Understanding oral spelling: a review and synthesis.
This article reviews a number of studies that report discrepancies between written and oral spelling that cannot easily be explained in terms of deficits to modality-specific output routines. For instance, some patients appear to be 'surface dysgraphic' for oral spelling but 'phonological dysgraphic' for written spelling (e.g. Lesser, 1990). A model is proposed to account for these findings which contains the basic premise that the mappings between phonemes and letter names (in oral spelling) is generally non-arbitrary, whereas the mappings between phonemes and letter shapes (in written spelling) is entirely arbitrary. For example, the phoneme /t/ sounds similar to the oral letter name "Tee" but is arbitrarily related to the written letter 'T' or 't'. An important consequence of this is that oral spelling, in normal spellers, may be more biased by phonological correspondences than written spelling. Other discrepancies between written and oral spelling are reviewed and accommodated within this model, and the model is extended to include recognition of oral spellings and transcoding between spoken and written letter forms.


Manganese superoxide dismutase Ala-9Val polymorphism and risk of breast cancer in a population-based case-control study of African Americans and whites.
A polymorphism in the manganese superoxide dismutase (MnSOD) gene, Ala-9Val, has been examined in association with breast cancer risk in several epidemiologic studies. Results suggest that the Ala allele increases the risk of breast cancer and modifies the effects of environmental exposures that produce oxidative damage to DNA. We examined the role of the MnSOD Ala-9Val polymorphism in a population-based case-control study of invasive and in situ breast cancer in North Carolina. Genotypes were evaluated for 2025 cases (760 African Americans and 1265 whites) and for 1812 controls (677 African Americans and 1135 whites). The odds ratio for MnSOD Ala/Ala versus any MnSOD Val genotypes was not elevated in African Americans (odds ratio = 0.9, 95% confidence interval = 0.7-1.2) or in whites (odds ratio = 1.0, 95% confidence interval = 0.8-1.2). Greater than additive joint effects were observed for the Ala/Ala genotype and smoking, radiation to the chest, and occupational exposure to ionizing radiation. Antagonism was observed between the Ala/Ala genotype and the use of nonsteroidal anti-inflammatory drugs. The MnSOD genotype may contribute to an increased risk of breast cancer in the presence of specific environmental exposures. These results provide further evidence for the importance of reactive oxygen species and of oxidative DNA damage in the etiology of breast cancer.


Deep genome annotation of the opportunistic human pathogen Streptococcus pneumoniae D39.
A precise understanding of the genomic organization into transcriptional units and their regulation is essential for our comprehension of opportunistic human pathogens and how they cause disease. Using single-molecule real-time (PacBio) sequencing we unambiguously determined the genome sequence of Streptococcus pneumoniae strain D39 and revealed several inversions previously undetected by short-read sequencing. Significantly, a chromosomal inversion results in antigenic variation of PhtD, an important surface-exposed virulence factor. We generated a new genome annotation using automated tools, followed by manual curation, reflecting the current knowledge in the field. By combining sequence-driven terminator prediction, deep paired-end transcriptome sequencing and enrichment of primary transcripts by Cappable-Seq, we mapped 1015 transcriptional start sites and 748 termination sites. We show that the pneumococcal transcriptional landscape is complex and includes many secondary, antisense and internal promoters. Using this new genomic map, we identified several new small RNAs (sRNAs), RNA switches (including sixteen previously misidentified as sRNAs), and antisense RNAs. In total, we annotated 89 new protein-encoding genes, 34 sRNAs and 165 pseudogenes, bringing the S. pneumoniae D39 repertoire to 2146 genetic elements. We report operon structures and observed that 9% of operons are leaderless. The genome data are accessible in an online resource called PneumoBrowse (https://veeninglab.com/pneumobrowse) providing one of the most complete inventories of a bacterial genome to date. PneumoBrowse will accelerate pneumococcal research and the development of new prevention and treatment strategies.


Traffic speeds on interstates and freeways 10 years after repeal of national maximum speed limit.
Essentially all published analyses of operational and safety outcomes related to enactment or repeal of the national maximum speed limit (NMSL) were based on data limited to the initial 1-3 years. The purpose of the present study was to collect and analyze longer term speed data. In 2006, traffic speeds were surveyed at 26 locations on urban and rural expressways in five states (California, Montana, Nevada, New Mexico, and Texas) where speeds had been measured in 1996, immediately after repeal of NMSL. Most speed limits were unchanged during the approximately 10-year period. However, Montana introduced a numeric 75 mph limit for passenger vehicles in place of a "reasonable and prudent" limit. In Texas, urban freeway speed limits for passenger vehicles were reduced 5 mph, and truck limits were increased 5 mph. On rural interstates without speed limit changes, travel speeds increased for both passenger vehicles and large trucks; the proportion of passenger vehicles exceeding 80 mph tripled. On rural interstates in Montana where speed limits were lowered for passenger vehicles, travel speeds decreased, even for large trucks whose speed limits had not changed. On urban freeways where speed limits did not change, travel speeds declined somewhat for both passenger vehicles and large trucks; during the study period there also were large increases in traffic volume and development of surrounding areas. On urban freeways in Texas where speed limits declined for passenger vehicles, travel speeds generally decreased, even for large trucks whose speed limits actually had increased. The data suggest that where traffic volumes allow, travel speeds still are increasing 10 years after repeal of NMSL, and many drivers are speeding. The study also shows that speed increases can be curbed and even reversed when speed limits are lowered. Increased enforcement is needed to curb speed increases and the increased risk of serious crashes.


Social class and self-reported health status among men and women: what is the role of work organisation, household material standards and household labour?
Social class understood as social relations of ownership and control over productive assets taps into parts of the social variation in health that are not captured by conventional measures of social stratification. The objectives of this study are to analyse the association between self-reported health status and social class and to examine the role of work organisation, material standards and household labour as potential mediating factors in explaining this association. We used the Barcelona Health Interview Survey, a cross-sectional survey of 10,000 residents of the city's non-institutionalised population in 2000. This was a stratified sample, strata being the 10 districts of the city. The present study was conducted on the working population, aged 16-64 years (2345 men and 1874 women). Social class position was measured with Erik Olin Wright's indicators according to ownership and control over productive assets. The dependent variable was self-reported health status. The independent variables were social class, age, psychosocial and physical working conditions, job insecurity, type of labour contract, number of hours worked per week, possession of appliances at home, as well as household labour (number of hours per week, doing the housework alone and having children, elderly or disabled at home). Several hierarchical logistic regression models were performed by adding different blocks of independent variables. Among men the prevalence of poor reported health was higher among small employers and petit bourgeois, supervisors, semi-skilled (adjusted odds ratio-aOR: 4.92; 95% CI: 1.88-12.88) and unskilled workers (aOR: 7.69; 95%CI: 3.01-19.64). Work organisation and household material standards were associated with poor health status with the exception of number of hours worked per week. Work organisation variables were the main explanatory variables of social class inequalities in health, although material standards also contributed. Among women, only unskilled workers had poorer health status than the referent category of manager and skilled supervisors (aOR: 3.25; 95%CI: 1.37-7.74). All indicators of work organisation and household material standards reached statistical significance, excepting the number of hours worked per week. In contrast to men, among women the number of hours per week of household labour was associated with poor health status (aOR: 1.02; 95% CI: 1.01-1.03). Showing a different pattern from men in the full model, household material deprivation and hours of household labour per week were associated with poor health status among women. Our findings suggest that among men, part of the association between social class positions and poor health can be accounted for psychosocial and physical working conditions and job insecurity. Among women, the association between the worker (non-owner, non-managerial, and un-credentiated) class positions and health is substantially explained by working conditions, material well being at home and amount of household labour.


Reproductive history and mortality later in life: a comparative study of England and Wales and Austria.
Does a woman's reproductive history influence her life span? This study explores the question with data from the contemporary female populations of England and Wales and Austria. It is the first comparative study to investigate the relationship between fertility and mortality late in life. We find similar patterns and age-specific trends of excess mortality in both populations: parity significantly influences longevity, as do both an early and a late birth. These differences in longevity are not explained by differences in educational or family status. The impact of a woman's reproductive history on her life span is small, however, compared to the influence of her level of education or family status.


Electric and magnetic senses in marine animals, and potential behavioral effects of electromagnetic surveys.
Electromagnetic surveys generate electromagnetic fields to map petroleum deposits under the seabed with unknown consequences for marine animals. The electric and magnetic fields induced by electromagnetic surveys can be detected by many marine animals, and the generated fields may potentially affect the behavior of perceptive animals. Animals using magnetic cues for migration or local orientation, especially during a restricted time-window, risk being affected by electromagnetic surveys. In electrosensitive animals, anthropogenic electric fields could disrupt a range of behaviors. The lack of studies on effects of the electromagnetic fields induced by electromagnetic surveys on the behavior of magneto- and electrosensitive animals is a reason for concern. Here, we review the use of electric and magnetic fields among marine animals, present data on survey generated and natural electromagnetic fields, and discuss potential effects of electromagnetic surveys on the behavior of marine animals.


Subsensitivity to cholinoceptor stimulation of the human iris sphincter in situ following acute and chronic administration of cholinomimetic miotic drugs.
1 Maximal pupillary miosis was obtained with single topical applications of 4 cholinomimetic drugs in therapeutic concentrations to normal human subjects. 2 When the pupil had recovered from the miosis, there remained a reduced light reflex response of 22.7% at 24 h after aceclidine, 18.0% at 31 h after pilocarpine, 10.3% at 48 h after physostigmine and 4.9% at 7 h after arecoline. 3 This reduced sensitivity to light was accompanied by an overshoot of the resting pupil diameter and, after aceclidine miosis, a reduced response to a second application of miotic. 4 Similar findings were observed in glaucoma patients following withdrawal of chronic pilocarpine therapy. 5 It is suggested that the slowly reversible after-effects of acute and chronic administration of cholinomimetic miotics can be explained by desensitization of iris sphincter cholinoceptors.


