibility that inverse Compton emission is commonly produced in GRBs.


Computer-designed active human butyrylcholinesterase double mutant with a new catalytic triad.
A computer-designed mutant of human butyrylcholinesterase (BChE), N322E/E325G, with a novel catalytic triad was made. The catalytic triad of the wild-type enzyme (S198·H438·E325) was replaced by S198·H438·N322E in silico. Molecular dynamics for 1.5 μs and Markov state model analysis showed that the new catalytic triad should be operative in the mutant enzyme, suggesting functionality. QM/MM modeling performed for the reaction of wild-type BChE and double mutant with echothiophate showed high reactivity of the mutant towards the organophosphate. A truncated monomeric (L530 stop) double mutant was expressed in Expi293 cells. Non-purified transfected cell culture medium was analyzed. Polyacrylamide gel electrophoresis under native conditions followed by activity staining with BTC as the substrate provided evidence that the monomeric BChE mutant was active. Inhibition of the double mutant by echothiophate followed by polyacrylamide gel electrophoresis and activity staining showed that this enzyme slowly self-reactivated. However, because Expi293 cells secrete an endogenous BChE tetramer and several organophosphate-reacting enzymes, catalytic parameters and self-reactivation constants after phosphorylation of the new mutant were not determined in the crude cell culture medium. The study shows that the computer-designed double mutant (N322E/E325G) with a new catalytic triad (S198·H438·N322E) is a suitable template for design of novel active human BChE mutants that display an organophosphate hydrolase activity.


Serotonin innervation of basal ganglia in monkeys and humans.
This review paper summarizes our previous contributions to the study of serotonin (5-hydroxytryptamine; 5-HT) innervation of basal ganglia in human and nonhuman primates under normal conditions. We have visualized the 5-HT neuronal system in squirrel monkey (Saimiri sciureus) and human postmortem materials with antibodies directed against either 5-HT, 5-HT transporter (SERT) or 5-HT synthesizing enzyme tryptophan hydroxylase (TPH). Confocal microscopy was used to compare the distribution of 5-HT and dopamine (DA; tyrosine hydroxylase-immunolabeled) axons in human, while the ultrastructural features of 5-HT axon terminals in monkey subthalamic nucleus were characterized at electron microscopic level. In monkeys and humans, midbrain raphe neurons emit axons that traverse the brainstem via the transtegmental system, ascend within the medial forebrain bundle and reach their targets by coursing along the major output pathways of the basal ganglia. These 5-HT axons arborize in virtually all basal ganglia components with the substantia nigra receiving the densest innervation and the striatum the most heterogeneous one. Although the striatum - the major basal ganglia input structure - appears to be a common termination site for many of 5-HT ascending axons, our results reveal that the widely distributed 5-HT neuronal system can also act directly upon neurons located within the two major output structures of the basal ganglia, namely the internal pallidum and the substantia nigra pars reticulata in monkeys and humans. This system also has a direct access to neurons of the DA nigrostriatal pathway, a finding that underlines the importance of the 5-HT/DA interactions in the physiopathology of basal ganglia.


Genetic diversification of Panstrongylus geniculatus (Reduviidae: Triatominae) in northern South America.
Triatomines are the vectors of Trypanosoma cruzi, the etiological agent of Chagas disease. Although Triatoma and Rhodnius are the most-studied vector genera, other triatomines, such as Panstrongylus, also transmit T. cruzi, creating new epidemiological scenarios. Panstrongylus has at least 13 reported species but there is limited information about its intraspecific genetic variation and patterns of diversification. Here, we begin to fill this gap by studying populations of P. geniculatus from Colombia and Venezuela and including other epidemiologically important species from the region. We examined the pattern of diversification of P. geniculatus in Colombia using mitochondrial and nuclear ribosomal data. Genetic diversity and differentiation were calculated within and among populations of P. geniculatus. Moreover, we constructed maximum likelihood and Bayesian inference phylogenies and haplotype networks using P. geniculatus and other species from the genus (P. megistus, P. lignarius, P. lutzi, P. tupynambai, P. chinai, P. rufotuberculatus and P. howardi). Using a coalescence framework, we also dated the P. geniculatus lineages. The total evidence tree showed that P. geniculatus is a monophyletic species, with four clades that are concordant with its geographic distribution and are partly explained by the Andes orogeny. However, other factors, including anthropogenic and eco-epidemiological effects must be investigated to explain the existence of recent geographic P. geniculatus lineages. The epidemiological dynamics in structured vector populations, such as those found here, warrant further investigation. Extending our knowledge of P. geniculatus is necessary for the accurate development of effective strategies for the control of Chagas disease vectors.


Associations of serum sex hormone-binding globulin and sex hormone concentrations with hip fracture risk in postmenopausal women.
Endogenous estradiol, testosterone, and SHBG may influence the risk of hip fracture. From the Women's Health Initiative Observational Study, 39,793 eligible postmenopausal women did not have a previous hip fracture and were not using estrogen or other bone-active therapies. Of these, 400 who had a first-time nonpathological hip fracture (median follow-up, 7 yr) were matched to 400 controls by age, ethnicity, and baseline blood draw date. Estradiol, testosterone, and SHBG were measured in banked baseline serum. Compared with women in the lowest tertiles, those with bioavailable testosterone in the highest tertile had a lower risk [odds ratio (OR) = 0.62; 95% confidence interval (CI) = 0.44-0.88]; those with bioavailable estradiol in the highest tertile had a lower risk (OR = 0.44; 95% CI = 0.29-0.66), and those with SHBG in the highest tertile had a higher risk (OR = 1.90; 95% CI = 1.31-2.74) of hip fracture. In models with all three hormones and potential confounders, high SHBG remained a strong independent risk factor (OR = 1.76; 95% CI = 1.12-2.78), high bioavailable testosterone remained protective (OR = 0.64; 95% CI = 0.40-1.00), but estradiol no longer was associated (OR = 0.72; 95% CI = 0.42-1.23). High serum SHBG is associated with an increased risk of subsequent hip fracture and high endogenous testosterone with a decreased risk, independent of each other, serum estradiol concentration, and other putative risk factors. But endogenous estradiol has no independent association with hip fracture.


The circadian clock of fruit flies is blind after elimination of all known photoreceptors.
Circadian rhythms are entrained by light to follow the daily solar cycle. We show that Drosophila uses at least three light input pathways for this entrainment: (1) cryptochrome, acting in the pacemaker cells themselves, (2) the compound eyes, and (3) extraocular photoreception, possibly involving an internal structure known as the Hofbauer-Buchner eyelet, which is located underneath the compound eye and projects to the pacemaker center in the brain. Although influencing the circadian system in different ways, each input pathway appears capable of entraining circadian rhythms at the molecular and behavioral level. This entrainment is completely abolished in glass(60j) cry(b) double mutants, which lack all known external and internal eye structures in addition to being devoid of cryptochrome.


Neural Mechanisms of High-Level Vision.
The last three decades have seen major strides in our understanding of neural mechanisms of high-level vision, or visual cognition of the world around us. Vision has also served as a model system for the study of brain function. Several broad insights, as yet incomplete, have recently emerged. First, visual perception is best understood not as an end unto itself, but as a sensory process that subserves the animal's behavioral goal at hand. Visual perception is likely to be simply a side effect that reflects the readout of visual information processing that leads to behavior. Second, the brain is essentially a probabilistic computational system that produces behaviors by collectively evaluating, not necessarily consciously or always optimally, the available information about the outside world received from the senses, the behavioral goals, prior knowledge about the world, and possible risks and benefits of a given behavior. Vision plays a prominent role in the overall functioning of the brain providing the lion's share of information about the outside world. Third, the visual system does not function in isolation, but rather interacts actively and reciprocally with other brain systems, including other sensory faculties. Finally, various regions of the visual system process information not in a strict hierarchical manner, but as parts of various dynamic brain-wide networks, collectively referred to as the "connectome." Thus, a full understanding of vision will ultimately entail understanding, in granular, quantitative detail, various aspects of dynamic brain networks that use visual sensory information to produce behavior under real-world conditions. © 2017 American Physiological Society. Compr Physiol 8:903-953, 2018.


Hypokalemia, its contributing factors and renal outcomes in patients with chronic kidney disease.
In the chronic kidney disease (CKD) population, the impact of serum potassium (sK) on renal outcomes has been controversial. Moreover, the reasons for the potential prognostic value of hypokalemia have not been elucidated. 2500 participants with CKD stage 1-4 in the Integrated CKD care program Kaohsiung for delaying Dialysis (ICKD) prospective observational study were analyzed and followed up for 2.7 years. Generalized additive model was fitted to determine the cutpoints and the U-shape association between sK and end-stage renal disease (ESRD). sK was classified into five groups with the cutpoints of 3.5, 4, 4.5 and 5 mEq/L. Cox proportional hazard regression models predicting the outcomes were used. The mean age was 62.4 years, mean sK level was 4.2±0.5 mEq/L and average eGFR was 40.6 ml/min per 1.73 m(2). Female vs male, diuretic use vs. non-use, hypertension, higher eGFR, bicarbonate, CRP and hemoglobin levels significantly correlated with hypokalemia. In patients with lower sK, nephrotic range proteinuria, and hypoalbuminemia were more prevalent but the use of RAS (renin-angiotensin system) inhibitors was less frequent. Hypokalemia was significantly associated with ESRD with hazard ratios (HRs) of 1.82 (95% CI, 1.03-3.22) in sK <3.5mEq/L and 1.67 (95% CI,1.19-2.35) in sK = 3.5-4 mEq/L, respectively, compared with sK = 4.5-5 mEq/L. Hyperkalemia defined as sK >5 mEq/L conferred 1.6-fold (95% CI,1.09-2.34) increased risk of ESRD compared with sK = 4.5-5 mEq/L. Hypokalemia was also associated with rapid decline of renal function defined as eGFR slope below 20% of the distribution range. In conclusion, both hypokalemia and hyperkalemia are associated with increased risk of ESRD in CKD population. Hypokalemia is related to increased use of diuretics, decreased use of RAS blockade and malnutrition, all of which may impose additive deleterious effects on renal outcomes.


