Asymptomatic bacterial vaginosis: response to therapy.
Bacterial vaginosis causes symptomatic vaginal discharge and has been associated with preterm birth and with the acquisition of human immunodeficiency virus. Half of all women with bacterial vaginosis are free of symptoms, and treatment of these women is controversial. The objective of this study was to determine the extent of poor symptom recognition in this group of women. Seventy-five women attending a sexually transmitted disease clinic who had asymptomatic bacterial vaginosis were entered into a randomized, double-blind, placebo-controlled trial comparing metronidazole gel with placebo. Subjects' perceptions about changes in vaginal discharge and odor were determined, and treatment and placebo groups were compared by means of standard statistical analysis. When subjects were stratified by treatment group, there were no differences in their retrospective assessments of vaginal discharge and odor. A subset of women who had normalization of clinical parameters or of Gram stain scores did admit retrospectively to improvement; however, the difference between this group and the group without normalization was not statistically significant. Twenty-one percent of treated women subsequently had vaginal candidiasis. A greater percentage of women with resolution of bacterial vaginosis did retrospectively notice improvement in vaginal discharge and odor in comparison with those women without resolution; however, this was not statistically significant. These findings do not support routine treatment of women with asymptomatic bacterial vaginosis.


Frequency tunability of solid-core photonic crystal fibers filled with nanoparticle-doped liquid crystals.
We infiltrate liquid crystals doped with BaTiO3 nanoparticles in a photonic crystal fiber and compare the measured transmission spectrum with the one achieved without dopant. New interesting features, such as frequency modulation response of the device and a transmission spectrum with tunable attenuation on the short wavelength side of the widest bandgap, suggest a potential application of this device as a tunable all-in-fiber gain equalization filter with an adjustable slope. The tunability of the device is achieved by varying the amplitude and the frequency of the applied external electric field. The threshold voltage for doped and undoped liquid crystals in a silica capillary and in a glass cell are also measured as a function of the frequency of the external electric field and the achieved results are compared.


Rapid rate magnetic stimulation of human sacral nerve roots alters excitability within the cortico-anal pathway.
Sacral nerve root stimulation (SNS) can produce dramatic symptomatic improvement in faecal incontinence (FI). However, the physiological mechanism behind this improvement remains unknown. One hypothesis is that SNS may modulate cortico-anal pathways and drive compensatory changes within the spinal cord or cerebral cortex that beneficially alter sphincter function. Our aim was to assess whether short-term experimental SNS can induce changes in the human cortico-anal pathway. Eight healthy volunteers (mean age 30 years) were studied. Subjects were investigated on three separate occasions and randomized to either active (5 and 15 Hz) or sham rapid-rate lumbosacral magnetic stimulation (rLSMS). Anal sphincter electromyograms (EMG) were recorded from an anal probe following single-pulse transcranial magnetic stimulation, at baseline, immediately, 30 and 60 min following rLSMS at either (i) 5 Hz for 15 min, (ii) 15 Hz for 15 min or (iii) sham stimulation for 15 min. In addition, manometry and anal sphincter sensation was measured in a subset of subjects. Interventions were compared to sham using anova. Fifteen hertz rLSMS increased cortico-anal EMG response amplitude in the 1 h postintervention (F(4, 28) = 3.2, P = 0.027), without a shift in response latency. This effect was not demonstrated with either 5 Hz or sham stimulation. rLSMS had no short-term effect on sensation or physiology. Short-term magnetic stimulation of the sacral nerve roots induces changes in cortico-anal excitability which is frequency specific. These data support the hypothesis that SNS produces some of its beneficial effect in patients with FI by altering the excitability of the cortico-anal pathway.


Mineral preservatives in the wood of Stradivari and Guarneri.
Following the futile efforts of generations to reach the high standard of excellence achieved by the luthiers in Cremona, Italy, by variations of design and plate tuning, current interest is being focused on differences in material properties. The long-standing question whether the wood of Stradivari and Guarneri were treated with wood preservative materials could be answered only by the examination of wood specimens from the precious antique instruments. In a recent communication (Nature, 2006), we reported about the degradation of the wood polymers in instruments of Stradivari and Guarneri, which could be explained only by chemical manipulations, possibly by preservatives. The aim of the current work was to identify the minerals from the small samples of the maple wood which were available to us from the antique instruments. The ashes of wood from one violin and one cello by Stradivari, two violins by Guarneri, one viola by H. Jay, one violin by Gand-Bernardel were analyzed and compared with a variety of commercial tone woods. The methods of analysis were the following: back-scattered electron imaging, X-ray fluorescence maps for individual elements, wave-length dispersive spectroscopy, energy dispersive X-ray spectroscopy and quantitative microprobe analysis. All four Cremonese instruments showed the unmistakable signs of chemical treatments in the form of chemicals which are not present in natural woods, such as BaSO4, CaF2, borate, and ZrSiO4. In addition to these, there were also changes in the common wood minerals. Statistical evaluation of 12 minerals by discriminant analysis revealed: a. a difference among all four Cremona instruments, b. the difference of the Cremonese instruments from the French and English antiques, and c. only the Cremonese instruments differed from all commercial woods. These findings may provide the answer why all attempts to recreate the Stradivarius from natural wood have failed. There are many obvious implications with regard to how the green tone wood should be treated, which chould lead to changes in the practice of violin-making. This research should inspire others to analyze more antique violins for their chemical contents.


Hyperuricemia and metabolic syndrome in Taiwanese children.
Metabolic fitness in childhood is of increasing concern in transitional and advanced economies as the metabolic syndrome (MS) is recognized more often in this age group. As the MS appears, so also does hyperuricemia. Studies in Taiwan have identified both indigenous and Chinese with high prevalence of hyperuricemia. Data (1227 boys and 1057 girls, aged 6-12) from the Nutrition and Health Survey in Taiwan Elementary School Children (NAHSIT Children 2001-2002) were used to appraise the association between uric acid (UA) and MS in children. Mean serum urate increases by age, ranging from 5.69 mg/dL to 7.11 mg/dL for boys and 5.61 mg/dL to 6.13 md/dL for girls. Boys have higher UA concentrations (6.07 mg/dL vs. 5.74 mg/dL) and hyperuricemia (UA > or = 7 mg/dL) rate (26.5% vs. 18.8%) than girls. Children of Mountain areas have higher rates of hyperuricemia (boys: 39.2%, girls: 30.1%). 5.56% of boys and 6.39% of girls were classified as having the MS by ATP III criteria. Serum urate was closely correlated with the MS parameters, and waist circumference (WC) in particular (r=0.387). WC alone accounted for 18% of variance of serum urate concentration. Both serum urate and hyperuricemia are significant risk factors for the MS (serum urate in mg/dL, OR: 1.54, 95% CI: 1.36-1.74; hyperuricemia, OR: 3.73, 95% CI: 2.47-5.62). Adjustment for age and region accentuate these relationships. Not only abdominal fatness, but also uric acid status, or both together may be of interest to public health workers and clinicians in regard to the transitional health problem of MS.


Lamina-specific expression of adhesion molecules in developing chick optic tectum.
The optic tectum is the major synaptic target of retinal axons in birds. In the chick, retinal ganglion cell axons enter the optic tectum through a superficial lamina (the stratum opticum), extended branches into deeper laminae, and arborize in specific "retinorecipient" laminae, where they form synapses. Studies using an organotypic culture system have provided evidence that the tectum bears a series of distinct, lamina-specific, cell surface-associated cues that direct these axonal behaviors (Yamagata and Sanes, 1995). Here, we have used a panel of antibodies to 30 membrane and matrix components to ask whether known adhesive molecules are distributed in lamina-specific patterns. Among many spatiotemporal pattern of expression documented, three were particularly noteworthy: (1) The cell adhesion molecules NgCAM/L1 and TAG-1/axonin-1 were concentrated in the stratum opticum. (2) SC1/JC7/DM-GRASP/BEN, N-cadherin, neuropilin, polysialylated N-CAM, and glycoconjugates recognized by the lectin VVA-B4 were concentrated in retinorecipient laminae. (3) Neurofascin, tenascin-C/cytotactin, and a matrix molecule defined by the "Sigma" antibody were present at highest levels in areas that border the retinorecipient laminae. Some members of each group (NgCAM/L1, TAG-1/axonin, SC1/JC7, polysialic acid, VVA-B4-receptors, and neurofascin) appeared on schedule and in lamina-restricted patterns in tecta from embryos that had been enucleated before retinal axons left the eye. Thus, molecules in these three categories could provide signals to retinal axons that promote extension through the stratum opticum, induce arborization or synaptogenesis in retinorecipient laminae, and prevent sprouting into adjoining laminae. Interestingly, N-cadherin accumulated in retinorecipient laminae only following the onset of synapse formation, and failed to accumulate in enucleated tecta. Immunoelectron microscopy of normal tecta demonstrated the presence of N-cadherin in the synaptic cleft, suggesting a role for this molecule in synaptic maintenance.


Effects of APOA5 -1131T>C (rs662799) on fasting plasma lipids and risk of metabolic syndrome: evidence from a case-control study in China and a meta-analysis.
The apolipoprotein A5 (APOA5) gene -1131T>C (rs662799) has been suggested to be involved in the pathway of lipid homeostasis and the development of metabolic syndrome (MetS). However, the findings are not consistent. To systematically evaluate the associations between -1131T>C polymorphism and fasting lipid parameters and the risk of MetS, we conducted a case-control study in a Chinese population and a meta-analysis. The findings from 1840 Chinese participants indicated that the C allele carriers had significantly higher fasting total cholesterol (TC), triglycerides (TG) and lower HDL-cholesterol (HDL-C) than the TT homozygotes carriers. The -1131C allele was also found to be significantly associated with increased risk of MetS (OR = 1.40, 95% confidence interval (CI) = 1.15, 1.69) compared to the TT homozygotes. In the meta-analysis of 51,868 participants from 46 East Asian studies, 26 European studies and 19 studies of other ethnic groups, the -1131C allele was associated with higher fasting TC (weighted mean difference (WMD) = 0.08 mmol/L, 95% CI = 0.05, 0.10, P = 1.74×10(-9)), TG (WMD = 0.30 mmol/L, 95% CI = 0.26, 0.33, P = 1.87×10(-55)), LDL-cholesterol (LDL-C) (WMD = 0.04 mmol/L, 95% CI = 0.02, 0.07, P = 0.002), and lower HDL-C (WMD = -0.05 mmol/L, 95% CI = -0.06,-0.04, P = 1.88×10(-21)), respectively. Based on 12 studies with 5,573 MetS cases and 8,290 controls from 5 East Asian studies, 5 European studies and 2 studies of other ethnic groups, the -1131C allele was associated with increased risk of MetS with an OR (95% CI) = 1.33 (1.16, 1.53) in the overall population, 1.43 (1.29, 1.58) in East Asian and 1.30 (0.94, 1.78) in European populations. In conclusion, the -1131C allele may be associated with elevated levels of fasting TG, TC, LDL-C and decreased HDL-C, and increased risk of MetS, especially in East Asians.


