Helicobacter pylori Depletes Cholesterol in Gastric Glands to Prevent Interferon Gamma Signaling and Escape the Inflammatory Response.
Despite inducing an inflammatory response, Helicobacter pylori can persist in the gastric mucosa for decades. H pylori expression of cholesterol-α-glucosyltransferase (encoded by cgt) is required for gastric colonization and T-cell activation. We investigated how cgt affects gastric epithelial cells and the host immune response. MKN45 gastric epithelial cells, AGS cells, and human primary gastric epithelial cells (obtained from patients undergoing gastrectomy or sleeve resection or gastric antral organoids) were incubated with interferon gamma (IFNG) or interferon beta (IFNB) and exposed to H pylori, including cagPAI and cgt mutant strains. Some cells were incubated with methyl-β-cyclodextrin (to deplete cholesterol from membranes) or myriocin and zaragozic acid to prevent biosynthesis of sphingolipids and cholesterol and analyzed by immunoblot, immunofluorescence, and reverse transcription quantitative polymerase chain reaction analyses. We compared gene expression patterns among primary human gastric cells, uninfected or infected with H pylori P12 wt or P12Δcgt, using microarray analysis. Mice with disruption of the IFNG receptor 1 (Ifngr1-/- mice) and C57BL6 (control) mice were infected with PMSS1 (wild-type) or PMSS1Δcgt H pylori; gastric tissues were collected and analyzed by reverse transcription quantitative polymerase chain reaction or confocal microscopy. In primary gastric cells and cell lines, infection with H pylori, but not cgt mutants, blocked IFNG-induced signaling via JAK and STAT. Cells infected with H pylori were depleted of cholesterol, which reduced IFNG signaling by disrupting lipid rafts, leading to reduced phosphorylation (activation) of JAK and STAT1. H pylori infection of cells also blocked signaling by IFNB, interleukin 6 (IL6), and IL22 and reduced activation of genes regulated by these signaling pathways, including cytokines that regulate T-cell function (MIG and IP10) and anti-microbial peptides such as human β-defensin 3 (hBD3). We found that this mechanism allows H pylori to persist in proximity to infected cells while inducing inflammation only in the neighboring, non-infected epithelium. Stomach tissues from mice infected with PMSS1 had increased levels of IFNG, but did not express higher levels of interferon-response genes. Expression of the IFNG-response gene IRF1 was substantially higher in PMSS1Δcgt-infected mice than PMSS1-infected mice. Ifngr1-/- mice were colonized by PMSS1 to a greater extent than control mice. H pylori expression of cgt reduces cholesterol levels in infected gastric epithelial cells and thereby blocks IFNG signaling, allowing the bacteria to escape the host inflammatory response. These findings provide insight into the mechanisms by which H pylori might promote gastric carcinogenesis (persisting despite constant inflammation) and ineffectiveness of T-cell-based vaccines against H pylori.


Binding of peripheral proteins to mixed lipid membranes: effect of lipid demixing upon binding.
Binding isotherms have been determined for the association of horse heart cytochrome c with dioleoyl phosphatidylglycerol (DOPG)/dioleoyl phosphatidylcholine (DOPC) bilayer membranes over a range of lipid compositions and ionic strengths. In the absence of protein, the DOPG and DOPC lipids mix nearly ideally. The binding isotherms have been analyzed using double layer theory to account for the electrostatics, either the Van der Waals or scaled particle theory equation of state to describe the protein surface distribution, and a statistical thermodynamic formulation consistent with the mass-action law to describe the lipid distribution. Basic parameters governing the electrostatics and intrinsic binding are established from the binding to membranes composed of anionic lipid (DOPG) alone. Both the Van der Waals and scaled particle equations of state can describe the effects of protein distribution on the DOPG binding isotherms equally well, but with different values of the maximum binding stoichiometry (13 lipids/protein for Van der Waals and 8 lipids/protein for scaled particle theory). With these parameters set, it is then possible to derive the association constant, Kr, of DOPG relative to DOPC for surface association with bound cytochrome c by using the binding isotherms obtained with the mixed lipid membranes. A value of Kr (DOPG:DOPC) = 3.3-4.8, depending on the lipid stoichiometry, is determined that consistently describes the binding at different lipid compositions and different ionic strengths. Using the value of Kr obtained it is possible to derive the average in-plane lipid distribution and the enhancement in protein binding induced by lipid redistribution using the statistical thermodynamic theory.


Loss of Hepatic Oscillatory Fed microRNAs Abrogates Refed Transition and Causes Liver Dysfunctions.
Inability to mediate fed-fast transitions in the liver is known to cause metabolic dysfunctions and diseases. Intuitively, a failure to inhibit futile translation of state-specific transcripts during fed-fast cycles would abrogate dynamic physiological transitions. Here, we have discovered hepatic fed microRNAs that target fasting-induced genes and are essential for a refed transition. Our findings highlight the role of these fed microRNAs in orchestrating system-level control over liver physiology and whole-body energetics. By targeting SIRT1, PGC1α, and their downstream genes, fed microRNAs regulate metabolic and mitochondrial pathways. MicroRNA expression, processing, and RISC loading oscillate during these cycles and possibly constitute an anticipatory mechanism. Fed-microRNA oscillations are deregulated during aging. Scavenging of hepatic fed microRNAs causes uncontrolled gluconeogenesis and failure in the catabolic-to-anabolic switching upon feeding, which are hallmarks of metabolic diseases. Besides identifying mechanisms that enable efficient physiological toggling, our study highlights fed microRNAs as candidate therapeutic targets.


Egg cell-secreted EC1 triggers sperm cell activation during double fertilization.
Double fertilization is the defining characteristic of flowering plants. However, the molecular mechanisms regulating the fusion of one sperm with the egg and the second sperm with the central cell are largely unknown. We show that gamete interactions in Arabidopsis depend on small cysteine-rich EC1 (EGG CELL 1) proteins accumulating in storage vesicles of the egg cell. Upon sperm arrival, EC1-containing vesicles are exocytosed. The sperm endomembrane system responds to exogenously applied EC1 peptides by redistributing the potential gamete fusogen HAP2/GCS1 (HAPLESS 2/GENERATIVE CELL SPECIFIC 1) to the cell surface. Furthermore, fertilization studies with ec1 quintuple mutants show that successful male-female gamete interactions are necessary to prevent multiple-sperm cell delivery. Our findings provide evidence that mutual gamete activation, regulated exocytosis, and sperm plasma membrane modifications govern flowering plant gamete interactions.


Effect of Early Adult Patterns of Physical Activity and Television Viewing on Midlife Cognitive Function.
Sedentary behaviors and physical inactivity are not only increasing worldwide but also are critical risk factors for adverse health outcomes. Yet, few studies have examined the effects of sedentary behavior on cognition or the long-term role of either behavior in early to middle adulthood. To investigate the association between 25-year patterns of television viewing and physical activity and midlife cognition. Prospective study of 3247 adults (black and white races; aged 18-30 years) enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study (March 25, 1985, to August 31, 2011). Data analysis was performed June 1, 2014, through April 15, 2015. We assessed television viewing and physical activity at repeated visits (≥3 assessments) over 25 years using a validated questionnaire. A 25-year pattern of high television viewing was defined as watching TV above the upper baseline quartile (>3 hours/d) for more than two-thirds of the visits, and a 25-year pattern of low physical activity was defined as activity levels below the lower, sex-specific baseline quartile for more than two-thirds of the of the visits. We evaluated cognitive function at year 25 using the Digit Symbol Substitution Test (DSST), Stroop test, and Rey Auditory Verbal Learning Test. At baseline, the mean (SD) age of the 3247 study participants was 25.1 (3.6) years, 1836 (56.5%) were female, 1771 (54.5%) were white, and 3015 (92.9%) had completed at least high school. Compared with participants with low television viewing, those with high television viewing during 25 years (353 of 3247 [10.9%]) were more likely to have poor cognitive performance (<1 SD below the race-specific mean) on the DSST and Stroop test, with findings reported as adjusted odds ratio (95% CI): DSST, 1.64 (1.21-2.23) and Stroop test, 1.56 (1.13-2.14), but not the Rey Auditory Verbal Learning Test, adjusted for age, race, sex, educational level, smoking, alcohol use, body mass index, and hypertension. Low physical activity during 25 years in 528 of 3247 participants (16.3%) was significantly associated with poor performance on the DSST, 1.47 (1.14-1.90). Compared with participants with low television viewing and high physical activity, the odds of poor performance were almost 2 times higher for adults with both high television viewing and low physical activity in 107 of 3247 (3.3%) (DSST, 1.95 [1.19-3.22], and Stroop test, 2.20 [1.36-3.56]). High television viewing and low physical activity in early adulthood were associated with worse midlife executive function and processing speed. This is one of the first studies to demonstrate that these risk behaviors may be critical targets for prevention of cognitive aging even before middle age.


Clinical and morphologic correlation after stapled transanal rectal resection for obstructed defecation syndrome.
The clinical and morphologic outcome of patients with obstructed defecation syndrome after stapled transanal rectal resection was prospectively evaluated. Twenty-four consecutive patients (22 women; median age, 61 (range, 36-74) years) who suffered from obstructed defecation syndrome and with rectal redundancy on magnetic resonance defecography were enrolled in the study. Constipation was assessed by using the Cleveland Constipation Score. Morphologic changes were determined by using closed-configuration magnetic resonance defecography before and after stapled transanal rectal resection. After a median follow-up of 18 (range, 6-36) months, Cleveland Constipation Score significantly decreased from 11 (range, 1-23) preoperatively to 5 (range, 1-15) postoperatively (P = 0.02). In 15 of 20 patients, preexisting intussusception was no longer visible in the magnetic resonance defecography. Anterior rectoceles were significantly reduced in depth, from 30 mm to 23 mm (P = 0.01), whereas the number of detectable rectoceles did not significantly change. Complications occurred in 6 of the 24 patients; however, only two were severe (1 bleeding and 1 persisting pain requiring reintervention). Clinical improvement of obstructed defecation syndrome after stapled transanal rectal resection correlates well with morphologic correction of the rectal redundancy, whereas correction of intussusception seems to be of particular importance in patients with obstructed defecation syndrome.