Multifunctional Polymeric Micelles Co-loaded with Anti-Survivin siRNA and Paclitaxel Overcome Drug Resistance in an Animal Model of Ovarian Cancer.
Ovarian cancer is a dreadful disease estimated to be the second most common gynecologic malignancy worldwide. Its current therapy, based on cytoreductive surgery followed by the combination of platinum and taxanes, is frequently complicated by the onset of multidrug resistance (MDR). The discovery that survivin, a small antiapoptotic protein, is involved in chemoresistance provided a new prospect to overcome MDR in cancer, because siRNA could be used to inhibit the expression of survivin in cancer cells. With this in mind, we have developed self-assembly polymeric micelles (PM) able to efficiently co-load an anti-survivin siRNA and a chemotherapeutic agent, such as paclitaxel (PXL; survivin siRNA/PXL PM). Previously, we have successfully demonstrated that the downregulation of survivin by using siRNA-containing PM strongly sensitizes different cancer cells to paclitaxel. Here, we have evaluated the applicability of the developed multifunctional PM in vivo. Changes in survivin expression, therapeutic efficacy, and biologic effects of the nanopreparation were investigated in an animal model of paclitaxel-resistant ovarian cancer. The results obtained in mice xenografed with SKOV3-tr revealed a significant downregulation of survivin expression in tumor tissues together with a potent anticancer activity of survivin siRNA/PXL PM, while the tumors remained unaffected with the same quantity of free paclitaxel. These promising results introduce a novel type of nontoxic and easy-to-obtain nanodevice for the combined therapy of siRNA and anticancer agents in the treatment of chemoresistant tumors.


Continuous T cell receptor signals maintain a functional regulatory T cell pool.
Regulatory T (Treg) cells maintain immune homeostasis and prevent inflammatory and autoimmune responses. During development, thymocytes bearing a moderately self-reactive T cell receptor (TCR) can be selected to become Treg cells. Several observations suggest that also in the periphery mature Treg cells continuously receive self-reactive TCR signals. However, the importance of this inherent autoreactivity for Treg cell biology remains poorly defined. To address this open question, we genetically ablated the TCR of mature Treg cells in vivo. These experiments revealed that TCR-induced Treg lineage-defining Foxp3 expression and gene hypomethylation were uncoupled from TCR input in mature Treg cells. However, Treg cell homeostasis, cell-type-specific gene expression and suppressive function critically depend on continuous triggering of their TCR.


Protein structure prediction on the Web: a case study using the Phyre server.
Determining the structure and function of a novel protein is a cornerstone of many aspects of modern biology. Over the past decades, a number of computational tools for structure prediction have been developed. It is critical that the biological community is aware of such tools and is able to interpret their results in an informed way. This protocol provides a guide to interpreting the output of structure prediction servers in general and one such tool in particular, the protein homology/analogy recognition engine (Phyre). New profile-profile matching algorithms have improved structure prediction considerably in recent years. Although the performance of Phyre is typical of many structure prediction systems using such algorithms, all these systems can reliably detect up to twice as many remote homologies as standard sequence-profile searching. Phyre is widely used by the biological community, with >150 submissions per day, and provides a simple interface to results. Phyre takes 30 min to predict the structure of a 250-residue protein.


Domestic Violence as a Risk Factor for Postpartum Depression Among Ethiopian Women: Facility Based Study.
Mental illness in women leads to an increased maternal morbidity and mortality. Postpartum depression accommodates various groups of depressive disorders and syndromes that occur within the first immediate year after delivery. Thus, this study aimed to assess the prevalence of postpartum depression symptoms and correlates among mothers attending public health centers of Addis Ababa, Ethiopia. Facility-based cross-sectional study was conducted on 618 women in their postpartum period. Simple random sampling technique was used to select three out of ten sub cities in Addis Ababa. Then, nine health centers were selected by lottery method from the three sub-cities. The number of women included from each health center was determined by proportional allocation. Study participants were enrolled by systematic random sampling. The Edinburgh Postnatal Depression Scale was used at a cutoff point >13 to detect depression. Descriptive statistics were done. The bivariate and multivariate analysis was also carried out to identify predictors of postpartum depression. Significant proportion 144 (23.3%) of the women had the symptom of postpartum depression. Respondents who were the victims of domestic violence [AOR 3.1; 95% CI: 1.6-5.9], reported to have diagnosed with postpartum depression [AOR 4.41; 95% CI: 2.4-8.3], and dissatisfied with their marriage [AOR 2.9; 95% CI: 1.5-5.6] had higher odds of reporting postpartum depression symptoms. Postpartum depression is a common mental health problem during the postnatal period. Domestic violence was positively and significantly associated with the symptom of postpartum depression. Maternity services shall consider a sector that provides health care for women who encounter violence and develop symptoms of postpartum depression.


The "Ice-Mile": Case Study of 2 Swimmers' Selected Physiological Responses and Performance.
"Ice-mile" swimming presents significant physiological challenges and potential safety issues, but few data are available. This study examined deep body temperature (BT), respiratory rate (RR), and swim performance in 2 swimmers completing an ice-mile swim of 1 mile (1600 m) in water less than 5°C. Two male cold-water-habituated swimmers completed a 1-mile lake swim in 3.9°C water. For comparative purposes, they completed an indoor 1-mile swim in 28.1°C water. The Equivital physiological monitoring system was used to record BT and RR before, during, and after each swim. Total time to complete the swims and 400-m splits were recorded. One swimmer became hypothermic after 27 min while swimming, reaching BT of 33.7°C at swim's end. On exiting the water the swimmers experienced large BT after-drops of -3.6°C and -2.4°C, reaching low points of 33.2°C and 31.3°C 38 and 23 min postswim, respectively. Respiratory rate and swim pace decreased over the course of the ice-mile swim for both swimmers. Swim pace for 1 swimmer declined sharply in the final 400-m lap of the ice mile when he was hypothermic. Both swimmers remained hypothermic 60 min postswim (34.2°C and 33.4°C). Ice-mile swimmers may become hypothermic while swimming, and the postswim BT after drop may expose them to dangerous levels of hypothermia. Pace and RR should be monitored as proxies for a swimmer's physiological state. Postswim recovery should also be monitored for hypothermia for at least 1 h.


Effectiveness of all-in-one adhesive systems tested by thermocycling following short and long-term water storage.
To evaluate and compare the marginal integrity of in vitro Class V restorations made with all-in-one adhesive systems by thermocycling after different periods of water storage, to provide an analysis of static and quasi-dynamic deterioration in water. Standardized Class V cavities (17 groups, 8 specimens each) were prepared in extracted human caries-free anterior teeth. The cavities were filled using 14 all-in-one adhesive systems/composite resin combinations in addition to the multi-bottle adhesive systems Syntac and OptiBond FL (etch-and-rinse technique) and Clearfil SE Bond (self-etching) as controls. The samples were thermocycled after water storage for 21 days, after 1 year and again after 3 years (2000 cycles between 5 and 55 degrees C) and replicas were made before and after each thermocycling treatment (TC) for quantitative marginal analysis in the SEM. In dentin, marginal adaptation showed no significant differences between all groups after the first TC. After one year of water storage and a second TC, the results for Prompt L-Pop (1999), Adper Prompt L-Pop/Tetric Ceram, and One-up Bond F Plus showed a statistically significant decrease of margin quality 1 (MQ1) score compared to the reference groups. When the all-in-one adhesives G-Bond, AQ-Bond, Hybrid Bond, and One-up Bond F Plus were used, the enamel margins of restorations showed lower percentages of "continuous margins" (p < 0.05) after 1 year of water storage and TC. Of the materials tested after 3 years of water storage and TC, only AQ Bond had a significantly lower MQ1 score. While all materials exhibited deterioration in the MQ1 quality score, the rate of deterioration varied, and the results show that different materials have different deterioration rates after initial vs long-term water storage. The deterioration along margins in dentin was not as extensive as predicted from other studies; however, the results from the enamel margins show that one-bottle all-in-one adhesives seem to be significantly affected by water storage. The results of this study suggest that the all-in-one adhesive group members perform very differently from each other: thus, data need to be explored further at the level of each different adhesive product.


Conical diffraction of linearly polarised light controls the angular position of a microscopic object.
Conical diffraction of linearly polarised light in a biaxial crystal produces a beam with a crescent-shaped intensity profile. Rotation of the plane of polarisation produces the unique effect of spatially moving the crescent-shaped beam around a ring. We use this effect to trap microspheres and white blood cells and to position them at any angular position on the ring. Continuous motion around the circle is also demonstrated. This crescent beam does not require an interferometeric arrangement to form it, nor does it carry optical angular momentum. The ability to spatially locate a beam and an associated trapped object simply by varying the polarisation of light suggests that this optical process should find application in the manipulation and actuation of micro- and nano-scale physical and biological objects.


Glucose significantly enhances enterotoxigenic Escherichia coli adherence to intestinal epithelial cells through its effects on heat-labile enterotoxin production.
The present study tested whether exposure of enterotoxigenic Escherichia coli (ETEC) to glucose at different concentrations in the media results in increased bacterial adherence to host cells through increased heat-labile enterotoxin (LT) production, thereby suggesting the effects are physiological. Porcine-origin ETEC strains grown in Casamino acid yeast extract medium containing different concentrations of glucose were washed and inoculated onto IPEC-J2 porcine intestinal epithelial cells to test for effects on adherence and host cell cAMP concentrations. Consistent with previous studies, all LT+ strains had higher ETEC adherence to IPEC-J2 cells than did LT- strains. Adherence of the LT- but not the LT+ strains was increased by pre-incubating the IPEC-J2 cells with LT and decreased by co-incubation with GM1 ganglioside in a dose-dependent manner (P<0.05). To determine whether the glucose concentration of the cell culture media has an effect on adherence, IPEC-J2 cells were inoculated with LT+ or LT- strains in cell culture media containing a final glucose concentration of 0, 0.25, 0.5, 1.0 or 2.0%, and incubated for 4 h. Only media containing 0.25% glucose resulted in increased adherence and cAMP levels, and this was limited to IPEC-J2 cells inoculated with LT+ strains. This study supports the hypothesis that glucose, at a concentration optimal for LT expression, enhances bacterial adherence through the promotion of LT production. Hence, these results establish the physiological relevance of the effects of glucose on LT production and provide a basis for how glucose intake may influence the severity of ETEC infection.