External auditory canal stenosis due to the use of powdered boric acid.
Acquired stenosis of the external auditory canal (EAC) may occur because of chronic external otitis, recurrent chronic catarrhal otitis media associated with tympanic membrane perforation, chronic dermatitis, tumors, and trauma. Stenosis occurs generally at the one-third bone part of the external auditory canal. In this article, we present 3 cases of acquired EAC stenosis due to the previous powdered boric acid application. Besides the presentation of surgical intervetions in these cases, we want to notify the physicians not to use or carefully use powdered boric acid because of the complication of EAC stenosis.


Learning to Optimize in Swarms.
Learning to optimize has emerged as a powerful framework for various optimization and machine learning tasks. Current such "meta-optimizers" often learn in the space of continuous optimization algorithms that are point-based and uncertainty-unaware. To overcome the limitations, we propose a meta-optimizer that learns in the algorithmic space of both point-based and population-based optimization algorithms. The meta-optimizer targets at a meta-loss function consisting of both cumulative regret and entropy. Specifically, we learn and interpret the update formula through a population of LSTMs embedded with sample- and feature-level attentions. Meanwhile, we estimate the posterior directly over the global optimum and use an uncertainty measure to help guide the learning process. Empirical results over non-convex test functions and the protein-docking application demonstrate that this new meta-optimizer outperforms existing competitors. The codes are publicly available at: https://github.com/Shen-Lab/LOIS.


Effects of copaiba oil on dermonecrosis induced by Loxosceles intermedia venom.
Accidents caused by spiders of the genus Loxosceles constitute an important public health problem in Brazil. The venom of Loxosceles sp induces dermonecrosis at the bite site and systemic disease in severe cases. Traditional medicine based on plant-derived products has been proven to reduce the local effects of envenomation. The present study verified the healing effects of copaiba oil on lesions induced by the venom of L. intermedia. Cutaneous lesions were induced on the backs of rabbits by intradermal injection of L. intermedia venom. Copaiba oil was applied topically 6 hours after injection; the treatment was repeated for 30 days, after which animal skins were removed and processed for histopathological analysis. Blood samples were also collected before and 24 hours after venom inoculation to measure the hematological parameters. Compared to the control group, the platelet count was reduced significantly in all groups inoculated with venom, accompanied by a decreased number of heterophils in the blood. The minimum necrotic dose (MND) was defined as 2.4 μg/kg. Topical treatment with copaiba oil demonstrated a differentiated healing profile: large skin lesions were observed 10 days after venom inoculation, whereas formation of a thick crust, without scarring was observed 30 days after venom inoculation. Histopathological analysis showed no significant difference after treatment. Nevertheless, the copaiba oil treatment induced a collagen distribution similar to control skin, in marked contrast to the group that received only the spider venom injection. We conclude that copaiba oil may interfere in the healing process and thus propose it as a possible topical treatment for cutaneous lesions induced by L. intermedia venom.


Latent structure of psychotic experiences in the general population.
There have been increasing pressures to adopt or incorporate dimensional representations in various sections of DSM-5 including the psychotic disorders section. Thus far, findings offered as evidence of a continuous distribution of psychosis are limited given their exclusive focus on the manifest rather than latent structure of psychotic experiences. The current study sought to determine whether or not psychotic experiences possess a taxonic or dimensional latent structure. We investigated the latent structure of psychotic experiences in the Collaborative Psychiatric Epidemiological Surveys (CPES) and the National Comorbidity Survey (NCS). We analyzed responses of participants in these surveys with three multivariate taxometric procedures (MAMBAC, MAXEIG, and L-Mode) after summing responses on the surveys into three indicators of positive psychosis. Taxometric results tended to support a dimensional, rather than taxonic structure for psychotic experiences. In the CPES, all taxometric methods produced graphical and numerical support for a dimensional structure. In the NCS, MAMBAC appeared to slightly support a taxonic structure, whereas MAXEIG and L-Mode supported a dimensional structure. There appears to be a dimensional distribution of psychotic experiences in the general population. This supports the incorporation of dimensional representations of psychotic symptoms in the current diagnostic system.


Potential subtherapeutic linezolid and meropenem antibiotic concentrations in a patient with severe burns and sepsis.
Altered pharmacokinetics in patients with major burns may result in serum antibiotic concentrations below those required to be effective against the common pathogens encountered in burns patients. The major changes in the fluid volumes of key body compartments, which occur with a large burn, may increase the apparent volume of distribution of a drug, thereby lowering its concentration when a standard dose is given. In addition, the observed increase in renal blood flow reported in burns patients, because of the change in cardiac output, may result in a higher drug clearance and a shorter elimination half-life. As a consequence, studies have recommended higher doses or more frequent dosing or both for some antibiotics in patients with major burns, but data are lacking for many of the antibiotics reserved for treatment of life-threatening infections. The authors measured serum concentrations of two antibiotics, linezolid and meropenem, in an immunosuppressed patient who presented with a severe burn to determine whether therapeutic concentrations were achieved, thereby improving the likelihood of infection control.


Autosomal, mitochondrial, and Y chromosome DNA variation in Finland: evidence for a male-specific bottleneck.
The high prevalence of rare genetic diseases in Finland has been attributed to a founder effect some 2,000 years ago. However, this hypothesis has not been supported from mtDNA sequence and autosomal microsatellite data which indicate high levels of gene diversity. Here we have identified genetic evidence for a population bottleneck by examining variable microsatellite loci on the nonrecombining portion of Y chromosomes from Finland and four populations from Europe and the Americas. Sequence data from segment I of the control region (HVS-1) of mtDNA (360 bases) and 20 autosomal dinucleotide repeat markers were also analyzed. Partitions of genetic variance within and between populations revealed significant levels of Y-chromosome differentiation between populations. Phylogenetic and diversity analyses revealed divergent Finnish Y-haplotype clades and significantly lower Y-haplotype diversity among Finns as compared to other populations. Surprisingly, Finnish Y-haplotype diversity was even lower than the Native American populations. These results provide support for the Finnish bottleneck hypothesis. Evidence for two separate founding Finnish Y-chromosome lineages was also observed from the Y-chromosome phylogeny. A limited number of closely related founding males may have contributed to the low number of paternal lineages in the Finnish population. In contrast, high levels of genetic diversity for mtDNA and autosomal STRs may be the result of sex-biased gene flow and recent immigration to urban areas from established internal isolates within Finland.


Information and communications technology in U.S. health care: why is adoption so slow and is slower better?
Politicians across the political spectrum support greater investment in health care information and communications technology (ICT) and expect it to significantly decrease costs and improve health outcomes. We address three policy questions about adoption of ICT in health care: First, why is there so little adoption? Second, what policies will facilitate and accelerate adoption? Third, what is the best pace for adoption? We first describe the unusual economics of ICT, particularly network externalities, and then determine how those economics interact with and are exacerbated by the unusual economics of health care. High replacement costs and the need for technical compatibility are general barriers to ICT adoption and often result in lock-in to adopted technologies. These effects are compounded in health care because the markets for health care services, health insurance, and labor are interlinked. In addition, the government interacts with all markets in its role as an insurer. Patient heterogeneity further exacerbates these effects. Finally, ICT markets are often characterized by natural monopolies, resulting in little product diversity, an effect ill-suited to patient heterogeneity. The ongoing process for setting technical standards for health care ICT is critical but needs to include all relevant stakeholders, including patient groups. The process must be careful (i.e., slow), flexible, and allow for as much diversity as possible. We find that waiting to adopt ICT is a surprisingly wise policy.


Persistence of Breakage in Specific Chromosome Bands 6 Years after Acute Exposure to Oil.
The identification of breakpoints involved in chromosomal damage could help to detect genes involved in genetic disorders, most notably cancer. Until now, only one published study, carried out by our group, has identified chromosome bands affected by exposure to oil from an oil spill. In that study, which was performed two years after the initial oil exposure in individuals who had participated in clean-up tasks following the wreck of the Prestige, three chromosomal bands (2q21, 3q27, 5q31) were found to be especially prone to breakage. A recent follow-up study, performed on the same individuals, revealed that the genotoxic damage had persisted six years after oil exposure. To determine whether there exist chromosome bands which are especially prone to breakages and to know if there is some correlation with those detected in the previous study. In addition, to investigate if the DNA repair problems detected previously persist in the present study. Follow-up study performed six years after the Prestige oil spill. Fishermen cooperatives in coastal villages. Fishermen highly exposed to oil spill who participated in previous genotoxic study six years after the oil. Chromosome damage in peripheral lymphocytes. For accurate identification of the breakpoints involved in chromosome damage of circulating lymphocytes, a sequential stain/G-banding technique was employed. To determine the most break-prone chromosome bands, two statistical methods, the Fragile Site Multinomial and the chi-square tests (where the bands were corrected by their length) were used. To compare the chromosome lesions, structural chromosome alterations and gaps/breaks between two groups of individuals we used the GEE test which takes into account a possible within-individual correlation. Dysfunctions in DNA repair mechanisms, expressed as chromosome damage, were assessed in cultures with aphidicolin by the GEE test. Cytogenetic analyses were performed in 47 exposed individuals. A total of 251 breakpoints in exposed individuals) were identified, showing a non-uniform distribution in the human ideogram. Ten chromosome bands were found to be especially prone to breakage through both statistical methods. By comparing these bands with those observed in certain exposed individuals who had already participated the previous study, it was found in both studies that four bands (2q21, 3q27, 5q31 and 17p11.2) are particularly sensitive to breakage. Additionally, the dysfunction in DNA repair mechanisms was not significantly higher in oil-exposed individuals than in non-exposed individuals. The sample size and the possibility of some kind of selection bias should be considered. Genotoxic results cannot be extrapolated to the high number of individuals who participated occasionally in clean-up tasks. Our findings show the existence of at least four target bands (2q21, 3q27, 5q31 and 17p11.2) with a greater propensity to break over time after an acute exposure to oil. The breaks in these bands, which are commonly involved in hematological cancer, may explain the increase of cancer risk reported in chronically benzene-exposed individuals. In addition, a more efficiency of the DNA repair mechanisms has been detected six years after in fishermen who were highly exposed to the oil spill. To date, only this study, performed by our group on the previous and present genotoxic effects, has analyzed the chromosomal regions affected by breakage after an acute oil exposure.