Fuzzy Clusterwise Growth Curve Models via Generalized Estimating Equations: An Application to the Antisocial Behavior of Children.
The growth curve model has been a useful tool for the analysis of repeated measures data. However, it is designed for an aggregate-sample analysis based on the assumption that the entire sample of respondents are from a single homogenous population. Thus, this method may not be suitable when heterogeneous subgroups exist in the population with qualitatively distinct patterns of trajectories. In this paper, the growth curve model is generalized to a fuzzy clustering framework, which explicitly accounts for such group-level heterogeneity in trajectories of change over time. Moreover, the proposed method estimates parameters based on generalized estimating equations thereby relaxing the assumption of correct specification of the population covariance structure among repeated responses. The performance of the proposed method in recovering parameters and the number of clusters is investigated based on two Monte Carlo analyses involving synthetic data. In addition, the empirical usefulness of the proposed method is illustrated by an application concerning the antisocial behavior of a sample of children.


Circumstances attending 100 sudden deaths from coronary artery disease with coroner's necropsies.
The deaths of 100 men due to coronary artery disease which occurred so suddenly and unexpectedly as to merit a coroner's necropsy have been studied, with special reference to the exact circumstances of their occurrence. The most significant relationship of sudden death was with acute psychological stress. Moderate physical activity, the time of day, the day of the week, and a recent meal, especially if accompanied by alcohol, were also significantly related. Very strenuous exercise, the season of the year, the environmental temperature or recent change of it, and chronic psychological stress were not so related. Neither were the actual smoking of a cigarette nor the composition of the meal immediately preceding death. Compared with previous series of proved acute myocardial infarction the necropsies in these cases showed that the right coronary artery had been recently occluded by a thrombus more often than the left anterior descending. Stenosis or occlusion of the right coronary artery bore a significant relation to the suddenness of death. Special analysis of the 52 cases in which neither recent thrombus nor infarction were found did not disclose any circumstances attending death which differed from the remainder. Some comparisons are made with the circumstances attending the onset of symptoms in 100 men studied while recovering from an acute myocardial infarct.


Are Dietary Patterns Associated with Depression in U.S. Adults?
Nutrition is one of the most important modifiable determinants for and consequences of both mental and physical heath. Depression has become an increasingly important public health issue. We tested whether dietary patterns derived from food group intake are associated with depression in U.S. adults in a cross-sectional study with national population. This study included 4180 men and 4196 women aged 20-79 years in the 2007-2010 National Health and Nutrition Examination Surveys (NHANES), with complete data of one 24-h dietary recall, sociodemographics, lifestyles, and Patient Health Questionnaires (PHQ-9) for screening depression. Two major dietary patterns identified by factor analysis were investigated for their associations with presence of depression (PHQ-9 score ≥10) by using linear and multivariate logistic regressions. One of two major patterns, labeled "Western" dietary pattern was characterized by high intakes of nonwhole grain, white potatoes, cheese, meat, discretionary oil and fat, and added sugar; the second dietary pattern that was labeled "Healthy" dietary pattern was characterized by high intakes of whole grains, vegetables, fruits, fish, nuts and seeds. The "Western" dietary pattern was not significantly associated with depression in both men and women. The "Healthy" dietary pattern scores were inversely associated with the PHQ-9 depression scores and odd ratios (ORs) of depression after adjustment for covariates in women but not in men. The OR of depression in women with the highest quintile of "Healthy" dietary pattern scores was 0.60 (95% confidence interval [CI]: 0.42-0.85, P < .001) compared to the lowest quintile as a reference. These findings warrant future interventions or clinical trials in elucidating causal and effect relations of depression and dietary patterns, an important public health concern.


Proline hydroxylation in collagen supports integrin binding by two distinct mechanisms.
Collagens are the most abundant extracellular matrix proteins in vertebrates and have a characteristic triple-helix structure. Hydroxylation of proline residues is critical for helix stability, and diminished prolyl hydroxylase activity causes wide-spread defects in connective tissues. Still, the role of proline hydroxylation in the binding of collagen receptors such as integrins is unclear. Here, we isolated skin collagen from genetically modified mice having reduced prolyl 4-hydroxylase activity. At room temperature, the reduced proline hydroxylation did not affect interactions with the recombinant integrin α2I domain, but at 37 °C, collagen hydroxylation correlated with the avidity of α2I domain binding. Of note, LC-MS/MS analysis of isolated skin collagens revealed no major changes in the hydroxyproline content of the main integrin-binding sites. Thus, the disrupted α2I domain binding at physiological temperatures was most likely due to structural destabilization of the collagenous helix. Integrin α2I binding to the triple-helical GFPGER motif was slightly weaker than to GFOGER (O = hydroxyproline). This phenomenon was more prominent when α1 integrin was tested. Integrin α1β1 expressed on CHO cells and recombinant α1I domain showed remarkably slower binding velocity and weaker avidity to GFPGER when compared with GFOGER. Structural modeling revealed the critical interaction between Arg-218 in α1I and the hydroxyproline residue in the integrin-binding motif. The role of Arg-218 was further validated by testing a variant R218D α1I domain in solid-phase binding assays. Thus, our results show that the lack of proline hydroxylation in collagen can affect integrin binding by a direct mechanism and via structural destabilization of the triple helix.


Ectopic integration of transforming DNA is rare among neurospora transformants selected for gene replacement.
In a variety of organisms, DNA-mediated transformation experiments commonly produce transformants with multiple copies of the transforming DNA, including both selected and unselected molecules. Such "cotransformants" are much more common than expected from the individual transformation frequencies, suggesting that subpopulations of cells, or nuclei, are particularly competent for transformation. We found that Neurospora crassa transformants selected for gene replacement at the am gene had not efficiently incorporated additional DNA, suggesting that nuclei that undergo transformation by homologous recombination are not highly competent at integration of DNA by illegitimate recombination. Spheroplasts were treated with DNA fragments homologous to am and with an Escherichia coli hph plasmid. Transformants were initially selected for hph (hygromycinR), allowed to conidiate to generate homokaryons and then selected for either Am- (gene replacements) or hph. Surprisingly, most am replacement strains were hygromycinS (124/140) and carried no extraneous DNA (116/140). Most transformants selected for hph also had ectopic copies of am DNA and/or multiple copies of hph sequences (32/35), generally at multiple sites, confirming that efficient cotransformation could occur. To test the implication that cotransformation involving gene replacement and ectopic integration is rare, we compared the yields of am replacement strains with or without prior selection for hph. The initial selection did not appreciably help (or hinder) recovery of strains with replacements.


The relationship between destination proximity, destination mix and physical activity behaviors.
The presence and mix of destinations is an important aspect of the built environment that may encourage or discourage physical activity. This study examined the association between the proximity and mix of neighbourhood destinations and physical activity. Secondary analysis was undertaken on physical activity data from Western Australian adults (n=1394). These data were linked with geographical information systems (GIS) data including the presence and the mix of destinations located within 400 and 1500 m from respondents' homes. Associations with walking for transport and recreation and vigorous physical activity were examined. Access to post boxes, bus stops, convenience stores, newsagencies, shopping malls, and transit stations within 400 m (OR 1.63-5.00) and schools, transit stations, newsagencies, convenience stores and shopping malls within 1500 m (OR 1.75-2.38) was associated with participation in regular transport-related walking. A dose-response relationship between the mix of destinations and walking for transport was also found. Each additional destination within 400 and 1500 m resulted in an additional 12 and 11 min/fortnight spent walking for transport, respectively. Proximity and mix of destinations appears strongly associated with walking for transport, but not walking for recreation or vigorous activity. Increasing the diversity of destinations may contribute to adults doing more transport-related walking and achieving recommended levels of physical activity.


Transdominant mutants of I kappa B alpha block Tat-tumor necrosis factor synergistic activation of human immunodeficiency virus type 1 gene expression and virus multiplication.
The human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) contains two binding sites for the NF-kappa B/Rel family of transcription factors which are required for the transcriptional activation of viral genes by inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin-1. In the present study, we examined the effect of transdominant mutants of I kappa B alpha on the synergistic activation of the HIV-1 LTR by TNF-alpha and the HIV-1 transactivator, Tat, in Jurkat T cells. The synergistic induction of HIV-1 LTR-driven gene expression represented a 50- to 70-fold stimulation and required both an intact HIV-1 enhancer and Tat-TAR element interaction, since mutations in Tat protein (R52Q, R53Q) or in the bulge region of the TAR element that eliminated Tat binding to TAR were unable to stimulate LTR expression. Coexpression of I kappa B alpha inhibited Tat-TNF-alpha activation of HIV LTR in a dose-dependent manner. Transdominant forms of I kappa B alpha, mutated in critical serine or threonine residues required for inducer-mediated (S32A, S36A) and/or constitutive (S283A, T291A, T299A) phosphorylation of I kappa B alpha were tested for their capacity to block HIV-1 LTR transactivation. I kappa B alpha molecules mutated in the N-terminal sites were not degraded following inducer-mediated stimulation (t1/2, > 4 h) and were able to efficiently block HIV-1 LTR transactivation. Strikingly, the I kappa B alpha (S32A, S36A) transdominant mutant was at least five times as effective as wild-type I kappa B alpha in inhibiting synergistic induction of the HIV-1 LTR. This mutant also effectively inhibited HIV-1 multiplication in a single-cycle infection model in Cos-1 cells, as measured by Northern (RNA) blot analysis of viral mRNA species and viral protein production. These experiments suggest a strategy that may contribute to inhibition of HIV-1 gene expression by interfering with the NF-kappa B/Rel signaling pathway.