Oxidation of pharmaceuticals during ozonation of municipal wastewater effluents: a pilot study.
To reduce the release of pharmaceuticals and endocrine disruptors into the aquatic environment or to remove them from wastewater intended for direct or indirect reuse, the application of advanced wastewater treatment may be required. In the present study, municipal wastewater effluents were treated with ozone (O3) in a pilot-scale plant consisting of two bubble columns. The investigated effluents, which varied in suspended solids concentrations, comprised an effluent of conventional activated sludge treatment (CAS), the same effluent dosed with 15 mg of TSS L(-1) of activated sludge (CAS + SS), and the effluent of a membrane bioreactor pilot plant (MBR). Selected classes of pharmaceuticals were spiked in the wastewater at realistic levels ranging from 0.5 to 5 microg L(-1). Samples taken at the inlet and the outlet of the pilot plant were analyzed with liquid chromatography (LC)-electrospray tandem mass spectrometry (MS). Macrolide and sulfonamide antibiotics, estrogens, and the acidic pharmaceuticals diclofenac, naproxen, and indomethacin were oxidized by more than 90-99% for O3 doses > or = 2 mg L(-1) in all effluents. X-ray contrast media and a few acidic pharmaceuticals were only partly oxidized, but no significant differences were observed among the three effluents. These results show that many pharmaceuticals present in wastewater can be efficiently oxidized with O3 and that suspended solids have only a minor influence on the oxidation efficiency of nonsorbing micropollutants.


Food commercials increase preference for energy-dense foods, particularly in children who watch more television.
Our aim was to determine if levels of television viewing (a proxy measure for habitual commercial exposure) affect children's food preference responses to television food commercials. A total of 281 children aged 6 to 13 years from northwest England viewed toy or food television commercials followed by a cartoon on 2 separate occasions; they then completed 3 food preference measures, a commercial recognition task, and a television viewing questionnaire. After viewing the food commercials, all children selected more branded and nonbranded fat-rich and carbohydrate-rich items from food preference checklists compared with after viewing the toy commercials. The food preferences of children with higher habitual levels of television viewing were more affected by food commercial exposure than those of low television viewers. After viewing food commercials, high television viewing children selected a greater number of branded food items compared with after the toy commercials as well as compared with the low television viewers. Children correctly recognized more food commercials than toy commercials. Exposure to television food commercials enhanced high television viewers' preferences for branded foods and increased reported preferences for all food items (branded and nonbranded) relative to the low television viewers. This is the first study to demonstrate that children with greater previous exposure to commercials (high television viewers) seemed to be more responsive to food promotion messages than children with lower previous advertising exposure.


Clinical characteristics of and response to combination chemotherapy and subsequent application of international prognostic index in non-Hodgkin's lymphoma--an experience from a medical center in Southern Taiwan.
A retrospective analysis was performed of 117 non-Hodgkin's lymphoma (NHL) patients (72 male and 45 female, mean age 55 years) treated at NCKUH between July 1988 and December 1993. Of the 115 patients who could be classified by Ann Arbor staging system, 26 patients (22.2%) were in stage 1; 23 (19.7%) in stage 2; 29 (24.8%) in stage 3; and 37 (31.6%) in stage 4. According to the International Working Formulation, three patients (2.6%) were low grade NHL, 90 (76.9%) were intermediate, and 8 (6.8%) were high grade NHL. Histologically, diffuse large cell NHL accounted for 52.1% of cases, followed by 16.2% of cases exhibiting diffuse mixed NHL. Immunophenotype analysis was available in 95 cases, which revealed 76 (80%) cases exhibiting B-cell origin, 17 (18%) cases exhibiting diffuse mixed NHL. Immunophenotype analysis was available in 95 cases, which revealed 76 (80%) cases exhibiting B-cell origin, 17 (18%) cases exhibiting T-cell origin and 2 (2%) cases were of null cell type. All patients underwent two groups of induction chemotherapy, either CHOP (Cyclophosphamide, Epirubicin, Oncovin, and Prednisolone), or "modified" COPBLAM (Cyclophosphamide, Epirubicin, Oncovin, and Prednisolone), or "modified" COPBLAM (Cyclophosphamide, Epirubicin, Oncovin, Vinblastine, Bleomycin, Procarbazine, and Prednisolone). Seventy-two cases treated through COPBLAM and 45 cases treated through CHOP were evaluated. The response rate (RR) to COPBLAM treatment was 72.2% and was 68.9% for the CHOP group (P = 0.51). The 5-year overall survival rate (OAS) was 44.1% for COPBLAM, versus 40% for CHOP (P = 0.15). The disease-free survival (DFS) was 72.6% at 63 months for COPBLAM and 58% at 51 months for CHOP (P = 0.16). Neither B cell nor T-cell lineages of NHL showed any statistical difference in RR (P = 0.53, DFS (P = 0.58) or OAS (P = 0.97) to the different treatments. Using multiple logistic analysis, two independent factors, high LDH and advanced stage, were found to adversely affect the rate of complete remission. The application of the International Prognostic Index to our patients needs modification, which suggests the necessity of more evaluation before it can accurately be applied to all international series of NHL.


Small sample sizes reduce the replicability of task-based fMRI studies.
Despite a growing body of research suggesting that task-based functional magnetic resonance imaging (fMRI) studies often suffer from a lack of statistical power due to too-small samples, the proliferation of such underpowered studies continues unabated. Using large independent samples across eleven tasks, we demonstrate the impact of sample size on replicability, assessed at different levels of analysis relevant to fMRI researchers. We find that the degree of replicability for typical sample sizes is modest and that sample sizes much larger than typical (e.g., N = 100) produce results that fall well short of perfectly replicable. Thus, our results join the existing line of work advocating for larger sample sizes. Moreover, because we test sample sizes over a fairly large range and use intuitive metrics of replicability, our hope is that our results are more understandable and convincing to researchers who may have found previous results advocating for larger samples inaccessible.


Sodium-glucose cotransporter 2 inhibition does not reduce hepatic steatosis in overweight, insulin-resistant patients without type 2 diabetes.
Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming the leading indication for liver transplant and is associated with increased cardiovascular and liver mortality, yet there are no licensed therapies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used for their glucose-lowering effects in patients with type 2 diabetes (T2D). Preclinical models have suggested a beneficial impact on NAFLD, but clinical data are limited, and there are currently no data on patients without T2D. We aimed to investigate the impact of SGLT2 inhibition on NAFLD in overweight, nondiabetic patients and establish the effect these agents may have on the processes that regulate hepatic steatosis in vivo. We conducted an open-label, experimental medicine pilot study on insulin-resistant overweight/obese individuals (n = 10) using gold-standard noninvasive assessments of NAFLD phenotype, including magnetic resonance spectroscopy, two-step hyperinsulinemic euglycemic clamps, and stable isotope tracers to assess lipid and glucose metabolism. Investigations were performed before and after a 12-week treatment with the SGLT2 inhibitor, dapagliflozin. Despite a body weight reduction of 4.4 kg, hepatic steatosis was unchanged following treatment. Hepatic glucose production increased, and there was impairment of glucose disposal during the low-dose insulin infusion. Although circulating, nonesterified, fatty acid levels did not change, the ability of insulin to suppress lipolysis was reduced. SGLT2 inhibition for 12 weeks does not improve hepatic steatosis in patients without T2D. Additional studies in patients with established T2D or impairments of fasting or postprandial glucose homeostasis are needed to determine whether SGLT2 inhibition represents a viable therapeutic strategy for NAFLD. (http://clinicaltrials.gov Number NCT02696941).


Low-threshold, slow-inactivating Na+ potentials in the cockroach giant axon.
Electrophysiological properties of the ventral giant axon in the abdominal nerve cord of the cockroach were studied by recording intracellular potentials following partial or complete block of the K+ conductance. When the K+ conductance was completely blocked by tetraethylammonium (TEA) and 3,4-diaminopyridine, the intensity of depolarizing currents necessary for eliciting the action potential was markedly decreased, and the action potential was followed by a prolonged plateau potential. During the plateau potential following the spike, the input resistance was significantly reduced. The plateau potential was not affected by changing the external Ca2+ concentration but depended on the external Na+ concentration in a manner expected from the Nernst equation and was blocked by tetrodotoxin (TTX). During the plateau potential, the Na+ conductance responsible for the spike was inactivated, whereas immediately after the plateau potential a newly evoked spike was not followed by a plateau potential, suggesting different inactivation kinetics between the spike and plateau Na+ conductances. When the K+ conductance was partially blocked by TEA alone, slow depolarizing responses were evoked at voltage levels a few millivolts more positive than the resting potential. The "threshold" for the slow potential was much lower than that for the spike potential. The slow potential produced after partial block of the K+ conductance was not affected by alterations of the external Ca2+ concentration but was blocked by TTX or in a Na+-free solution. Even in normal medium, a small TTX-sensitive depolarizing response was discernible. This response was similar in its time course and threshold to the slow potential observed after partial block of the K+ conductance. It is concluded that the cockroach giant axon has two populations of Na+ channels, which can be distinguished by differences in time course and voltage levels for activation and that the slow, low-threshold Na+-dependent potential is largely masked by delayed increases in the K+ conductance under normal conditions. It remains uncertain whether the low-threshold slow potential and the plateau potential originate from the same or different populations of Na+ channels.


Smoke-free laws and smoking and drinking among college students.
Little is known about the impact of smoke-free legislation on smoking and drinking alcohol among college students. The purpose was to examine whether strength and duration of municipal smoke-free laws are associated with cigarette and alcohol use among college students. Full-time undergraduates from two Southeastern universities participated in mailed (Site A) or electronic (Site B) surveys assessing tobacco and alcohol use and other risk behaviors pre and post comprehensive municipal smoke-free laws (Site A, N = 1,366. Site B, N = 1,404). The first cohort at each site participated prior to a municipal smoke-free law in the community. The second survey was conducted post-law (Site A, 3.5 years, Site B, 8 months). Past 30-day cigarette and alcohol use and other demographic and personal characteristics were assessed. At Site A, controlling for demographic differences and current alcohol use, the odds of being a current smoker were 32% lower post-law (28% pre-law vs. 19% post-law; odds ratio = 0.68, P = 0.02). At Site B, with demographics and drinking status in the model, the decrease in smoking rate from pre- to post-law was not significant. At both sites, controlling for demographics and current smoking status, change in the likelihood of drinking was not significant. Comprehensive smoke-free laws in the surrounding community may reduce smoking rates among college students who live, work and recreate there, particularly after the laws are well-established. While alcohol prevalence is very high among college students, enacting smoke-free legislation was not associated with alcohol use.