A multidimensional integrative medicine intervention to improve cardiovascular risk.
Integrative medicine is an individualized, patient-centered approach to health, combining a whole-person model with evidence-based medicine. Interventions based in integrative medicine theory have not been tested as cardiovascular risk-reduction strategies. Our objective was to determine whether personalized health planning (PHP), an intervention based on the theories and principles underlying integrative medicine, reduces 10-year risk of coronary heart disease (CHD). We conducted a randomized, controlled trial among 154 outpatients age 45 or over, with 1 or more known cardiovascular risk factors. Subjects were enrolled from primary care practices near an academic medical center, and the intervention was delivered at a university Center for Integrative Medicine. Following a health risk assessment, each subject in the intervention arm worked with a health coach and a medical provider to construct a personalized health plan. The plan identified specific health behaviors important for each subject to modify; the choice of behaviors was driven both by cardiovascular risk reduction and the interests of each individual subject. The coach then assisted each subject in implementing her/his health plan. Techniques used in implementation included mindfulness meditation, relaxation training, stress management, motivational techniques, and health education and coaching. Subjects randomized to the comparison group received usual care (UC) without access to the intervention. Our primary outcome measure was 10-year risk of CHD, as measured by a standard Framingham risk score, and assessed at baseline, 5, and 10 months. Differences between arms were assessed by linear mixed effects modeling, with time and study arm as independent variables. Baseline 10-year risk of CHD was 11.1% for subjects randomized to UC (n=77), and 9.3% for subjects randomized to PHP (n=77). Over 10 months of the intervention, CHD risk decreased to 9.8% for UC subjects and 7.8% for intervention subjects. Based on a linear mixed-effects model, there was a statistically significant difference in the rate of risk improvement between the 2 arms (P=.04). In secondary analyses, subjects in the PHP arm were found to have increased days of exercise per week compared with UC (3.7 vs 2.4, P=.002), and subjects who were overweight on entry into the study had greater weight loss in the PHP arm compared with UC (P=.06). A multidimensional intervention based on integrative medicine principles reduced risk of CHD, possibly by increasing exercise and improving weight loss.


Cytochrome P450-mediated hepatic metabolism of new fluorescent substrates in cats and dogs.
This study aimed to investigate the biotransformation of cat liver microsomes in comparison to dogs and humans using a high throughput method with fluorescent substrates and classical inhibitors specific for certain isozymes of the human cytochrome P450 (CYP) enzyme family. The metabolic activities associated with CYP1A, CYP2B, CYP2C, CYP2D, CYP2E and CYP3A were measured. Cat liver microsomes metabolized all substrates selected for the assessment of cytochrome P450 activity. The activities associated with CYP3A and CYP2B were higher than the activities of the other measured CYPs. Substrate selectivity could be demonstrated by inhibition studies with α-naphthoflavone (CYP1A), tranylcypromine/quercetine (CYP2C), quinidine (CYP2D), diethyldithiocarbamic acid (CYP2E) and ketoconazole (CYP3A) respectively. Other prototypical inhibitors used for characterization of human CYP activities such as furafylline (CYP1A), tranylcypromine (CYP2B) and sulfaphenazole (CYP2C) did not show significant effects in cat and dog liver microsomes. Moreover, IC50-values of cat CYPs differed from dog and human CYPs underlining the interspecies differences. Gender differences were observed in the oxidation of 7-ethoxy-4-trifluoromethylcoumarin (CYP2B) and 3-[2-(N, N-diethyl-N-methylamino)ethyl]-7-methoxy-4-methylcoumarin (CYP2D), which were significantly higher in male cats than in females. Conversely, oxidation of the substrates dibenzylfluorescein (CYP2C) and 7-methoxy-4-trifluoromethylcoumarin (CYP2E) showed significant higher activities in females than in male cats. Overall CYP-activities in cat liver microsomes were lower than in those from dogs or humans, except for CYP2B. The presented difference between feline and canine CYP-activities are useful to establish dose corrections for feline patients of intensively metabolized drugs licensed for dogs or humans.


Integration of Visual and Joint Information to Enable Linear Reaching Motions.
A new dynamics-driven control law was developed for a robot arm, based on the feedback control law which uses the linear transformation directly from work space to joint space. This was validated using a simulation of a two-joint planar robot arm and an optimisation algorithm was used to find the optimum matrix to generate straight trajectories of the end-effector in the work space. We found that this linear matrix can be decomposed into the rotation matrix representing the orientation of the goal direction and the joint relation matrix (MJRM) representing the joint response to errors in the Cartesian work space. The decomposition of the linear matrix indicates the separation of path planning in terms of the direction of the reaching motion and the synergies of joint coordination. Once the MJRM is numerically obtained, the feedfoward planning of reaching direction allows us to provide asymptotically stable, linear trajectories in the entire work space through rotational transformation, completely avoiding the use of inverse kinematics. Our dynamics-driven control law suggests an interesting framework for interpreting human reaching motion control alternative to the dominant inverse method based explanations, avoiding expensive computation of the inverse kinematics and the point-to-point control along the desired trajectories.


A compact and accurate semi-global potential energy surface for malonaldehyde from constrained least squares regression.
We present a new approach to semi-global potential energy surface fitting that uses the least absolute shrinkage and selection operator (LASSO) constrained least squares procedure to exploit an extremely flexible form for the potential function, while at the same time controlling the risk of overfitting and avoiding the introduction of unphysical features such as divergences or high-frequency oscillations. Drawing from a massively redundant set of overlapping distributed multi-dimensional Gaussian functions of inter-atomic separations we build a compact full-dimensional surface for malonaldehyde, fit to explicitly correlated coupled cluster CCSD(T)(F12*) energies with a root mean square deviations accuracy of 0.3%-0.5% up to 25,000 cm(-1) above equilibrium. Importance-sampled diffusion Monte Carlo calculations predict zero point energies for malonaldehyde and its deuterated isotopologue of 14 715.4(2) and 13 997.9(2) cm(-1) and hydrogen transfer tunnelling splittings of 21.0(4) and 3.2(4) cm(-1), respectively, which are in excellent agreement with the experimental values of 21.583 and 2.915(4) cm(-1).


Dynamics of naive and memory CD4+ T lymphocytes in HIV-1 disease progression.
Understanding the dynamics of naive and memory CD4+ T cells in the immune response to HIV-1 infection can help elucidate typical disease progression patterns observed in HIV-1 patients. Although infection markers such as CD4+ T-cell count and viral load are monitored in patient blood, the lymphatic tissues (LT) have been shown to be an important viral reservoir. Here, we introduce the first comprehensive theoretical model of disease progression based on T-cell subsets and virus circulating between the two compartments of LT and blood. We use this model to predict several trademarks observed in adult HIV-1 disease progression such as the establishment of a setpoint in the asymptomatic stage. Our model predicts that both host and viral elements play a role in determining different disease progression patterns. Viral factors include viral infectivity and production rates, whereas host factors include elements of specific immunity. We also predict the effect of highly active antiretroviral therapy and treatment cessation on cellular and viral dynamics in both blood and LT.


Anti-inflammatory mechanism of polyunsaturated fatty acids in Helicobacter pylori-infected gastric epithelial cells.
Helicobacter pylori is an important risk factor for gastric inflammation, which is mediated by multiple signaling pathways. The aim of this study was to investigate the effects of polyunsaturated fatty acids (PUFAs), such as linoleic acid (LA), alpha-linolenic acid (ALA), and docosahexaenoic acid (DHA), on the expression of the proinflammatory chemokine interleukin-8 (IL-8) in H. pylori-infected gastric epithelial AGS cells. To investigate whether PUFAs modulate H. pylori-induced inflammatory signaling, we determined the activation of epidermal growth factor receptor (EGFR), protein kinase C-δ (PKC δ), mitogen-activated protein kinases (MAPKs), nuclear factor-kappa B (NF- κB), and activator protein-1 (AP-1) as well as IL-8 expression in H. pylori-infected gastric epithelial cells that had been treated with or without PUFAs. We found that PUFAs inhibited IL-8 mRNA and protein expression in H. pylori-infected cells. ω-3 fatty acids (ALA, and DHA) suppressed the activation of EGFR, PKC δ, MAPK, NF- κB, and AP-1 in these infected cells. LA did not prevent EGFR transactivation and exhibited a less potent inhibitory effect on IL-8 expression than did ALA and DHA. In conclusion, PUFAs may be beneficial for prevention of H. pylori-associated gastric inflammation by inhibiting proinflammatory IL-8 expression.


Controlled study of psychiatric comorbidity in psychiatrically hospitalized young adults with substance use disorders.
The purpose of this study was to examine DSM-III-R axis I and axis II comorbidity in psychiatrically hospitalized young adults with substance use disorders. Structured diagnostic interviews were given to 117 consecutive inpatients. Seventy patients with substance use disorders and 47 patients without substance use disorders were compared. High rates of co-occurrence of axis I disorders were observed, but no disorder coexisted in the group with substance use disorders at a significantly higher rate than in the group without substance use disorders. Among axis II disorders, borderline personality disorder was diagnosed significantly more frequently in the group with substance use disorders. Significant additional diagnostic co-occurrence, defined as comorbidity, was observed only between borderline personality disorder and substance use disorders. The use of a relevant psychiatric comparison group allows for finer distinctions between covariation based on shared severity and comorbidity possibly based on shared pathophysiology.


A role for Cdc48/p97 and Aurora B in controlling chromatin condensation during exit from mitosis.
During cell division, chromosomes condense so that the replicated chromatids can be segregated by the mitotic spindle. While condensation is governed by cyclin-dependent kinase 1 (Cdk1) during mitotic entry and early mitosis, it is still poorly understood how condensation is maintained during anaphase after Cdk1 inactivation, and how decondensation is triggered in telophase. Here, we review recent reports that point to a novel role of Aurora B kinase in maintaining condensation and preventing premature nuclear envelope formation during exit from mitosis. Timely decondensation and nuclear envelope formation at the end of mitosis may then be triggered by two mechanisms. One is removing Aurora B phosphorylation marks from chromatin by specific phosphatases. The other is removing and inactivating Aurora B kinase itself by the ubiquitin system. We have recently provided evidence that the AAA ATPase Cdc48/p97 plays a central role in the inactivation of Aurora B, as it extracts ubiquitinated Aurora B from chromosomes and thus reduces chromatinassociated Aurora B activity.