Modelling decay in effectiveness for evaluation of behaviour change interventions: a tutorial for public health economists.
Recent methodological reviews of evaluations of behaviour change interventions in public health have highlighted that the decay in effectiveness over time has been mostly overlooked, potentially leading to suboptimal decision-making. While, in principle, discrete-time Markov chains-the most commonly used modelling approach-can be adapted to account for decay in effectiveness, this framework inherently lends itself to strong model simplifications. The application of formal and more appropriate modelling approaches has been supported, but limited progress has been made to date. The purpose of this paper is to encourage this shift by offering a practical guide on how to model decay in effectiveness using a continuous-time Markov chain (CTMC)-based approach. A CTMC approach is demonstrated, with a contextualized tutorial being presented to facilitate learning and uptake. A worked example based on the stylized case study in physical activity promotion is illustrated with accompanying R code. The proposed framework presents a relatively small incremental change from the current modelling practice. CTMC represents a technical solution which, in absence of relevant data, allows for formally testing the sensitivity of results to assumptions regarding the long-term sustainability of intervention effects and improving model transparency. The use of CTMC should be considered in evaluations where decay in effectiveness is likely to be a key factor to consider. This would enable more robust model-based evaluations of population-level programmes to promote behaviour change and reduce the uncertainty surrounding the decision to invest in these public health interventions.


Arterial atherosclerosis in patients with chronic kidney disease and its relationship with serum and tissue endothelin-1. [corrected].
Instruction. We investigated the correlation between atherosclerosis and tissue and serum levels of endothelin-1 in patients with chronic kidney disease (CKD). MATERIALS AND METHODS. Arterial samples were obtained from 35 patients with CKD during arteriovenous fistula placement. Thirty-one patients with cardiovascular disease who underwent coronary artery bypass graft (CABG) were selected as the atherosclerotic group, and a piece of their aorta punched during CABG was obtained. Also, a small piece of the renal artery was dissected during donation in 24 kidney donors (control group). Tissue endothelin-1 level was measured and atherosclerosis grading was determined by pathologic examination. Serum levels of endothelin-1 were also measured in the three groups. Results. The mean tissue endothelin-1 levels were 10.73+/-7.57 pg/mL, 12.16 +/- 3.95 pg/mL, and 0.93 +/- 1.06 pg/mL in the patients with CKD, those with CABG, and donors, respectively (P < .001). The mean serum endothelin-1 level was 25.23 +/- 15.15 pg/mL in the patients with CKD, 21.13 +/- 17.22 pg/mL in the patients with CABG, and 2.66 +/- 1.51 pg/mL in the donors (P < .001). Atherosclerosis grades correlated with tissue endothelin-1 level (r = 0.823, P < .001) and serum endothelin-1 level (r = 0.608, P < .001) in the patients with CKD. Multiple regression analysis showed tissue endothelin-1 level as the main predicting factor of atherosclerosis (P < .001). CONCLUSIONS. Tissue endothelin-1 concentration is more important than serum endothelin-1 or lipids levels in prediction of atherosclerosis. Thus, blockade of tissue endothelin-1 receptors with its antagonists may prevent atherosclerosis progression.


Protein unfolding rates correlate as strongly as folding rates with native structure.
Although the folding rates of proteins have been studied extensively, both experimentally and theoretically, and many native state topological parameters have been proposed to correlate with or predict these rates, unfolding rates have received much less attention. Moreover, unfolding rates have generally been thought either to not relate to native topology in the same manner as folding rates, perhaps depending on different topological parameters, or to be more difficult to predict. Using a dataset of 108 proteins including two-state and multistate folders, we find that both unfolding and folding rates correlate strongly, and comparably well, with well-established measures of native topology, the absolute contact order and the long range order, with correlation coefficient values of 0.75 or higher. In addition, compared to folding rates, the absolute values of unfolding rates vary more strongly with native topology, have a larger range of values, and correlate better with thermodynamic stability. Similar trends are observed for subsets of different protein structural classes. Taken together, these results suggest that choosing a scaffold for protein engineering may require a compromise between a simple topology that will fold sufficiently quickly but also unfold quickly, and a complex topology that will unfold slowly and hence have kinetic stability, but fold slowly. These observations, together with the established role of kinetic stability in determining resistance to thermal and chemical denaturation as well as proteases, have important implications for understanding fundamental aspects of protein unfolding and folding and for protein engineering and design.


Highly heterogeneous genomic landscape of uterine leiomyomas by whole exome sequencing and genome-wide arrays.
To determine the genomic signatures of human uterine leiomyomas and prevalence of MED12 mutations in human uterine leiomyosarcomas. Retrospective cohort study. Not applicable. This study included a set of 16 fresh frozen leiomyoma and corresponding unaffected myometrium specimens as well as 153 leiomyosarcomas collected from women diagnosed with uterine leiomyomas or leiomyosarcomas who underwent clinically indicated abdominal hysterectomy. None. Whole exome sequencing and high-resolution X-chromosome and whole genome single nucleotide polymorphism microarray analyses were performed on leiomyoma samples negative for the known MED12 mutations and compared with their corresponding myometrium. Leiomyosarcoma specimens were examined for exon 2 MED12 mutations to evaluate the frequency of MED12 mutated leiomyosarcomas. Our results indicate remarkable genomic heterogeneity of leiomyoma lesions. MED12-negative leiomyomas contain copy number alterations involving the Mediator complex subunits such as MED8, MED18, CDK8, and long intergenic nonprotein coding RNA340 (CASC15), which may affect the Mediator architecture and/or its transcriptional activity. We also identified mutations in a number of genes that were implicated in leiomyomagenesis such as COL4A6, DCN, and AHR, as well as novel genes: NRG1, ADAM18, HUWE1, FBXW4, FBXL13, and CAPRIN1. Mutations in genes implicated in cell-to-cell interactions and remodeling of the extracellular matrix and genomic aberrations involving genes coding for the Mediator complex subunits were identified in uterine leiomyomas. Additionally, we discovered that ∼4.6% of leiomyosarcomas harbored MED12 exon 2 mutations, but the relevance of this association with molecular pathogenesis of leiomyosarcoma remains unknown.


Inosine may be an endogenous ligand for benzodiazepine receptors on cultured spinal neurons.
Mouse spinal neurons grown in tissue culture were used to study the membrane effects of the benzodiazepine flurazepam and the naturally occurring purine nucleoside inosine, which competes for benzodiazepine receptor sites in the central nervous system. Application of inosine elicited two types of transmitter-like membrane effects: a rapidly desensitizing excitatory response and a nondesensitizing inhibitory response. Flurazepam produced a similar excitatory response which showed cross-desensitization with the purine excitation. Flurazepam also blocked the inhibitory inosine response. The results provide electrophysiological evidence that an endogenous purine can activate two different conductances on spinal neurons and that flurazepam can activate one of the conductances and antagonize the other.


The effect of Emdogain gel on periodontal regeneration in autogenous transplanted dog's teeth.
The aim of this study was to assess the enamel matrix derivative (EMD) as biomaterial used in autogenous tooth transplantation. The study consisted of 3 beagle dogs, 5 months old, in which six incisors and six premolars were transplanted to mechanically prepared recipient alveolar sockets. One group of teeth was transplanted to a recipient bed, with EMD in the root surface. The second groups of teeth were transplanted using saline solution in the root surface. Every week, clinical examinations were done. Nine weeks later, the animals were killed and the specimens decalcified and prepared for histological and imunohistochemical analysis. Periodontal healing was evaluated by undertaking histomorphometric investigation and analyzed using the Mann- Whitney test (P = 0.05). In both groups, all the transplanted teeth survived. Between the experimental groups, there was statistically significant difference in the complete healing (P = 0.004). There was statistically significant difference between the treatment group in the occurrence of inflammatory root resorption (P = 0.015) and the occurrence of replacement root resorption (P = 0.041). Emdogain gel used on the surface of transplanted teeth improves the occurrence of complete healing and reduces root resorption.


Neuropsychological, Psychiatric, and Functional Correlates of Clinical Trial Enrollment.
Screen failure rates in Alzheimer's disease (AD) clinical trial research are unsustainable, with participant recruitment being a top barrier to AD research progress. The purpose of this project was to understand the neuropsychological, psychiatric, and functional features of individuals who failed screening measures for AD trials. Previously collected clinical data from 38 patients (aged 50-83) screened for a specific industry-sponsored clinical trial of MCI/early AD (Biogen 221AD302, [EMERGE]) were analyzed to identify predictors of AD trial screen pass/fail status. Worse performance on non-memory cognitive domains like crystalized knowledge, executive functioning, and attention, and higher self-reported anxiety, was associated with failing the screening visit for the EMERGE AD clinical trial, whereas we were not able to detect a relationship between screening status and memory performance, self-reported depression, or self-reported daily functioning. By identifying predictors of AD trial screen passing/failure, this research may influence decision-making about which patients are most likely to successfully enroll in a trial, thereby potentially lowering participant burden, maximizing study resources, and reducing costs.


How valid are the responses to nursing home survey questions? Some issues and concerns.
Although surveys are usually piloted before fielding, cognitive-based testing of surveys is not standard practice in nursing home (NH) research. Many terms used in the literature do not have standard definitions and may be interpreted differently by researchers, respondents, and policy makers. The purpose of this study was to ensure that survey respondents understood questions as intended, determine whether the Nursing Home Administrator (NHA) or the Director of Nursing (DON) was better able to answer questions on certain topics, and to inform the answer choices provided for questions. Using existing survey questions and input from experts, we developed surveys to be administered to DONs and NHAs. Cognitive-based interviews were conducted with 45 participants. We took detailed notes during all interviews, and 2 researchers independently coded these notes for key themes. Many terms and concepts routinely used by NH researchers and policy makers, such as "direct-care workers" and "palliative care," were not uniformly interpreted by those managing NHs. For example, respondents' definitions of direct-care workers ranged from nursing assistants to broader categories of clinical and other staff members, including nurses, activities staff, and social workers. We also found NHAs and DONs, at times, did not possess or have access to information the researchers expected them to. Our results may help explain discrepant findings across NH studies. They also underscore the necessity of cognitive-based testing for survey development and have important implications for policy decisions.