Age- and Gender-related Disparities in Primary Percutaneous Coronary Interventions for Acute ST-segment elevation Myocardial Infarction.
Previous analyses reported age- and gender-related differences in the provision of cardiac care. The objective of the study was to compare circadian disparities in the delivery of primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) according to the patient's age and gender. We investigated patients included into the Acute Myocardial Infarction in Switzerland (AMIS) registry presenting to one of 11 centers in Switzerland providing primary PCI around the clock, and stratified patients according to gender and age. A total of 4723 patients presented with AMI between 2005 and 2010; 1319 (28%) were women and 2172 (54%) were ≥65 years of age. More than 90% of patients <65 years of age underwent primary PCI without differences between gender. Elderly patients and particularly women were at increased risk of being withheld primary PCI (males adj. HR 4.91, 95% CI 3.93-6.13; females adj. HR 9.31, 95% CI 7.37-11.75) as compared to males <65 years of age. An increased risk of a delay in door-to-balloon time >90 minutes was found in elderly males (adj HR 1.66 (95% CI 1.40-1.95), p<0.001) and females (adj HR 1.57 (95% CI 1.27-1.93), p<0.001), as well as in females <65 years (adj HR 1.47 (95% CI 1.13-1.91), p = 0.004) as compared to males <65 years of age, with significant differences in circadian patterns during on- and off-duty hours. In a cohort of patients with AMI in Switzerland, we observed discrimination of elderly patients and females in the circadian provision of primary PCI.


A new mixed-valence lead(II) mangan-ese(II/III) phosphate(V): PbMn(II) 2Mn(III)(PO4)3.
The title compound, lead trimanganese tris(orthophosphate), has been synthesized by hydro-thermal methods. In this structure, only two O atoms are in general positions and all others atoms are in the special positions of the Imma space group. Indeed, the atoms in the Wyckoff positions are namely: Pb1 and P1 on 4e (mm2); Mn1 on 4b (2/m); Mn2 and P2 on 8g (2); O1 on 8h (m); O2 on 8i (m). The crystal structure can be viewed as a three-dimensional network of corner- and edge-sharing PO4 tetra-hedra and MnO6 octa-hedra, building two types of chains running along the b axis. The first is an infinite linear chain, formed by alternating Mn(III)O6 octa-hedra and PO4 tetra-hedra which share one vertex. The second chain is built up from two adjacent edge-sharing octa-hedra (Mn(II) 2O10 dimers) whose ends are linked to two PO4 tetra-hedra by a common edge. These chains are linked together by common vertices of polyhedra in such a way as to form porous layers parallel to (001). These sheets are bonded by the first linear chains, leading to the appearance of two types of tunnels, one propagating along the a axis and the other along b. The Pb(II) ions are located within the inter-sections of the tunnels with eight neighbouring O atoms in form of a trigonal prism that is capped by two O atoms on one side. The three-dimensional framework of this structure is compared with similar phosphates such as Ag2Co3(HPO4)(PO4)2 and Ag2Ni3(HPO4)(PO4)2.


Thermodynamic Analysis of Chemically Reacting Mixtures-Comparison of First and Second Order Models.
Recently, a method based on non-equilibrium continuum thermodynamics which derives thermodynamically consistent reaction rate models together with thermodynamic constraints on their parameters was analyzed using a triangular reaction scheme. The scheme was kinetically of the first order. Here, the analysis is further developed for several first and second order schemes to gain a deeper insight into the thermodynamic consistency of rate equations and relationships between chemical thermodynamic and kinetics. It is shown that the thermodynamic constraints on the so-called proper rate coefficient are usually simple sign restrictions consistent with the supposed reaction directions. Constraints on the so-called coupling rate coefficients are more complex and weaker. This means more freedom in kinetic coupling between reaction steps in a scheme, i.e., in the kinetic effects of other reactions on the rate of some reaction in a reacting system. When compared with traditional mass-action rate equations, the method allows a reduction in the number of traditional rate constants to be evaluated from data, i.e., a reduction in the dimensionality of the parameter estimation problem. This is due to identifying relationships between mass-action rate constants (relationships which also include thermodynamic equilibrium constants) which have so far been unknown.


Antigenic diversity of the serotype antigen complex of Neisseria gonorrhoeae: analysis by an indirect enzyme-linked immunoassay.
An indirect enzyme-linked immunoassay (ELISA) has been developed to analyze the antigenic profile of the outer membrane serotype complex of Neisseria gonorrhoeae. Antisera raised in rabbits to serotype-specific vesicles (SSV) reacted primarily with homologous SSV; however, there was significant cross-reactivity (less than 50%) with heterologous SSV. N. meningitidis SSV cross-reacted with all antigonococcal SSV but at a lower degree (less than 20%). Preimmune sera did not cross-react significantly with all antigonoccoccal SSV. The sensitivity of the ELISA was enhanced when the integral SSV proteins 1a and 2 were used as adsorbed antigen. Heterologous anti-SSV cross-reacted slightly, having ELISA values less than 15% of the homologous reaction. Antisera prepared by immunoabsorbent affinity columns were highly specific. Homologous affinity anti-SSV reacted only with proteins 1a and 2. The reaction of immune sera was inhibited by homologous proteins 1a and 2; lipopolysaccharide and proteins 1a and 2 isolated from heterologous serotypes did not inhibit the reaction. The reaction of affinity-purified antisera could be inhibited only by homologous protein 1a. By the use of affinity-purified antisera, a specific and highly sensitive ELISA was developed to analyze the antigenic profile of strains of N. gonorrhoeae.


Observation of antiferromagnetic correlations in the Hubbard model with ultracold atoms.
Ultracold atoms in optical lattices have great potential to contribute to a better understanding of some of the most important issues in many-body physics, such as high-temperature superconductivity. The Hubbard model--a simplified representation of fermions moving on a periodic lattice--is thought to describe the essential details of copper oxide superconductivity. This model describes many of the features shared by the copper oxides, including an interaction-driven Mott insulating state and an antiferromagnetic (AFM) state. Optical lattices filled with a two-spin-component Fermi gas of ultracold atoms can faithfully realize the Hubbard model with readily tunable parameters, and thus provide a platform for the systematic exploration of its phase diagram. Realization of strongly correlated phases, however, has been hindered by the need to cool the atoms to temperatures as low as the magnetic exchange energy, and also by the lack of reliable thermometry. Here we demonstrate spin-sensitive Bragg scattering of light to measure AFM spin correlations in a realization of the three-dimensional Hubbard model at temperatures down to 1.4 times that of the AFM phase transition. This temperature regime is beyond the range of validity of a simple high-temperature series expansion, which brings our experiment close to the limit of the capabilities of current numerical techniques, particularly at metallic densities. We reach these low temperatures using a compensated optical lattice technique, in which the confinement of each lattice beam is compensated by a blue-detuned laser beam. The temperature of the atoms in the lattice is deduced by comparing the light scattering to determinant quantum Monte Carlo simulations and numerical linked-cluster expansion calculations. Further refinement of the compensated lattice may produce even lower temperatures which, along with light scattering thermometry, would open avenues for producing and characterizing other novel quantum states of matter, such as the pseudogap regime and correlated metallic states of the two-dimensional Hubbard model.


Comparative genotyping of Campylobacter jejuni by amplified fragment length polymorphism, multilocus sequence typing, and short repeat sequencing: strain diversity, host range, and recombination.
Three molecular typing methods were used to study the relationships among 184 Campylobacter strains isolated from humans, cattle, and chickens. All strains were genotyped by amplified fragment length polymorphism (AFLP) analysis, multilocus sequence typing (MLST), and sequence analysis of a genomic region with short tandem repeats designated clustered regularly interspaced short palindromic repeats (CRISPRs). MLST and AFLP analysis yielded more than 100 different profiles and patterns, respectively. These multiple-locus typing methods resulted in similar genetic clustering, indicating that both are useful in disclosing genetic relationships between Campylobacter jejuni isolates. Group separation analysis of the AFLP analysis and MLST data revealed an unexpected association between cattle and human strains, suggesting a common source of infection. Analysis of the polymorphic CRISPR region carrying short repeats allowed about two-thirds of the typeable strains to be distinguished, similar to AFLP analysis and MLST. The three methods proved to be equally powerful in identifying strains from outbreaks of human campylobacteriosis. Analysis of the MLST data showed that intra- and interspecies recombination occurs frequently and that the role of recombination in sequence variation is 50 times greater than that of mutation. Examination of strains cultured from cecum swabs revealed that individual chickens harbored multiple Campylobacter strain types and that some genotypes were found in more than one chicken. We conclude that typing of Campylobacter strains is useful for identification of outbreaks but is probably not useful for source tracing and global epidemiology because of carriage of strains of multiple types and an extremely high diversity of strains in animals.