Adolescent perspectives about their participation in alcohol intervention research in emergency care: A qualitative exploration using ethical principles as an analytical framework.
To explore adolescents' experiences of consenting to, and participating in, alcohol intervention trials when attending for emergency care. In-depth semi-structured interviews with 27 adolescents (16 males; aged 14-17 years (Mage = 15.7)) who had taken part in one of two linked brief alcohol intervention trials based in 10 accident and emergency departments in England. Interviews were transcribed verbatim and subject to thematic analysis. Research and intervention methods were generally found to be acceptable though confidentiality was important and parental presence could hinder truthful disclosures regarding alcohol use. Participants discussed the importance of being involved in research that was relevant to them and recognised alcohol consumption as a normative part of adolescence, highlighting the importance of having access to appropriate health information. Beyond this, they recognised the benefits and risks of trial participation for themselves and others with the majority showing a degree of altruism in considering longer term implications for others as well as themselves. Alcohol screening and intervention in emergency care is both acceptable and relevant to adolescents but acceptability is reliant on confidentiality being assured and may be inhibited by parental presence. ISRCTN Number: 45300218.


The responsiveness of the Liverpool Oral Rehabilitation Questionnaire (LORQ): a pilot study.
This study aimed to evaluate the responsiveness of denture patients to the Liverpool Oral Rehabilitation Questionnaire (LORQ). Changes in scores for 20 core items completed from 2000 to 2005 by 16 patients both before and after oral rehabilitation were assessed. The median age of respondents was 68 years and the median time between questionnaires was 2.6 years. Results indicated that masticatory efficiency impacted both food choice (P = .03) and social life (P = .06). After rehabilitation there was less worry about maxillary prostheses falling out (P = .07), less embarrassment while conversing (P = .02), and less worry about losing self-confidence from embarrassment caused by dentures (P = .06). Also, drooling problems deteriorated (P = .03). This exploratory study reports encouraging findings, but a larger prospective multicenter study is required to determine the responsiveness of the current version of the LORQ (version 3).


Investigation of the prevalence of bovine tuberculosis and risk factors for human infection with bovine tuberculosis among dairy and non-dairy farming neighbour households in Dagoretti Division, Nairobi, Kenya.
To determine the prevalence of bovine tuberculosis in urban dairy cattle and examine possible risk factors for human infection with bovine tuberculosis (BTB). Cross sectional study. Urban and peri-urban dairy and non-dairy farming neighbour households. One hundred forty three dairy cattle and 299 and 149 dairy and non-dairy neighbour households respectively. Ten percent of the animals (15/143) were found to be reactors to the tuberculin test. The majority of the respondents 57% (168/295) and 72% (106/147) in dairy farming and non-farming households respectively, had limited knowledge of the disease in cattle thus making them unable to adopt any precautionary measures to protect themselves from contracting bovine tuberculosis. Distance from the main house and cattle shed, the time spent attending to the cattle, (on average 4.8 hours), and making of traditionally fermented milk were considered to be the major risk factors. Due to the presumed high background prevalence of human tuberculosis, the specificity of the test employed was unknown. Therefore no definite estimate of the prevalence of BTB was made. It is therefore necessary for further investigation involving culture, isolation and molecular typing from reactors to establish the prevalence of M. bovis in this setting.


Age-related somatic mutations in the cancer genome.
Aging is associated with an increased risk of cancer, possibly in part because of an age-related increase in mutations in normal tissues. Due to their extremely low abundance, somatic mutations in normal tissues frequently escape detection. Tumors, as clonal expansions of single cells, can provide information about the somatic mutations present in these cells prior to tumorigenesis. Here, we used data from The Cancer Genome Atlas (TCGA), to systematically study the frequency and spectrum of somatic mutations in a total of 6,969 patients and 34 different tumor types as a function of the age of the patient. After using linear modeling to control for the age structure of different tumor types, we found that the number of identified somatic mutations increases exponentially with age. Using additional data from the literature, we found that accumulation of somatic mutations is associated with cell division rate, cancer risk and cigarette smoking, with the latter also associated with a distinct spectrum of mutations. Our results confirm that aging is associated with the accumulation of somatic mutations, and strongly suggest that the level of genome instability of normal cells, modified by both endogenous and environmental factors, is the main risk factor for cancer.


The carnivorous bladderwort (Utricularia, Lentibulariaceae): a system inflates.
Carnivorous plants inhabit nutrient-poor environments, where prominent targets of prey capture are organic nitrogen and phosphorus. Some carnivorous plants also acquire carbon from their victims. A new report focusing on Utricularia, the bladderwort, demonstrates that carbon assimilated from photosynthesis is paradoxically secreted into the trapping environment, where it may help to support a mutualistic bacterial community. This bacterial community may also secrete allelochemicals that attract microcrustaceans which bear a strong overt resemblance to bladderwort traps. Furthermore, Utricularia and its sister genus Genlisea share anomalous molecular evolutionary features, such as highly increased rates of nucleotide substitution and dynamic evolution of genome size, from approximately 60-1500 megabases depending on the species or even population. A mechanistic hypothesis, based on the mutagenic action of reactive oxygen species (ROS) is proposed to underlie these phenomena, involving error-prone repair at the level of DNA bases and double-strand breaks. It is argued that these plants are prime candidates for further research on the complexities of plant physiology associated with carnivory, metagenomic surveys of trap microbial communities, novel plant nitrogen/nutrient utilization pathways, the ecology of prey attraction, whole-plant and trap comparative development, and, finally, evolution of the minimal angiosperm genome.


Outcomes Among Patients Transferred for Revascularization With Impella for Acute Myocardial Infarction With Cardiogenic Shock from the cVAD Registry.
The outcomes for patients transferred with cardiogenic shock and later treated with revascularization and Impella support have not previously been studied. To evaluate these outcomes, patients in cardiogenic shock were recruited from the catheter-based ventricular assist device registry, a prospective registry enrolling patients who underwent percutaneous coronary intervention with hemodynamic support using Impella 2.5 or CP. Analysis was performed on subgroups of patients who were characterized as those directly admitted to a tertiary care hospital (direct), or those transferred from an outside hospital (transfer). Patients who were transferred with acute myocardial infarction with cardiogenic shock (AMICS) more often presented in shock were in shock longer than 24 hours, and were more likely to be on intra-aortic balloon pump but were less likely to sustain cardiac arrest. The number of pressors, EF, diseased, and treated vessels were similar between the 2 groups. Despite baseline differences, the mortality was similar in the transfer versus direct patients (47.0% vs 53.5% p = 0.19). In a multivariate model, the factors independently associated with 30-day mortality in AMICS treated with revascularization and Impella support were cardiopulmonary resuscitation (CPR) (p <0.01), age (p <0.01), and ST-segment elevation myocardial infarction (STEMI) (p = 0.02). Whether the patient was transferred or directly admittedly with AMICS was not an independent predictor of death. In conclusion, these findings suggest that considerations should be given to transfer patients with AMICS to allow them to be treated in a contemporary manner.


Bows and arrows and complex symbolic displays 48,000 years ago in the South Asian tropics.
Archaeologists contend that it was our aptitude for symbolic, technological, and social behaviors that was central to Homo sapiens rapidly expanding across the majority of Earth's continents during the Late Pleistocene. This expansion included movement into extreme environments and appears to have resulted in the displacement of numerous archaic human populations across the Old World. Tropical rainforests are thought to have been particularly challenging and, until recently, impenetrable by early H. sapiens. Here, we describe evidence for bow-and-arrow hunting toolkits alongside a complex symbolic repertoire from 48,000 years before present at the Sri Lankan site of Fa-Hien Lena-the earliest bow-and-arrow technology outside of Africa. As one of the oldest H. sapiens rainforest sites outside of Africa, this exceptional assemblage provides the first detailed insights into how our species met the extreme adaptive challenges that were encountered in Asia during global expansion.


Incidence, clinical spectrum, risk factors and impact of HIV-associated immune reconstitution inflammatory syndrome in South Africa.
Immune reconstitution inflammatory syndrome (IRIS) is a widely recognised complication of antiretroviral therapy (ART), but there are still limited data from resource-limited settings. Our objective was to characterize the incidence, clinical spectrum, risk factors and contribution to mortality of IRIS in two urban ART clinics in South Africa. 498 adults initiating ART in Durban, South Africa were followed prospectively for 24 weeks. IRIS diagnosis was based on consensus expert opinion, and classified by mode of presentation (paradoxical worsening of known opportunistic infection [OI] or unmasking of subclinical disease). 114 patients (22.9%) developed IRIS (36% paradoxical, 64% unmasking). Mucocutaneous conditions accounted for 68% of IRIS events, mainly folliculitis, warts, genital ulcers and herpes zoster. Tuberculosis (TB) accounted for 25% of IRIS events. 18/135 (13.3%) patients with major pre-ART OIs (e.g. TB, cryptococcosis) developed paradoxical IRIS related to the same OI. Risk factors for this type of IRIS were baseline viral load >5.5 vs. <4.5 log(10) (adjusted hazard ratio 7.23; 95% confidence interval 1.35-38.76) and ≤30 vs. >30 days of OI treatment prior to ART (2.66; 1.16-6.09). Unmasking IRIS related to major OIs occurred in 25/498 patients (5.0%), and risk factors for this type of IRIS were baseline C-reactive protein ≥25 vs. <25 mg/L (2.77; 1.31-5.85), haemoglobin <10 vs. >12 g/dL (3.36; 1.32-8.52), ≥10% vs. <10% weight loss prior to ART (2.31; 1.05-5.11) and mediastinal lymphadenopathy on pre-ART chest x-ray (9.15; 4.10-20.42). IRIS accounted for 6/25 (24%) deaths, 13/65 (20%) hospitalizations and 10/35 (29%) ART interruptions or discontinuations. IRIS occurred in almost one quarter of patients initiating ART, and accounted for one quarter of deaths in the first 6 months. Priority strategies to reduce IRIS-associated morbidity and mortality in ART programmes include earlier ART initiation before onset of advanced immunodeficiency, improved pre-ART screening for TB and cryptococcal infection, optimization of OI therapy prior to ART initiation, more intensive clinical monitoring in initial weeks of ART, and education of health care workers and patients about IRIS.