Evaluation of whether the ACE gene I/D polymorphism constitutes a risk factor for chronic obstructive pulmonary disease in the Turkish population.
Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow obstruction that occurs as a result of the normal inflammatory process to protect against harmful irritants and chemicals. Another physiological regulatory process, the renin angiotensin system (RAS), plays an important role in the pathology of many diseases. Angiotensin converting enzyme (ACE) is a key enzyme of RAS. We investigated the frequency of the ACE gene I/D polymorphism in patients with COPD in Turkey. This study was performed on 47 unrelated patients with COPD and 64 healthy subjects. DNA samples were isolated from peripheral blood, and ACE DNA was amplified by polymerase chain reaction. The frequencies of ACE genotypes were 27.7, 55.3, and 17% for DD, ID, and II in the COPD group, respectively, and 43.8, 43.8, and 12.4% in the control group. There was no statistically significant difference between groups (X(2) = 3.078; df = 2; P = 0.220). The distributions of ACE gene D alleles were 38.2% (N = 52) in the COPD group and 61.8% (N = 84) in the control group; and those of I alleles were 48.8% (N = 42) in the COPD group and 51.2% (N = 44) in the control group. There was no statistically significant difference between groups for allele frequency (X(2) = 2.419; df = 2; P = 0.120). We believe these results can be useful for large-scale population genetic research considering the frequency of the ACE gene variation in COPD patients in the Turkish population.


Follow-up of patients with adrenal incidentaloma, in accordance with the European society of endocrinology guidelines: Could we be safe?
Recently, the European Society of Endocrinology (ESE) published new guidelines on the management of adrenal incidentalomas. At the same time Lopez and coworkers published on the Annals of Internal Medicine an important study showing that even patients with non-functioning adrenal tumors have an increased risk of incident diabetes. In consideration of previous data and of the results of the study of Lopez and coworkers, some points emerge from the ESE Guidelines that deserve attention. Firstly, it must be observed that the term "autonomous cortisol secretion," introduced by the ESE Panel in the place of the commonly used "subclinical hypercortisolism," seems questionable, since the guidelines do not suggest determining the adrenocorticotroph hormone levels that could give the certain proof of a truly autonomous cortisol secretion. Secondly, the ESE Guidelines suggest against repeated hormonal workup in AI patients with a normal hormonal secretion at initial evaluation, but also in those with a "possible autonomous cortisol secretion," if in the absence of comorbidities potentially related to hypercortisolism. Thirdly, the ESE Guidelines suggest against further imaging during follow-up in patients with an adrenal mass below 4 cm in size with clear benign features on imaging studies. Considering the available literature data that are briefly summarized in this comment, we believe that no sufficient evidence is available to date for giving sharp-cutting recommendations about the uselessness of a biochemical and morphological follow-up in AI patients, even in those with initially benign and not hypersecreting adrenal adenomas. However, if a recommendation has to be given on the basis of the present evidences, we should suggest to biochemically and morphologically follow-up AI patients for at least 5 years.


Coincidence of a novel KCNJ11 missense variant R365H with a paternally inherited 6q24 duplication in a patient with transient neonatal diabetes.
Neonatal diabetes is a heterogeneous group of disorders with diabetes manifestation in the first 6 months of life. The most common etiology in permanent neonatal diabetes is mutations of the ATP-sensitive K(+) channel subunits; in transient neonatal diabetes, chromosome 6q24 abnormalities are the most common cause. We report a sporadic case of diabetes without ketoacidosis diagnosed on the fourth day of life. Analysis of the KCNJ11 gene found a novel R365H mutation in the proband and her unaffected father. The functional analysis did not support pathogenicity of this variant. When the patient's diabetes remitted in the seventh month of life, the 6q24 region was analyzed and a paternally inherited duplication was identified. Our case reports a coincidental novel KCNJ11 variant in a patient with transient neonatal diabetes due to a 6q24 duplication, illustrating the difficulty in testing neonates before the clinical course of neonatal diabetes is known.


Implications of Raman scattering and phase noise on multiple four-wave mixing processes in an optical fiber.
Implications of spontaneous and stimulated Raman scattering (SSRS) and phase noise on the spatial evolution of multiple-order sidebands arising from four-wave mixing (FWM) along the length of an optical fiber are investigated. A modified split-step Fourier method is used to solve the governing coupled nonlinear Schrödinger equations. The phase noise overcomes the depletive nature of SSRS and stabilizes the FWM sidebands, in good agreement with experimental results.


The transferome of metabolic genes explored: analysis of the horizontal transfer of enzyme encoding genes in unicellular eukaryotes.
Metabolic networks are responsible for many essential cellular processes, and exhibit a high level of evolutionary conservation from bacteria to eukaryotes. If genes encoding metabolic enzymes are horizontally transferred and are advantageous, they are likely to become fixed. Horizontal gene transfer (HGT) has played a key role in prokaryotic evolution and its importance in eukaryotes is increasingly evident. High levels of endosymbiotic gene transfer (EGT) accompanied the establishment of plastids and mitochondria, and more recent events have allowed further acquisition of bacterial genes. Here, we present the first comprehensive multi-species analysis of E/HGT of genes encoding metabolic enzymes from bacteria to unicellular eukaryotes. The phylogenetic trees of 2,257 metabolic enzymes were used to make E/HGT assertions in ten groups of unicellular eukaryotes, revealing the sources and metabolic processes of the transferred genes. Analyses revealed a preference for enzymes encoded by genes gained through horizontal and endosymbiotic transfers to be connected in the metabolic network. Enrichment in particular functional classes was particularly revealing: alongside plastid related processes and carbohydrate metabolism, this highlighted a number of pathways in eukaryotic parasites that are rich in enzymes encoded by transferred genes, and potentially key to pathogenicity. The plant parasites Phytophthora were discovered to have a potential pathway for lipopolysaccharide biosynthesis of E/HGT origin not seen before in eukaryotes outside the Plantae. The number of enzymes encoded by genes gained through E/HGT has been established, providing insight into functional gain during the evolution of unicellular eukaryotes. In eukaryotic parasites, genes encoding enzymes that have been gained through horizontal transfer may be attractive drug targets if they are part of processes not present in the host, or are significantly diverged from equivalent host enzymes.


Simultaneous multi-slice readout-segmented echo planar imaging for accelerated diffusion-weighted imaging of the breast.
Readout-segmented echo planar imaging (rs-EPI) significantly reduces susceptibility artifacts in diffusion-weighted imaging (DWI) of the breast compared to single-shot EPI but is limited by longer scan times. To compensate for this, we tested a new simultaneous multi-slice (SMS) acquisition for accelerated rs-EPI. After approval by the local ethics committee, eight healthy female volunteers (age, 38.9 ± 13.1 years) underwent breast MRI at 3T. Conventional as well as two-fold (2× SMS) and three-fold (3× SMS) slice-accelerated rs-EPI sequences were acquired at b-values of 50 and 800 s/mm(2). Two independent readers analyzed the apparent diffusion coefficient (ADC) in fibroglandular breast parenchyma. The signal-to-noise ratio (SNR) was estimated based on the subtraction method. ADC and SNR were compared between sequences by using the Friedman test. The acquisition time was 4:21 min for conventional rs-EPI, 2:35 min for 2× SMS rs-EPI and 1:44 min for 3× SMS rs-EPI. ADC values were similar in all sequences (mean values 1.62 × 10(-3)mm(2)/s, p=0.99). Mean SNR was 27.7-29.6, and no significant differences were found among the sequences (p=0.83). SMS rs-EPI yields similar ADC values and SNR compared to conventional rs-EPI at markedly reduced scan time. Thus, SMS excitation increases the clinical applicability of rs-EPI for DWI of the breast.


Extended-gate field-effect transistor (EG-FET) with molecularly imprinted polymer (MIP) film for selective inosine determination.
A novel recognition unit of chemical sensor for selective determination of the inosine, renal disfunction biomarker, was devised and prepared. For that purpose, inosine-templated molecularly imprinted polymer (MIP) film was deposited on an extended-gate field-effect transistor (EG-FET) signal transducing unit. The MIP film was prepared by electrochemical polymerization of bis(bithiophene) derivatives bearing cytosine and boronic acid substituents, in the presence of the inosine template and a thiophene cross-linker. After MIP film deposition, the template was removed, and was confirmed by UV-visible spectroscopy. Subsequently, the film composition was characterized by spectroscopic techniques, and its morphology and thickness were determined by AFM. The finally MIP film-coated extended-gate field-effect transistor (EG-FET) was used for signal transduction. This combination is not widely studied in the literature, despite the fact that it allows for facile integration of electrodeposited MIP film with FET transducer. The linear dynamic concentration range of the chemosensor was 0.5-50 μM with inosine detectability of 0.62 μM. The obtained detectability compares well to the levels of the inosine in body fluids which are in the range 0-2.9 µM for patients with diagnosed diabetic nephropathy, gout or hyperuricemia, and can reach 25 µM in certain cases. The imprinting factor for inosine, determined from piezomicrogravimetric experiments with use of the MIP film-coated quartz crystal resonator, was found to be 5.5. Higher selectivity for inosine with respect to common interferents was also achieved with the present molecularly engineered sensing element. The obtained analytical parameters of the devised chemosensor allow for its use for practical sample measurements.


Robotic assisted radical prostatectomy: a different treatment for prostate cancer?
Considering the Health Care System in Brazil, a developing country, and public healthcare policies, robotic surgery is a reality to very few citizens. Therefore, robotic assisted radical prostatectomy is far removed from the daily practice of the vast majority of Brazilian urologists. Scientific evidence of the superiority of robotic assisted radical prostatectomy does not presently justify public investments for widespread development of robotic centers. Maybe over time and with reductions in costs, robotic technology will become a more established practice, as observed in other countries, and more feasible for the Brazilian urological community.