MICA ∗012:01 Allele Facilitates the Metastasis of KRAS-Mutant Colorectal Cancer.
Major histocompatibility complex (HLA) class I chain-related protein A (MICA) regulates immune surveillance through activation of NKG2D (natural killer group 2D) receptor. However, the genetic association, potential function, and predictive ability of MICA alleles with colorectal cancer (CRC) prognosis remain undefined. In this study, we characterized MICA alleles in tissue samples from 104 patients with CRC and 536 healthy controls and carried out genetic association studies by molecular and clinical CRC phenotypes. Preliminary sequence analysis revealed that MICA ∗009:01 or ∗049 alleles were significantly decreased in patients with CRC (p = 0.0049), and further stratification analysis indicated that MICA ∗012:01 allele was associated with patients with CRC and carrying KRAS codon 12 mutation (p = 0.027). The functional consequences of MICA alleles were examined via transfected CRC cell lines which showed that overexpression of MICA ∗012:01 enhanced the proliferation, invasion, and metastatic phenotype of CRC. Preliminary analysis of disease-free survival time in patients with and without MICA ∗012:01 suggest this allele may be predictive for poor prognosis of patients with KRAS codon 12 mutated CRC, as no somatic mutation of MICA gene was detected in CRC tumors compared to paracancerous tissues. Our study indicates that MICA ∗012:01 allele is associated with KRAS-mutated CRC, facilitates CRC invasion and metastasis, and possibly reduces the survival of patients with KRAS-mutated CRC.


Do you see what I see? Mobile eye-tracker contextual analysis and inter-rater reliability.
Mobile eye-trackers are currently used during real-world tasks (e.g. gait) to monitor visual and cognitive processes, particularly in ageing and Parkinson's disease (PD). However, contextual analysis involving fixation locations during such tasks is rarely performed due to its complexity. This study adapted a validated algorithm and developed a classification method to semi-automate contextual analysis of mobile eye-tracking data. We further assessed inter-rater reliability of the proposed classification method. A mobile eye-tracker recorded eye-movements during walking in five healthy older adult controls (HC) and five people with PD. Fixations were identified using a previously validated algorithm, which was adapted to provide still images of fixation locations (n = 116). The fixation location was manually identified by two raters (DH, JN), who classified the locations. Cohen's kappa correlation coefficients determined the inter-rater reliability. The algorithm successfully provided still images for each fixation, allowing manual contextual analysis to be performed. The inter-rater reliability for classifying the fixation location was high for both PD (kappa = 0.80, 95% agreement) and HC groups (kappa = 0.80, 91% agreement), which indicated a reliable classification method. This study developed a reliable semi-automated contextual analysis method for gait studies in HC and PD. Future studies could adapt this methodology for various gait-related eye-tracking studies.


Oligonol Alleviates Sarcopenia by Regulation of Signaling Pathways Involved in Protein Turnover and Mitochondrial Quality.
Oligonol has been shown to moderate mitochondrial biogenesis, protein synthesis, and protein degradation in diabetic mice in a previous study. It is therefore hypothesized that oligonol alleviated sarcopenia by regulating pathways involved in protein turnover and mitochondrial quality. The 32-week-old senescence-accelerated mouse prone 8 (SAMP8) mice are fed with chow diet containing 200 mg kg-1 oligonol for 8 weeks. Oligonol supplementation increased skeletal muscle mass, cross-sectional areas, and grip strength in SAMP8 mice. Oligonol increased phosphorylation of AKT/mTOR/p70sk6, inhibited nuclear localization of FoxO3a and NFκB, and decreased transcription of MuRF-1 and MAFbx in skeletal muscle of SAMP8 mice. Downregulation of mitochondrial biogenesis genes (PGC-1α and Tfam) and mitochondrial fusion genes (Mfn2 and Opa1), loss of PINK1, overexpression of Atg13, LC3-II, and p62, and abundant accumulation of autophagosomes and lysosomes in skeletal muscle of SAMP8 mice are limited by oligonol. Furthermore, oligonol reduced expression of released cytochrome c and cleaved caspase-9 in skeletal muscle of SAMP8 mice. Regulating pathways involved in protein synthesis and degradation, mitochondrial biogenesis, mitochondrial fusion/fission, autophagy, and mitochondria-dependent apoptosis by oligonol contribute to positive protein turnover and mitochondrial quality, thus increasing muscle mass and strength in SAMP8 mice.


Skeletal carbonate mineralogy of Scottish bryozoans.
This paper describes the skeletal carbonate mineralogy of 156 bryozoan species collected from Scotland (sourced both from museum collections and from waters around Scotland) and collated from literature. This collection represents 79% of the species which inhabit Scottish waters and is a greater number and proportion of extant species than any previous regional study. The study is also of significance globally where the data augment the growing database of mineralogical analyses and offers first analyses for 26 genera and four families. Specimens were collated through a combination of field sampling and existing collections and were analysed by X-ray diffraction (XRD) and micro-XRD to determine wt% MgCO3 in calcite and wt% aragonite. Species distribution data and phylogenetic organisation were applied to understand distributional, taxonomic and phylo-mineralogical patterns. Analysis of the skeletal composition of Scottish bryozoans shows that the group is statistically different from neighbouring Arctic fauna but features a range of mineralogy comparable to other temperate regions. As has been previously reported, cyclostomes feature low Mg in calcite and very little aragonite, whereas cheilostomes show much more variability, including bimineralic species. Scotland is a highly variable region, open to biological and environmental influx from all directions, and bryozoans exhibit this in the wide range of within-species mineralogical variability they present. This plasticity in skeletal composition may be driven by a combination of environmentally-induced phenotypic variation, or physiological factors. A flexible response to environment, as manifested in a wide range of skeletal mineralogy within a species, may be one characteristic of successful invasive bryozoans.


MRI reconstruction of multi-image acquisitions using a rank regularizer with data reordering.
To improve rank constrained reconstructions for undersampled multi-image MRI acquisitions. Motivated by the recent developments in low-rank matrix completion theory and its applicability to rapid dynamic MRI, a new reordering-based rank constrained reconstruction of undersampled multi-image data that uses prior image information is proposed. Instead of directly minimizing the nuclear norm of a matrix of estimated images, the nuclear norm of reordered matrix values is minimized. The reordering is based on the prior image estimates. The method is tested on brain diffusion imaging data and dynamic contrast enhanced myocardial perfusion data. Good quality images from data undersampled by a factor of three for diffusion imaging and by a factor of 3.5 for dynamic cardiac perfusion imaging with respiratory motion were obtained. Reordering gave visually improved image quality over standard nuclear norm minimization reconstructions. Root mean squared errors with respect to ground truth images were improved by ∼18% and ∼16% with reordering for diffusion and perfusion applications, respectively. The reordered low-rank constraint is a way to inject prior image information that offers improvements over a standard low-rank constraint for undersampled multi-image MRI reconstructions.


Influence of Peripheral Neuropathy and Microangiopathy on Skin Hydration in the Feet of Patients With Diabetes Mellitus.
Maintaining adequate skin hydration is crucial in the feet of patients with diabetes because xerotic skin may crack and develop fissures, thereby increasing vulnerability to ulceration and infection. The nervous system is considered the powerhouse for maintaining adequate skin hydration; however, no clinical study has assessed the effect of the nervous system on skin hydration. In addition, it is hypothesized that microcirculation may play an important role in maintaining adequate hydration in patients with diabetes. This study aims to evaluate the influence of peripheral nerve function and microvascularity on skin hydration in the feet of patients with diabetes mellitus and compare the effects of these 2 functions on skin hydration. This study included 266 patients with diabetic foot disease. Skin hydration was evaluated using corneometry and microvascularity by measuring the transcutaneous oximetry (TcpO₂) of the foot. The Semmes-Weinstein 5.07/10-g monofilament test, electromyography, and nerve conduction velocity test were conducted to evaluate peripheral neuropathy. Patient data were divided into 3 subgroups according to test values, and statistical comparisons were performed using the linear-by-linear association trend and Pearson's chi-square tests. There was a significant correlation between skin hydration and TcpO₂. However, there was no significant correlation between skin hydration and peripheral nerve function (P = .338). The results of this study demonstrated that skin hydration in the feet of patients with diabetes mellitus mainly is influenced by microcirculation rather than peripheral nerve function.


Renal medullary carcinoma in a six-year-old boy with sickle cell trait.
Renal medullary carcinoma (RMC), an aggressive malignant epithelial neoplasm, first emerged as a distinct clinicopathologic entity in 1995. It affects individuals 40 years of age or younger and is strongly associated with sickle cell disease or trait. The majority of patients with RMC have widely disseminated disease at the time of diagnosis and most fail to respond to both chemotherapy and radiotherapy. Mortality approaches 100%, and death usually occurs within a few months to a year of diagnosis. We report a 6-year-old African-American boy with a history of gross hematuria who died four weeks after diagnosis of disseminated metastatic disease. Autopsy showed a 4.4-cm renal mass with metastases to the contra lateral kidney, liver, lungs and multiregional lymph nodes. RMC should be included in the differential diagnosis of any patient 40 years old or younger with a history of hemoglobinopathy and gross hematuria and/or abdominal or flank pain. A brief discussion of the differential diagnosis, histogenesis and treatment is presented in this study.