Oral health status and access to oral health care for U.S. adults aged 18-64: National Health Interview Survey, 2008.
This report presents statistics from the 2008 National Health Interview Survey (NHIS) on selected measures of oral health status and oral health care access for adults aged 18-64. Estimates are presented by sex, age, race and ethnicity, nativity, education, poverty status, health and dental insurance status, region, place of residence, dentition status, current smoking status, current drinking status, and diabetes status. NHIS is a multistage probability sample survey conducted annually by interviewers of the U.S. Census Bureau for the Centers for Disease Control and Prevention's National Center for Health Statistics, and is representative of the civilian noninstitutionalized population of the United States. Data are collected for all family members during face-to-face interviews with adults present at the time of interview. Additional health information is obtained from one randomly selected adult. If the selected adult is physically or mentally incapable of responding for himself or herself, a proxy respondent is used. Among adults aged 18-64, about three-quarters had very good or good oral health, 17% had fair oral health, and 7% had poor oral health. Adults with Medicaid were almost five times as likely as adults with private health insurance to have poor oral health. Adults with Medicaid (21%) were almost twice as likely as adults overall (12%) to not have had a dental visit in more than 5 years. Among adults aged 18-64, the main reason to forgo a dental visit for an oral health problem in the past 6 months was cost; 42% could not afford treatment or did not have insurance. Fear was the reason that 1 out of 10 adults did not visit the dentist for an oral health problem.


Measurement of 13C enrichment of plasma lactate by gas chromatography/isotope ratio mass spectrometry.
An application of a gas chromatography/isotope ratio mass spectrometry (GC/IRMS) method for stable carbon isotope analysis of blood plasma lactic acid is presented. The method involves a simple extraction procedure followed by derivatization with diazomethane. It is shown that derivatization is by single methylation, thus minimizing the dilution of the derivative's 13C content, yet still ensuring good chromatographic behaviour on a polar capillary column. This ensures a high sensitivity of the isotopic analysis. Repeatability, expressed by the coefficient of variation, varied from 0.3% to 19%, depending on sample enrichment. Reproducibility was 2.3% over a 10 day period. The detection limit, defined as 2SD, was about 0.0004 atom % excess (APE), equivalent to 0.001 mol % excess, when based on a measured precision of about 0.2/1000 in delta notation. A comparison is made between enrichments obtained using a calibration curve and those obtained using a correction for the added methyl carbon. The two methods agreed well, with a relative difference (delta APE/APE x 100%) of less than 0.5% for samples enriched with between 0.004 and 1.28 APE. It is concluded that the method provides simple and precise isotope analysis of picomole quantities of blood lactate.


Genetic variation for maize root architecture in response to drought stress at the seedling stage.
Although the root system is indispensable for absorption of nutrients and water, it is poorly studied in maize owing to the difficulties of direct measurement of roots. Here, 103 maize lines were used to compare root architectures under well-watered and water-stressed conditions. Significant genetic variation, with medium to high heritability and significant correlations, was observed for root traits. Total root length (TRL) and total root surface area (TSA) had high phenotypical diversity, and TRL was positively correlated with TSA, root volume, and root forks. The first two principal components explained 94.01% and 91.15% of total root variation in well-watered and water-stressed conditions, respectively. Thus, TRL and TSA, major contributors to root variation, can be used as favorable selection criteria at the seedling stage. We found that stiff stalk and non-stiff stalk groups (temperate backgrounds) showed relatively higher mean values for root morphological diversity than the TST group (tropical/subtropical background). Of the tested lines, 7, 42, 45, and 9 were classified as drought sensitive, moderately sensitive, moderately drought tolerant, and highly drought tolerant, respectively. Seven of the 9 extremely drought tolerant lines were from the TST group, suggesting that TST germplasms harbor valuable genetic resources for drought tolerance that could be used in breeding to improve abiotic stress tolerance in maize.


Background modeling for moving object detection in long-distance imaging through turbulent medium.
A basic step in automatic moving objects detection is often modeling the background (i.e., the scene excluding the moving objects). The background model describes the temporal intensity distribution expected at different image locations. Long-distance imaging through atmospheric turbulent medium is affected mainly by blur and spatiotemporal movements in the image, which have contradicting effects on the temporal intensity distribution, mainly at edge locations. This paper addresses this modeling problem theoretically, and experimentally, for various long-distance imaging conditions. Results show that a unimodal distribution is usually a more appropriate model. However, if image deblurring is performed, a multimodal modeling might be more appropriate.


BiGG Models: A platform for integrating, standardizing and sharing genome-scale models.
Genome-scale metabolic models are mathematically-structured knowledge bases that can be used to predict metabolic pathway usage and growth phenotypes. Furthermore, they can generate and test hypotheses when integrated with experimental data. To maximize the value of these models, centralized repositories of high-quality models must be established, models must adhere to established standards and model components must be linked to relevant databases. Tools for model visualization further enhance their utility. To meet these needs, we present BiGG Models (http://bigg.ucsd.edu), a completely redesigned Biochemical, Genetic and Genomic knowledge base. BiGG Models contains more than 75 high-quality, manually-curated genome-scale metabolic models. On the website, users can browse, search and visualize models. BiGG Models connects genome-scale models to genome annotations and external databases. Reaction and metabolite identifiers have been standardized across models to conform to community standards and enable rapid comparison across models. Furthermore, BiGG Models provides a comprehensive application programming interface for accessing BiGG Models with modeling and analysis tools. As a resource for highly curated, standardized and accessible models of metabolism, BiGG Models will facilitate diverse systems biology studies and support knowledge-based analysis of diverse experimental data.


Systemic antibiotics for symptomatic apical periodontitis and acute apical abscess in adults.
Dental pain can have a detrimental effect on quality of life. Symptomatic apical periodontitis and acute apical abscess are common causes of dental pain and arise from an inflamed or necrotic dental pulp, or infection of the pulpless root canal system. Clinical guidelines recommend that the first-line treatment for teeth with these conditions should be removal of the source of inflammation or infection by local, operative measures, and that systemic antibiotics are currently only recommended for situations where there is evidence of spreading infection (cellulitis, lymph node involvement, diffuse swelling) or systemic involvement (fever, malaise). Despite this, there is evidence that dentists frequently prescribe antibiotics in the absence of these signs. There is concern that this could contribute to the development of antibiotic-resistant bacterial colonies within both the individual and the community. This review is an update of the original version that was published in 2014. To evaluate the effects of systemic antibiotics provided with or without surgical intervention (such as extraction, incision and drainage of a swelling, or endodontic treatment), with or without analgesics, for symptomatic apical periodontitis and acute apical abscess in adults. Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 26 February 2018), the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 1) in the Cochrane Library (searched 26 February 2018), MEDLINE Ovid (1946 to 26 February 2018), Embase Ovid (1980 to 26 February 2018), and CINAHL EBSCO (1937 to 26 February 2018). The US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. A grey literature search was conducted using OpenGrey (to 26 February 2018) and ZETOC Conference Proceedings (1993 to 26 February 2018). No restrictions were placed on the language or date of publication when searching the electronic databases. Randomised controlled trials of systemic antibiotics in adults with a clinical diagnosis of symptomatic apical periodontitis or acute apical abscess, with or without surgical intervention (considered in this situation to be extraction, incision and drainage or endodontic treatment) and with or without analgesics. Two authors screened the results of the searches against inclusion criteria, extracted data and assessed risk of bias independently and in duplicate. We calculated mean differences (MD) (standardised mean difference (SMD) when different scales were reported) and 95% confidence intervals (CI) for continuous data. A fixed-effect model was used in the meta-analysis as there were fewer than four studies. We contacted study authors to obtain missing information. We included two trials in this review, with 62 participants included in the analyses. Both trials were conducted in university dental schools in the USA and compared the effects of oral penicillin V potassium (penicillin VK) versus a matched placebo when provided in conjunction with a surgical intervention (total or partial pulpectomy) and analgesics to adults with acute apical abscess or symptomatic necrotic tooth. The patients included in these trials had no signs of spreading infection or systemic involvement (fever, malaise). We assessed one study as having a high risk of bias and the other study as having unclear risk of bias.The primary outcome variables reported in both studies were participant-reported pain and swelling (one trial also reported participant-reported percussion pain). One study reported the type and number of analgesics taken by participants. One study recorded the incidence of postoperative endodontic flare-ups (people who returned with symptoms that necessitated further treatment). Adverse effects, as reported in one study, were diarrhoea (one participant, placebo group) and fatigue and reduced energy postoperatively (one participant, antibiotic group). Neither study reported quality of life measurements.Objective 1: systemic antibiotics versus placebo with surgical intervention and analgesics for symptomatic apical periodontitis or acute apical abscessTwo studies provided data for the comparison between systemic antibiotics (penicillin VK) and a matched placebo for adults with acute apical abscess or a symptomatic necrotic tooth when provided in conjunction with a surgical intervention. Participants in one study all underwent a total pulpectomy of the affected tooth, while participants in the other study had their tooth treated by either partial or total pulpectomy. Participants in both trials received oral analgesics. There were no statistically significant differences in participant-reported measures of pain or swelling at any of the time points assessed within the review. The MD for pain (short ordinal numerical scale 0 to 3) was -0.03 (95% CI -0.53 to 0.47) at 24 hours; 0.32 (95% CI -0.22 to 0.86) at 48 hours; and 0.08 (95% CI -0.38 to 0.54) at 72 hours. The SMD for swelling was 0.27 (95% CI -0.23 to 0.78) at 24 hours; 0.04 (95% CI -0.47 to 0.55) at 48 hours; and 0.02 (95% CI -0.49 to 0.52) at 72 hours. The body of evidence was assessed as at very low quality.Objective 2: systemic antibiotics without surgical intervention for adults with symptomatic apical periodontitis or acute apical abscessWe found no studies that compared the effects of systemic antibiotics with a matched placebo delivered without a surgical intervention for symptomatic apical periodontitis or acute apical abscess in adults. There is very low-quality evidence that is insufficient to determine the effects of systemic antibiotics on adults with symptomatic apical periodontitis or acute apical abscess.