Hearing in Drosophila: development of Johnston's organ and emerging parallels to vertebrate ear development.
In this review, I describe recent progress toward understanding the developmental genetics governing formation of the Drosophila auditory apparatus. The Drosophila auditory organ, Johnston's organ, is housed in the antenna. Intriguingly, key genes needed for specification or function of auditory cell types in the Drosophila antenna also are required for normal development or function of the vertebrate ear. These genes include distal-less, spalt and spalt-related, atonal, crinkled, nanchung and inactive, and prestin, and their vertebrate counterparts Dlx, spalt-like (sall), atonal homolog (ath), myosin VIIA, TRPV, and prestin, respectively. In addition, Drosophila auditory neurons recently were shown to serve actuating as well as transducing roles, much like their hair cell counterparts of the vertebrate cochlea. The emerging genetic and physiologic parallels have come as something of a surprise, because conventional wisdom holds that vertebrate and invertebrate hearing organs have separate evolutionary origins. The new findings raise the possibility that auditory organs are more ancient than previously thought and indicate that Drosophila is likely to be a powerful model system in which to gain insights regarding the etiologies of human deafness disorders.


Correntropy-based nonlinearity test applied to patients with chronic heart failure.
In this study we propose the correntropy function as a discriminative measure for detecting nonlinearities in the respiratory pattern of chronic heart failure (CHF) patients with periodic or nonperiodic breathing pattern (PB or nPB, respectively). The complexity seems to be reduced in CHF patients with higher risk level. Correntropy reflects information on both, statistical distribution and temporal structure of the underlying dataset. It is a suitable measure due to its capability to preserve nonlinear information. The null hypothesis considered is that the analyzed data is generated by a Gaussian linear stochastic process. Correntropy is used in a statistical test to reject the null hypothesis through surrogate data methods. Various parameters, derived from the correntropy and correntropy spectral density (CSD) to characterize the respiratory pattern, presented no significant differences when extracted from the iteratively refined amplitude adjusted Fourier transform (IAAFT) surrogate data. The ratio between the powers in the modulation and respiratory frequency bands R was significantly different in nPB patients, but not in PB patients, which reflects a higher presence of nonlinearities in nPB patients than in PB patients.


Blood leukocyte response in hosts parasitized by the hematophagous arthropods Triatoma protracta and Lutzomyia longipalpis.
The kinetics of peripheral blood basophil and eosinophil responses in guinea pigs to multiple infestation by nymphal and adult Triatoma protracta (vessel feeder) and adult Lutzomyia longipalpis (pool feeder) were examined. Hosts exhibited significant blood basophil and eosinophil responses to feeding by both arthropods. Basophilia was slow to develop and mild in intensity following primary Triatoma infestation but exhibited immediate anamnestic-type responses to secondary infestation, with marked but delayed-type responses to tertiary infestation. Basophilia developed quickly in guinea pigs infested with Lutzomyia, and this response remained fairly consistent throughout the three infestation periods. Eosinophils did not respond to primary Triatoma infestation but exhibited marked immediate responses to both secondary and tertiary infestations. Lutzomyia-infested hosts exhibited marked eosinophilia in response to all infestations. Eosinophil levels returned to control levels 10 days post-tertiary infestation in Triatoma hosts, whereas Lutzomyia hosts exhibited normal eosinophil levels within 3-4 days after peak response. This study demonstrates that hosts respond to fast-feeding hematophagous arthropods with a peripheral blood basophilia and eosinophilia, as reported for slow-feeding (ticks) hematophagous arthropods. The difference in feeding strategy, whether vessel or pool feeder, appears to be reflected by differences in host blood leukocyte kinetics in response to parasitization by specific arthropods.


Hydroxyproline excretion in patients with breast cancer and response to treatment.
The urinary excretion of hydroxyproline, measured as the hydroxyproline: creatinine ratio, was useful in monitoring the progression of metastatic cancer of the breast. After new treatment was started changes in the hydroxyproline excretion occurred earlier than other clinically observable responses. The test could therefore be used for predicting the response to treatment and early detection of the sensitivity of the tumour to hormone therapy.


Comparison of Transcutaneous Electrical Nerve Stimulation and Lidocaine on Episiotomy Complication in Primiparous Women: A Randomized Clinical Trial.
Transcutaneous electrical nerve stimulation (TENS) through the skin is a nonpharmacological method of pain relief. The present study aimed to compare TENS and lidocaine on episiotomy complication in primiparous women. In a randomized, controlled clinical trial, 80 participants were included from March to July 2011 at the antenatal clinic and postdelivery ward in the Social Security Organization Hospital, Khorramabad, Lorestan, Iran. Data were collected using a demographic questionnaire, visual analog scale and redness, edema, ecchymosis, discharge, and approximation scales. The participants were randomized into two groups with equal number of participants. All participants received 5 cc of local infiltration of 1% lidocaine before episiotomy, and TENS electrodes were placed on He Gu and Shenmen points during the crowning of fetal head. The TENS group received TENS with 100; 250 μs, the output range of 15-20 mm amplifier from crowning of first stage of labor to the end of the episiotomy repairing. The lidocaine group received 10 cc of local infiltration of 1% lidocaine before episiotomy repair while did not receive TENS electrodes. The pain intensity during and after episiotomy repair was recorded. TENS and lidocaine have similar effects on pain relief at the episiotomy cutting, the start of the episiotomy repair, and at end of the episiotomy repair; however, the pain relief of both the interventions was different during the episiotomy repair. The effect of TENS in reducing edema was statistically significant (P = 0.001). TENS and lidocaine are effective for the episiotomy complications during and after episiotomy repair.


Comparative microbiological features of Bartonella henselae infection in a dog with fever of unknown origin and granulomatous lymphadenitis.
We report the first documented case of Bartonella henselae infection in a dog from France and the first isolation of B. henselae from a dog with fever of unknown origin. This observation contributes to the "One Health" concept focusing on zoonotic pathogens emerging from companion animals. A 1-year-old female German shepherd dog was referred for evaluation of fever of unknown origin of 1 month duration. Diagnostic investigations confirmed diffuse pyogranulomatous lymphadenitis. The dog became afebrile, and lymph node size normalized in response to a 6-week course of doxycycline. Retrospectively, Bartonella DNA was amplified from an EDTA-anticoagulated blood sample obtained before antimicrobial therapy, with the gtlA fragment sharing 99 % identity with the 350-bp gtlA fragment of the B. henselae Houston-1 strain. The same strain was isolated in the blood of three healthy cats from the household. Two months after discontinuation of doxycycline, the dog experienced a febrile relapse. Bartonella DNA was again amplified from blood prior to and immediately after administration of a 6-week course azithromycin therapy. However, without administration of additional medications, PCR was negative 9 months after azithromycin therapy and the dog remains clinically healthy 12 months following the second course of antibiotics. The medical management of this case raises several clinically relevant comparative infectious disease issues, including the extent to which Bartonella spp. contribute to fever of unknown origin and pyogranulomatous inflammatory diseases in dogs and humans, and the potential of doxycycline and azithromycin treatment failures. The possibility that dogs could constitute an underestimated reservoir for B. henselae transmission to people is also discussed.


Bridging Static and Dynamical Descriptions of Chemical Reactions: An ab Initio Study of CO2 Interacting with Water Molecules.
Extracting reliable thermochemical parameters from molecular dynamics simulations of chemical reactions, although based on ab initio methods, is generally hampered by difficulties in reproducing the results and controlling the statistical errors. This is a serious drawback with respect to the quantum-chemical description based on potential energy surfaces. This work is an attempt to fill this gap. We apply molecular dynamics, based on density functional theory (DFT) and empowered by path metadynamics (MTD), to simulate the reaction of CO2 with (one, two, and three) water molecules in the gas phase. This study relies on a strategy that ensures a precise control of the accuracy of the reaction coordinates and of the reconstructed free-energy surface on this space, namely, on (i) fully reversible MTD simulations, (ii) a committor probability analysis for the diagnosis of the collective variables, and (iii) a cluster analysis for the characterization of the reconstructed free-energy surfaces. This robust procedure permits a meaningful comparison with more traditional calculations of the potential energy surfaces that we also perform within the same DFT computational scheme. This comparison shows in particular that the reactants and products of systems with only three water molecules can no longer be understood in terms of one structure but must be described as statistical configuration ensembles. Calculations carried out with different prescriptions for the exchange-correlation functionals also allow us to establish their quantitative effect on the activation barriers for the formation and the dissociation of carbonic acid. Their decrease induced by the addition of one water molecule (catalytic effect) is found to be largely independent of the specific functional.


A comprehensive study of genic variation in natural populations of Drosophila melanogaster. VI. Patterns and processes of genic divergence between D. melanogaster and its sibling species, Drosophila simulans.
We present here an extensive set of data on allelic differences between homologous proteins of Drosophila melanogaster and its sibling species, Drosophila simulans, obtained by nondenaturing one-dimensional, and denaturing two-dimensional gel electrophoresis. The data suggest that, for these two species, (1) approximately 10% of protein-coding loci have no alleles in common in our sample, (2) the extent of genic variation at a locus (mean heterozygosity) within a species is not correlated with the extent of divergence (Nei's genetic distance) at that locus between species, and (3) significant heterogeneity of divergence rates exists for different structural/functional classes of loci. These results are discussed in the context of the dynamics of genetic variation within and between species.


Rapid manufacture of monolithic micro-actuated forceps inspired by echinoderm pedicellariae.
The concept of biomimetics and bioinspiration has been used to enhance the function of materials and devices in fields ranging from healthcare to renewable energy. By developing advanced design and manufacturing processes, researchers are rapidly accelerating their ability to mimic natural systems. In this paper we show how micro-actuated forceps inspired by echinoderm pedicellarie have been produced using the rapid manufacturing technology of micro-stereolithography. The manufactured monolithic devices are composed of sets of jaws on the surface of thin polymer resin membranes, which serve as musculature for the jaws. The membranes are suspended above a pneumatic chamber with the jaws opened and closed through pneumatic pressure changes exerted by a simple syringe. The forceps can be used for tasks such as grasping of microparticles. Furthermore, when an object is placed in the centre of the membrane, the membrane flexes and the jaws of the device close and grasp the object in a responsive manner. When uncured liquid photopolymer is used to actuate the devices hydraulically instead of pneumatically, the devices exhibit self-healing behaviour, sealing the damaged regions and maintaining hydraulic integrity. The manufactured devices present exciting possibilities in fields such as micromanipulation and micro-robotics for healthcare.