Disease pathways and novel therapeutic targets in hypertrophic cardiomyopathy.
As described in earlier reviews in this series on the molecular basis of hypertrophic cardiomyopathy (HCM), HCM is one of the archetypal monogenic cardiovascular disorders to be understood at the molecular level. Twenty years after the discovery of the first HCM disease gene, genetic studies still confirm that HCM is principally a disease of the sarcomere. At the biophysical level, myofilament mutations generally enhance Ca(2+) sensitivity, maximal force production, and ATPase activity. These defects ultimately appear to converge on energy deficiency and altered Ca(2+) handling as major common paths leading to the anatomic (hypertrophy, myofiber disarray, and fibrosis) and functional features (pathological signaling and diastolic dysfunction) characteristic of HCM. In this review, we provide an account of the consequences of HCM mutations and describe how specifically targeting these molecular features has already yielded early promise for novel therapies for HCM. Although substantial efforts are still required to understand the molecular link between HCM mutations and their clinical consequences, HCM endures as an exemplar of how novel insights derived from molecular characterization of Mendelian disorders can inform the understanding of biological processes and translate into rational therapies.


G Protein betagamma subunits stimulate p114RhoGEF, a guanine nucleotide exchange factor for RhoA and Rac1: regulation of cell shape and reactive oxygen species production.
Rho GTPases integrate the intracellular signaling in a wide range of cellular processes. Activation of these G proteins is tightly controlled by a number of guanine nucleotide exchange factors (GEFs). In this study, we addressed the functional role of the recently identified p114RhoGEF in in vivo experiments. Activation of endogenous G protein-coupled receptors with lysophosphatidic acid resulted in activation of a transcription factor, serum response element (SRE), that was enhanced by p114RhoGEF. This stimulation was inhibited by the functional scavenger of Gbetagamma subunits, transducin. We have determined that Gbetagamma subunits but not Galpha subunits of heterotrimeric G proteins stimulated p114RhoGEF-dependent SRE activity. Using coimmunoprecipitation assay, we have determined that Gbetagamma subunits interacted with full-length and DH/PH domain of p114RhoGEF. Similarly, Gbetagamma subunits stimulated SRE activity induced by full-length and DH/PH domain of p114RhoGEF. Using in vivo pull-down assays and dominant-negative mutants of Rho GTPases, we have determined that p114RhoGEF activated RhoA and Rac1 but not Cdc42 proteins. Functional significance of RhoA activation was established by the ability of p114RhoGEF to induce actin stress fibers and cell rounding. Functional significance of Rac1 activation was established by the ability of p114RhoGEF to induce production of reactive oxygen species (ROS) followed by activation of NADPH oxidase enzyme complex. In summary, our data showed that the novel guanine nucleotide exchange factor p114RhoGEF regulates the activity of RhoA and Rac1, and that Gbetagamma subunits of heterotrimeric G proteins are activators of p114RhoGEF under physiological conditions. The findings help to explain the integrated effects of LPA and other G-protein receptor-coupled agonists on actin stress fiber formation, cell shape change, and ROS production.


Association of p53 expression with poor prognosis in patients with triple-negative breast invasive ductal carcinoma.
TP53 gene is mutated in approximately 80% of triple-negative breast cancer (TNBC). However, the prognostic significance of immunohistochemical (IHC)-detected p53 protein expression remains controversial in TNBC. In this study, we retrospectively analyzed the association between IHC-detected p53 expression and the prognosis in a cohort of 278 patients with stage I-III triple-negative breast invasive ductal carcinoma (IDC), who received surgery at the department of breast surgery in the Fourth Hospital of Hebei Medical University from 2010-01 to 2012-12. We found a positive expression ratio of IHC-detected p53 in triple-negative breast IDC of 58.6% (163/278). Furthermore, levels of expression were significantly associated with vessel tumor emboli and higher histologic grade (P = .038, P = .043, respectively), with the highest expression level observed in G3 breast cancer (64.7%). Additionally, Kaplan-Meier analysis showed that p53 expression indicated worse overall survival (OS) in the whole cohort (79.6% vs 89.6%, Log-rank test P = .025) as well as in stratified prognostic stage II patients (90.8% vs 100%, Log-rank test P = .027). The mortality risk of p53 expression patients was 2.22 times higher than that of p53 negative patients (HR: 2.222; 95%CI: 1.147-4.308). In addition, p53 expression was also associated with poor disease-free survival (DFS) (76.7% vs 86.8%, P = .020). Cox proportional hazard ratio model showed p53 expression was an independent risk factor for OS (P = .018) and DFS (P = .018) after controlling for tumor size, lymph node status, and vessel tumor emboli. Altogether, our data showed that IHC-detected p53 expression is a promising prognostic candidate for poor survival in triple-negative breast IDC patients. However, more studies are needed to determine if p53 may be applied to clinical practice as a biomarker and/or novel therapeutic target for TNBC.


Effects of Transcranial Direct Current Stimulation on episodic memory related to emotional visual stimuli.
The present study investigated emotional memory following bilateral transcranial electrical stimulation (direct current of 1 mA, for 20 minutes) over fronto-temporal cortical areas of healthy participants during the encoding of images that differed in affective arousal and valence. The main result was a significant interaction between the side of anodal stimulation and image emotional valence. Specifically, right anodal/left cathodal stimulation selectively facilitated the recall of pleasant images with respect to both unpleasant and neutral images whereas left anodal/right cathodal stimulation selectively facilitated the recall of unpleasant images with respect to both pleasant and neutral images. From a theoretical perspective, this double dissociation between the side of anodal stimulation and the advantage in the memory performance for a specific type of stimulus depending on its pleasantness supported the specific-valence hypothesis of emotional processes, which assumes a specialization of the right hemisphere in processing unpleasant stimuli and a specialization of the left hemisphere in processing pleasant stimuli. From a methodological point of view, first we found tDCS effects strictly dependent on the stimulus category, and second a pattern of results in line with an interfering and inhibitory account of anodal stimulation on memory performance. These findings need to be carefully considered in applied contexts, such as the rehabilitation of altered emotional processing or eye-witness memory, and deserve to be further investigated in order to understand their underlying mechanisms of action.


Anti-viral gene induction is absent upon secondary challenge with double-stranded RNA in the Pacific oyster, Crassostrea gigas.
Oyster farming is one of the most important aquaculture industries in the world. However, its productivity is increasingly limited by viral disease and we do not yet have management practices, such as protective vaccination, that can control these disease outbreaks. Hence, in the current study we investigated the expression of known anti-viral genes in oysters (Crassostrea gigas) in response to primary and secondary encounter with a virus associated molecular pattern (dsRNA), and tested whether a common form of epigenetic gene regulation (DNA methylation) was associated with the expression of these anti-viral genes. Injection of dsRNA into the adductor muscle resulted in the rapid and transient expression of virus recognition receptors (TLR & MDA5), whereas several anti-viral signalling (IRF & SOC-1) and effector (PKR & viperin) genes were still up-regulated at one week post primary challenge (p < 0.05). This primary encounter with dsRNA appeared to deplete the immune system because anti-viral gene induction was absent in the gills when oysters were given a second injection of dsRNA at 1-week post-primary injection. The expression of DNA methylation genes (DNMT1, DNMT3b, TDG, TET2) and DNA methylation profiles up-stream of specific anti-viral genes (STING, SOC-1 & Viperin) did not change in response to dsRNA injection (p > 0.05). These results collectively suggest that C. gigas does not have an enhanced anti-viral gene response (immune-priming) to secondary dsRNA challenge and that the sustained up-regulation of anti-viral signalling and effector genes following primary challenge is unlikely to be associated with upstream DNA methylation levels.


Venom and Purified Toxins of the Spectacled Cobra (Naja naja) from Pakistan: Insights into Toxicity and Antivenom Neutralization.
Geographical variations of snake venoms can result in suboptimal effectiveness of Indian antivenoms that are currently used in most South Asian countries. This study investigated the toxicity and neutralization profile of the venom and toxins from Pakistani spectacled cobra, Naja naja, using VINS polyvalent antivenom (VPAV, India), Naja kaouthia monovalent antivenom (NKMAV, Thailand), and neuro bivalent antivenom (NBAV, Taiwan). Cation-exchange and reverse-phase high-performance liquid chromatography fractionations followed by toxin identification through liquid chromatography-mass spectrometry (MS)/MS indicated that the venom comprised mainly of postsynaptic neurotoxins (NTXs) (long neurotoxins [LNTXs], 28.3%; short neurotoxins [SNTXs], 8%), cytotoxins (CTXs) (31.2%), and acidic phospholipases A2 (12.3%). NKMAV is the most effective in neutralizing the lethal effect of the venom (potency = 1.1 mg venom/mL) and its LNTX (potency = 0.5 mg toxin/mL), consistent with the high content of LNTX in N. kaouthia venom. VPAV was effective in neutralizing the CTX (potency = 0.4 mg toxin/mL), in agreement with the higher CTX abundance in Indian cobra venom. All the three antivenoms were weak in neutralizing the SNTX (potency = 0.03-0.04 mg toxin/mL), including NBAV that was raised from the SNTX-rich Taiwanese cobra venom. In a challenge-rescue experiment, envenomed mice were prevented from death by a maximal dose of VPAV (intravenous 200 μL) but the recovery from paralysis was slow, indicating the need for higher or repeated doses of VPAV. Our results suggest that optimal neutralization for Pakistani N. naja venom may be achieved by improving the formulation of antivenom production to enhance antivenom immunoreactivity against long and SNTXs.


