INtra-procedural ultraSound Imaging for DEtermination of atrial wall thickness and acute tissue changes after isolation of the pulmonary veins with radiofrequency, cryoballoon or laser balloon energy: the INSIDE PVs study.
Preliminary data in human suggest that both Intracardiac echocardiography (ICE) and Intravascular ultrasound (IVUS) can be used for real-time information on the left atrial (LA) wall thickness and on the acute tissue changes produced by energy delivery. This pilot study was conducted to compare ICE and IVUS for real-time LA wall imaging and assessment of acute tissue changes produced by radiofrequency (RF), cryo and laser catheter ablation. Patients scheduled for RF, cryoballoon or laser balloon Pulmonary Vein Isolation (PVI) catheter ablation were enrolled. Each pulmonary vein (PV) was imaged before and immediately after ablation with either ICE or IVUS. The performance of ICE and IVUS for imaging were compared. Pre- and post-ablation measurements (lumen and vessel diameters, areas and sphericity indexes, wall thickness and muscular sleeve thickness) were taken at the level of each PV ostium. A total of 48 PVs in 12 patients were imaged before and after ablation. Both ICE and IVUS showed acute tissue changes. Compared to IVUS, ICE showed higher imaging quality and inter-observer reproducibility of the PV measurements obtained. Acute wall thickening suggestive of oedema was observed after RF treatment (p = 0.003) and laser treatment (p = 0.003) but not after cryoablation (p = 0.69). Our pilot study suggests that ICE might be preferable to IVUS for LA wall thickness imaging at the LA-PV junctions during ablation. Ablation causes acute wall thickening when using RF or laser energy, but not cryoenergy delivery. Larger studies are needed to confirm these preliminary findings.


Acupuncture in critically ill patients improves delayed gastric emptying: a randomized controlled trial.
Malnutrition remains a severe problem in the recovery of critically ill patients and leads to increased in-hospital morbidity and in-hospital stay. Even though early enteral nutrition has been shown to improve overall patient outcomes in the intensive care unit (ICU), tubefeed administration is often complicated by delayed gastric emptying and gastroesophageal reflux. Acupuncture has been successfully used in the treatment and prevention of perioperative nausea and vomiting. In this study we evaluated whether acupuncture can improve gastric emptying in comparison with standard promotility drugs in critically ill patients receiving enteral feeding. Thirty mechanically ventilated neurosurgical ICU patients with delayed gastric emptying, defined as a gastric residual volume (GRV) >500 mL for ≥ 2 days, were prospectively and randomly assigned to either the acupoint stimulation group (ASG; bilateral transcutaneous electrical acupoint stimulation at Neiguan, PC-6) or the conventional promotility drug treatment group (DTG) over a period of 6 days (metoclopramide, cisapride, erythromycin). Patients in the ASG group did not receive any conventional promotility drugs. Successful treatment (feeding tolerance) was defined as GRV <200 mL per 24 hours. Demographic and hemodynamic data were similar in both groups. After 5 days of treatment, 80% of patients in the ASG group successfully developed feeding tolerance versus 60% in the DTG group. On treatment day 1, GRV decreased from 970 ± 87 mL to 346 ± 71 mL with acupoint stimulation (P = 0.003), whereas patients in the DTG group showed a significant increase in GRV from 903 ± 60 mL to 1040 ± 211 mL (P = 0.015). In addition, GRV decreased and feeding balance (defined as enteral feeding volume minus GRV) increased in more patients in the ASG group (14 of 15) than in the DTG group (7 of 15; P = 0.014). On treatment day 1, the mean feeding balance was significantly higher in the ASG group (121 ± 128 mL) than in the DTG group (-727 ± 259 mL) (P = 0.005). Overall, the feeding balance improved significantly on all days of treatment in comparison with the DTG group. Patients in the DTG group did not show an increase in feeding balance until day 6. We introduce a new protocol for acupuncture administration in the critical care setting. We demonstrated that this protocol was more effective than standard promotility medication in the treatment of delayed gastric emptying in critically ill patients. Acupoint stimulation at Neiguan (PC-6) may be a convenient and inexpensive option (with few side effects) for the prevention and treatment of malnutrition in critically ill patients.


A pathway in the yeast cell division cycle linking protein kinase C (Pkc1) to activation of Cdc28 at START.
In an effort to study further the mechanism of Cdc28 function and cell cycle commitment, we describe here a genetic approach to identify components of pathways downstream of the Cdc28 kinase at START by screening for mutations that decrease the effectiveness of signaling by Cdc28. The first locus to be characterized in detail using this approach was PKC1 which encodes a homolog of the Ca(2+)-dependent isozymes of the mammalian protein kinase C (PKC) superfamily (Levin et al., 1990). By several genetic criteria, we show a functional interaction between CDC28 and PKC1 with PKC1 apparently functioning with respect to bud emergence downstream of START. Consistent with this, activity of the MAP kinase homolog Mpk1 (a putative Pkc1 effector) is stimulated by activation of Cdc28. Furthermore, we demonstrate a cell cycle-dependent hydrolysis of phosphatidylcholine to diacylglycerol (a PKC activator) and choline phosphate at START. Diacylglycerol production is stimulated by Cdc28 in cycling cells and is closely associated with Cdc28 activation at START. These results imply that the activation of Pkc1, which is known to be necessary during bud morphogenesis, is mediated via the CDC28-dependent stimulation of PC-PLC activity in a novel cell cycle-regulated signaling pathway.