Electroacupuncture therapy in inflammation regulation: current perspectives.
Although acupuncture therapy is increasingly used to treat diverse symptoms and disorders in humans, its underlying mechanism is not known well. Only recently have experimental studies begun to provide insights into how acupuncture stimulation generates and relates to pathophysiological responsiveness. Acupuncture intervention is frequently used to control pathologic symptoms in several visceral organs, and a growing number of studies using experimental animal models suggest that acupuncture stimulation may be involved in inducing anti-inflammatory responses. The vagus nerve, a principal parasympathetic nerve connecting neurons in the central nervous system to cardiovascular systems and a majority of visceral organs, is known to modulate neuroimmune communication and anti-inflammatory responses in target organs. Here, we review a broad range of experimental studies demonstrating anti-inflammatory effects of electroacupuncture in pathologic animal models of cardiovascular and visceral organs and also ischemic brains. Then, we provide recent progress on the role of autonomic nerve activity in anti-inflammation mediated by electroacupuncture. We also discuss a perspective on the role of sensory signals generated by acupuncture stimulation, which may induce a neural code unique to acupuncture in the central nervous system.


Disparate geographic prevalences of asthma, allergic rhinoconjunctivitis and atopic eczema among adolescents in five Canadian cities.
To assess concordance of prevalence rates of asthma, allergic rhinoconjunctivitis and atopic eczema symptoms among adolescents in five Canadian cities. The International Study of Asthma and Allergies in Childhood Phase 3 written questionnaires were answered by 8334 adolescents aged 13 to 14 in Vancouver, Saskatoon, Winnipeg, Hamilton and Halifax, Canada. Prevalence rates of current symptoms ranged from 13.7-33.0% for wheezing, 14.6-22.6% for allergic rhinoconjunctivitis and 8.2-10.4% for atopic eczema. Using Hamilton as reference, the prevalence of wheezing was significantly higher in Halifax (OR = 1.58; 95% CI 1.36-1.84) and Saskatoon (1.27; 1.07-1.50) and significantly lower in Vancouver (0.51; 0.44-0.59). In contrast, allergic rhinoconjunctivitis was significantly more prevalent in Winnipeg (1.39; 1.16-1.68) and Halifax (1.36; 1.14-1.61) and trended lower in Saskatoon (0.81; 0.66-1.00). Atopic eczema was significantly more prevalent in Winnipeg (1.31; 1.01-1.69) and Vancouver (1.28; 1.04-1.58). Multivariable logistic regression analyses showed the region of residence, being born in Canada, recent use of acetaminophen and heavy exposure to traffic exhaust were significantly associated with all three allergic conditions, while obesity and having two or more smokers at home was only associated with increased risk for wheezing. Chinese ethnicity decreased that risk. Among five Canadian centres, the highest prevalence rates of allergic rhinoconjunctivitis or atopic eczema were not observed in the same regions as the highest prevalence rates of wheezing. This disparity in regional variations in the prevalence rates suggests dissimilar risk factors for the development or expression of wheezing (asthma), allergic rhinoconjunctivitis and atopic eczema.


The quality of treatment of hyperacute ischemic stroke in Canada: a retrospective chart audit.
The use of thrombolysis in acute stroke is an important indicator of the quality of stroke care, because it requires health care providers to work collaboratively, rapidly and accurately to optimize patient outcomes. We sought to assess the quality of hyperacute stroke care in Canada using the rate of thrombolysis as the key indicator. We used national administrative data and a chart audit in a retrospective cohort design. We identified discharge diagnoses of stroke in the 10 Canadian provinces between 2008 and 2009. We drew a sample (over-weighted by population and hospital size) for a detailed chart review that was focused on identifying indicators of acute stroke care. We determined the proportions of thrombolysis use, complications and outcomes, adjusted for age and sex and stratified by type of hospital. Our final audit sample included 9588 patient charts, representative of 88% of the 43 651 cases of stroke for which patients were admitted to hospital in Canada. A total of 5.4% (95% confidence interval [CI] 5.1-5.6) of patients with stroke and 6.1% (95% CI 5.8-6.4) of patients with ischemic stroke received thrombolysis. Comprehensive stroke centres used thrombolysis in about one-third of ischemic cases - double the rate seen in primary stroke centres. Often (35%-49% of the time), thrombolysis was not given owing to an interval of more than 4.5 hours between stroke onset and arrival at hospital. The use of thrombolysis for acute stroke in Canada remains low and is limited by delays in both the arrival of patients to hospital and the in-hospital processes of neuroimaging and thrombolysis administration. Our data show the critical need for concerted national efforts to improve education regarding the treatment of acute stroke and speed up stroke management in the hospital setting.


The impact of negative emotions on self-concept abstraction depends on accessible information processing styles.
Research suggests that anger promotes global, abstract processing whereas sadness and fear promote local, concrete processing (see Schwarz & Clore, 2007 for a review). Contrary to a large and influential body of work suggesting that specific affective experiences are tethered to specific cognitive outcomes, the affect-as-cognitive-feedback account maintains that affective experiences confer positive or negative value on currently dominant processing styles, and thus can lead to either global or local processing (Huntsinger, Isbell, & Clore, 2014). The current work extends this theoretical perspective by investigating the impact of discrete negative emotions on the self-concept. By experimentally manipulating information processing styles and discrete negative emotions that vary in appraisals of certainty, we demonstrate that the impact of discrete negative emotions on the spontaneous self-concept depends on accessible processing styles. When global processing was accessible, individuals in angry (negative, high certainty) states generated more abstract statements about themselves than individuals in either sad (Experiment 1) or fearful (Experiment 2; negative, low certainty) states. When local processing was made accessible, however, the opposite pattern emerged, whereby individuals in angry states generated fewer abstract statements than individuals in sad or fearful states. Together these studies provide new insights into the mechanisms through which discrete emotions influence cognition. In contrast to theories assuming a dedicated link between emotions and processing styles, these results suggest that discrete emotions provide feedback about accessible ways of thinking, and are consistent with recent evidence suggesting that the impact of affect on cognition is highly context-dependent. (PsycINFO Database Record


DDMGD: the database of text-mined associations between genes methylated in diseases from different species.
Gathering information about associations between methylated genes and diseases is important for diseases diagnosis and treatment decisions. Recent advancements in epigenetics research allow for large-scale discoveries of associations of genes methylated in diseases in different species. Searching manually for such information is not easy, as it is scattered across a large number of electronic publications and repositories. Therefore, we developed DDMGD database (http://www.cbrc.kaust.edu.sa/ddmgd/) to provide a comprehensive repository of information related to genes methylated in diseases that can be found through text mining. DDMGD's scope is not limited to a particular group of genes, diseases or species. Using the text mining system DEMGD we developed earlier and additional post-processing, we extracted associations of genes methylated in different diseases from PubMed Central articles and PubMed abstracts. The accuracy of extracted associations is 82% as estimated on 2500 hand-curated entries. DDMGD provides a user-friendly interface facilitating retrieval of these associations ranked according to confidence scores. Submission of new associations to DDMGD is provided. A comparison analysis of DDMGD with several other databases focused on genes methylated in diseases shows that DDMGD is comprehensive and includes most of the recent information on genes methylated in diseases.


Reporting performance of prognostic models in cancer: a review.
Appropriate choice and use of prognostic models in clinical practice require the use of good methods for both model development, and for developing prognostic indices and risk groups from the models. In order to assess reliability and generalizability for use, models need to have been validated and measures of model performance reported. We reviewed published articles to assess the methods and reporting used to develop and evaluate performance of prognostic indices and risk groups from prognostic models. We developed a systematic search string and identified articles from PubMed. Forty-seven articles were included that satisfied the following inclusion criteria: published in 2005; aiming to predict patient outcome; presenting new prognostic models in cancer with outcome time to an event and including a combination of at least two separate variables; and analysing data using multivariable analysis suitable for time to event data. In 47 studies, Cox models were used in 94% (44), but the coefficients or hazard ratios for the variables in the final model were reported in only 72% (34). The reproducibility of the derived model was assessed in only 11% (5) of the articles. A prognostic index was developed from the model in 81% (38) of the articles, but researchers derived the prognostic index from the final prognostic model in only 34% (13) of the studies; different coefficients or variables from those in the final model were used in 50% (19) of models and the methods used were unclear in 16% (6) of the articles. Methods used to derive prognostic groups were also poor, with researchers not reporting the methods used in 39% (14 of 36) of the studies and data derived methods likely to bias estimates of differences between risk groups being used in 28% (10) of the studies. Validation of their models was reported in only 34% (16) of the studies. In 15 studies validation used data from the same population and in five studies from a different population. Including reports of validation with external data from publications up to four years following model development, external validation was attempted for only 21% (10) of models. Insufficient information was provided on the performance of models in terms of discrimination and calibration. Many published prognostic models have been developed using poor methods and many with poor reporting, both of which compromise the reliability and clinical relevance of models, prognostic indices and risk groups derived from them.