Adult medulloblastoma: an analysis of survival and prognostic factors.
This analysis aimed to review the experience in the management of adult medulloblastoma at the University of California, San Francisco, and to identify important prognostic factors for survival and posterior fossa control. We performed a retrospective review of 34 adult patients, age > or = 15, with cerebellar medulloblastoma treated with radiotherapy at the University of California, San Francisco from 1970 to 1994. All patients underwent a surgical procedure (complete resection in 17, subtotal resection in 10, and biopsy alone in seven), followed by craniospinal irradiation. Most patients treated after 1979 also received chemotherapy. Twenty were classified as poor-risk due to either incomplete resection or evidence of disease outside of the posterior fossa at diagnosis. The 5-year posterior fossa control and overall survival rates were 61% and 58%, respectively. The majority of relapses occurred in the posterior fossa (14 of 17). Multivariate analysis revealed that age (favoring older patients), gender (favoring female patients), and extent of disease at diagnosis (favoring localized disease) were important prognostic factors for posterior fossa control. There was a trend toward improved posterior fossa control with higher radiation dose to the posterior fossa in patients with a complete resection. Gender and extent of disease at presentation were significant prognostic factors for survival. The 5-year survival rates were 92% for female patients versus 40% for male patients, and 67% for patients with localized disease versus 25% for those with disseminated disease. The prognosis following recurrence was poor; all died of the disease. Survival for adult medulloblastoma was comparable to its pediatric counterpart. In patients with localized disease at presentation, gender (favoring female patients) and age (favoring older patients) were important prognostic factors for posterior fossa control and survival. In patients with disseminated disease at presentation, the prognosis is poor, and innovative therapy is needed to improve survival.


Choosing criteria to screen for specific medical conditions from nonspecific sources: an application to injury surveillance.
The authors examine an approach for identifying which criteria to use when screening for persons with a relatively rare medical condition. They considered various subsets of an inclusive set of criteria by examining the statistical effectiveness per unit cost of deleting various criteria using three statistical measures of effectiveness. An application to injury surveillance, where categories of the patient's chief complaint were used for screening via emergency department logs, illustrates two implications of the approach. First, deletion priorities may differ somewhat by effectiveness measure. When using sensitivity to measure statistical efficiency, the tendency is first to drop the larger categories with the smaller proportions of injury. On the other hand, using specificity to gauge effectiveness calls for large categories with the highest injury rates to be deleted first; while for a measure of effectiveness derived from relative bias, the tendency is first to drop those categories with the fewest injuries. Second, an unequivocal set of criteria may not emerge, thus forcing one to decide among options. The authors suggest several rationales for making this decision.


Care of the undocumented immigrant in the United States with ESRD.
The growth of the undocumented immigrant population in the United States has been explosive. The absence of a uniform policy regarding health care for this population has created a unique problem for nephrologists. How should provision of care for undocumented immigrants with end-stage renal disease be delivered and compensated? This problem is exacerbated by the multiple complex laws that govern delivery of and payment for care, as well as that state regulations vary widely and are not easily understood. Furthermore, the ethical and moral commitments of providers to ensure adequate and appropriate care for any patient whose life is at stake, irrespective of his or her immigration status, place nephrologists in a difficult position. This review focuses on the scope of this problem, relevant case law and legislation, current care and payment models, the response of nephrology groups, and ethical dilemmas inherent in caring for this vulnerable population. Recommendations for further study, including convening of a consensus conference, are discussed.


CT perfusion imaging as an early biomarker of differential response to stereotactic radiosurgery in C6 rat gliomas.
The therapeutic efficacy of stereotactic radiosurgery for glioblastoma is not well understood, and there needs to be an effective biomarker to identify patients who might benefit from this treatment. This study investigated the efficacy of computed tomography (CT) perfusion imaging as an early imaging biomarker of response to stereotactic radiosurgery in a malignant rat glioma model. Rats with orthotopic C6 glioma tumors received either mock irradiation (controls, N = 8) or stereotactic radiosurgery (N = 25, 12 Gy in one fraction) delivered by Helical Tomotherapy. Twelve irradiated animals were sacrificed four days after stereotactic radiosurgery to assess acute CT perfusion and histological changes, and 13 irradiated animals were used to study survival. Irradiated animals with survival >15 days were designated as responders while those with survival ≤15 days were non-responders. Longitudinal CT perfusion imaging was performed at baseline and regularly for eight weeks post-baseline. Early signs of radiation-induced injury were observed on histology. There was an overall survival benefit following stereotactic radiosurgery when compared to the controls (log-rank P<0.04). Responders to stereotactic radiosurgery showed lower relative blood volume (rBV), and permeability-surface area (PS) product on day 7 post-stereotactic radiosurgery when compared to controls and non-responders (P<0.05). rBV and PS on day 7 showed correlations with overall survival (P<0.05), and were predictive of survival with 92% accuracy. Response to stereotactic radiosurgery was heterogeneous, and early selection of responders and non-responders was possible using CT perfusion imaging. Validation of CT perfusion indices for response assessment is necessary before clinical implementation.


Diagnostic utility of serum and pleural fluid carcinoembryonic antigen, and cytokeratin 19 fragments in patients with effusion from nonsmall cell lung cancer.
To assess the diagnostic value of CEA and CYFRA 21-1 (cytokeratin 19 fragments) in serum and pleural fluid in non small cell lung cancer with malignant pleural effusion (MPE). Two subsets of patients were recruited with lymphocytic exudative effusion, one subset constituted diagnosed patients of NSCLC with malignant pleural effusion and the other subset of constituted with Tubercular pleural effusion. CYFRA 21-1 and CEA levels were measured using Electrochemilumiscence Immunoassay (ECLIA). The test principle used the Sandwich method. For both the tests, results are determined via a calibration curve which is instrument specifically generated by 2 - point calibration and a master curve provided via reagent barcode. All data are expressed as means ± SD and percentage. All the parametric variables were analysed by student-t test where as non parametric variables were compared by Mann-Whitney U-test Statistical significance was accepted for P values < 0.05. Software used were SPSS 11.5, and MS excel 2007. In order to compare the performance of the tumor markers, receiver operating characteristic (ROC) curves were constructed and compared with area under the curve (AUC). The threshold for each marker was selected based on the best diagnostic efficacy having achieved equilibrium between sensitivity and specificity. In cases serum CYFRA21-1 levels had mean value of 34.1 ± 29.9 with a range of 1.6-128.3 where as in controls serum CYFRA21-1 levels had mean value of 1.9 ± 1.0 with a range of 0.5-4.7. In cases serum CEA levels had mean value of 24.9 ± 47.3 with a range of 1.0, 267.9 where as in controls serum CEA levels had mean value of 1.9 ± 1.4 with a range of 0.2-6.8. The difference in the means of serum CYFRA 21-l (P = 0.000) and CEA (P = 0.046) were statistically significant. In cases pleural fluid CYFRA21-1 levels had mean value of 160.1 ± 177.1 with a range of 5.4-517.2 where as in controls pleural fluid CYFRA21-1 levels had mean value of 15.9 ± 5.7 with a range of 7.2-29.6. In cases CEA pleural fluid levels had mean value of 89.8 ± 207.4 with a range of 1.0-861.2 where as in controls CEA levels had mean value of 2.5 ± 2.3 with a range of 1-8.9. The difference in the means of CYERA 21-1 (P = 0.001) between cases and controls is statistically significant. CYFRA21-1 (serum - pleural fluid) is a sensitive marker for NSCLC with sensitivity of 96.7%, highest of any combination [Serum (CYFRA 21-1 - CEA). CEA (Serum + Pleural Fluid), Pleural Fluid (CYFRA 21-1 + CEA)] and specificity of 77.8%. Levels of CYFRA21-l (serum + pleural fluid) are increased in malignant pleural effusion, so it is better to be used in suspicious malignant pleural effusion showing negative cytology, particularly in the absence of a visible tumor and or unsuitability for invasive procedure.


Effects of diet-induced obesity and voluntary wheel running on the microstructure of the murine distal femur.
Obesity and osteoporosis, two possibly related conditions, are rapidly expanding health concerns in modern society. Both of them are associated with sedentary life style and nutrition. To investigate the effects of diet-induced obesity and voluntary physical activity we used high resolution micro-computed tomography (μCT) together with peripheral quantitative computed tomography (pQCT) to examine the microstructure of the distal femoral metaphysis in mice. Forty 7-week-old male C57BL/6J mice were assigned to 4 groups: control (C), control + running (CR), high-fat diet (HF), and high-fat diet + running (HFR). After a 21-week intervention, all the mice were sacrificed and the left femur dissected for pQCT and μCT measurements. The mice fed the high-fat diet showed a significant weight gain (over 70% for HF and 60% for HFR), with increased epididymal fat pad mass and impaired insulin sensitivity. These obese mice had significantly higher trabecular connectivity density, volume, number, thickness, area and mass, and smaller trabecular separation. At the whole bone level, they had larger bone circumference and cross-sectional area and higher density-weighted maximal, minimal, and polar moments of inertia. Voluntary wheel running decreased all the cortical bone parameters, but increased the trabecular mineral density, and decreased the pattern factor and structure model index towards a more plate-like structure. The results suggest that in mice the femur adapts to obesity by improving bone strength both at the whole bone and micro-structural level. Adaptation to running exercise manifests itself in increased trabecular density and improved 3D structure, but in a limited overall bone growth.


The orbitozygomatic stich: A technical modification of the lateral supraorbital approach.
The lateral supraorbital approach (LSO) provides access to a variety of pathologies including anterior and some posterior circulation aneurysms, sellar and suprasellar lesions, and anterior fossa tumors. Technical modifications of LSO improve the surgical exposure of the skull base. We retrospectively analyzed 73 consecutive patients treated by the senior author (Juha A. Hernesniemi), at the Department of Neurosurgery, Helsinki University Hospital in Helsinki, Finland from May 2013 to October 2013. This study cohort underwent a modified LSO to access anterior circulation aneurysms, sellar and suprasellar tumors, and anterior fossa tumors. The studied population comprised 30 men and 43 women, with a mean age at treatment of 54 years (9-83 years). LSO was successfully used to access anterior circulation aneurysms in 59 (81%) patients, 10 (14%) patients with anterior cranial fossa tumors, and 4 (5%) patients with suprasellar tumors. The skull base drilling provided a mean of 6.8 mm (1.7-22 mm) in increased exposure. LSO provides adequate access to vascular and neoplastic lesions of the anterior cranial fossa, by drilling approximately 6.8 mm (1.7-22 mm) of the lateral orbital wall and sphenoid wing. This enhances surgical exposure and trajectory. An additional trick while performing an LSO is to place a single or multiple stiches (orbitozygomatic stich) at the base of the dura once opened, eliminating the dead space between the dura and anterior skull base.