Development of a miniaturized protein microarray as a new serological IgG screening test for zoonotic agents and production diseases in pigs.
In order to monitor the occurrence of zoonotic agents in pig herds as well as to improve herd health management, the development of new cost-effective diagnostic methods for pigs is necessary. In this study, a protein microarray-based assay for the simultaneous detection of immunoglobulin G (IgG) antibodies against different zoonotic agents and pathogens causing production diseases in pigs was developed. Therefore, antigens of ten different important swine pathogens (Toxoplasma gondii, Yersinia enterocolitica, Salmonella spp., Trichinella spp., Mycobacterium avium, Hepatitis E virus, Mycoplasma hyopneumoniae, Actinobacillus pleuropneumoniae, the porcine reproductive and respiratory syndrome virus, Influenza A virus) were spotted and covalently immobilized as 'antigen-spots' on microarray chips in order to test pig serum for the occurrence of antibodies. Pig serum was sampled at three German abattoirs and ELISA tests for the different pathogens were conducted with the purpose of creating a panel of reference samples for microarray analysis. To evaluate the accuracy of the antigens on the microarray, receiver operating characteristic (ROC) curve analysis using the ELISA test results as reference was performed for the different antigens. High area under curve values were achieved for the antigens of two zoonotic agents: Toxoplasma gondii (0.91), Yersinia enterocolitica (0.97) and for three production diseases: Actinobacillus pleuropneumoniae (0.77), Mycoplasma hyopneumoniae (0.94) and the porcine reproductive and respiratory syndrome virus (0.87). With the help of the newly developed microarray assay, collecting data on the occurrence of antibodies against zoonotic agents and production diseases in pig herds could be minimized to one measurement, resulting in an efficient screening test.


Activation of human platelets by C5a-stimulated neutrophils: a role for cathepsin G.
Human platelets can be stimulated by recombinant human fifth component of complement (rhC5a) in the presence of human neutrophils. After challenge with N-formyl-Met-Leu-Phe or rhC5a, concentrated neutrophils release cathepsin G into the supernatant. The concentrations of cathepsin G recovered by titration of the enzymatic activity correlate with the capability of these supernatants to induce platelet stimulation as measured by serotonin release. Cathepsin G purified from neutrophil granules triggered platelet aggregation and serotonin release independent of arachidonic acid metabolites and platelet-activating factor formation. A concentration of 100 nM of cathepsin G, which was reached in the surrounding space of activated neutrophils, induced a 50% platelet stimulation. Three distinct antiproteinases were tested against cathepsin G-induced platelet activation. Z-Gly-Leu-Phe-CH2Cl, a specific inhibitor of cathepsin G enzymatic activity, proved to be nonspecific in our biological system. By contrast, alpha 1-antichymotrypsin and alpha 1-antitrypsin displayed specific activities. The physiological specific inhibitor of cathepsin G, alpha 1-antichymotrypsin, was the most potent and was used in the rhC5a-induced neutrophils-mediated platelet activation. A complete inhibition was achieved, showing that release of cathepsin G from neutrophils accounts for platelet activation. Such a chain of events involving C5a, neutrophils, cathepsin G, and platelets may be of relevance in certain inflammatory states, particularly the adult respiratory distress syndrome.


Immune regulation of ovarian development: programming by neonatal immune challenge.
Neonatal immune challenge by administration of lipopolysaccharide (LPS) produces enduring alterations in the development and activity of neuroendocrine, immune and other physiological systems. We have recently reported that neonatal exposure to an immune challenge by administration of LPS results in altered reproductive development in the female Wistar rat. Specifically, LPS-treated animals exhibited diminished ovarian reserve and altered reproductive lifespan. In the current study, we examined the cellular mechanisms that lead to the previously documented impaired ovulation and reduced follicular pool. Rats were administered intraperitoneally either 0.05 mg/kg of LPS (Salmonella Enteritidis) or an equivalent volume of non-pyrogenic saline on postnatal days (PNDs) 3 and 5, and ovaries were obtained on PND 7. Microarray analysis revealed a significant upregulation in transcript expression (2-fold change; p < 0.05) for a substantial number of genes in the ovaries of LPS-treated animals, implicated in immune cell signaling, inflammatory responses, reproductive system development and disease. Several canonical pathways involved in immune recognition were affected by LPS treatment, such as nuclear factor-κB (NF-κB) activation and LPS-stimulated mitogen-activated protein kinase (MAPK) signaling. Quantitative Real-time PCR analysis supported the microarray results. Protein expression analysis of several components of the MAPK signaling pathway revealed a significant upregulation in the expression of Toll-like receptor 4 (TLR4) in the neonatal ovary of LPS-treated animals. These results indicate that neonatal immune challenge by administration of LPS has a direct effect on the ovary during the sensitive period of follicular formation. Given the pivotal role of inflammatory processes in the regulation of reproductive health, our findings suggest that early life immune activation via TLR signaling may have significant implications for the programming of ovarian development and fertility.