Enhanced Wear Resistance of Transparent Epoxy Composite Coatings with Vertically Aligned Halloysite Nanotubes.
The influence of nanoparticle orientation on wear resistance of transparent composite coatings has been studied. Using a nozzle spray coating method, halloysite nanotubes (HNTs) were aligned in the in-plane and out-of-plane directions and in various randomly oriented states. Nanoscratching, falling sand, and Taber Abrasion tests were used to characterize the wear resistance at different length scales. Composites consistently displayed better wear resistance than pure epoxy. Samples with out-of-plane particle orientations exhibited better wear-resistant behavior than those with in-plane particle distributions. In nanoscratching tests, the out-of-plane orientation decreases the normalized scratch volume by as much as 60% compared to pure epoxy. In the falling sand and Taber Abrasion tests, out-of-plane aligned halloysite particles resulted in surfaces with smaller roughness based on stylus profilometry and SEM observations. The decrease in roughness values after these wear tests can be as large as 67% from pure epoxy to composites. Composites with higher out-of-plane particle orientation factors exhibited better light transmittance after sand impingements and other wear tests. This study suggests a useful strategy for producing material systems with enhanced mechanical durability and more durable optical properties.


Improving diagnostic accuracy in pregnancy with individualised, gestational age-specific reference intervals.
Investigations in pregnancy should be interpreted using pregnancy-specific reference intervals (RIs). However, because of the progressive nature of pregnancy, even pregnancy-specific RIs may not be equally representative at different gestations. We proposed that gestational age-specific RIs may increase diagnostic accuracy over those with fixed limits. The trajectory of platelets was mapped in 32,778 pregnant women, using 116,798 results. Then we evaluated the accuracy with which a low measurement in early pregnancy (<3rd centile) predicted thrombocytopaenia at term, compared to the existing limit (<150 × 109/L). Platelets fell by 14.8% between 8 and 40 weeks. Platelets below the 3rd centile before 20 weeks predicted thrombocytopaenia at term (<100 × 109/L) with a significantly greater degree of accuracy than a fixed limit (AUC 0.86 vs. 0.76, p = 0.004). Pregnancy-specific RIs can be defined using routinely collected hospital data, and the abundance of such freely available data enables a detailed investigation of temporal changes throughout gestation. Individualised RIs offer improved accuracy profiles, over and above those already derived specifically from pregnant populations. Clinicians should consider how this may be used to improve diagnostic accuracy for biomarkers used in current clinical practice, and those yet to be defined.


Forceps delivery volumes in teaching and nonteaching hospitals: are volumes sufficient for physicians to acquire and maintain competence?
The decline in the use of forceps in operative deliveries over the last two decades raises questions about teaching hospitals' ability to provide trainees with adequate experience in the use of forceps. The authors examined (1) the number of operative deliveries performed in teaching and nonteaching hospitals, and (2) whether teaching hospitals performed a sufficient number of forceps deliveries for physicians to acquire and maintain competence. The authors used State Inpatient Data from nine states to identify all women hospitalized for childbirth in 2008. They divided hospitals into three categories: major teaching, minor teaching, and nonteaching. They calculated delivery volumes (total operative, cesarean, vacuum, forceps, two or more methods) for each hospital and compared data across hospital categories. The sample included 1,344,305 childbirths in 835 hospitals. The mean cesarean volumes for major teaching, minor teaching, and nonteaching hospitals were 969.8, 757.8, and 406.9. The mean vacuum volumes were 301.0, 304.2, and 190.4, and the mean forceps volumes were 25.2, 15.3, and 8.9. In 2008, 31 hospitals (3.7% of all hospitals) performed no vacuum extractions, and 320 (38.3%) performed no forceps deliveries. In 2008, 13 (23%) major teaching and 44 (44%) minor teaching hospitals performed five or fewer forceps deliveries. Low forceps delivery volumes may preclude many trainees from acquiring adequate experience and proficiency. These findings highlighted broader challenges, faced by many specialties, in ensuring that trainees and practicing physicians acquire and maintain competence in infrequently performed, highly technical procedures.


Neoehrlichia mikurensis in Danish immunocompromised patients: a retrospective cohort study.
The tick-borne bacterium, Neoehrlichia mikurensis (N. mikurensis) can cause severe febrile illness and thromboembolic complications in immunocompromised individuals. We investigated the presence of N. mikurensis DNA in retrospectively collected plasma from a well-characterized cohort of Danish immunocompromised patients. Plasma samples from 239 patients with immune dysfunction related to hematological or rheumatological disease or due to immunosuppressive therapy, were retrieved from a transdisciplinary biobank (PERSIMUNE) at Rigshospitalet, Copenhagen, Denmark. Serving as immunocompetent controls, plasma samples from 192 blood donors were included. All samples were collected between 2015 and 2019. Real-time PCR targeting the groEL gene was used to detect N. mikurensis DNA. Sequencing was used for confirmation. Borrelia burgdorferi sensu lato IgG antibodies were detected by ELISA as a proxy of tick exposure. Prevalence was compared using Fisher's exact test. Neoehrlichia mikurensis DNA was detected in 3/239 (1.3%, 95% confidence interval (CI): 0.3 - 3.6%) patients, all of whom primarily had a hematological disease. Follow-up samples of these patients were negative. N. mikurensis DNA was not detected in any of the blood donor samples. IgG antibodies against B. burgdorferi s.l. were detected with similar prevalence in immunocompromised patients and blood donors, i.e., 18/239 (7.5%, 95% CI: 4.8-11.5%) and 11/192 (5.7%, 95%: CI 3.2-10.0%). In this study, patients with N. mikurensis were not identified by clinical indication and N. mikurensis may therefore be underdiagnosed in Danish patients. Further investigations are needed to explore the clinical significance and implications of this infection.


N-Nitroso compounds and childhood brain tumors: a case-control study.
We questioned mothers of 209 young brain tumor patients and mothers of 209 controls about experiences of possible etiological relevance which they had during pregnancy or which their children had while growing up. Long-suspected brain tumor risk factors such as head trauma and X-rays appeared to be factors for relatively few cases. Increased risk was associated with maternal contact with nitrosamine-containing substances such as burning incense (odds ratio, 3.3; p = 0.005), sidestream cigarette smoke (odds ratio, 1.5; p = 0.03), and face makeup (odds ratio, 1.6; p = 0.02); with maternal use of diuretics (odds ratio, 2.0; p = 0.03) and antihistamines (odds ratio, 3.4; p = 0.002); and with the level of maternal consumption of cured meats (p = 0.008). These drugs contain nitrosatable amines and amides, and the cured meats contain nitrites, chemicals which are precursors of N-nitroso compounds. We propose a hypothesis that brain tumors in these young people are related to in utero exposure to N-nitroso compounds and their precursors, the most potent nervous system carcinogens known in experimental animals.


Blinding Trachoma: Systematic Review of Rates and Risk Factors for Progressive Disease.
Sight loss from trachoma is the end result of a scarring disease process starting in early childhood and characterised by repeated episodes of conjunctival inflammation (active trachoma). Subsequently, the conjunctiva becomes scarred, causing the eyelashes to turn inwards and scratch the cornea (trichiasis), damaging the corneal surface and leading to corneal opacification and visual impairment. It is thought that this process is initiated and driven by repeated infection with Chlamydia trachomatis. We review published longitudinal studies to re-examine the disease process, its progression rates and risk factors. We searched PubMed for studies presenting incidence and progression data for the different stages of trachoma natural history. We only included studies reporting longitudinal data and identified 11 publications meeting this criterion. The studies were very heterogeneous in design, disease stage, duration, size and location, precluding meta-analysis. Severe conjunctival inflammation was consistently associated with incident and progressive scarring in five studies in which this was examined. One study reported an association between C. trachomatis infection and incident scarring. No studies have yet demonstrated an association between C. trachomatis infection and progressive scarring. Several studies conducted in regions with low prevalence active disease and C. trachomatis infection found evidence of on-going scarring progression. Overall, there are few longitudinal studies that provide estimates of progression rates and risk factors, reflecting the challenges of conducting such studies. Our understanding of this disease process and the long-term impact of control measures is partial. Intense conjunctival inflammation was consistently associated with scarring, however, direct evidence demonstrating an association between C. trachomatis and progression is limited. This suggests that on-going chlamydial reinfection may not be mandatory for progression of established scarring, indicating that sight threatening trichiasis may continue to evolve in older people in formerly endemic populations, that will require service provision for years after active disease is controlled.


Is pain the price of empathy? The perception of others' pain in patients with congenital insensitivity to pain.
Empathy is a complex form of psychological inference that enables us to understand the personal experience of another person through cognitive/evaluative and affective processes. Recent findings suggest that empathy for pain may involve a 'mirror-matching' simulation of the affective and sensory features of others' pain. Despite such evidence for a shared representation of self and other pain at the neural level, the possible influence of the observer's own sensitivity to pain upon his perception of others' pain has not been investigated yet. The aim of this study was to explore how patients with congenital insensitivity to pain (CIP), who are largely deprived of common stimulus-induced pain experiences, perceive the pain of others. Ratings of verbally presented imaginary painful situations showed that CIP patients' semantic knowledge regarding the pain of others did not differ from control subjects. Moreover, the propensity to infer pain from facial expressions was very similar between CIP patients and control subjects. On the other hand, when asked to rate pain-inducing events seen in video clips in the absence of visible or audible pain-related behaviour, CIP patients showed more variable and significantly lower pain ratings, as well as a reduction in aversive emotional responses, compared with control subjects. Interestingly, pain judgements, inferred either from facial pain expressions or from pain-inducing events, were strongly related to inter-individual differences in emotional empathy among CIP patients, while such correlation between pain judgement and empathy was not found in control subjects. The results suggest that a normal personal experience of pain is not necessarily required for perceiving and feeling empathy for others' pain. In the absence of functional somatic resonance mechanisms shaped by previous pain experiences, others' pain might be greatly underestimated, however, especially when emotional cues are lacking, unless the observer is endowed with sufficient empathic abilities to fully acknowledge the suffering experience of others in spite of his own insensitivity.