Changes in T-Cell and Monocyte Phenotypes In Vitro by Schistosoma mansoni Antigens in Cutaneous Leishmaniasis Patients.
High levels of proinflammatory cytokines such as IFN-γ and TNF are associated with tissue lesions in cutaneous leishmaniasis (CL). We previously demonstrated that Schistosoma mansoni antigens downmodulate the in vitro cytokine response in CL. In the current study we evaluated whether S. mansoni antigens alter monocyte and T-lymphocyte phenotypes in leishmaniasis. Peripheral blood mononuclear cells of CL patients were cultured with L. braziliensis antigen in the presence or absence of the S. mansoni antigens rSm29, rSmTSP-2- and PIII. Cells were stained with fluorochrome conjugated antibodies and analyzed by flow cytometry. The addition of rSm29 to the cultures decreased the expression of HLA-DR in nonclassical (CD14(+)CD16(++)) monocytes, while the addition of PIII diminished the expression of this molecule in classical (CD14(++)CD16(-)) and intermediate (CD14(++)CD16(+)) monocytes. The addition of PIII and rSmTSP-2 resulted in downmodulation of CD80 expression in nonclassical and CD86 expression in intermediate monocytes, respectively. These two antigens increased the expression of CTLA-4 in CD4(+) T cells and they also expanded the frequency of CD4(+)CD25(high)Foxp3(+) T cells. Taken together, we show that S. mansoni antigens, mainly rSmTSP-2 and PIII, are able to decrease the activation status of monocytes and also to upregulate the expression of modulatory molecules in T lymphocytes.


Radiographic and clinical outcomes of the treatment of immature permanent teeth by revascularization or apexification: a pilot retrospective cohort study.
This retrospective cohort study compared clinical and radiographic outcomes of endodontic treatment performed in immature nonvital permanent teeth by apexification (calcium hydroxide or apical barrier with mineral trioxide aggregate) versus revascularization. A comprehensive chart review was performed to obtain a cohort of previously completed cases with recalls. Clinical and radiographic data were collected for 31 treated teeth (19 revascularization and 12 apexification) with an average follow-up time of 17 months and a recall rate of 63%. Tooth survival, success rate, and adverse events were analyzed. Changes in radiographic root length, width, and area were quantified. The majority of treated teeth survived throughout the study period, with 30 of 31 (97%) teeth surviving (18/19 [95%] revascularization and 12/12 apexification). Most cases were also clinically successful, with 27 of 31 (87%) meeting criteria for success (15/19 [78%] revascularization and 12/12 apexification; nonsignificant difference). A greater incidence of adverse events was observed in the revascularization group (8/19 [42%] vs 1/12 [11%] in apexification) (risk ratio = 5.1; P = .04; 95% confidence interval, 0.719-35.48). Although more revascularization cases than apexification cases showed an increase in radiographic root area and width, the effect was not statistically significant. In this study, revascularization was not superior to other apexification techniques in either clinical or radiographic outcomes. Studies with large subject cohorts and long follow-up periods are needed to evaluate outcomes of revascularization and apexification while accounting for important covariants relevant to clinical success.


Acceptance and Commitment Therapy for Problematic Internet Pornography Use: A Randomized Trial.
Problematic Internet pornography use is the inability to control the use of pornography, the experience of negative cognitions or emotions regarding pornography use, and the resulting negative effects on quality of life or general functioning. This study compared a 12-session individual protocol of acceptance and commitment therapy (ACT) for problematic Internet pornography use to a waitlist control condition with 28 adult males, all but 1 of whom were members of the Church of Jesus Christ of Latter-day Saints. Measures of self-reported pornography viewing, standardized measures of compulsive sexual behavior and related cognitions, and quality of life occurred at pretreatment, posttreatment, and 3-month follow-up. Results demonstrate significant between-condition reductions in pornography viewing compared to the waitlist condition (93% reduction ACT vs. 21% waitlist). When combining all participants (N=26), a 92% reduction was seen at posttreatment and an 86% reduction at 3-month follow-up. Complete cessation was seen in 54% of participants at posttreatment and at least a 70% reduction was seen in 93% of participants. At the 3-month follow-up assessment, 35% of participants showed complete cessation, with 74% of participants showing at least 70% reduction in viewing. Treatment suggestions and future directions are discussed.


Dissecting the steps of CO₂ reduction: 2. The interaction of CO and CO₂ with Pd/γ-Al₂O₃: an in situ FTIR study.
Alumina supported Pd catalysts with metal loadings of 0.5, 2.5 and 10 wt% were investigated by in situ FTIR spectroscopy in order to understand the nature of adsorbed species formed during their exposure to CO2 and CO. Exposing the annealed samples to CO2 at 295 K resulted in the formation of alumina support-bound surface species only: linear adsorbed CO2, bidentate carbonates and bicarbonates. Room temperature exposure of all three samples to CO produced IR features characteristic of both ionic and metallic Pd, as well as bands we observed upon CO2 adsorption (alumina support-bound species). Low temperature (100 K) adsorption of CO on the three samples provided information about the state of Pd after oxidation and reduction. Oxidized samples contained exclusively ionic Pd, while mostly metallic Pd was present in the reduced samples. Subsequent annealing of the CO-saturated samples revealed the facile (low temperature) reduction of PdO(x) species by adsorbed CO. This process was evidenced by the variations in IR bands characteristic of ionic and metallic Pd-bound CO, as well as by the appearance of IR bands associated with CO2 adsorption as a function of annealing temperature. Samples containing oxidized Pd species (oxidized, annealed or reduced) always produced CO2 upon their exposure to CO, while no CO2-related surface entities were observed on samples having only fully reduced (metallic) Pd.


Coping with painful sex: Development and initial validation of the CHAMP Sexual Pain Coping Scale.
Background and purpose Recurrent vulvar pain is a common and debilitating condition which has received remarkably little attention in pain research. For instance, little is known about how these women cope with sexual activities, and there are no structured assessment tools. The purpose of this study was to explore coping strategies in this group, with a view to develop a measure to assess how women with vulvar pain cope with sexual activities. Methods The current study is based on a subsample from a longitudinal study about vulvar pain in a student sample consisting of women between 18 and 35 years old (N = 964). Only data from the ones reporting recurrent vulvar pain during the last six months (N = 289) were used in the analyses. First, the CHAMP Sexual Pain Coping Scale (CSPCS) was created, with the aim of assessing how women with vulvar pain cope with sexual activities. The scale was inspired by previous research on women with vulvar pain as well as well-known coping strategies in other pain populations. Second, the psychometric properties of the scale were explored by analyzing the factor structure and internal reliability. Third, validity features were examined in terms of criterion validity and construct validity. Results The analyses supported a three-factor solution, embracing the strategies endurance, avoidance and alternative coping. The internal reliability of the subscales turned out to be good, and the criterion validity was supported for all three subscales. The construct validity was clearly supported for the endurance and the avoidance subscales, but not for the alternative coping subscale. Conclusions The findings support the CSPCS as an instrument for assessing how women with vulvar pain cope with sexual activities. The strategies endurance, avoidance and alternative coping correspond with findings from earlier research. Endurance reflects a tendency to engage in and continue with sexual activities despite pain, while attempting to minimize or suppress thoughts of pain. Avoidance, on the other hand, involves efforts to stay away from sexual activities, in particular vaginal penetration, because of fear of pain. Alternative coping refers to endeavours to find alternative sexual activities that do not necessarily involve vaginal penetration. Even though this first study indicates that the CSPCS may be psychometrically sound, more studies are needed to confirm the psychometric properties and clinical application of this instrument. In particular, the construct validity of the alternative coping subscale needs to be further evaluated. Implications A valid instrument for assessing strategies for coping with sexual activities in this population has important clinical implications, since it provides a method that may enhance assessment procedures, be used in research, and stimulate the development of treatment.


A comparison of two-dimensional techniques for converting magnetocardiogram maps into effective current source distributions.
The aim of this study was to develop a method for converting the pseudo two-dimensional current given by a current-arrow map (CAM) into the physical current. The physical current distribution is obtained by the optimal solution in a least mean square sense with Tikhonov regularization (LMSTR). In the current dipole simulation, the current pattern differences (ΔJ) between the results of the CAM and the LMSTR with several regularization parameters (α = 10(-1)-10(-15)) are calculated. In magnetocardiographic (MCG) analysis, the depth (z(d)) of a reconstruction plane is chosen by using the coordinates of the sinus node, which is estimated from MCG signals at the early p-wave. The ΔJs at p-wave peaks, QRS-complex peaks, and T-wave peaks of MCG signals for healthy subjects are calculated. Furthermore, correlation coefficients and regression lines are also calculated from the current values of the CAM and the LMSTR during p-waves, QRS-complex, and T-waves of MCG signals. In the simulation, the ΔJs (α ≈ 10(-10)) had a minimal value. The ΔJs (α = 10(-10)) at p-wave peaks, QRS-complex peaks, and T-wave peaks of MCG signals for healthy subjects also had minimal value. The correlation coefficients of the current values given by the CAM and the LMSTR (α = 10(-10)) were greater than 0.9. Furthermore, slopes (y) of the regression lines are correlated with the depth (z(d)) (r = -0.93). Consequently, the CAM value can be transformed into the LMSTR current value by multiplying it by the slope (y) obtained from the depth (z(d)). In conclusion, the result given by the CAM can be converted into an effective physical current distribution by using the depth (z(d)).


The small eye phenotype in the EPIC-Norfolk eye study: prevalence and visual impairment in microphthalmos and nanophthalmos.
To describe the prevalence and phenotypic characteristics of small eyes in the European Prospective Investigation of Cancer (EPIC)-Norfolk Eye Study. Community cross-sectional study. East England population (Norwich, Norfolk and surrounding area). 8033 participants aged 48-92 years old from the EPIC-Norfolk Eye Study, Norfolk, UK with axial length measurements. Participants underwent a standardised ocular examination including visual acuity (LogMAR), ocular biometry, non-contact tonometry, autorefraction and fundal photography. A small eye phenotype was defined as a participant with one or both eyes with axial length of <21 mm. Prevalence of small eyes, proportion with visual impairment, demographic and biometric factors. Ninety-six participants (1.20%, 95% CI 0.98% to 1.46%) had an eye with axial length less than 21 mm, of which 74 (77%) were women. Prevalence values for shorter axial lengths were <20 mm: 0.27% (0.18% to 0.41%); <19 mm: 0.17% (0.11% to 0.29%); <18 mm: 0.14% (0.08% to 0.25%). Two participants (2.1%) had low vision (presenting visual acuity >0.48 LogMAR) and one participant was blind (>1.3 LogMAR). The prevalence of unilateral visual impairment was higher in participants with a small eye. Multiple logistic regression modelling showed presence of a small eye to be significantly associated with shorter height, lower body mass index, higher systolic blood pressure and lower intraocular pressure. The prevalence of people with small eyes is higher than previously thought. While small eyes were more common in women, this appears to be related to shorter height and lower body mass index. Participants with small eyes were more likely to be blind or to have unilateral visual impairment.