Prevalence of peripheral arterial disease in patients with diabetes mellitus in a primary care setting.
The aims of the study were to determine the prevalence of peripheral arterial disease (PAD) in diabetic patients and in different ethnic groups at a primary care setting, and to evaluate risk factors associated with PAD in these diabetic patients. A cross sectional study of 200 diabetic patients over 18 years old who attended a primary care clinic at a teaching hospital in Kuala Lumpur, Malaysia was carried out. Face-to-face interviews were conducted using structured questionnaires for demographic characteristics and risk factors evaluation. Blood pressure measurements, assessment of peripheral neuropathy and ankle brachial pressures were performed. PAD was diagnosed by an ankle brachial pressure index (ABPI) of <0.9 on either leg. The overall prevalence of PAD was 16% in this diabetic population. The prevalence of PAD was 5.8% in Malays, 19.4% in Chinese and 19.8% in Indians. The prevalence of peripheral neuropathy was 41%, foot ulcer 9.5%, and gangrene 3.0%. The presence of foot ulcer was weakly associated with PAD (P=0.052). No significant relationships were found between age, gender, smoking status, duration of diabetes mellitus, hypertension, dyslipidaemia, and PAD. PAD is common in the diabetic population of this study.


A comparison of exposure estimates by worker raters and industrial hygienists.
The validity and reliability of nine senior sawmill workers' estimates of frequency, duration, and routes of exposure were compared with individual workers' ratings of their own job titles and industrial hygienists' ratings of all job titles in the plant. The reliability of the senior workers' mean exposure estimates [group intraclass correlation coefficient (ICC) = 0.71] compared favorably with those of three pairs of hygienists (group ICC = 0.57, 0.67, and 0.81). The validity of their ratings was assessed in a comparison with urinary chlorophenate measurements representing 92% of the job titles in the sawmill. The senior workers' ratings [coefficient of determination (R2) = 0.22] resembled those of two pairs of industrial hygienists (R2 = 0.24, 0.22) and was significantly greater than that of the third pair (R2 = 0.08). The validity of the self-reports was also low (R2 = 0.15), but the difference was not statistically significant. Senior workers' exposure ratings appear to be as effective as the other methods tested.


Key roles for the lipid signaling enzyme phospholipase d1 in the tumor microenvironment during tumor angiogenesis and metastasis.
Angiogenesis inhibitors, which target tumor cells, confer only short-term benefits on tumor growth. We report that ablation of the lipid signaling enzyme phospholipase D1 (PLD1) in the tumor environment compromised the neovascularization and growth of tumors. PLD1 deficiency suppressed the activation of Akt and mitogen-activated protein kinase signaling pathways by vascular endothelial growth factor in vascular endothelial cells, resulting in decreased integrin-dependent cell adhesion to, and migration on, extracellular matrices, as well as reduced tumor angiogenesis in a xenograft model. In addition, mice lacking PLD1 incurred fewer lung metastases than did wild-type mice. Bone marrow transplantation and binding studies identified a platelet-derived mechanism involving decreased tumor cell-platelet interactions, in part because of impaired activation of αIIbβ3 integrin in platelets, which decreased the seeding of tumor cells into the lung parenchyma. Treatment with a small-molecule inhibitor of PLD1 phenocopied PLD1 deficiency, efficiently suppressing both tumor growth and metastasis in mice. These findings reveal that PLD1 in the tumor environment promotes tumor growth and metastasis and, taken together with previous reports on the roles of PLD in tumor cell-intrinsic adaptations to stress, suggest the potential use of PLD inhibitors as cancer therapeutics.


Slow slip source characterized by lithological and geometric heterogeneity.
Slow slip events (SSEs) accommodate a significant proportion of tectonic plate motion at subduction zones, yet little is known about the faults that actually host them. The shallow depth (<2 km) of well-documented SSEs at the Hikurangi subduction zone offshore New Zealand offers a unique opportunity to link geophysical imaging of the subduction zone with direct access to incoming material that represents the megathrust fault rocks hosting slow slip. Two recent International Ocean Discovery Program Expeditions sampled this incoming material before it is entrained immediately down-dip along the shallow plate interface. Drilling results, tied to regional seismic reflection images, reveal heterogeneous lithologies with highly variable physical properties entering the SSE source region. These observations suggest that SSEs and associated slow earthquake phenomena are promoted by lithological, mechanical, and frictional heterogeneity within the fault zone, enhanced by geometric complexity associated with subduction of rough crust.


A spatially variant white-patch and gray-world method for color image enhancement driven by local contrast.
Starting from the revolutionary Retinex by Land and McCann, several further perceptually inspired color correction models have been developed with different aims, e.g. reproduction of color sensation, robust features recognition, enhancement of color images. Such models have a differential, spatially-variant and non-linear nature and they can coarsely be distinguished between white-patch (WP) and gray-world (GW) algorithms. In this paper we show that the combination of a pure WP algorithm (Random Spray Retinex (RSR) )and an essentially GW one (Automatic Color Equalization (ACE)) leads to a more robust and better performing model (RACE). The choice of RSR and ACE follows from the recent identification of a unified spatially-variant approach for both algorithms. Mathematically, the originally distinct non-linear and differential mechanisms of RSR and ACE have been fused using the spray technique and local average operations. The investigation of RACE allowed us to put in evidence a common drawback of differential models: corruption of uniform image areas. To overcome this intrinsic defect, we devised a local and global contrast-based and image-driven regulation mechanism that has a general applicability to perceptually inspired color correction algorithms. Tests, comparisons and discussions are presented.