Extreme oxygen sensitivity of electronic properties of carbon nanotubes
The electronic properties of single-walled carbon nanotubes are shown here to be extremely sensitive to the chemical environment. Exposure to air or oxygen dramatically influences the nanotubes' electrical resistance, thermoelectric power, and local density of states, as determined by transport measurements and scanning tunneling spectroscopy. These electronic parameters can be reversibly "tuned" by surprisingly small concentrations of adsorbed gases, and an apparently semiconducting nanotube can be converted into an apparent metal through such exposure. These results, although demonstrating that nanotubes could find use as sensitive chemical gas sensors, likewise indicate that many supposedly intrinsic properties measured on as-prepared nanotubes may be severely compromised by extrinsic air exposure effects.


Effects of energy drinks mixed with alcohol on behavioral control: risks for college students consuming trendy cocktails.
There has been a dramatic rise in the consumption of alcohol mixed with energy drinks (AmED) in young people. AmED have been implicated in risky drinking practices and greater accidents and injuries have been associated with their consumption. Despite the increased popularity of these beverages (e.g., Red Bull and vodka), there is little laboratory research examining how the effects of AmED differ from alcohol alone. This experiment was designed to investigate if the consumption of AmED alters neurocognitive and subjective measures of intoxication compared with the consumption of alcohol alone. Participants (n=56) attended 1 session where they were randomly assigned to receive one of 4 doses (0.65 g/kg alcohol, 3.57 ml/kg energy drink, AmED, or a placebo beverage). Performance on a cued go/no-go task was used to measure the response of inhibitory and activational mechanisms of behavioral control following dose administration. Subjective ratings of stimulation, sedation, impairment, and level of intoxication were recorded. Alcohol alone impaired both inhibitory and activational mechanisms of behavioral control, as evidenced by increased inhibitory failures and increased response times compared to baseline performance. Coadministration of the energy drink with alcohol counteracted some of the alcohol-induced impairment of response activation, but not response inhibition. For subjective effects, alcohol increased ratings of stimulation, feeling the drink, liking the drink, impairment, and level of intoxication, and alcohol decreased the rating of ability to drive. Coadministration of the energy drink with alcohol increased self-reported stimulation, but resulted in similar ratings of the other subjective effects as when alcohol was administered alone. An energy drink appears to alter some of the objective and subjective impairing effects of alcohol, but not others. Thus, AmED may contribute to a high-risk scenario for the drinker. The mix of impaired behavioral inhibition and enhanced stimulation is a combination that may make AmED consumption riskier than alcohol consumption alone.


Asiatic acid and maslinic acid protected heart via anti-glycative and anti-coagulatory activities in diabetic mice.
The cardiac protective effects of asiatic acid (AA) and maslinic acid (MA) in diabetic mice were examined. These triterpenoids at 0.1 or 0.2% of the diet were supplied to diabetic mice for 12 weeks. The AA or MA treatments decreased plasma glucose and HbA1c levels, and creatine phosphokinase and lactate dehydrogenase activities in diabetic mice (p < 0.05). AA or MA intake increased the amount deposited in the heart which retained the cardiac glutathione content and reduced the production of reactive oxygen species, N(ε)-(carboxymethyl)-lysine, pentosidine, methylglyoxal, interleukin-6, tumor necrosis factor-alpha and monocyte chemoattractant protein-1 in the hearts of diabetic mice (p < 0.05). AA or MA intake lowered plasma von Willebrand factor and fibrinogen levels, and factor VII activity (p < 0.05), also AA or MA intake maintained circulating antithrombin-III and protein C activities (p < 0.05). AA or MA treatments down-regulated cardiac expression of NADPH oxidase, aldose reductase, nuclear factor kappa B (NF-κB) p65 and p-p38; as well as reserving glyoxalase 1 expression (p < 0.05). These two compounds at only 0.2% lowered cardiac expression of NF-κB p50, p-ERK1/2 and the receptor of the advanced glycation endproduct (p < 0.05). These findings support the conclusion that the supplement of these triterpenoids could protect the heart under diabetic conditions via attenuating glycative injury and coagulatory disorders.


Unilateral vibrissae stimulation during waking induces interhemispheric EEG asymmetry during subsequent sleep in the rat.
To test the theory that sleep is a regional, use-dependent process, rats were subjected to unilateral sensory stimulation during waking. This was achieved by cutting the whiskers on one side, in order to reduce the sensory input to the contralateral cortex. The animals were kept awake for 6 h in an enriched environment to activate the cortex contralateral to the intact side. Whiskers are known to be represented in the barrel field of the contralateral somatosensory cortex and their stimulation during exploratory behavior results in a specific activation of the projection area. In the 6 h recovery period following sleep deprivation, spectral power of the nonrapid eye-movement (NREM) sleep EEG in the 0.75-6.0 Hz range exhibited an interhemispheric shift towards the cortex that was contralateral to the intact whiskers. The results support the theory that sleep has a regional, use-dependent facet.


Learning Analytics in Medical Education Assessment: The Past, the Present, and the Future.
With the implementation of competency-based medical education (CBME) in emergency medicine, residency programs will amass substantial amounts of qualitative and quantitative data about trainees' performances. This increased volume of data will challenge traditional processes for assessing trainees and remediating training deficiencies. At the intersection of trainee performance data and statistical modeling lies the field of medical learning analytics. At a local training program level, learning analytics has the potential to assist program directors and competency committees with interpreting assessment data to inform decision making. On a broader level, learning analytics can be used to explore system questions and identify problems that may impact our educational programs. Scholars outside of health professions education have been exploring the use of learning analytics for years and their theories and applications have the potential to inform our implementation of CBME. The purpose of this review is to characterize the methodologies of learning analytics and explore their potential to guide new forms of assessment within medical education.


Hereditary ectodermal dysplasia: A retrospective study.
Ectodermal dysplasia (ED) is a group of rare, inherited disorders characterized by sparse hair, missing teeth and inability to sweat. To review and analyze cases of ED with an emphasis on clinical manifestations and parent's marriage history. The present retrospective study was conducted by assessing the clinical records of nineteen cases of ED, available in the archives of the department; for age, gender, family history of consanguineous marriage and clinical manifestations. It was observed that ED was more prevalent in males, with a ratio of 1.7:1. The hypohydrotic type was more common (78.95%) than hydrotic type (21.05%). The marriage history of parents revealed that 66.67% had consanguineous marriage and had 68.42% offspring's affected with ED; whereas 33.33% had history of non-consanguineous marriage and had 31.58% offspring's affected with ED. The clinical manifestations observed were- dry skin(94.74%); scaly skin(42.11%); sparse hair on scalp, eyebrows and eyelashes(100%); frontal bossing(63.18%); saddle nose (57.89%); hypertelorism (47.37%); nail abnormality(52.63%); normal sweat glands(21.05%); abnormal sweat glands(78.95%); hypoplastic maxilla(52.63%); protuberant lips (57.89%); palmo-plantar keratosis(21.05%); wrinkled & hyper pigmented facial skin(84.21%); partial anodontia(94.74%); conical shaped teeth(84.21%); high arched palate(68.42%); thin alveolar bone(100.00%); taurodontism(21.05%) and cleft lip & cleft palate(05.26%). The number of teeth present in all the cases ranged from 0 to 19. ED patients suffer from social problems and poor psychological and physiological development as a result of unacceptable esthetics and abnormal function of orofacial structures. Oral rehabilitation thus becomes mandatory, although it is often difficult; particularly in pediatric patients.


Computational modeling of chromosome re-replication in mutant strains of fission yeast.
Typically cells replicate their genome only once per division cycle, but under some circumstances, both natural and unnatural, cells synthesize an overabundance of DNA, either in a disorganized manner ("overreplication") or by a systematic doubling of chromosome number ("endoreplication"). These variations on the theme of DNA replication and division have been studied in strains of fission yeast, Schizosaccharomyces pombe, carrying mutations that interfere with the function of mitotic cyclin-dependent kinase (Cdk1:Cdc13) without impeding the roles of DNA-replication loading factor (Cdc18) and S-phase cyclin-dependent kinase (Cdk1:Cig2). Some of these mutations support endoreplication, and some overreplication. In this paper, we propose a dynamical model of the interactions among the proteins governing DNA replication and cell division in fission yeast. By computational simulations of the mathematical model, we account for the observed phenotypes of these re-replicating mutants, and by theoretical analysis of the dynamical system, we provide insight into the molecular distinctions between overreplicating and endoreplicating cells. In the case of induced overproduction of regulatory proteins, our model predicts that cells first switch from normal mitotic cell cycles to growth-controlled endoreplication, and ultimately to disorganized overreplication, parallel to the slow increase of protein to very high levels.


Molecular analysis of thermoregulation of phaseolotoxin-resistant ornithine carbamoyltransferase (argK) from Pseudomonas syringae pv. phaseolicola.
The phaseolotoxin-resistant ornithine carbamoyltransferase (ROCT) and phaseolotoxin are produced by Pseudomonas syringae pv. phaseolicola at 18 degrees C but not at 28 degrees C. At 28 degrees C, the pathogen produces a protein(s) that binds (in vitro) to a 485-bp fragment (thermoregulatory region, TRR) from a heterologous clone from the pathogen genomic library, which in multiple copies overrides thermoregulation of phaseolotoxin production in wild-type cells (K. B. Rowley, D. E. Clements, M. Mandel, T. Humphreys, and S. S. Patil, Mol. Microbiol. 8:625-635, 1993). We report here that DNase I protection analysis of the 485-bp fragment shows that a single site is protected from cleavage by the protein in the 28 degrees C extract and that this site contains two repeats of a core motif G/C AAAG separated by a 5-bp spacer. Partially purified binding protein forms specific complexes with a synthetic oligonucleotide containing four tandem repeats of this motif. A 492-bp upstream fragment from argK encoding ROCT also forms specific complexes with the protein in the 28 degrees C crude extract, and a 260-bp subfragment from the TRR containing the binding site cross competes with the argk fragment, indicating that the same protein binds to nucleotides in both fragments. DNase I protection analysis of the fragment from argK revealed four separate protected sequence elements, with element III containing half of the core motif sequence (CTTTG), and the other elements containing similar sequences. Gel shift assays were done with DNA fragments from which one or all of the sites were removed as competitor DNAs against the argK probe. The results of these experiments confirmed that the binding sites (in argK) are necessary for the protein to bind to the argK fragment in a specific manner. Taken together, the results of studies presented here suggest that in cells of P. syringae pv. phaseolicola grown at high temperature argK may be negatively regulated by the protein produced at this temperature.