Dual sensory loss and depressive symptoms: the importance of hearing, daily functioning, and activity engagement.
The association between dual sensory loss (DSL) and mental health has been well established. However, most studies have relied on self-report data and lacked measures that would enable researchers to examine causal pathways between DSL and depression. This study seeks to extend this research by examining the effects of DSL on mental health, and identify factors that explain the longitudinal associations between sensory loss and depressive symptoms. Piecewise linear-mixed models were used to analyze 16-years of longitudinal data collected on up to five occasions from 1611 adults (51% men) aged between 65 and 103 years. Depressive symptoms were assessed by the Centre for Epidemiological Studies Depression (CES-D). Vision loss (VL) was defined by corrected visual acuity >0.3 logMAR in the better eye, blindness, or glaucoma. Hearing loss (HL) was defined by pure-tone average (PTA) >25 dB in the better hearing ear. Analyses were adjusted for socio-demographics, medical conditions, lifestyle behaviors, activities of daily living (ADLs), cognitive function, and social engagement. Unadjusted models indicated that higher levels of depressive symptoms were associated with HL (B = 1.16, SE = 0.33) and DSL (B = 2.15, SE = 0.39) but not VL. Greater rates of change in depressive symptoms were also evident after the onset of HL (B = 0.16, SE = 0.06, p < 0.01) and DSL (B = 0.30, SE = 0.09, p < 0.01). The associations between depressive symptoms and sensory loss were explained by difficulties with ADLs, and social engagement. Vision and HL are highly prevalent among older adults and their co-occurrence may compound their respective impacts on health, functioning, and activity engagement, thereby exerting strong effects on the mental health and wellbeing of those affected. There is therefore a need for rehabilitation programs to be sensitive to the combined effects of sensory loss on individuals.


The role of coffee consumption on the 10-year (2004-2014) Acute Coronary Syndrome (ACS) incidence among cardiac patients: the GREECS observational study.
The association between long-term coffee consumption and 10-year cardiovascular disease incidence among Acute Coronary Syndrome (ACS) patients was evaluated. From 2003 to 2004, 2172 ACS consecutive patients from six major Greek hospitals were enrolled. During 2013-2014, the 10-year follow-up was performed (88% participation rate) and recurrent fatal or non-fatal ACS was recorded. Baseline coffee consumption (cups/day) was assessed using a semi-quantitative Food Frequency Questionnaire. Multi adjusted analysis revealed that 1-2 cups of coffee/day versus no consumption had an adverse effect on the ACS incidence [odds ratio (OR) = 1.35, 95% confidence interval (CI) 1.01, 1.79]. In subgroup analysis, with hypertension as strata, only the normotensive reached significance. Odds ratios for 1-2 and ≥3 cups relative to no consumption were [OR = 1.66, 95% CI 1.07, 2.60] and [OR = 1.86, 95% CI 1.06, 3.27], respectively, after controlling for potential confounders. Thus, avoidance of coffee may be of high importance to ameliorate disease prognosis among cardiac patients.


Microbial community dynamics in a chemolithotrophic denitrification reactor inoculated with methanogenic granular sludge.
Denitrification is applied in the tertiary treatment of wastewater to reduce nitrogen pollution. Fluorescence in situ hybridization (FISH), catalyzed reporter deposition (CARD)-FISH, cloning, and scanning electron microscopy (SEM) were applied to follow the evolution of the microbial composition and structure of granular sludge in chemolithotrophic denitrifying bioreactors fed with nitrate and thiosulfate. FISH oligonucleotide probes for the chemolitoautotrophic denitrifiers Thiobacillus denitrificans and Thiomicrospira denitrificans were designed and their utility tested. CARD-FISH and cloning data showed that bacterial diversity in the biofilms changed during the reactor operation. Chemoorganotrophic fermentative Gram-positive strains in the phyla, Actinobacteria and Firmicutes, were dominant in the methanogenic inoculum, both in terms of biodiversity and in number. Other significant phyla were Bacteroidetes and Chloroflexi. After 6 months of operation, Proteobacteria became dominant (83% of the clones). The diversity of Gram-positive bacteria was partially maintained although their abundance decreased notably. After 110 d of operation, the abundance of Tb. denitrificans cells increased considerably, from 1% to 35% of total DAPI-stained cells and from no isolated clones to 15% of the total clones. Tm. denitrificans only represented a minor fraction of the microorganisms in the sludge (1-4% of the DAPI-stained cells). These findings confirm that Tb. denitrificans was the dominant chemolitoautotrophic denitrifying microorganism in the bioreactors. The Archaeal diversity remained almost unchanged and it was represented mostly by Methanosaeta soehngenii. SEM results indicated a considerable loss in the integrity of the sludge granules during the operation, with risk of sludge buoyancy.


Staphylococcal surface display of metal-binding polyhistidyl peptides.
Recombinant Staphylococcus xylosus and Staphylococcus carnosus strains were generated with surface-exposed chimeric proteins containing polyhistidyl peptides designed for binding to divalent metal ions. Surface accessibility of the chimeric surface proteins was demonstrated and the chimeric surface proteins were found to be functional in terms of metal binding, since the recombinant staphylococcal cells were shown to have gained Ni(2+)- and Cd(2+)-binding capacity, suggesting that such bacteria could find use in bioremediation of heavy metals. This is, to our knowledge, the first time that recombinant, surface-exposed metal-binding peptides have been expressed on gram-positive bacteria. Potential environmental or biosensor applications for such recombinant staphylococci as biosorbents are discussed.


Rhythm analysis during cardiopulmonary resuscitation: past, present, and future.
Survival from out-of-hospital cardiac arrest depends largely on two factors: early cardiopulmonary resuscitation (CPR) and early defibrillation. CPR must be interrupted for a reliable automated rhythm analysis because chest compressions induce artifacts in the ECG. Unfortunately, interrupting CPR adversely affects survival. In the last twenty years, research has been focused on designing methods for analysis of ECG during chest compressions. Most approaches are based either on adaptive filters to remove the CPR artifact or on robust algorithms which directly diagnose the corrupted ECG. In general, all the methods report low specificity values when tested on short ECG segments, but how to evaluate the real impact on CPR delivery of continuous rhythm analysis during CPR is still unknown. Recently, researchers have proposed a new methodology to measure this impact. Moreover, new strategies for fast rhythm analysis during ventilation pauses or high-specificity algorithms have been reported. Our objective is to present a thorough review of the field as the starting point for these late developments and to underline the open questions and future lines of research to be explored in the following years.


Human interindividual variability in susceptibility to airborne particles.
Part of the explanation for the persistent epidemiological findings of associations between mortality and morbidity with relatively modest ambient exposures to airborne particles may be that some people are much more susceptible to particle-induced responses than others. This study assembled a database of quantitative observations of interindividual variability in pharmacokinetic and pharmacodynamic parameters likely to affect particle response. The pharmacodynamic responses studied included data drawn from epidemiologic studies of doses of methacholine, flour dust, and other agents that induce acute changes in lung function. In general, the amount of interindividual variability in several of these pharmacodynamic response parameters was greater than the variability in pharmacokinetic (breathing rate, deposition, and clearance) parameters. Quantitatively the results indicated that human interindividual variability of breathing rates and major pharmacokinetic parameters-total deposition and tracheobronchial clearance-were in the region of Log(GSD) = 0.1 to 0.2 (corresponding to geometric standard deviations of 10(.1)-10(.2) or 1.26-1.58). Deposition to the deep lung (alveolar region) appeared to be somewhat more variable: Log(GSD) of about 0.3 (GSD of about 2). Among pharmacodynamic parameters, changes in FEV1 in response to ozone and metabisulfite (an agent that is said to act primarily on neural receptors in the lung) were in the region of Log(GSD) of 0.2 to 0.4. However, similar responses to methacholine, an agent that acts on smooth muscle, seemed to have still more variability (0.4 to somewhat over 1.0, depending on the type of population studied). Similarly high values were suggested for particulate allergens. Central estimates of this kind of variability, and the close correspondence of the data to lognormal distributions, indicate that 99.9th percentile individuals are likely to respond at doses that are 150 to 450-fold less than would be needed in median individuals. It seems plausible that acute responses with this amount of variability could form part of the mechanistic basis for epidemiological observations of enhanced mortality in relation to ambient exposures to fine particles.


Functional outcomes assessment for cervical degenerative disease.
The objective of this systematic review was to use evidence-based medicine to identify valid, reliable, and responsive measures of functional outcome after treatment for cervical degenerative disease. The National Library of Medicine and Cochrane Database were queried using MeSH headings and key words relevant to functional outcomes. Abstracts were reviewed after which studies meeting inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I-III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons. Myelopathy Disability Index, Japanese Orthopaedic Association scale, 36-Item Short Form Health Survey, and gait analysis were found to be valid and reliable measures (Class II) for assessing cervical spondylotic myelopathy. The Patient-Specific Functional Scale, the North American Spine Society scale, and the Neck Disability Index were found to be reliable, valid, and responsive (Class II) for assessing radiculopathy for nonoperative therapy. The Cervical Spine Outcomes Questionnaire was a reliable and valid method (Class II) to assess operative therapy for cervical radiculopathy. Several functional outcome measures are available to assess cervical spondylotic myelopathy and cervical radiculopathy.