A biodiversity hotspot losing its top predator: The challenge of jaguar conservation in the Atlantic Forest of South America.
The jaguar is the top predator of the Atlantic Forest (AF), which is a highly threatened biodiversity hotspot that occurs in Brazil, Paraguay and Argentina. By combining data sets from 14 research groups across the region, we determine the population status of the jaguar and propose a spatial prioritization for conservation actions. About 85% of the jaguar's habitat in the AF has been lost and only 7% remains in good condition. Jaguars persist in around 2.8% of the region, and live in very low densities in most of the areas. The population of jaguars in the AF is probably lower than 300 individuals scattered in small sub-populations. We identified seven Jaguar Conservation Units (JCUs) and seven potential JCUs, and only three of these areas may have ≥50 individuals. A connectivity analysis shows that most of the JCUs are isolated. Habitat loss and fragmentation were the major causes for jaguar decline, but human induced mortality is the main threat for the remaining population. We classified areas according to their contribution to jaguar conservation and we recommend management actions for each of them. The methodology in this study could be used for conservation planning of other carnivore species.


Using the Chinese herb Scutellaria barbata against extensively drug-resistant Acinetobacter baumannii infections: in vitro and in vivo studies.
No animal model studies have been conducted in which the efficacy of herbal compounds has been tested against multidrug-resistant Acinetobacter baumannii infections. Very few antibiotics are available for the treatment of pulmonary infections caused by extensively drug-resistant Acinetobacter baumannii (XDRAB). To find alternative treatments, traditional Chinese herbs were screened for their antimicrobial potential. The present study screened 30 herbs that are traditionally used in Taiwan and that are commonly prescribed for heat clearing and detoxification. The herbs with antibacterial activities were analysed by disc diffusion assays, time-kill assays and a murine lung infection model. Of the 30 herbs tested, only Scutellaria barbata demonstrated 100% in vitro activity against XDRAB. Furthermore, we compared the antibacterial effect of the S. barbata extract with that of colistin, and the S. barbata extract showed better antibacterial effect. In the XDRAB pneumonia murine model, we compared the antimicrobial effects of the orally administered S. barbata extract (200 mg/kg, every 24 h), the intratracheally administered colistin (75,000 U/kg, every 12 h), and the control group. The bacterial load in the lungs of the treatment group that received the oral S. barbata extract showed a significant decrease in comparison to that in the lungs of the control group. In addition, histopathological examinations also revealed better resolution of perivascular, peribronchial, and alveolar inflammation in the oral S. barbata extract-treated group. Our in vitro and in vivo data from the animal model support the use of S. barbata as an alternate drug to treat XDRAB pulmonary infections. However, detailed animal studies and clinical trials are necessary to establish the clinical utility of S. barbata in treating XDRAB pulmonary infections.


Gastroesophageal reflux symptoms not responding to proton pump inhibitor: GERD, NERD, NARD, esophageal hypersensitivity or dyspepsia?
Gastroesophageal reflux (GER) is a common gastrointestinal process that can generate symptoms of heartburn and chest pain. Proton pump inhibitors (PPIs) are the gold standard for the treatment of GER; however, a substantial group of GER patients fail to respond to PPIs. In the past, it was believed that acid reflux into the esophagus causes all, or at least the majority, of symptoms attributed to GER, with both erosive esophagitis and nonerosive outcomes. However, with modern testing techniques it has been shown that, in addition to acid reflux, the reflux of nonacid gastric and duodenal contents into the esophagus may also induce GER symptoms. It remains unknown how weakly acidic or alkaline refluxate with a pH similar to a normal diet induces GER symptoms. Esophageal hypersensitivity or functional dyspepsia with superimposed heartburn may be other mechanisms of symptom generation, often completely unrelated to GER. Detailed studies investigating the pathophysiology of esophageal hypersensitivity are not conclusive, and definitions of the various disease states may overlap and are often confusing. The authors aim to clarify the pathophysiology, definition, diagnostic techniques and medical treatment of patients with heartburn symptoms who fail PPI therapy.


Identification of a TAL1 target gene reveals a positive role for the LIM domain-binding protein Ldb1 in erythroid gene expression and differentiation.
The TAL1 (or SCL) gene, originally identified from its involvement by a recurrent chromosomal translocation, encodes a basic helix-loop-helix transcription factor essential for erythropoiesis. Although presumed to regulate transcription, its target genes are largely unknown. We show here that a nuclear complex containing TAL1, its DNA-binding partner E47, zinc finger transcription factor GATA-1, LIM domain protein LMO2, and LIM domain-binding protein Ldb1 transactivates the protein 4.2 (P4.2) gene through two E box GATA elements in its proximal promoter. Binding of this complex to DNA was dependent on the integrity of both E box and GATA sites and was demonstrated to occur on the P4.2 promoter in cells. Maximal transcription in transiently transfected cells required both E box GATA elements and expression of all five components of the complex. This complex was shown, in addition, to be capable of linking in solution double-stranded oligonucleotides corresponding to the two P4.2 E box GATA elements. This DNA-linking activity required Ldb1 and increased with dimethyl sulfoxide-induced differentiation of murine erythroleukemia (MEL) cells. In contrast, enforced expression in MEL cells of dimerization-defective mutant Ldb1, as well as wild-type Ldb1, significantly decreased E box GATA DNA-binding activities, P4.2 promoter activity, and accumulation of P4.2 and beta-globin mRNAs. These studies define a physiologic target for a TAL1- and GATA-1-containing ternary complex and reveal a positive role for Ldb1 in erythroid gene expression and differentiation.