Escherichia coli UmuC active site mutants: effects on translesion DNA synthesis, mutagenesis and cell survival.
Escherichia coli polymerase V (pol V/UmuD(2)'C) is a low-fidelity DNA polymerase that has recently been shown to avidly incorporate ribonucleotides (rNTPs) into undamaged DNA. The fidelity and sugar selectivity of pol V can be modified by missense mutations around the "steric gate" of UmuC. Here, we analyze the ability of three steric gate mutants of UmuC to facilitate translesion DNA synthesis (TLS) of a cyclobutane pyrimidine dimer (CPD) in vitro, and to promote UV-induced mutagenesis and cell survival in vivo. The pol V (UmuC_F10L) mutant discriminates against rNTP and incorrect dNTP incorporation much better than wild-type pol V and although exhibiting a reduced ability to bypass a CPD in vitro, does so with high-fidelity and consequently produces minimal UV-induced mutagenesis in vivo. In contrast, pol V (UmuC_Y11A) readily misincorporates both rNTPs and dNTPs during efficient TLS of the CPD in vitro. However, cells expressing umuD'C(Y11A) were considerably more UV-sensitive and exhibited lower levels of UV-induced mutagenesis than cells expressing wild-type umuD'C or umuD'C(Y11F). We propose that the increased UV-sensitivity and reduced UV-mutability of umuD'C(Y11A) is due to excessive incorporation of rNTPs during TLS that are subsequently targeted for repair, rather than an inability to traverse UV-induced lesions.


The efficacy and safety of natural honey on the healing of foot ulcers: a case series.
This clinical observation investigated the efficacy, cost-effectiveness, and acceptability of natural honey on the healing of a variety of chronic foot ulcers at the primary care level. A total of 12 patients with foot ulcers utilizing natural honey as an effective alternative to more expensive, advanced wound products were followed. Cases were referred to Umgwailinah Primary Health Care Center, Doha, Qatar from different health centers and from Hamad General Hospital, Doha, Qatar. There were also self-referred cases. After rinsing the site with normal saline, natural honey was applied and the wound was covered by glycerin-impregnated gauze (Adaptic Non-Adhering Dressing, Systagenix, San Antonio, TX) to prevent the absorption of honey into the cotton gauze and away from the wound site. Patients were followed on a daily basis for an average of 4 weeks. All ulcers healed with no contractures or scars with a mean healing time of 3 weeks. There was a 75% reduction in the dressing budget of the health center and a high level of satisfaction among both health professionals and patients. Patients' pain levels were reduced significantly after using natural honey, as evidenced by the use of the Visual Analog Scale. The use of natural honey in the management of chronic foot ulcers proved to be efficacious, cost-effective, and acceptable by both clinicians and patients.


Generation, Coordination, and Evolution of Neural Circuits for Vocal Communication.
In many species, vocal communication is essential for coordinating social behaviors including courtship, mating, parenting, rivalry, and alarm signaling. Effective communication requires accurate production, detection, and classification of signals, as well as selection of socially appropriate responses. Understanding how signals are generated and how acoustic signals are perceived is key to understanding the neurobiology of social behaviors. Here we review our long-standing research program focused on Xenopus, a frog genus which has provided valuable insights into the mechanisms and evolution of vertebrate social behaviors. In Xenopus laevis, vocal signals differ between the sexes, through development, and across the genus, reflecting evolutionary divergence in sensory and motor circuits that can be interrogated mechanistically. Using two ex vivo preparations, the isolated brain and vocal organ, we have identified essential components of the vocal production system: the sexually differentiated larynx at the periphery, and the hindbrain vocal central pattern generator (CPG) centrally, that produce sex- and species-characteristic sound pulse frequencies and temporal patterns, respectively. Within the hindbrain, we have described how intrinsic membrane properties of neurons in the vocal CPG generate species-specific vocal patterns, how vocal nuclei are connected to generate vocal patterns, as well as the roles of neurotransmitters and neuromodulators in activating the circuit. For sensorimotor integration, we identified a key forebrain node that links auditory and vocal production circuits to match socially appropriate vocal responses to acoustic features of male and female calls. The availability of a well supported phylogeny as well as reference genomes from several species now support analysis of the genetic architecture and the evolutionary divergence of neural circuits for vocal communication. Xenopus thus provides a vertebrate model in which to study vocal communication at many levels, from physiology, to behavior, and from development to evolution. As one of the most comprehensively studied phylogenetic groups within vertebrate vocal communication systems, Xenopus provides insights that can inform social communication across phyla.


Transient Receptor Potential Canonical 1 (TRPC1) Channels as Regulators of Sphingolipid and VEGF Receptor Expression: IMPLICATIONS FOR THYROID CANCER CELL MIGRATION AND PROLIFERATION.
The identity of calcium channels in the thyroid is unclear. In human follicular thyroid ML-1 cancer cells, sphingolipid sphingosine 1-phosphate (S1P), through S1P receptors 1 and 3 (S1P1/S1P3), and VEGF receptor 2 (VEGFR2) stimulates migration. We show that human thyroid cells express several forms of transient receptor potential canonical (TRPC) channels, including TRPC1. In TRPC1 knockdown (TRPC1-KD) ML-1 cells, the basal and S1P-evoked invasion and migration was attenuated. Furthermore, the expression of S1P3 and VEGFR2 was significantly down-regulated. Transfecting wild-type ML-1 cells with a nonconducting TRPC1 mutant decreased S1P3 and VEGFR2 expression. In TRPC1-KD cells, receptor-operated calcium entry was decreased. To investigate whether the decreased receptor expression was due to attenuated calcium entry, cells were incubated with the calcium chelator BAPTA-AM (1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid). In these cells, and in cells where calmodulin and calmodulin-dependent kinase were blocked pharmacologically, S1P3 and VEGFR2 expression was decreased. In TRPC1-KD cells, both hypoxia-inducible factor 1α expression and the secretion and activity of MMP2 and MMP9 were attenuated, and proliferation was decreased in TRPC1-KD cells. This was due to a prolonged G1 phase of the cell cycle, a significant increase in the expression of the cyclin-dependent kinase inhibitors p21 and p27, and a decrease in the expression of cyclin D2, cyclin D3, and CDK6. Transfecting TRPC1 to TRPC1-KD cells rescued receptor expression, migration, and proliferation. Thus, the expression of S1P3 and VEGFR2 is mediated by a calcium-dependent mechanism. TRPC1 has a crucial role in this process. This regulation is important for the invasion, migration, and proliferation of thyroid cancer cells.


Direct visualization and quantitation of cytomegalovirus-specific CD8+ cytotoxic T-lymphocytes in liver transplant patients.
CMV infection remains a significant clinical problem in the context of LT. Changes in the magnitude of the CMV-specific CTL response after LT have not previously been assessed but may be important in determining the outcome of CMV infection. We used a fluorescent HLA-B*0702-CMV peptide tetrameric complex to directly visualize and quantitate CMV-specific CD8+ CTL both in immunosuppressed patients after LT and in immunocompetent controls. CMV-specific CD8+ CTL, at a frequency ranging from 0.1 to 5.8% of CD8+, were detected in the peripheral blood of 22 of 25 B*0702, CMV immunoglobulin G seropositive individuals, with no difference observed between immunocompetent controls and patients >3 years after LT. In CMV seropositive LT recipients who did not have symptomatic CMV infection during the first 3 months after LT, CMV-specific CD8+ CTL magnitude initially decreased, then increased up to 5 times higher than pre-LT levels within 3 months. Two CMV seronegative recipients of seropositive donors had symptomatic CMV infection in association with high viral load. In both patients, no CD8+ CTL response was detected before the onset of symptoms, and a reduction in viral load was observed during antiviral therapy. However, polymerase chain reaction negativity was achieved only when a demonstrable CMV-specific CD8+ CTL response was generated. Responses were never observed in asymptomatic CMV seronegative patients. We suggest that the generation of CMV-specific CD8+ CTL may be driven by, and seems to coincide with the suppression of, viral reactivation. Direct monitoring of CMV-specific CD8+ CTL using an HLA-peptide tetramer may prove to be of value in the management of patients after LT.


Tinnitus with a normal audiogram: physiological evidence for hidden hearing loss and computational model.
Ever since Pliny the Elder coined the term tinnitus, the perception of sound in the absence of an external sound source has remained enigmatic. Traditional theories assume that tinnitus is triggered by cochlear damage, but many tinnitus patients present with a normal audiogram, i.e., with no direct signs of cochlear damage. Here, we report that in human subjects with tinnitus and a normal audiogram, auditory brainstem responses show a significantly reduced amplitude of the wave I potential (generated by primary auditory nerve fibers) but normal amplitudes of the more centrally generated wave V. This provides direct physiological evidence of "hidden hearing loss" that manifests as reduced neural output from the cochlea, and consequent renormalization of neuronal response magnitude within the brainstem. Employing an established computational model, we demonstrate how tinnitus could arise from a homeostatic response of neurons in the central auditory system to reduced auditory nerve input in the absence of elevated hearing thresholds.


Education and adult mortality in middle-income countries: Surprising gradients in six nationally-representative longitudinal surveys.
There are large differences in adult mortality across schooling groups in many high-income countries (HICs). An important open question is whether there are similar gradients in adult mortality in middle-income countries (MICs), where schooling and healthcare quality tends to be lower and health-related behaviors are often not strongly patterned by schooling. We present one of the first international-comparative studies on schooling differences in adult mortality across MICs using harmonizedlongitudinal data on adults ages 50+ from China, Costa Rica, Indonesia, Mexico, South Africa, and South Korea. We use Cox proportional hazards models to estimate differences in the hazard of mortality across schooling groups overall and separately by sex and broad age groups. We also estimate schooling gradients in smoking and body mass index to determine whether risk factor gradients potentially explain mortality patterns. Only adults with tertiary schooling have a consistent adult mortality advantage compared to those with no schooling. We do not find evidence that individuals with primary schooling have a lower hazard of mortality compared to individuals with no schooling in five of the six countries. The mortality advantage for individuals with secondary schooling is mixed, with evidence of lower mortality relative to those with no schooling in Mexico, South Africa, and South Korea. Gradients in BMI and smoking are inconsistent across countries and unlikely to explain mortality differences. We find that adult mortality and risk factor gradients in MICs can be much different than the established patterns seen in modern HICs. Our results highlight that adult mortality gradients are not an inevitability and are not found in all populations. Understanding what factors give rise to inequalities in adult mortality and what can be done to minimize gradients while still ensuring continued mortality improvements in MICs is a crucial focus for research and policy.