Home vs hospital treatment of low-risk venous thromboembolism: a systematic review and meta-analysis.
Increasing evidence supports the safety and effectiveness of managing low-risk deep vein thrombosis (DVT) or pulmonary embolism (PE) in outpatient settings. We performed a systematic review to assess safety and effectiveness of managing patients with DVT or PE at home compared with the hospital. Medline, Embase, and Cochrane databases were searched up to July 2019 for relevant randomized clinical trials (RCTs), and prospective cohort studies. Two investigators independently screened titles and abstracts of identified citations and extracted data from relevant full-text papers. Risk ratios (RRs) were calculated, and certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Seven RCTs (1922 patients) were included in meta-analyses on managing patients with DVT. Pooled estimates indicated decreased risk of PE (RR = 0.64; 95% confidence interval [CI], 0.44-0.93) and recurrent DVT (RR = 0.61; 95% CI, 0.42-0.90) for home management, both with moderate certainty of the evidence. Reductions in mortality and major bleeding were not significant, both with low certainty of the evidence. Two RCTs (445 patients) were included in meta-analyses on home management of low-risk patients with PE. Pooled estimates indicated no significant difference in all-cause mortality, recurrent PE, and major bleeding, all with low certainty of the evidence. Results of pooled estimates from 3 prospective cohort studies (234 patients) on home management of PE showed similar results. Our findings indicate that low-risk DVT patients had similar or lower risk of patient-important outcomes with home treatment compared with hospital treatment. In patients with low-risk PE, there was important uncertainty about a difference between home and hospital treatment.


MicroRNA-30 regulates left ventricular hypertrophy in chronic kidney disease.
Left ventricular hypertrophy (LVH) is a primary feature of cardiovascular complications in patients with chronic kidney disease (CKD). miRNA-30 is an important posttranscriptional regulator of LVH, but it is unknown whether miRNA-30 participates in the process of CKD-induced LVH. In the present study, we found that CKD not only resulted in LVH but also suppressed miRNA-30 expression in the myocardium. Rescue of cardiomyocyte-specific miRNA-30 attenuated LVH in CKD rats without altering CKD progression. Importantly, in vivo and in vitro knockdown of miRNA-30 in cardiomyocytes led to cardiomyocyte hypertrophy by upregulating the calcineurin signaling directly. Furthermore, CKD-related detrimental factors, such as fibroblast growth factor-23, uremic toxin, angiotensin II, and transforming growth factor-β, suppressed cardiac miRNA-30 expression, while miRNA-30 supplementation blunted cardiomyocyte hypertrophy induced by such factors. These results uncover a potentially novel mechanism of CKD-induced LVH and provide a potential therapeutic target for CKD patients with LVH.


Evaluating treatments with topical anaesthetic and buccal meloxicam for pain and inflammation caused by amputation dehorning of calves.
To assess the effects of a topical anaesthetic (TA) and buccal meloxicam (BM) on behaviour, maximum wound temperature and wound morphology following amputation dehorning of beef calves, 50 unweaned Hereford calves were randomly allocated to: (1) sham dehorning / control (CON, n = 14); (2) amputation dehorning (D, n = 12); (3) amputation dehorning with pre-operative buccal meloxicam (DBM, n = 12); and (4) amputation dehorning with post-operative topical anaesthetic (DTA, n = 12). Videos of the calves were captured for 3 h following treatment. Each calf was later observed for 5 min every hour and the frequency and duration of specific behaviours displayed during these focal periods was recorded. Infrared and digital photographs of dehorning wounds were collected from all dehorned calves on days 1, 3 and 7 following treatment. Infrared photographs were used to identify the maximum temperature within the wound area. Digital photographs were used to score wounds based on visual signs of inflammation and healing, using a numerical rating scale of 1 to 3, with morphological aspects of inflammation increasing and morphological aspects of healing decreasing with progressive scores. CON calves displayed fewer head shakes than all dehorned calves at 2 and 3 h following treatment (P = 0.025). CON and DTA calves displayed less head turns than DBM calves at 2 h following treatment (P = 0.036). CON calves displayed fewer combined point behaviours than all dehorned calves at 2 h following treatment (P = 0.037). All dehorning wounds had a greater maximum temperature on days 3 and 7 compared to day 1 (P = 0.003). All wound morphology scores decreased from day 1 to day 3 and wound morphology scores of DBM and DTA calves increased from day 3 to day 7 (P = 0.03). Although flystrike may have confounded these observations, no clear effects of TA or BM on behaviour, maximum wound temperature or wound morphology following dehorning of calves were observed. Further research is required to evaluate the analgesic efficacy of these products for amputation dehorning of calves.


Fabrication of extended-release patient-tailored prednisolone tablets via fused deposition modelling (FDM) 3D printing.
Rapid and reliable tailoring of the dose of controlled release tablets to suit an individual patient is a major challenge for personalized medicine. The aim of this work was to investigate the feasibility of using a fused deposition modelling (FDM) based 3D printer to fabricate extended release tablet using prednisolone loaded poly(vinyl alcohol) (PVA) filaments and to control its dose. Prednisolone was loaded into a PVA-based (1.75 mm) filament at approximately 1.9% w/w via incubation in a saturated methanolic solution of prednisolone. The physical form of the drug was assessed using differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). Dose accuracy and in vitro drug release patterns were assessed using HPLC and pH change flow-through dissolution test. Prednisolone loaded PVA filament demonstrated an ability to be fabricated into regular ellipse-shaped solid tablets using the FDM-based 3D printer. It was possible to control the mass of printed tablet through manipulating the volume of the design (R(2) = 0.9983). On printing tablets with target drug contents of 2, 3, 4, 5, 7.5 and 10mg, a good correlation between target and achieved dose was obtained (R(2) = 0.9904) with a dose accuracy range of 88.7-107%. Thermal analysis and XRPD indicated that the majority of prednisolone existed in amorphous form within the tablets. In vitro drug release from 3D printed tablets was extended up to 24h. FDM based 3D printing is a promising method to produce and control the dose of extended release tablets, providing a highly adjustable, affordable, minimally sized, digitally controlled platform for producing patient-tailored medicines.


T cell recognition of HIV synthetic peptides in a natural infection.
Because T cell responses are critical for defense against viral infections, a series of synthetic peptides derived from the predicted sequence for HIV-1 proteins gp41, pg120, gag, and viral polymerase were used to test the T cell proliferative response of HIV-1 seropositive individuals. Of HIV-1-infected donors from various clinical categories 90% (27/30) had sensitized cells that proliferated in response to at least one of 21 HIV peptides tested. Cells from HIV seronegative controls did not proliferate (0/9) in response to these HIV peptides. Individuals with fewer clinical manifestations of HIV-1 disease responded to a greater number of peptides (average for asymptomatic seropositives = 8.1 peptides; AIDS patients averaged 2.0). The number of peptides recognized also correlated with absolute number of CD4+ cells, but not with delayed cutaneous hypersensitivity to a (non-HIV) battery of Ag. However, clinical stage at no time correlated with the response to any particular peptide. Response patterns differed considerably among individuals, and some peptides stimulated proliferation in many (48%) HIV-infected donors (peptides gp41-2 and pol-3), whereas another peptide elicited no T cell response in any donor tested (peptide gp120-8). We have also begun to investigate the basis for individual heterogeneity of T lymphocyte proliferative responses of HIV-infected donors to the 21 HIV synthetic peptides. Peptide structure and HLA class II determinants both influenced patterns of lymphocyte responses. Reactivity correlated with peptide size, the presence of alpha and beta secondary structure and lack of reverse turn potential. Hydropathy and charge had no predictive value. Peptides derived from HIV sequences that vary highly among strains tended to be recognized less frequently. HIV-infected lymphocyte donors were HLA typed to examine the influence of the MHC on T lymphocyte proliferation. Analysis of the frequencies of individuals reacting to specific peptides, when compared to the allele frequencies in the population at large, indicated association of some responses to DR alleles. More DR association was observed with peptides that showed "moderate" reactivity than with those that were "highly" reactive. We suggest that highly reactive peptides are capable of forming a structure closer to an "ideal" T cell epitope that can associate with many DR alleles. In contrast, "moderately" reactive determinants have less favorable structures for interaction, are more limited in their ability to interact and therefore show more restriction to specific class II alleles.


Nativity differentials in first births in the United States: Patterns by race and ethnicity.
While recent decades have seen gradual convergence in ethno-racial disparities in completed fertility in the United States, differences in the age pattern of first births remain. The role of nativity has not been fully understood. This paper examines how first births vary by nativity, and how this variation contributes to more significant racial and ethnic differentials. Using data from the National Survey of Family Growth (1997-2017), we jointly estimate the correlates of the timing of first births and childlessness. We assess differences between immigrants and US-born and child-migrant women across ethno-racial groups. The unique first-birth patterns among foreign-born women have a notable impact on Hispanics, reducing differences from Whites in the average age at first birth and contributing to more significant differentials in childlessness. The impact of immigrant women on White and Black first births is more modest in scope. Our work shows the importance of nativity for ethnic/racial disparities in the timing and quantum of fertility in the United States. We demonstrate how the migrant population is more determinant for Hispanic fertility patterns than for Black or White. We conclude by elaborating on the implications of these results for future research as the immigrant population in the United States becomes ethnically and racially more diverse.