A multicenter randomized, controlled clinical trial comparing the use of displacement cords, an aluminum chloride paste, and a combination of paste and cords for tissue displacement.
Gingival recession after soft tissue displacement for impression making in fixed prosthodontics may pose a problem for treatment success in the esthetic areas of the mouth. Knowledge about the soft tissue reaction of common gingival displacement methods is limited. The purpose of this clinical randomized controlled trial (RCT) was to evaluate changes in the marginal soft tissue height with 3 different gingival tissue displacement techniques for definitive impression making of natural teeth. A total of 67 individuals were randomized to 3 groups. In test group 1 (P; n=22), only aluminum chloride paste was used to displace the gingiva. In test group 2 (CP; n=23), a cord was inserted, and aluminum chloride paste was also used. In the control group (C; n=22), 2 cords were used to displace the gingiva (double-cord technique). Clinical measurements of the gingival position were made before treatment began and at 30 ±10 days after prosthesis delivery. Study casts were fabricated at different stages of the treatment, standardized photographs were made, and changes in the buccal gingival position were measured using graphics editing software. In addition, the participants' perception of the clinical procedure and the technicians' evaluation of the die preparation were recorded. One-way ANOVA models were applied to compare the response variables among the groups: (a) the position of the gingival margin (millimeters), (b) mean probing pocket depth (millimeters), (c) gingival thickness (millimeters), (d) amount of keratinized tissue (millimeters), and (e) mean changes in gingival margin height (millimeters). Unpaired t tests were also used to compare the mean values between groups. For comparisons between different categories, chi-square tests were performed (α=.05 for all tests). In the period between impression and delivery, a minor gain in gingival height of 0.058 mm (±0.13 SD) for P and 0.013 mm (±1.19 SD) for CP. However, a minor gingival recession of 0.049 mm (±0.13 SD) was reported for group C. The results for all groups showed that 21% of abutment teeth gained >0.1 mm in gingival height, 58% had stable gingival height (0 ±0.10 mm), 21% showed minor gingival recession (0.1 to 0.5 mm), and no abutment teeth showed moderate or severe gingival recession (>0.5 mm). The incidence of minor gingival recession was 8% in group P, 23% in group CP, and 32% in group C (P=.015). Fifteen participants (24%) experienced some discomfort after the procedure. The differences between the groups were not significant (P>.05). The laboratory technicians found the definitive die preparation significantly more challenging for group P (visual analog scale [VAS], 79) and CP (VAS, 82) than group C (mean VAS, 93; P=.003). Minor or moderate gingival recession (<1 mm) is more likely to occur when conventional cords are used during impression making. However, the laboratory technicians found the die preparation significantly less challenging when the double-cord technique was used than when impressions were made using the paste displacement technique.


Swedish Version of Mood Spectrum Self-Report Questionnaire: Psychometric Properties of Lifetime and Last-week Version.
Mood Spectrum Self Report (MOODS-SR) is an instrument that assesses mood spectrum symptomatology including subthreshold manifestations and temperamental features. There are different versions of the MOODS-SR for different time frames of symptom assessment: lifetime (MOODS-LT), last-month and last-week (MOODS-LW) versions. To evaluate the psychometric properties of the MOODS-LT the MOODS-LW. The reliability of the MOODS-LT and MOODS-LW was evaluated in terms of internal consistency and partial correlations among domains and subdomains. The known-group validity was tested by comparing out-patients with bipolar disorder (n=27), unipolar depression (n=8) healthy controls (n=68). The convergent and divergent validity of MOODS-LW were evaluated using the Montgomery Åsberg Depression Rating Scale (MADRS), the Young-Ziegler Mania Rating Scale (YMRS) in outpatients as well the General Health Questionnaire (GHQ-12) in healthy controls. Both MOODS-LT and MOOODS-LW showed high internal consistency with the Kuder-Richardson coefficient ranging from 0.823 to 0.985 as well as consistent correlations for all domains and subdomains. The last-week version correlated significantly with MADRS (r= 0.79) and YMRS (r=0.46) in outpatients and with GHQ-12 (r= 0.50 for depression domain, r= 0.29 for rhythmicity) in healthy controls. The Swedish version of the MOODS-LT showed similar psychometric properties to other translated versions. Regarding MOODS-LW, this first published psychometric evaluation of the scale showed promising psychometric properties including good correlation to established symptom assessment scales. In healthy controls, the depression and rhythmicity domain scores of the last-week version correlated significantly with the occurrence of mild psychological distress.


A low-cost stoma simulator.
Stoma formation is a common paediatric surgical procedure and yet, there is no low-cost stoma model for technical skills training. We describe a low-cost low-fidelity simulator for stoma formation made from simple easily available materials using porcine bowel and skin. The model was introduced at a regional training day for paediatric surgical registrars. All the trainees rated it as excellent and life-like. We describe an inexpensive stoma model for simulation-based training in technical skills especially in low-middle-income countries (LMICs) due to the cost benefit.