Assessment of platelet-derived growth factor using A splinted full thickness dermal wound model in bearded dragons (Pogona vitticeps).
Wounds in reptiles are a common reason for presentation to a veterinarian. At this time there is limited information on effective topical medications to aid in wound closure. The objectives of this study were to translate the splinted, full-thickness dermal wound model, validated in mice, to the bearded dragon (Pogona vitticeps) and to determine the effect of topical becaplermin (BP), a platelet-derived growth factor (0.01%), on the rate of wound closure. Ten bearded dragons were anesthetized and two full-thickness cutaneous wounds were made on the dorsum of each lizard. Encircling splints were applied surrounding each wound and subsequently covered by a semi-occlusive dressing. Five lizards had one wound treated with BP and the adjacent wound treated with a vehicle control. Five additional lizards had one wound treated with saline and the second wound treated with a vehicle control. Wounds were imaged daily, and the wound area was measured using digital image analysis. The change in percentage wound closure over 17 days and the time to 50% wound closure was compared among the four treatment groups. There was no significant difference in wound closure rates between BP-treated and saline-treated wounds or in the time to 50% wound closure between any treatments. Vehicle-treated wounds adjacent to saline-treated wounds closed significantly slower than did BP (P < 0.010), saline (P < 0.001), and vehicle-treated wounds adjacent to BP-treated wounds (P < 0.013). Our preliminary study indicates that the splinted wound model, with modifications, may be used to determine wound closure rates in bearded dragons. When compared with saline, BP did not have a significant effect on wound closure rates, while the vehicle alone delayed wound closure. Histologic analysis of experimentally created wounds throughout the wound healing process is needed to further evaluate the effects of these treatments on reptile dermal wound healing.


Time-dependent compressive deformation of the ageing spine: relevance to spinal stenosis.
Mechanical testing of cadaveric spines. To test the hypothesis that, in the ageing spine, vertebrae deform more than discs, and contribute to time-dependent creep. Intervertebral discs and vertebrae deform under load, narrowing the intervertebral foramen and increasing the risk of nerve root entrapment. Little is known about compressive deformations when elderly spines are subjected to sustained physiologic loading. A total of 117 thoracolumbar motion segments, aged 19 to 96 yrs (mean, 69), were subjected to 1kN compressive loading for 0.5, 1, or 2 hours. Deformations during the first 7 seconds were designated "elastic" and subsequent deformations as "creep". A 3-parameter model was fitted to experimental data in order to characterize their viscous modulus E1, elastic modulus E2 (initial stiffness), and viscosity eta (resistance to fluid flow). Intradiscal pressure (IDP) was measured using a miniature needle-mounted transducer. In 17 specimens loaded for 0.5 hours, an optical MacReflex system measured compressive deformations separately in the disc and each vertebral body. On average, the disc contributed 28% of the spine's elastic deformation, 51% of the creep deformation, and 38% of total deformation. Elastic, creep, and total deformations of 84 motion segments in 2-hour tests averaged 0.87, 1.37, and 2.24 mm respectively. Measured deformations were predicted accurately by the model (average r2 = 0.97), but E1, E2, and eta depended on the duration of loading. E1 and eta decreased with advancing age and disc degeneration, in proportion to falling IDP (P < 0.001). Total compressive deformation increased with age, but rarely exceeded 3 mm. When the ageing spine is compressed, vertebral bodies show greater elastic deformations than intervertebral discs, and creep by a similar amount. Responses to axial compression depend largely on IDP, but deformations appear to be limited by impaction of adjacent neural arches. Total compressive deformations are sufficient to cause foraminal stenosis in some individuals.


Influence of the menstrual cycle on nonlinear properties of heart rate variability in young women.
This study was designed to assess the changes in nonlinear properties of heart rate (HR) variability (HRV) during the menstrual cycle by means of complexity measures, including sample entropy (SampEn) and correlation dimension (CD), and explore probable physiological interpretations for them. In 16 healthy women (mean age: 23.8 +/- 2.7 yr), complexity measures along with the spectral components of HRV (sympathovagal markers) were analyzed over 1,500 R-R intervals recorded during both the follicular phase (day 11.9 +/- 1.4) and the luteal phase (day 22.0 +/- 1.4) of each woman's menstrual cycle. Simultaneously, serum ovarian hormone (estradiol-17 and progesterone) and thyroid-related hormone [free triiodothyronine, free thyroxine (T(4)), and thyroid-stimulating hormone] concentrations were measured. With regard to HRV measures, SampEn, CD, and high-frequency (HF) components decreased from the follicular phase to the luteal phase, whereas normalized low-frequency (LF) components and the LF-to-HF ratio as well as resting HR increased. In regard to hormone levels, whereas progesterone was increased, the other hormone concentrations were unchanged. Furthermore, across the menstrual cycle, both SampEn and CD were well correlated with the spectral indexes and free T(4) concentrations, and SampEn also showed significant correlations with the ratio of estradiol-17 to progesterone concentrations. These results suggest that the nonlinear properties in HRV are altered during the regular menstrual cycle and that the autonomic nervous system, ovarian hormone balance, and free T(4) may be involved in nonlinear HR control in healthy women. All of these factors may enrich the physiological meanings of complexity measures.


Handwriting Delay in Dyslexia: Children at the End of Primary School Still Make Numerous Short Pauses When Producing Letters.
Developmental dyslexia is defined as a specific reading disorder but is also thought to be underpinned by a deficit in motor skills that may well affect handwriting performance. However, the results of studies addressing this issue are not consistent. The present study was, therefore, designed to better understand the functioning of handwriting in children with dyslexia, by conducting an analysis of the legibility and fluency of handwritten letters, supplemented by an assessment of motor skills. The performances of 15 children with dyslexia (Mage = 11.4 years) were compared with those of two groups of typically developing children, one matched for chronological age, the other for orthographic level (Mage = 8.7 years) on two handwriting measures (production of the letters of the alphabet and the child's first name and surname). Results revealed a delay in motor skills, as well as in letter legibility, letter production duration, and the number of short pauses (i.e., lasting between 20 and 199 ms) made during letter production, in the children with dyslexia, with strong negative correlations between motor skills and the number of short pauses. Results are discussed in the context of handwriting control development in children, and perspectives are set out for practitioners.


One Year Genome Evolution of Lausannevirus in Allopatric versus Sympatric Conditions.
Amoeba-resisting microorganisms raised a great interest during the last decade. Among them, some large DNA viruses present huge genomes up to 2.5 Mb long, exceeding the size of small bacterial genomes. The rate of genome evolution in terms of mutation, deletion, and gene acquisition in these genomes is yet unknown. Given the suspected high plasticity of viral genomes, the microevolution of the 346 kb genome of Lausannevirus, a member of Megavirales, was studied. Hence, Lausannevirus was co-cultured within the amoeba Acanthamoeba castellanii over one year. Despite a low number of mutations, the virus showed a genome reduction of 3.7% after 12 months. Lausannevirus genome evolution in sympatric conditions was investigated by its co-culture with Estrella lausannensis, an obligate intracellular bacterium, in the amoeba A. castellanii during one year. Cultures were split every 3 months. Genome sequencing revealed that in these conditions both, Lausannevirus and E. lausannensis, show stable genome, presenting no major rearrangement. In fact, after one year they acquired from 2 to 7 and from 4 to 10 mutations per culture for Lausannevirus and E. lausannensis, respectively. Interestingly, different mutations in the endonuclease encoding genes of Lausannevirus were observed in different subcultures, highlighting the importance of this gene product in the replication of Lausannevirus. Conversely, mutations in E. lausannensis were mainly located in a gene encoding for a phosphoenolpyruvate-protein phosphotransferase (PtsI), implicated in sugar metabolism. Moreover, in our conditions and with our analyses we detected no horizontal gene transfer during one year of co-culture.


Recent Progress in the Medical Therapy of Pituitary Tumors.
Management of pituitary tumors is multidisciplinary, with medical therapy playing an increasingly important role. With the exception of prolactin-secreting tumors, surgery is still considered the first-line treatment for the majority of pituitary adenomas. However, medical/pharmacological therapy plays an important role in controlling hormone-producing pituitary adenomas, especially for patients with acromegaly and Cushing disease (CD). In the case of non-functioning pituitary adenomas (NFAs), pharmacological therapy plays a minor role, the main objective of which is to reduce tumor growth, but this role requires further studies. For pituitary carcinomas and atypical adenomas, medical therapy, including chemotherapy, acts as an adjuvant to surgery and radiation therapy, which is often required to control these aggressive tumors. In the last decade, knowledge about the pathophysiological mechanisms of various pituitary adenomas has increased, thus novel medical therapies that target specific pathways implicated in tumor synthesis and hormonal over secretion are now available. Advancement in patient selection and determination of prognostic factors has also helped to individualize therapy for patients with pituitary tumors. Improvements in biochemical and "tumor mass" disease control can positively affect patient quality of life, comorbidities and overall survival. In this review, the medical armamentarium for treating CD, acromegaly, prolactinomas, NFA, and carcinomas/aggressive atypical adenomas will be presented. Pharmacological therapies, including doses, mode of administration, efficacy, adverse effects, and use in special circumstances are provided. Medical therapies currently under clinical investigation are also briefly discussed.


Identification of randomized controlled trials in systematic reviews: accuracy and reliability of screening records.
A study was conducted to estimate the accuracy and reliability of reviewers when screening records for relevant trials for a systematic review. A sensitive search of ten electronic bibliographic databases yielded 22 571 records of potentially relevant trials. Records were allocated to four reviewers such that two reviewers examined each record and so that identification of trials by each reviewer could be compared with those identified by each of the other reviewers. Agreement between reviewers was assessed using Cohen's kappa statistic. Ascertainment intersection methods were used to estimate the likely number of trials missed by reviewers. Full copies of reports were obtained and assessed independently by two researchers for eligibility for the review. Eligible reports formed the 'gold standard' against which an assessment was made about the accuracy of screening by reviewers. After screening, 301 of 22 571 records were identified by at least one reviewer as potentially relevant. Agreement was 'almost perfect' (kappa>0.8) within two pairs, 'substantial' (kappa>0.6) within three pairs and 'moderate' (kappa>0.4) within one pair. Of the 301 records selected, 273 complete reports were available. When pairs of reviewers agreed on the potential relevance of records, 81 per cent were eligible (range 69 to 91 per cent). If reviewers disagreed, 22 per cent were eligible (range 12 to 45 per cent). Single reviewers missed on average 8 per cent of eligible reports (range 0 to 24 per cent), whereas pairs of reviewers did not miss any (range 0 to 1 per cent). The use of two reviewers to screen records increased the number of randomized trials identified by an average of 9 per cent (range 0 to 32 per cent). Reviewers can reliably identify potentially relevant records when screening thousands of records for eligibility. Two reviewers should screen records for eligibility, whenever possible, in order to maximize ascertainment of relevant trials.