Use of a computerized guideline for glucose regulation in the intensive care unit improved both guideline adherence and glucose regulation.
To measure the impact of a computerized guideline for glucose regulation in an ICU. A randomized, controlled trial with an off-on-off design. We implemented a glucose regulation guideline in an intensive care unit in paper form during the first study period. During the second period, the guideline was randomly applied in either paper or computerized form. In the third period, the guideline was available only in paper form. We analyzed data for 484 patients. During the intervention period, the control group included 54 patients and the computerized intervention group included 66 patients. The two guideline-related outcome measures consisted of compliance with: (a) glucose measurement timing recommendations and (b) insulin dose advice. We measured clinical impact as the proportion of time that glucose levels fell within target range. In the first (paper-based) study period, 29.0% of samples occurred with optimal timing; during the second period, this increased to 35.5% for paper-based and to 40.2% for computerized protocols. The third study period timeliness scores reverted to the first period rates. Late (suboptimal) sampling occurred for 66% of glucose measurements in the first study period, for 42% of paper-based and 28% of computer-based protocol samples in the second period, and for 50.0% of samples in the third study period. In the first study period, insulin-dosing guideline compliance was 56.3%; in the second period, it was 64.2% for paper-based and 77.3% for computer-based protocols, and it fell to 42.4% in the third period. For the second study period, the time that a patient's glucose values fell within target range improved for both the control (52.9%) and the computerized groups (54.2%) compared with the first study period (44.3%) and the third period (42.3%). Implementing a computerized version of a guideline significantly improved timeliness of measurements and glucose level regulation for critically ill patients compared with implementing a paper-based version of the guideline.


Ratiometric fluorescent probes based on through-bond energy transfer of cyanine donors to near-infrared hemicyanine acceptors for mitochondrial pH detection and monitoring of mitophagy.
Two ratiometric near-infrared fluorescent probes have been developed to selectively detect mitochondrial pH changes based on highly efficient through-bond energy transfer (TBET) from cyanine donors to near-infrared hemicyanine acceptors. The probes consist of identical cyanine donors connected to different hemicyanine acceptors with a spirolactam ring structure linked via a biphenyl linkage. At neutral or basic pH, the probes display only fluorescence of the cyanine donors when they are excited at 520 nm. However, acidic pH conditions trigger spirolactam ring opening, leading to increased π-conjugation of the hemicyanine acceptors, resulting in new near-infrared fluorescence peaks at 740 nm and 780 nm for probes A and B, respectively. This results in ratiometric fluorescence responses of the probes to pH changes indicated by decreases of the donor fluorescence and increases of the acceptor fluorescence under donor excitation at 520 nm due to a highly efficient TBET from the donors to the acceptors. The probes only show cyanine donor fluorescence in alkaline-pH mitochondria. However, the probes show moderate fluorescence decreases of the cyanine donor and considerable fluorescence increases of hemicyanine acceptors during the mitophagy process induced by nutrient starvation or under drug treatment. The probes display rapid, selective, and sensitive responses to pH changes over metal ions, good membrane penetration, good photostability, large pseudo-Stokes shifts, low cytotoxicity, mitochondria-targeting, and mitophagy-tracking capabilities.


Persistent oxidative stress in the corpus mucosa is evoked by long-term treatment of H. pylori-infected patients with proton pump inhibitors.
To examine the influence of long-term treatment of H. pylori-infected patients with proton pump inhibitors (PPI) on the toxic oxidant production in the stomach. Eight H. pylori-positive patients with gastric ulcer were enrolled, and tissue samples were obtained endoscopically from the antrum and corpus. The tissue contents of neutrophil myeloperoxidase (MPO) and oxygen-derived free radicals were quantified by ELISA and chemiluminescence (ChL) assay. The H. pylori density in the tissue specimens was scored by immunohistochemistry and the mucosal infiltration by neutrophils and monocytes was scored by histopathology. The effects of PPI on these parameters were evaluated by oral administration of lansoprazole (LPZ) at the dose of 30mg od for 8 weeks, followed by 15mg for 24 weeks. Eight-week treatment with LPZ significantly increased the corpus ChL by 400%, which remained unchanged at this level during the subsequent 24 weeks, but the antrum ChL decreased slightly following LPZ-treatment. No significant changes in the mucosal MPO activity or the histologically determined parameters of H. pylori density and neutrophil/monocyte infiltration were observed in either portion of the stomach. The mucosal oxidative stress level significantly increased in the corpus mucosa after long-term treatment with LPZ, which may be independent of inflammatory cell infiltration.


Classifying adolescent attention-deficit/hyperactivity disorder (ADHD) based on functional and structural imaging.
Attention-deficit/hyperactivity disorder (ADHD) is a common disabling psychiatric disorder associated with consistent deficits in error processing, inhibition and regionally decreased grey matter volumes. The diagnosis is based on clinical presentation, interviews and questionnaires, which are to some degree subjective and would benefit from verification through biomarkers. Here, pattern recognition of multiple discriminative functional and structural brain patterns was applied to classify adolescents with ADHD and controls. Functional activation features in a Flanker/NoGo task probing error processing and inhibition along with structural magnetic resonance imaging data served to predict group membership using support vector machines (SVMs). The SVM pattern recognition algorithm correctly classified 77.78% of the subjects with a sensitivity and specificity of 77.78% based on error processing. Predictive regions for controls were mainly detected in core areas for error processing and attention such as the medial and dorsolateral frontal areas reflecting deficient processing in ADHD (Hart et al., in Hum Brain Mapp 35:3083-3094, 2014), and overlapped with decreased activations in patients in conventional group comparisons. Regions more predictive for ADHD patients were identified in the posterior cingulate, temporal and occipital cortex. Interestingly despite pronounced univariate group differences in inhibition-related activation and grey matter volumes the corresponding classifiers failed or only yielded a poor discrimination. The present study corroborates the potential of task-related brain activation for classification shown in previous studies. It remains to be clarified whether error processing, which performed best here, also contributes to the discrimination of useful dimensions and subtypes, different psychiatric disorders, and prediction of treatment success across studies and sites.


Recent advances in the understanding and therapeutic management of mastocytosis.
Mastocytosis is a rare disease due to the abnormal accumulation of mast cells in various tissues. Its clinical presentation is heterogeneous depending on mast cell infiltration and mediators release. In some cases, it is associated with hematological malignancies. Prognosis varies from very good with a life expectancy similar to the general population in indolent forms of the disease to a survival time of just a few months in mast cell leukemia. Although in most cases a somatic KIT D816V mutation is found in tumor mast cells, the physiopathology of the disease is not yet fully understood. Additional germline and somatic mutations may explain this heterogeneity. Treatments aim at blocking effect of mast cell mediators, reducing mast cell activation and tumor burden. New drugs mainly directed against the tyrosine kinase activity of KIT have dramatically changed the quality of life and prognosis of mast cell diseases. Present and future therapeutic strategies are discussed in this review.


Pupil-linked arousal determines variability in perceptual decision making.
Decision making between several alternatives is thought to involve the gradual accumulation of evidence in favor of each available choice. This process is profoundly variable even for nominally identical stimuli, yet the neuro-cognitive substrates that determine the magnitude of this variability are poorly understood. Here, we demonstrate that arousal state is a powerful determinant of variability in perceptual decision making. We measured pupil size, a highly sensitive index of arousal, while human subjects performed a motion-discrimination task, and decomposed task behavior into latent decision making parameters using an established computational model of the decision process. In direct contrast to previous theoretical accounts specifying a role for arousal in several discrete aspects of decision making, we found that pupil diameter was uniquely related to a model parameter representing variability in the rate of decision evidence accumulation: Periods of increased pupil size, reflecting heightened arousal, were characterized by greater variability in accumulation rate. Pupil diameter also correlated trial-by-trial with specific patterns of behavior that collectively are diagnostic of changing accumulation rate variability, and explained substantial individual differences in this computational quantity. These findings provide a uniquely clear account of how arousal state impacts decision making, and may point to a relationship between pupil-linked neuromodulation and behavioral variability. They also pave the way for future studies aimed at augmenting the precision with which people make decisions.


A rat excised larynx model of vocal fold scar.
To develop and evaluate a rat excised larynx model for the measurement of acoustic, aerodynamic, and vocal fold vibratory changes resulting from vocal fold scar. Twenty-four 4-month-old male Sprague-Dawley rats were assigned to 1 of 4 experimental groups: chronic vocal fold scar, chronic vocal fold scar treated with 100-ng basic fibroblast growth factor (bFGF), chronic vocal fold scar treated with saline (sham treatment), and unscarred untreated control. Following tissue harvest, histological and immunohistochemical data were collected to confirm extracellular matrix alteration in the chronic scar group; acoustic, aerodynamic, and high-speed digital imaging data were collected using an excised larynx setup in all groups. Phonation threshold pressure (P(th)), glottal resistance (R(g)), glottal efficiency (E(g)), vibratory amplitude, and vibratory area were used as dependent variables. Chronically scarred vocal folds were characterized by elevated collagen Types I and III and reduced hyaluronic acid abundance. Phonation was achieved, and data were collected from all control and bFGF-treated larynges; however, phonation was not achieved with 3 of 6 chronically scarred and 1 of 6 saline-treated larynges. Compared with control, the chronic scar group was characterized by elevated P(th), reduced E(g), and intralarynx vibratory amplitude and area asymmetry. The bFGF group was characterized by P(th) below control-group levels, E(g) comparable with control, and vocal fold vibratory amplitude and area symmetry comparable with control. The sham group was characterized by P(th) comparable with control, E(g) superior to control, and vocal fold vibratory amplitude and area symmetry comparable with control. The excised larynx model reported here demonstrated robust deterioration across phonatory indices under the scar condition and sensitivity to treatment-induced change under the bFGF condition. The improvement observed under the sham condition may reflect unanticipated therapeutic benefit or artifact. This model holds promise as a tool for the functional characterization of biomechanical tissue changes resulting from vocal fold scar and the evaluation of experimental therapies.


Real-time photodisplacement microscope for high-sensitivity simultaneous surface and subsurface inspection.
We have developed a new photodisplacement microscope system for practical use that achieves high-sensitivity simultaneous real-time imaging of surface and subsurface structures from a single space-frequency multiplexed interferogram. In this system a linear region of photothermal displacement is excited on the sample surface for subsurface imaging by a line-focused intensity-modulated laser beam. Surface information such as reflectivity and topography along with the displacement is detected with a charge-coupled device sensor-based parallel heterodyne interferometer. Surface and subsurface information components are space-frequency multiplexed into the sensor signal as orthogonal functions based on a frequency-optimized undersampling scheme, allowing each to be discretely reproduced by using a real-time Fourier analysis technique. Preliminary experiments demonstrate that this system is effective, simultaneously imaging reflectivity, topography, and photodisplacement for the detection of subsurface lattice defects in silicon, at a remarkable speed of only 0.26 s/256x256 pixel area. This new microscope is promising for nondestructive hybrid surface and subsurface inspection and other applications.