Synthesis and biological evaluation of radio and dye labeled amino functionalized dendritic polyglycerol sulfates as multivalent anti-inflammatory compounds.
Herein we describe a platform technology for the synthesis and characterization of partially aminated, (35)S-labeled, dendritic polyglycerol sulfate (dPG(35)S amine) and fluorescent dPGS indocarbocyanine (ICC) dye conjugates. These polymer conjugates, based on a biocompatible dendritic polyglycerol scaffold, exhibit a high affinity to inflamed tissue in vivo and represent promising candidates for therapeutic and diagnostic applications. By utilizing a one-step sequential copolymerization approach, dendritic polyglycerol (Mn ≈ 4.5 kDa) containing 9.4% N-phthalimide protected amine functionalities was prepared on a large scale. Sulfation and simultaneous radio labeling with (35)SO3 pyridine complex, followed by cleavage of the N-phthalimide protecting groups, yielded dPG(35)S amine as a beta emitting, inflammation specific probe with free amino functionalities for conjugation. Furthermore, efficient labeling procedures with ICC via iminothiolane modification and subsequent "Michael" addition of the maleimide functionalized ICC dye, as well as by amide formation via NHS derivatized ICC on a dPGS amine scaffold, are described. The dPGS-ICC conjugates were investigated with respect to their photophysical properties, and both the radiolabeled and fluorescent compounds were comparatively visualized in histological tissue sections (radio detection and fluorescence microscopy) of animals treated with dPGS. Furthermore, cellular uptake of dPGS-ICC was found in endothelial cord blood (HUVEC) and the epithelial lung cells (A549). The presented synthetic routes allow a reproducible, controlled synthesis of dPGS amine on kilogram scale applying a one-pot batch reaction process. dPGS amine can be used for analysis via radioactivity or fluorescence, thereby creating a new platform for inflammation specific, multimodal imaging purposes using other attachable probes or contrast agents.


Ablation of atrial fibrillation after the retirement age: considerations on safety and outcome.
Although the incidence of atrial fibrillation (AF) progressively increases with age, the vast majority of AF ablation is done in middle-aged patients. We evaluated the feasibility and safety of catheter ablation in patients older than 65 years of age with paroxysmal and persistent AF. Out of a total of 230 consecutive AF ablation procedures, 45 patients were older than 65 years of age and underwent 53 procedures. The ablation strategy consisted of wide-area circumferential lines around both ipsilateral pulmonary veins using a three-dimensional mapping system. The mean age was 69 ± 3.5 years (35 males). The mean duration for AF was 8.7 ± 6.5 years. Thirty-nine had paroxysmal and six persistent AF despite use of 1.38 ± 0.77 antiarrhythmic drugs. All patients had a structurally normal heart. Eleven had systemic hypertension. Mean procedure time was 187 ± 33 min. Acute procedural success rate with abolition of all pulmonary vein potentials was achieved in all patients. Pericardial tamponade requiring percutaneous drainage occurred in one (1.9%) patient. There were no cardioembolic events. Among the 43 patients whose clinical outcome was assessed at 6 months, 34 (79%) had a significant reduction (>90%) of the total symptomatic AF burden, compared to pre-ablation, with a complete lack of symptomatic AF in 32 (74%) patients. The success rate was higher for patients with paroxysmal versus persistent AF (81 vs. 67%). Six patients (11%) underwent repeat procedures. Catheter ablation is a safe and effective treatment for patients over the age of 65 years with symptomatic, drug-refractory AF. Therefore, patients should not be excluded from undergoing AF catheter ablation on the basis of age alone.


Sox7 controls arterial specification in conjunction with hey2 and efnb2 function.
SoxF family members have been linked to arterio-venous specification events and human pathological conditions, but in contrast to Sox17 and Sox18, a detailed in vivo analysis of a Sox7 mutant model is still lacking. In this study we generated zebrafish sox7 mutants to understand the role of Sox7 during vascular development. By in vivo imaging of transgenic zebrafish lines we show that sox7 mutants display a short circulatory loop around the heart as a result of aberrant connections between the lateral dorsal aorta (LDA) and either the venous primary head sinus (PHS) or the common cardinal vein (CCV). In situ hybridization and live observations in flt4:mCitrine transgenic embryos revealed increased expression levels of flt4 in arterial endothelial cells at the exact location of the aberrant vascular connections in sox7 mutants. An identical circulatory short loop could also be observed in newly generated mutants for hey2 and efnb2. By genetically modulating levels of sox7, hey2 and efnb2 we demonstrate a genetic interaction of sox7 with hey2 and efnb2. The specific spatially confined effect of loss of Sox7 function can be rescued by overexpressing the Notch intracellular domain (NICD) in arterial cells of sox7 mutants, placing Sox7 upstream of Notch in this aspect of arterial development. Hence, sox7 levels are crucial in arterial specification in conjunction with hey2 and efnb2 function, with mutants in all three genes displaying shunt formation and an arterial block.


Estimating Second Order Probability Beliefs from Subjective Survival Data.
Based on subjective survival probability questions in the Health and Retirement Study (HRS), we use an econometric model to estimate the determinants of individual-level uncertainty about personal longevity. This model is built around the modal response hypothesis (MRH), a mathematical expression of the idea that survey responses of 0%, 50%, or 100% to probability questions indicate a high level of uncertainty about the relevant probability. We show that subjective survival expectations in 2002 line up very well with realized mortality of the HRS respondents between 2002 and 2010. We show that the MRH model performs better than typically used models in the literature of subjective probabilities. Our model gives more accurate estimates of low probability events and it is able to predict the unusually high fraction of focal 0%, 50%, and 100% answers observed in many data sets on subjective probabilities. We show that subjects place too much weight on parents' age at death when forming expectations about their own longevity, whereas other covariates such as demographics, cognition, personality, subjective health, and health behavior are under weighted. We also find that less educated people, smokers, and women have less certain beliefs, and recent health shocks increase uncertainty about survival, too.


A Single Conserved Amino Acid Residue as a Critical Context-Specific Determinant of the Differential Ability of Mdm2 and MdmX RING Domains to Dimerize.
Mdm2 and MdmX are related proteins serving in the form of the Mdm2 homodimer or Mdm2/MdmX heterodimer as an E3 ubiquitin ligase for the tumor suppressor p53. The dimerization is required for the E3 activity and is mediated by the conserved RING domains present in both proteins, but only the RING domain of Mdm2 can form homodimers efficiently. We performed a systematic mutational analysis of human Mdm2, exchanging parts of the RING with the corresponding MdmX sequence, to identify the molecular determinants of this difference. Mdm2 can also promote MdmX degradation, and we identified several mutations blocking it. They were located mainly at the Mdm2/E2 interface and did not disrupt the MdmX-Mdm2 interaction. Surprisingly, some mutations of the Mdm2/E2 interface inhibited MdmX degradation, which is mediated by the Mdm2/MdmX heterodimer, but did not affect p53 degradation, mediated by the Mdm2 homodimer. Only one mutant, replacing a conserved cysteine 449 with asparagine (C449N), disrupted the ability of Mdm2 to dimerize with MdmX. When we introduced the cysteine residue into the corresponding site in MdmX, the RING domain became capable of forming dimers with other MdmX molecules in vivo, suggesting that one conserved amino acid residue in the RINGs of Mdm2 and MdmX could serve as the determinant of the differential ability of these domains to form dimers and their E3 activity. In immunoprecipitations, however, the homodimerization of MdmX could be observed only when the asparagine residue was replaced with cysteine in both RINGs. This result suggested that heterocomplexes consisting of one mutated MdmX RING with cysteine and one wild-type MdmX RING with asparagine might be less stable, despite being readily detectable in the cell-based assay. Moreover, Mdm2 C449N blocked Mdm2-MdmX heterodimerization but did not disrupt the ability of Mdm2 homodimer to promote p53 degradation, suggesting that the effect of the conserved cysteine and asparagine residues on dimerization was context-specific. Collectively, our results indicate that the effects of individual exchanges of conserved residues between Mdm2 and MdmX RING domains might be context-specific, supporting the hypothesis that Mdm2 RING homodimers and Mdm2-MdmX heterodimers may not be entirely structurally equivalent, despite their apparent similarity.


Compositional reflectance and transmittance model for multilayer specimens.
We propose a compositional model for predicting the reflectance and the transmittance of multilayer specimens composed of layers having possibly distinct refractive indices. The model relies on the laws of geometrical optics and on a description of the multiple reflection-transmission of light between the different layers and interfaces. The highly complex multiple reflection-transmission process occurring between several superposed layers is described by Markov chains. An optical element such as a layer or an interface forms a biface. The multiple reflection-transmission process is developed for a superposition of two bifaces. We obtain general composition formulas for the reflectance and the transmittance of a pair of layers and/or interfaces. Thanks to these compositional expressions, we can calculate the reflectance and the transmittance of three or more superposed bifaces. The model is applicable to regular compositions of bifaces, i.e., multifaces having on each face an angular light distribution that remains constant along successive reflection and transmission events. Kubelka's layering model, Saunderson's correction of the Kubelka-Munk model, and the Williams-Clapper model of a color layer superposed on a diffusing substrate are special cases of the proposed compositional model.


The Geobacillus stearothermophilus V iscS gene, encoding cysteine desulfurase, confers resistance to potassium tellurite in Escherichia coli K-12.
Many eubacteria are resistant to the toxic oxidizing agent potassium tellurite, and tellurite resistance involves diverse biochemical mechanisms. Expression of the iscS gene from Geobacillus stearothermophilus V, which is naturally resistant to tellurite, confers tellurite resistance in Escherichia coli K-12, which is naturally sensitive to tellurite. The G. stearothermophilus iscS gene encodes a cysteine desulfurase. A site-directed mutation in iscS that prevents binding of its pyridoxal phosphate cofactor abolishes both enzyme activity and its ability to confer tellurite resistance in E. coli. Expression of the G. stearothermophilus iscS gene confers tellurite resistance in tellurite-hypersensitive E. coli iscS and sodA sodB mutants (deficient in superoxide dismutase) and complements the auxotrophic requirement of an E. coli iscS mutant for thiamine but not for nicotinic acid. These and other results support the hypothesis that the reduction of tellurite generates superoxide anions and that the primary targets of superoxide damage in E. coli are enzymes with iron-sulfur clusters.