Inactivation of Salmonella and Escherichia coli O157:H7 on lettuce and poultry skin by combinations of levulinic acid and sodium dodecyl sulfate.
Four organic acids (lactic acid, acetic acid, caprylic acid, and levulinic acid) and sodium dodecyl sulfate (SDS) were evaluated individually or in combination for their ability to inactivate Salmonella and Escherichia coli O157:H7. Results from pure culture assays in water with the treatment chemical revealed that 0.5% organic acid and 0.05 to 1% SDS, when used individually, reduced pathogen cell numbers by < or = 2 log CFU/ml within 20 min at 21 degrees C. The combination of any of these organic acids at 0.5% with 0.05% SDS resulted in > 7 log CFU/ml inactivation of Salmonella and E. coli O157:H7 within 10 s at 21 degrees C. A combination of levulinic acid and SDS was evaluated at different concentrations for pathogen reduction on lettuce at 21 degrees C, on poultry (wings and skin) at 8 degrees C, and in water containing chicken feces or feathers at 21 degrees C. Results revealed that treatment of lettuce with a combination of 3% levulinic acid plus 1% SDS for < 20 s reduced both Salmonella and E. coli O157:H7 populations by > 6.7 log CFU/g on lettuce. Salmonella and aerobic bacterial populations on chicken wings were reduced by > 5 log CFU/g by treatment with 3% levulinic acid plus 2% SDS for 1 min. Treating water heavily contaminated with chicken feces with 3% levulinic acid plus 2% SDS reduced Salmonella populations by > 7 log CFU/ml within 20 s. The use of levulinic acid plus SDS as a wash solution may have practical application for killing foodborne enteric pathogens on fresh produce and uncooked poultry.


Solution Conformation of Polymer Brushes Determines Their Interactions with DNA and Transfection Efficiency.
Polymer brush-functionalized nanomaterials offer interesting features for the design of gene delivery vectors as their physicochemical and structural properties can be designed independently of the chemistry, size and shape of the nanomaterial core. However, little is known of the parameters regulating the adsorption and infiltration of DNA molecules at the surface of positively charged polymer brushes, despite the importance of such processes for gene delivery. Here we investigate the role of the molecular environment (e.g., pH, type of buffer, concentration) on the interactions between plasmid DNA and positively charged poly(dimethylaminoethyl methacrylate) (PDMAEMA) brushes using a combination of light scattering, electrophoretic light scattering, in situ ellipsometry, and surface plasmon resonance. We show that the conformation of swollen PDMAEMA brushes is modulated by the surrounding buffer and that this impacts strongly on the ability of such brushes and nanomaterials based on these coatings to complex DNA molecules. In turn, the levels of transfection efficiency measured correlate with changes in brush conformation and DNA binding. Therefore, this work demonstrates the importance of molecular design of polymer brushes to control DNA complexation and release in order to optimize the performance of polymer brush-functionalized nanomaterials for gene delivery applications.


Long-term risk of cardiovascular disease in individuals with latent autoimmune diabetes in adults (UKPDS 85).
Latent autoimmune diabetes in adults (LADA) is diagnosed in up to 12% of adults with clinically diagnosed type 2 diabetes (T2D). LADA tends to have healthier cardiovascular (CV) risk profiles than T2D, but it remains uncertain whether the risk of CV events differs between the two. We examined the risk of CV events in patients enrolled in the United Kingdom Prospective Diabetes Study (UKPDS) according to LADA status. Diabetes autoantibodies (AAb) were measured in 5062 UKPDS participants. The incidence of major adverse CV events (MACE), defined as CV death, non-fatal myocardial infarction or non-fatal stroke, was compared in those with LADA (≥1 AAb test positive) and those without LADA (AAb negative). There were 567 participants (11.2%) with LADA. Compared with participants with T2D, they were younger, with higher mean HbA1c and HDL-cholesterol values, and with lower body mass index and total cholesterol and systolic blood pressure values (all P < 0.01). After a median (25th, 75th percentile) 17.3 (12.6-20.7) years of follow-up, MACE occurred in 157 (17.4 per 1000 person-years) participants with LADA and in 1544 (23.5 per 1000 person-years) participants with T2D (HR, 0.73; 95% confidence interval [CI], 0.62-0.86; P < 0.001). However, after adjustment for confounders, this difference was no longer significant (HRadj , 0.90; 95% CI, 0.76-1.07; P = 0.22). In adults thought to have newly diagnosed T2D, the long-term risk of MACE was lower in those with LADA. However, this did not differ after adjustment for traditional CV risk factors, suggesting that measurement of AAb in addition to traditional CV risk factors will not aid in stratification of CV risk in clinically diagnosed T2D.


Synchronization of mothers and offspring promotes tolerance and limits allergy.
Allergic disorders, characterized by Th2 immune responses to environmental substances, are increasingly common in children in Western societies. Multiple studies indicate that breastfeeding, early complementary introduction of food allergens, and antibiotic avoidance in the first year of life reduces allergic outcomes in at-risk children. Why the benefit of these practices is restricted to early life is largely unknown. We identified a preweaning interval during which dietary antigens are assimilated by the colonic immune system. This interval is under maternal control via temporal changes in breast milk, coincides with an influx of naive T cells into the colon, and is followed by the development of a long-lived population of colonic peripherally derived Tregs (pTregs) that can be specific for dietary antigens encountered during this interval. Desynchronization of mothers and offspring produced durable deficits in these pTregs, impaired tolerance to dietary antigens introduced during and after this preweaning interval, and resulted in spontaneous Th2 responses. These effects could be rescued by pTregs from the periweaning colon or by Tregs generated in vitro using periweaning colonic antigen-presenting cells. These findings demonstrate that mothers and their offspring are synchronized for the development of a balanced immune system.


Exploring the adult life of men and women with fragile X syndrome: results from a national survey.
Using data from a national family survey, the authors describe the adult lives (i.e., residence, employment, level of assistance needed with everyday life, friendships, and leisure activities) of 328 adults with the full mutation of the FMR1 gene and identify characteristics related to independence in these domains. Level of functional skills was the strongest predictor of independence in adult life for men, whereas ability to interact appropriately was the strongest predictor for women. Co-occurring mental health conditions influenced independence in adult life for men and women, in particular, autism spectrum disorders for men and affect problems for women. Services for adults with fragile X syndrome should not only target functional skills but interpersonal skills and co-occurring mental health conditions.


Development of a core capability framework for qualified health professionals to optimise care for people with osteoarthritis: an OARSI initiative.
Develop a generic trans-disciplinary, skills-based capability framework for health professionals providing care for people with OA. e-Delphi survey. An international inter-professional Delphi Panel (researchers; clinicians; consumer representatives) considered a draft framework (adapted from elsewhere) of 131 specific capabilities mapped to 14 broader capability areas across four domains (A: person-centred approaches; B: assessment, investigation and diagnosis; C: management, interventions and prevention; D: service and professional development). Over three rounds, the Panel rated their agreement (Likert or numerical rating scales) on whether each specific capability in Domains B and C was essential (core) for all health professionals when providing care for all people with OA. Those achieving consensus (≥80% of Panel) rating of ≥ seven out of ten (Round 3) were retained. Generic domains (A and D) were included in the final framework and amended based on Panel comments. 173 people from 31 countries, spanning 18 disciplines and including 26 consumer representatives, participated. The final framework comprised 70 specific capabilities across 13 broad areas i) communication; ii) person-centred care; iii) history-taking; iv) physical assessment; v) investigations and diagnosis; vi) interventions and care planning; vii) prevention and lifestyle interventions; viii) self-management and behaviour change; ix) rehabilitative interventions; x) pharmacotherapy; xi) surgical interventions; xii) referrals and collaborative working; and xiii) evidence-based practice and service development). Experts agree that health professionals require an array of skills in person-centred approaches; assessment, investigation and diagnosis; management, interventions and prevention; and service and professional development to provide optimal care for people with OA.


Cdk1 Phosphorylates Drosophila Sas-4 to Recruit Polo to Daughter Centrioles and Convert Them to Centrosomes.
Centrosomes and cilia are organized by a centriole pair comprising an older mother and a younger daughter. Centriole numbers are tightly regulated, and daughter centrioles (which assemble in S phase) cannot themselves duplicate or organize centrosomes until they have passed through mitosis. It is unclear how this mitotic "centriole conversion" is regulated, but it requires Plk1/Polo kinase. Here we show that in flies, Cdk1 phosphorylates the conserved centriole protein Sas-4 during mitosis. This creates a Polo-docking site that helps recruit Polo to daughter centrioles and is required for the subsequent recruitment of Asterless (Asl), a protein essential for centriole duplication and mitotic centrosome assembly. Point mutations in Sas-4 that prevent Cdk1 phosphorylation or Polo docking do not block centriole disengagement during mitosis, but block efficient centriole conversion and lead to embryonic lethality. These observations can explain why daughter centrioles have to pass through mitosis before they can duplicate and organize a centrosome.