Chain dynamics in a hexadecane melt as seen by neutron scattering and identified by molecular dynamics simulations.
Different local and global chain dynamics in a C(16)H(34) melt could be revealed by resolution resolved time-of-flight quasielastic neutron scattering and complementary molecular dynamics simulations. Thereby it has been demonstrated that the measured intermediate scattering functions can validate the simulated data on the pico- to nanosecond timescale. Remarkably the shape of the experimentally measured intermediate scattering functions can be reproduced excellently by molecular dynamics simulations. It was found that although the extracted apparent activation energy corresponds to the long-range diffusion value, the molecular dynamics in this time range are mainly due to local bond rotations and the rotation of entire molecules.


Quality indicators as a tool in improving the introduction of new medicines.
Quality indicators are increasingly used as a tool to achieve safe and quality clinical care, cost-effective therapy, for professional learning, remuneration, accreditation and financial incentives. A substantial number focus on drug therapy but few address the introduction of new medicines even though this is a burning issue. The objective was to describe the issues and challenges in designing and implementing a transparent indicator framework and evaluation protocol for the introduction of new medicines and to provide guidance on how to apply quality indicators in the managed entry of new medicines. Quality indicators need to be developed early to assess whether new medicines are introduced appropriately. A number of key factors need to be addressed when developing, applying and evaluating indicators including dimensions of quality, suggested testing protocols, potential data sources, key implementation factors such as intended and unintended consequences, budget impact and cost-effectiveness, assuring the involvement of the medical professions, patients and the public, and reliable and easy-to-use computerized tools for data collection and management. Transparent approaches include the need for any quality indicators developed to handle conflict of interests to enhance their validity and acceptance. The suggested framework and indicator testing protocol may be useful in assessing the applicability of indicators for new medicines and may be adapted to healthcare settings worldwide. The suggestions build on existing literature to create a field testing methodology that can be used to produce country-specific quality indicators for new medicines as well as a cross international approach to facilitate access to new medicines.


Functional impairment in protein kinase C by RACK1 (receptor for activated C kinase 1) deficiency in aged rat brain cortex.
Several laboratories have reported a lack of protein kinase C (PKC) activation in response to various stimuli in the brain of aged rats. It has been suggested that changes in lipid membrane composition could be related to this functional deficit. However, recent evidence has indicated that the translocation of PKC to the different subcellular compartments is controlled by protein-protein interactions. Recently, a class of proteins, termed receptors for activated C kinase (RACKs), have been described that bind PKC. The present study was conducted to determine whether alterations in RACK1, the best-characterized member of RACKs, were associated with changes in translocation and expression of PKC. Quantitative immunoblotting revealed that RACK1 content was decreased by approximately 50% in aged rat brain cortex, compared with that in adult and middle-aged animals. The levels of calcium-independent PKC delta and epsilon, interacting with RACK1, and related calcium-independent PKC activity were not modified by the aging process. By comparison, phorbol ester-stimulated translocation of this activity and of PKC delta and epsilon immunoreactivity was absent in cortex from aged animals, as well as the translocation of the calcium-dependent PKC beta, also known to interact with RACK1. These results indicate that a deficit in RACK1 may contribute to the functional impairment in PKC activation observed in aged rat brain.


D-dimer assays--a help or hindrance in suspected pulmonary thromboembolism assessment?
Suspected pulmonary thromboembolism (PTE) is a common presentation to acute medical units and can cause diagnostic difficulty. National guidelines on PTE management highlight the need for clinical probability assessment and D-dimer assays to ensure appropriate use of diagnostic imaging. D-dimers are used widely in UK hospitals, yet concern exists regarding their misuse. In this study we aimed to assess the impact of the introduction of D-dimer assays, combined with clinical probability assessment, for evaluation of suspected PTE in our unit. This was a prospective audit of all patients presenting with suspected PTE over two 12-week periods, exactly 1 year apart. D-dimers were introduced into our unit between these two periods. We recorded the clinical probability score, potential causes of false-positive D-dimer assay, diagnostic imaging result, patient outcome, admission rates, and length of inpatient stay. Categorical variables were compared using a 2 x 2 chi-square test or Fisher's exact test. Groups were compared utilizing the two-sample t-test or Mann-Whitney U test. A total of 190 patients were included in the study; 65% were female. PTE was confirmed in 8.4%. Patients in both audit periods were comparable with regard to suitability for D-dimer measurement. Following D-dimer introduction, 40 out of 110 patients in period 2 could be discharged directly from the emergency department. Of those admitted to hospital, the median length of stay was significantly reduced in period 2 (3 days in period 1 vs 1 day in period 2; P=0.0007). Use of diagnostic imaging was significantly reduced following the introduction of D-dimers (90% in period 1 vs 40% in period 2; P<0.0001). The positive diagnostic yield for PTE on CT pulmonary angiogram (CTPA) increased significantly from 10% in period 1 to 23% in period 2 (P=0.039). D-dimers must be used judiciously in the assessment of suspected PTE. Appropriate use of D-dimers can provide many benefits, including reductions in diagnostic imaging (and thus radiation exposure), admission rates, and length of inpatient stay.


Amitriptyline in the treatment of fibromyalgia: a systematic review of its efficacy.
The objective of this study was to assess the efficacy and safety of amitriptyline as a treatment of FM. A comprehensive computerized search in Medline (Pubmed), EMBASE and The Cochrane Library was performed. Randomized controlled trials (RCTs) comparing amitriptyline vs placebo in adult patients suffering from FM were identified, the methodological quality was assessed and the results of the main outcomes were evaluated. Ten RCTs were identified. Large clinical variability and statistical heterogeneity precluded quantitative meta-analysis. Overall, the study quality was moderate to high. Amitriptyline 25 mg/day (six RCTs) demonstrated a therapeutic response compared with placebo in the domains of pain, sleep, fatigue and overall patient and investigator impression. This benefit was generally seen at 6-8 weeks of treatment but no effect was noted at 12 weeks. Amitriptyline 50 mg/day (four RCTs) did not demonstrate a therapeutic effect compared with placebo. Neither dose of amitriptyline had an effect on tender points count. No clear statements on adverse events with amitriptyline can be made due to inconsistencies in data among the studies. A definitive clinical recommendation regarding the efficacy of amitriptyline for FM symptoms cannot be made. There is some evidence to support the short-term efficacy of amitriptyline 25 mg/day in FM. There is no evidence to support the efficacy of amitriptyline at higher doses or for periods >8 weeks. More stringent RCTs with longer follow-up periods are required to determine the long-term efficacy and safety of the amitriptyline and define its role in the multidisciplinary management of FM.


Lay epidemiology and the interpretation of low-risk drinking guidelines by adults in the United Kingdom.
To explore how the concept of lay epidemiology can enhance understandings of how drinkers make sense of current UK drinking guidelines. Qualitative study using 12 focus groups in four sites in northern England and four sites in central Scotland. Participants were 66 male and female drinkers, aged between 19 and 65 years, of different socio-economic backgrounds. Data were analysed thematically using a conceptual framework of lay epidemiology. Current drinking guidelines were perceived as having little relevance to participants' drinking behaviours and were generally disregarded. Daily guidelines were seen as irrelevant by drinkers whose drinking patterns comprised heavy weekend drinking. The amounts given in the guidelines were seen as unrealistic for those motivated to drink for intoxication, and participants measured alcohol intake in numbers of drinks or containers rather than units. Participants reported moderating their drinking, but this was out of a desire to fulfil work and family responsibilities, rather than concerns for their own health. The current Australian and Canadian guidelines were preferred to UK guidelines, as they were seen to address many of the above problems. Drinking guidelines derived from, and framed within, solely epidemiological paradigms lack relevance for adult drinkers who monitor and moderate their alcohol intake according to their own knowledge and risk perceptions derived primarily from experience. Insights from lay epidemiology into how drinkers regulate and monitor their drinking should be used in the construction of drinking guidelines to enhance their credibility and efficacy.


Gliomatosis peritonei: the value of a "second look" operation.
The case history of a 10-year-old black girl with gliomatosis peritonei, Grade 0, is presented. The primary tumour was resected and a "second look" operation carried out 3 months later. The glial implants demonstrated distinct circumferential and intra glial fibrosis (resolution). Because the peritoneal implants had undergone resolution, further therapy became unnecessary. We believe gliomatosis peritonei fully justifies a second laparotomy in order to be able to accurately grade the implants. The grade of the peritoneal implants influences the prognosis and therefore determines the type of therapy to be instituted.


STIM1 overexpression promotes colorectal cancer progression, cell motility and COX-2 expression.
Tumor metastasis is the major cause of death among cancer patients, with >90% of cancer-related death attributable to the spreading of metastatic cells to secondary organs. Store-operated Ca(2+) entry (SOCE) is the predominant Ca(2+) entry mechanism in most cancer cells, and stromal interaction molecule 1 (STIM1) is the endoplasmic reticulum (ER) Ca(2+) sensor for store-operated channels. Here we reported that the STIM1 was overexpressed in colorectal cancer (CRC) patients. STIM1 overexpression in CRC was significantly associated with tumor size, depth of invasion, lymph node metastasis status and serum levels of carcinoembryonic antigen. Furthermore, ectopic expression of STIM1 promoted CRC cell motility, while depletion of STIM1 with short hairpin RNA inhibited CRC cell migration. Our data further suggested that STIM1 promoted CRC cell migration through increasing the expression of cyclooxygenase-2 (COX-2) and production of prostaglandin E2 (PGE2). Importantly, ectopically expressed COX-2 or exogenous PGE2 were able to rescue migration defect in STIM1 knockdown CRC cells, and inhibition of COX-2 with ibuprofen and indomethacin abrogated STIM1-mediated CRC cell motility. In short, our data provided clinicopathological significance for STIM1 and SOCE in CRC progression, and implicated a role for COX-2 in STIM1-mediated CRC metastasis. Our studies also suggested a new approach to inhibit STIM1-mediated metastasis with COX-2 inhibitors.