Binding of two flaviolin substrate molecules, oxidative coupling, and crystal structure of Streptomyces coelicolor A3(2) cytochrome P450 158A2.
Cytochrome P450 158A2 (CYP158A2) is encoded within a three-gene operon (sco1206-sco1208) in the prototypic soil bacterium Streptomyces coelicolor A3(2). This operon is widely conserved among streptomycetes. CYP158A2 has been suggested to produce polymers of flaviolin, a pigment that may protect microbes from UV radiation, in combination with the adjacent rppA gene, which encodes the type III polyketide synthase, 1,3,6,8-tetrahydroxynaphthalene synthase. Following cloning, expression, and purification of this cytochrome P450, we have shown that it can produce dimer and trimer products from the substrate flaviolin and that the structures of two of the dimeric products were established using mass spectrometry and multiple NMR methods. A comparison of the x-ray structures of ligand-free (1.75 angstroms) and flaviolin-bound (1.62 angstroms) forms of CYP158A2 demonstrates a major conformational change upon ligand binding that closes the entry into the active site, partly due to repositioning of the F and G helices. Particularly interesting is the presence of two molecules of flaviolin in the closed active site. The flaviolin molecules form a quasi-planar three-molecule stack including the heme of CYP158A2, suggesting that oxidative C-C coupling of these phenolic molecules leads to the production of flaviolin dimers.


N,O-Chelating Four-Membered Metallacyclic Titanium(IV) Complexes for Atom-Economic Catalytic Reactions.
Titanium, as the second most abundant transition metal in the earth's crust, lends itself as a sustainable and inexpensive resource in catalysis. Its nontoxicity and biocompatibility are also attractive features for handling and disposal. Titanium has excelled as a catalyst for a broad range of transformations, including ethylene and α-olefin polymerizations. However, many reactions relevant to fine chemical synthesis have preferrentially employed late transition metals, and reactive, inexpensive early transition metals have been largely overlooked. In addition to promising reactivity, titanium complexes feature more robust character compared with some other highly Lewis-acidic metals such as those found in the lanthanide series. Since the advent of modulating ligand scaffolds, titanium has found use in a growing variety of reactions as a versatile homogeneous catalyst. These catalytic transformations include hydrofunctionalization reactions (adding an element-hydrogen (E-H) bond across a C-C multiple bond), as well as the ring-opening polymerization of cyclic esters, all of which are atom-economic transformations. Our investigations have focused on tight bite angle monoanionic N,O-chelating ligands, forming four-membered metallacycles. These ligand sets, including amidates, ureates, pyridonates, and sulfonamidates, have flexible binding modes offering a range of stable and reactive intermediates necessary for catalytic activity. Additionally, the simple form of these ligands leads to easily prepared proligands, along with facile tuning of steric and electronic factors. A sterically bulky titanium amidate complex has proven to be a leading catalyst for the selective formation of anti-Markovnikov addition products via intermolecular hydroamination of terminal alkynes, while sterically less demanding titanium pyridonates have opened the path to the selective formation of amine substituted cycloalkanes via the intramolecular hydroaminoalkylation of aminoalkenes over the competing hydroamination pathway. Sulfonamidates have boosted reactivity for hydrofunctionalization and polymerization reactions compared with amide ligands not bearing a sulfonyl group. N,O-Chelated titanium complexes have been used to synthesize ultrahigh molecular weight polyethylene and have been utilized in the challenging task of realizing equal incorporation of two different cyclic esters in a random ring-opening copolymerization. These discrete complexes have allowed for careful study of fundamental coordination chemistry and stoichiometric organometallic investigations. With inexpensive starting materials and modular ligands, titanium N,O-chelated complexes are well-suited to address the challenges of achieving greener chemical processes while accessing useful reaction manifolds for sustainable synthesis.


Preventive health care, 1999 update: 3. Follow-up after breast cancer. Canadian Task Force on Preventive Health Care.
To make recommendations to physicians who provide follow-up care for women who have been treated for early-stage breast cancer. Combination of blood tests, bone scans, liver echography and chest radiography for detection of distant disease; physical examination with or without mammography for detection of contralateral breast cancer; and physical examination with or without mammography for detection of ipsilateral recurrent disease after breast-conserving therapy. Survival, disease recurrence and quality-of-life measures for distant disease, local recurrence of disease and disease in the contralateral breast. A MEDLINE search for relevant articles published between January 1966 and January 1998 with the MeSH terms "breast neoplasms" and "neoplasm recurrence" (local and distant) with limits to "human" was done. A subsequent MEDLINE search using the MeSH terms "breast neoplasms," "neoplasm recurrence," "local/diagnosis" and "mammography" was done to address issues of mammography. The literature search was reviewed by a medical librarian and 2 breast cancer specialists to ensure completeness. Breast cancer is the most common cancer in Canadian women and is the second leading cause of death after lung cancer. Even with early-stage breast cancer, recurrence after treatment for primary breast cancer is frequent. Traditionally, follow-up has been felt to facilitate early detection and improve survival. Randomized controlled trials (RCTs) have shown that routine screening (blood tests and diagnostic imaging) for distant disease does not alter survival or quality of life over routine physical examination. In an underpowered secondary analysis of RCT data, the detection of contralateral breast cancer did not affect survival. However, there have been no RCTs examining the role of mammography and physical examination and their effect on survival in the detection of contralateral breast cancer. The sensitivity and specificity of mammography after local excision and radiotherapy is unknown. There have been no RCTs examining the role of mammography or physical examination, or both, and their effect on survival in the detection of ipsilateral breast recurrence. The strength of evidence was evaluated using the methods of the Canadian Task Force on Preventive Health Care. A high value was placed on interventions that changed survival. When evidence was available, high value was also placed on interventions that affected quality of life. There is good evidence not to include blood work and diagnostic imaging as part of screening for distant disease (grade E recommendation). There is no evidence to suggest that mammography decreases mortality by detecting ipsilateral disease in the conservatively treated breast; however, there is indirect evidence that it may be beneficial (grade C recommendation). There is no direct evidence to suggest that physical examination or mammography, or both, should be used to detect contralateral breast cancer; however, there is indirect evidence that it may be beneficial (grade C recommendation). The findings of this analysis were reviewed through an iterative process by the members of the Canadian Task Force on Preventive Health Care.