Principles of regulatory information conservation between mouse and human.
To broaden our understanding of the evolution of gene regulation mechanisms, we generated occupancy profiles for 34 orthologous transcription factors (TFs) in human-mouse erythroid progenitor, lymphoblast and embryonic stem-cell lines. By combining the genome-wide transcription factor occupancy repertoires, associated epigenetic signals, and co-association patterns, here we deduce several evolutionary principles of gene regulatory features operating since the mouse and human lineages diverged. The genomic distribution profiles, primary binding motifs, chromatin states, and DNA methylation preferences are well conserved for TF-occupied sequences. However, the extent to which orthologous DNA segments are bound by orthologous TFs varies both among TFs and with genomic location: binding at promoters is more highly conserved than binding at distal elements. Notably, occupancy-conserved TF-occupied sequences tend to be pleiotropic; they function in several tissues and also co-associate with many TFs. Single nucleotide variants at sites with potential regulatory functions are enriched in occupancy-conserved TF-occupied sequences.


Methodological assessment of behavioural problem dimensions in adults with dental fear.
In the assessment and treatment of persons with dental fear, there may be other psychological/behavioural factors than fear itself and traditional measures of psychopathology that should be considered. Longitudinal natural history studies are needed to find such variables. The present study investigated whether the same behavioural problem dimensions (internalizing, externalizing, attention) found among children and adolescents with behaviour management problems and/or dental fear could also be found among severely fearful adult patients. The participants were 230 consecutive adult patients applying for treatment for severe dental anxiety at a specialized clinic. Patients completed a version of the Rutter behaviour questionnaire that was adapted for adults. Comparison data were the Hospital Anxiety and Depression scale and self-rated anger evoked by dental fear. Background data, including dental fear, were also collected. Descriptive statistics, principal components analyses, group comparisons and correlations were calculated. Of the three behaviour problems scales we adapted for adults, two (Internalizing and Attention) had acceptable psychometric properties and meaningful relations with the comparison variables. In contrast, the third problem scale (Externalizing) proved to have less satisfactory properties and relations, especially for men. Patients with severe phobia had higher levels of problem behaviours than patients with less severe phobia. Internalizing and Attention scales for adults seem promising for use in future prospective studies of the natural history of dental fear. The Externalizing scale, however, needs to be studied with a wider range of comparison variables and measures of social desirability.


Risk of Cerebrovascular Events in 178 962 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of Age: The TYACSS (Teenage and Young Adult Cancer Survivor Study).
Survivors of teenage and young adult cancer are at risk of cerebrovascular events, but the magnitude of and extent to which this risk varies by cancer type, decade of diagnosis, age at diagnosis, and attained age remains uncertain. This is the largest-ever cohort study to evaluate the risks of hospitalization for a cerebrovascular event among long-term survivors of teenage and young adult cancer. The population-based TYACSS (Teenage and Young Adult Cancer Survivor Study) (N=178,962) was linked to Hospital Episode Statistics data for England to investigate the risks of hospitalization for a cerebrovascular event among 5-year survivors of cancer diagnosed when 15 to 39 years of age. Observed numbers of first hospitalizations for cerebrovascular events were compared with that expected from the general population using standardized hospitalization ratios (SHRs) and absolute excess risks per 10 000 person-years. Cumulative incidence was calculated with death considered a competing risk. Overall, 2782 cancer survivors were hospitalized for a cerebrovascular event-40% higher than expected (SHR=1.4, 95% confidence interval, 1.3-1.4). Survivors of central nervous system (CNS) tumors (SHR=4.6, 95% confidence interval, 4.3-5.0), head and neck tumors (SHR=2.6, 95% confidence interval, 2.2-3.1), and leukemia (SHR=2.5, 95% confidence interval, 1.9-3.1) were at greatest risk. Males had significantly higher absolute excess risks than females (absolute excess risks =7 versus 3), especially among head and neck tumor survivors (absolute excess risks =30 versus 11). By 60 years of age, 9%, 6%, and 5% of CNS tumor, head and neck tumor, and leukemia survivors, respectively, had been hospitalized for a cerebrovascular event. Beyond 60 years of age, every year, 0.4% of CNS tumor survivors were hospitalized for a cerebral infarction (versus 0.1% expected), whereas at any age, every year, 0.2% of head and neck tumor survivors were hospitalized for a cerebral infarction (versus 0.06% expected). Survivors of a CNS tumor, head and neck tumor, and leukemia are particularly at risk of hospitalization for a cerebrovascular event. The excess risk of cerebral infarction among CNS tumor survivors increases with attained age. For head and neck tumor survivors, this excess risk remains high across all ages. These groups of survivors, particularly males, should be considered for surveillance of cerebrovascular risk factors and potential pharmacological interventions for cerebral infarction prevention.


The Challenges in Designing a Prevention Chatbot for Eating Disorders: Observational Study.
Chatbots have the potential to provide cost-effective mental health prevention programs at scale and increase interactivity, ease of use, and accessibility of intervention programs. The development of chatbot prevention for eating disorders (EDs) is still in its infancy. Our aim is to present examples of and solutions to challenges in designing and refining a rule-based prevention chatbot program for EDs, targeted at adult women at risk for developing an ED. Participants were 2409 individuals who at least began to use an EDs prevention chatbot in response to social media advertising. Over 6 months, the research team reviewed up to 52,129 comments from these users to identify inappropriate responses that negatively impacted users' experience and technical glitches. Problems identified by reviewers were then presented to the entire research team, who then generated possible solutions and implemented new responses. The most common problem with the chatbot was a general limitation in understanding and responding appropriately to unanticipated user responses. We developed several workarounds to limit these problems while retaining some interactivity. Rule-based chatbots have the potential to reach large populations at low cost but are limited in understanding and responding appropriately to unanticipated user responses. They can be most effective in providing information and simple conversations. Workarounds can reduce conversation errors.


Memory for child sexual abuse information: simulated memory error and individual differences.
Building on the simulated-amnesia work of Christianson and Bylin (Applied Cognitive Psychology, 13, 495-511, 1999), the present research introduces a new paradigm for the scientific study of memory of childhood sexual abuse information. In Session 1, participants mentally took the part of an abuse victim as they read an account of the sexual assault of a 7-year-old. After reading the narrative, participants were randomly assigned to one of four experimental conditions: They (1) rehearsed the story truthfully (truth group), (2) left out the abuse details of the story (omission group), (3) lied about the abuse details to indicate that no abuse had occurred (commission group), or (4) did not recall the story during Session 1 (no-rehearsal group). One week later, participants returned for Session 2 and were asked to truthfully recall the narrative. The results indicated that, relative to truthful recall, untruthful recall or no rehearsal at Session 1 adversely affected memory performance at Session 2. However, untruthful recall resulted in better memory than did no rehearsal. Moreover, gender, PTSD symptoms, depression, adult attachment, and sexual abuse history significantly predicted memory for the childhood sexual abuse scenario. Implications for theory and application are discussed.


Osteoporosis in patients with inflammatory bowel disease.
Bone mineral content in spinal trabecular and peripheral cortical bone was measured in 75 unselected patients with small and/or large intestinal inflammatory bowel disease. Osteoporosis, defined as a bone mineral content greater than 2 SD below the age and sex matched normal mean value was present in 23 patients (30.6%). Three amenorrhoeic females aged 34, 38, and 42 years had severe clinical osteoporosis and a further three patients had one or more vertebral crush fractures. Eighteen of the 23 patients with osteoporosis had small intestinal disease with one or more resections and the mean lifetime steroid dose in those with osteoporosis was significantly higher than in those with normal bone mineral content. Bone mineral content in spinal trabecular bone showed significant negative correlations with lifetime steroid dose and serum alkaline phosphatase and a significant positive correlation with serum albumin. Peripheral cortical bone mineral content was positively correlated with body weight, height and body mass index. We conclude that the prevalence of osteoporosis is increased in patients with inflammatory bowel disease, severe clinical osteoporosis developing in some relatively young patients. The pathogenesis of this bone loss is probably multifactorial; steroid therapy is likely to be an important contributory factor.


Highlights from the first ecancer-Liga Colombiana contra el Cancer conference, 17-18 November 2016, Bogota, Colombia.
The first oncology conference organised by ecancer and the Liga Colombiana contra el Cancer took place on 17-18 November 2016 in Bogota. It was a highly successful event owing to the number of participants, the quality of the speakers, and the academic programme. Around 48 professors from 8 different countries came and shared their knowledge and experience of cancer management. They also talked about the most recent developments noted or achieved in this area. The keynote speech from Dr Nubia Muñoz was of great interest which was related to the safety of a HPV vaccine and the implications of a mass vaccination programme in developing countries. Geriatric oncology and palliative care were also topics that sparked great interest during the event.


Streamlined 3D Cerebellar Differentiation Protocol with Optional 2D Modification.
Reducing the complexity and cost of differentiation protocols is important for researchers. This interest fits with concerns about possible unintended effects that extrinsic patterning factors might introduce into human pluripotent stem cell (hPSC) models of brain development or pathophysiology, such as masking disease phenotype. Here, we present two cerebellar differentiation protocols for hPSCs, designed with simpler startup method, fewer patterning factors, and less material requirements than previous protocols. Recently, we developed culture procedures, which generate free-floating 3-dimensional (3D) products consistent with other brain "organoid" protocols, including morphologies relevant to modeling brain development such as sub/ventricular zone- and rhombic lip-like structures. The second uses an adherent, 2D monolayer procedure to complete differentiation, which is shown capable of generating functional cerebellar neurons, as products are positive for cerebellar-associated markers, and exhibit neuron-like calcium influxes. Together, these protocols offer scientists a choice of options suited to different research purposes, as well as a basic model for testing other types of streamlined neural differentiations.