Effect of Bariatric Surgery on CKD Risk.
Obesity is linked to the development and progression of CKD, but whether bariatric surgery protects against CKD is poorly understood. We, therefore, examined whether bariatric surgery influences CKD risk. The study included 2144 adults who underwent bariatric surgery from March of 2006 to April of 2009 and participated in the Longitudinal Assessment of Bariatric Surgery-2 Study cohort. The primary outcome was CKD risk categories as assessed by the Kidney Disease Improving Global Outcomes (KDIGO) consortium criteria using a combination of eGFR and albuminuria. Patients were 79% women and 87% white, with a median age of 46 years old. Improvements were observed in CKD risk at 1 and 7 years after surgery in patients with moderate baseline CKD risk (63% and 53%, respectively), high baseline risk (78% and 56%, respectively), and very high baseline risk (59% and 23%, respectively). The proportion of patients whose CKD risk worsened was ≤10%; five patients developed ESRD. Sensitivity analyses using year 1 as baseline to minimize the effect of weight loss on serum creatinine and differing eGFR equations offered qualitatively similar results. Treatment with bariatric surgery associated with an improvement in CKD risk categories in a large proportion of patients for up to 7 years, especially in those with moderate and high baseline risk. These findings support consideration of CKD risk in evaluation for bariatric surgery and further study of bariatric surgery as a treatment for high-risk obese patients with CKD.


Turkish assessment of SURF (SUrvey of Risk Factor Management) study: Control rates of cardiovascular risk factors derived from databases of 15 different levels of health centers in Turkey.
The aim of this study was to evaluate the adherence to recommendations for secondary prevention and the achievement of treatment targets for the control of risk factors in patients with established coronary heart disease (CHD) who were followed-up at various healthcare facilities in Turkey. According to the protocol of the international Survey of Risk Factor Management study, questionnaire forms were completed and demographic, anthropometric, and laboratory data of CHD patients who were followed-up at a total of 15 selected primary, secondary, and tertiary healthcare centers were recorded. Among a total of 724 CHD patients (69.8% male; mean age: 63.3±10.7 years) included in the study, 18.4% were current smokers, only 19.1% had normal body mass index, and 22.1% had waist circumference below the limit of abdominal obesity. Physical activity was insufficient in 53% of the patients, 47.3% had low high-density lipoprotein cholesterol value, 46% had triglyceride level above 150 mg/dL, and 67% had glycated hemoglobin value of 6.5% or above. Of all the patients, 88.1% were using antiplatelet drugs, 71.4% were using beta-blockers, 55.7% were using statins, and 41.9% were using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Blood pressure was under control in 56.7% of the hypertensive patients using antihypertensive drugs, and the proportion of diabetic patients who reached glycemic control targets using antidiabetic drugs was 35.9%. Low-density lipoprotein cholesterol was below 70 mg/dL in 12.2% of the patients using statins. According to the data obtained, among Turkish CHD patients, the control rate of cardiovascular risk factors is low, and implementation of the recommendations regarding lifestyle modification and medication use for secondary prevention in the current guidelines are insufficient.


Widespread natural variation of DNA methylation within angiosperms.
DNA methylation is an important feature of plant epigenomes, involved in the formation of heterochromatin and affecting gene expression. Extensive variation of DNA methylation patterns within a species has been uncovered from studies of natural variation. However, the extent to which DNA methylation varies between flowering plant species is still unclear. To understand the variation in genomic patterning of DNA methylation across flowering plant species, we compared single base resolution DNA methylomes of 34 diverse angiosperm species. By analyzing whole-genome bisulfite sequencing data in a phylogenetic context, it becomes clear that there is extensive variation throughout angiosperms in gene body DNA methylation, euchromatic silencing of transposons and repeats, as well as silencing of heterochromatic transposons. The Brassicaceae have reduced CHG methylation levels and also reduced or loss of CG gene body methylation. The Poaceae are characterized by a lack or reduction of heterochromatic CHH methylation and enrichment of CHH methylation in genic regions. Furthermore, low levels of CHH methylation are observed in a number of species, especially in clonally propagated species. These results reveal the extent of variation in DNA methylation in angiosperms and show that DNA methylation patterns are broadly a reflection of the evolutionary and life histories of plant species.


Assessing coral health and disease from digital photographs and in situ surveys.
Methods for monitoring the status of marine communities are increasingly adopting the use of images captured in the field. However, it is not always clear how data collected from photographic images relate to historic data collected using traditional underwater visual census methods. Here, we compare coral health and disease data collected in situ by scuba divers with photographic images collected simultaneously at 12 coral reef sites. Five globally relevant coral diseases were detected on 194 colonies from in situ surveys and 79 colonies from photos, whilst 698 colonies from in situ surveys and 535 colonies from photos exhibited signs of compromised health other than disease. Comparisons of in situ surveys with photographic analyses indicated that the number of disease cases occurring in the examined coral populations (prevalence) was six times higher (4.5 vs. 0.8% of colonies), whilst compromised health was three times higher (14 vs. 4% of colonies) from in situ surveys. Skeletal eroding band disease, sponge overgrowth and presence of Waminoa flatworms were not detected in photographs, though they were identified in situ. Estimates of black band disease and abnormally pigmented coral tissues were similar between the two methods. Estimates of the bleached and healthy colonies were also similar between methods and photographic analyses were a strong predictor of bleached (r 2 = 0.8) and healthy (r 2 = 0.5) colony prevalence from in situ surveys. Moreover, when data on disease and compromised health states resulting in white or pale coral colony appearance were pooled, the prevalence of 'white' colonies from in situ (14%) and photographic analyses (11%) were statistically similar. Our results indicate that information on coral disease and health collected by in situ surveys and photographic analyses are not directly comparable, with in situ surveys generally providing higher estimates of prevalence and greater ability to identify some diseases and compromised states. Careful sampling of photographs can however identify signs of coral stress, including some coral diseases, which may be used to trigger early-warning management interventions.


Harmonising the response to DSBs: a new string in the ATM bow.
Ataxia telangiestasia mutated protein (ATM) is the major kinase that initiates the DNA damage signal transduction response following exposure to ionising radiation (IR) in mammalian cells. DNA non-homologous end-joining (NHEJ) is the most significant double strand break (DSB) repair pathway in mammalian cells. ATM-defective cell lines display cell cycle checkpoint defects and show pronounced radiosensitivity. ATM signalling was previously thought to be dispensable for NHEJ. This review discusses recent findings that ATM activates an end-processing mechanism dependent upon Artemis, a nuclease that also functions to cleave the hairpin intermediate generated during V(D)J recombination. ATM/Artemis-dependent end-processing is required for the repair of a sub-fraction (approximately 10%) of DSBs induced by IR and makes a significant contribution to survival following exposure to ionising radiation. This result represents a new role for ATM and demonstrates a novel cross communication between the DNA repair and signal transduction machinery.


Updating the natural history of human papillomavirus and anogenital cancers.
This chapter addresses the natural history of anogenital human papillomavirus (HPV) infection. Cervical infections are the best understood HPV infection. Cervical HPV persistence is the known necessary event for the development of cervical cancer. New infections appearing at any age are benign unless they persist. Several long-term natural history studies have now shed light on the very low risk of cervical intraepithelial neoplasia (CIN) 3+ in women past the peak of HPV acquisition (e.g., 30 or older) who are HPV-negative or clear their HPV. Although data on transmission of HPV are finally emerging, rates of transmission between heterosexual couples vary widely among studies. Factors that affect the calculations of these rates include a) intervals between testing points, b) rates of concordance or discordance at baseline, and c) difficulty in defining established infections versus contamination. Both cervix to anus and anus to cervix autoinoculation in the same woman appears to be quite common. Whether either site serves as a long-term reservoir is unknown. Studies show that anal infections in women and in men who have sex with men are quite common with cumulative rates up to 70-90%. Similarly, clearance of anal HPV is also common, with few individuals showing persistence unless they are human immunodeficiency virus (HIV)-infected. HIV strongly influences the development of anal intraepithelial neoplasia (AIN). The few studies on the natural history of AIN in HIV-infected men suggest that high-grade AIN is a precursor to invasive anal cancer. Although no natural history studies of AIN are available in women, women with other HPV-associated lesions, including CIN3+ and vulvar cancer, have higher rates of anal cancer. Data on the natural history of HPV of the male genitalia are also emerging, although penile intraepithelial neoplasia is poorly understood. Cumulative rates of HPV are extremely high in men and risks are associated with sexual behavior. Unlike women, prevalence rates are steady across all ages, suggesting that men do not develop protection against reinfection. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.


Treatment of thermomechanical pulping condensate using thermophilic and mesophilic sequencing batch reactors.
In-mill thermophilic treatment of individual wastewater streams to achieve water system closure has received much attention in pulp and paper mills. Aerobic biological treatment of thermomechanical pulping (TMP) condensate was conducted using thermophilic (55 °C) and mesophilic (35 °C) sequencing batch reactors (SBRs) for a period of 143 days at a cyclic time of 6, 8 and 12 h. A soluble chemical oxygen demand (SCOD) removal efficiency of 77 to 91% was achieved, given an organic loading rate of 0.7-1.3 kg/m³ d. The COD removal efficiency of the thermophilic SBR was slightly lower than that of the mesophilic SBR. Majority of the soluble COD was removed by biodegradation with a small portion (9-13%) of soluble COD stripped by aeration. The settleability (sludge volume index) and the flocculating ability (effluent suspended solids) of thermophilic sludge were comparable to or slightly poorer than that of the mesophilic sludge. The level of filaments in thermophilic sludge was usually higher than that in mesophilic sludge. The results of the study indicate that both thermophilic and mesophilic SBRs can be successfully operated for in-mill treatment of TMP condensate. The treated effluent has the potential for subsequent reuse in the mill.