The meaning of dopamine beta-hydroxylase in essential hypertension.
1. Resting plasma dopamine beta-hydroxylase (DBH) activity and haemodynamic parameters were studied in untreated borderline (twenty-nine) and permanent (twenty-seven) essential hypertensive patients. DBH was also measured in sixty-three apparently healthy subjects. 2. Mean DBH values were not significantly different between the groups. 3. Cardiac output, cardiopulmonary blood volume and the cardiopulmonary blood volume/total blood volume ratio (CPBV/TBV) were significantly higher in borderline than in permanent hypertensive patients. 4. In borderline hypertensive patients, plasma DBH activity was directly correlated with diastolic arterial pressure and with values of cardiac output, cardiopulmonary blood volume and CPBV/TBV ratio. No such correlations could be observed in the permanent hypertensive group. 5. These results suggest that plasma DBH activities in borderline hypertension mainly depend on the sympathetic activity responsible for the haemodynamic variations. Contrariwise, plasma DBH activities in permanent essential hypertensive patients appear to reflect other factors.


In situ NMR spectroscopy of supercapacitors: insight into the charge storage mechanism.
Electrochemical capacitors, commonly known as supercapacitors, are important energy storage devices with high power capabilities and long cycle lives. Here we report the development and application of in situ nuclear magnetic resonance (NMR) methodologies to study changes at the electrode-electrolyte interface in working devices as they charge and discharge. For a supercapacitor comprising activated carbon electrodes and an organic electrolyte, NMR experiments carried out at different charge states allow quantification of the number of charge storing species and show that there are at least two distinct charge storage regimes. At cell voltages below 0.75 V, electrolyte anions are increasingly desorbed from the carbon micropores at the negative electrode, while at the positive electrode there is little change in the number of anions that are adsorbed as the voltage is increased. However, above a cell voltage of 0.75 V, dramatic increases in the amount of adsorbed anions in the positive electrode are observed while anions continue to be desorbed at the negative electrode. NMR experiments with simultaneous cyclic voltammetry show that supercapacitor charging causes marked changes to the local environments of charge storing species, with periodic changes of their chemical shift observed. NMR calculations on a model carbon fragment show that the addition and removal of electrons from a delocalized system should lead to considerable increases in the nucleus-independent chemical shift of nearby species, in agreement with our experimental observations.


Antagonistic coevolution between a bacterium and a bacteriophage.
Antagonistic coevolution between hosts and parasites is believed to play a pivotal role in host and parasite population dynamics, the evolutionary maintenance of sex and the evolution of parasite virulence. Furthermore, antagonistic coevolution is believed to be responsible for rapid differentiation of both hosts and parasites between geographically structured populations. Yet empirical evidence for host-parasite antagonistic coevolution, and its impact on between-population genetic divergence, is limited. Here we demonstrate a long-term arms race between the infectivity of a viral parasite (bacteriophage; phage) and the resistance of its bacterial host. Coevolution was largely driven by directional selection, with hosts becoming resistant to a wider range of parasite genotypes and parasites infective to a wider range of host genotypes. Coevolution followed divergent trajectories between replicate communities despite establishment with isogenic bacteria and phage, and resulted in bacteria adapted to their own, compared with other, phage populations.


The effect of coimmobilizing heparin and fibronectin on titanium on hemocompatibility and endothelialization.
Currently available cardiovascular implants, such as heart valves and stents, exhibit suboptimal biocompatibility because of the incomplete endothelialization and sequential thrombosis formation especially after a long-term implantation. To improve the blood compatibility and endothelialization simultaneously and ensure the long-term effect of the cardiovascular implants, a technique of combining electrostatic interaction and coimmobilization was developed to form heparin and fibronectin (Hep/Fn) films on aminosilanized titanium (Ti) surfaces. The Hep/Fn coimmobilized films were stable after immersion in PBS for five days, probed by wettability studies and by the release kinetics of heparin and fibronectin. Blood compatibility tests showed that the coimmobilized Hep/Fn films displayed lower hemolysis rate, prolonged blood coagulation time, higher AT III binding density, less platelets activation and aggregation, and less fibrinogen conformational change compared with Ti surface. Endothelial cells (ECs) seeding and fibronectin bioactivity results showed more attached and proliferated ECs and exposed cell-binding sites on the Hep/Fn immobilized samples than that on Ti surfaces. Thus, the Hep/Fn coimmobilized films kept excellent bioactivity even after immersion in PBS for five days. Systemic evaluation suggests that the coimmobilization of Hep/Fn complex improves the blood compatibility and promotes the endothelialization simultaneously. We envisage that this method will provide a potential and effective selection for biomaterials surface modification of cardiovascular implants.


The Escherichia coli cytochrome c maturation (Ccm) system does not detectably attach heme to single cysteine variants of an apocytochrome c.
Cytochromes c are typically characterized by the covalent attachment of heme to polypeptide through two thioether bonds with the cysteine residues of a Cys-Xaa-Xaa-Cys-His peptide motif. In many Gram-negative bacteria, the heme is attached to the polypeptide by the periplasmically functioning cytochrome c maturation (Ccm) proteins. Exceptionally, Hydrogenobacter thermophilus cytochrome c(552), which has a normal CXXCH heme-binding motif, and variants with AXXCH, CXXAH, and AXXAH motifs, can be expressed as stable holocytochromes in the cytoplasm of Escherichia coli. By targeting these proteins to the periplasm using a signal peptide, with or without co-expression of the Ccm proteins, we have assessed the ability of the Ccm system to attach heme to proteins with no, one, or two cysteine residues in the heme-binding motif. Only the wild-type protein, with two cysteines, was effectively processed and thus accumulated in the periplasm as a holocytochrome. This is strong evidence for disulfide bond formation involving the two cysteine residues of apocytochrome c as an intermediate in Ccm-type Gram-negative bacterial cytochrome c biogenesis and/or that only a pair of cysteines can be recognized by the heme attachment apparatus.


Integration of GaN/AlN all-optical switch with SiN/AlN waveguide utilizing spot-size conversion.
Spot-size converters for an all-optical switch utilizing the intersubband transition in GaN/AlN multiple quantum wells are studied with the purpose of reducing operation power by improving the coupling efficiency between the input fiber and the switch. With a stair-like spot-size converter, the absorption saturation of 5 dB is achieved with a pulse energy of 25 pJ. The switch is integrated with a SiN/AlN waveguide and spot-size converters, and the structure provides the possibility of an integration of the switch with other functional devices. To further improve the coupling loss between the waveguide and the switch, triangular-shaped converters are investigated, demonstrating losses as low as 2 dB/facet.


The Association between t-PA Administration and In-Hospital Mortality following Acute Ischemic Stroke in Puerto Rican Patients.
Despite being the standard of care, thrombolytic therapy with tissue plasminogen activator (t-PA) is currently administered to only 5% of acute ischemic stroke (AIS) patients in the United States. Published scientific information regarding both the use of t-PA for AIS in Hispanic patients and its impact on short-term mortality is scarce. The objectives of this study are to investigate, among Puerto Rican patients hospitalized with AIS, the rate of t-PA administration, and the risk of in-hospital mortality in patients who received t-PA vs. those patients who did not receive t-PA. We performed a secondary analysis of data from patients with AIS admitted to acute care facilities throughout Puerto Rico in study years 2007, 2009, and 2011who were participating in the Puerto Rico Cardiovascular Disease Surveillance System. Multivariate logistic regression was used to determine the independent association between treatment with t-PA within 4.5 hours of symptom onset and in-hospital mortality. Of the 1968 study patients hospitalized with AIS, 104 (5%) received t-PA treatment. After adjustments for demographic and clinical confounders, patients receiving t-PA had similar odds of in-hospital mortality as patients not receiving t-PA did (OR = 2.49, 95% CI = 0.81-7.66). The receipt of concomitant anticoagulation medication was independently associated with relatively lower odds of in-hospital mortality (OR = 0.42, 95% CI = 0.20-0.88). Being over 80 years of age (OR = 2.03, 95% CI = 1.13-3.68), being obese (OR = 1.88, 95% CI = 1.01-3.49), and arriving in an ambulance (OR = 3.61, 95% CI = 1.95-6.68) were all independently associated with relatively higher odds of in-hospital mortality. Among patients hospitalized in Puerto Rico with acute ischemic stroke, t-PA treatment was not significantly associated with in-hospital mortality.


Demographic, physical, and radiographic factors associated with functional flatfoot deformity.
In 1 of our previous studies, the occurrence of self-reported flatfoot was associated with self-reported increased age, male gender, Asian and African American races, veteran status, poor health, increased body mass index, callus, bunion, hammertoe, and arthritis. However, we had to rely on survey data to identify these risk factors, and the accuracy of the survey results was unknown. Therefore, we decided to identify the risk factors associated with flatfeet using objectively and more accurately measured data. A total of 94 patients were enrolled in the present study. The demographic data and physical and radiographic examination results were recorded by the investigators in the clinic. The data were then analyzed to identify the factors unique to flatfoot, measured and defined using a plantar pressure measurement system during natural gait. We learned that a painful tibialis posterior tendon was associated with flatfoot. The calcaneal inclination angle was also decreased in the flatfoot group. The talar declination, intermetatarsal, hallux abductus, and calcaneal cuboid angles, and static calcaneal stance eversion were elevated in the flatfoot group compared with the non-flatfoot group. Systematic evaluation of these associated factors will help in the understanding of the functional status of the flatfoot deformity.


Correlation of cefpodoxime susceptibility with cephalothin and cefuroxime for urinary tract isolates.
This study attempted to determine whether cefuroxime was superior to cephalothin as a surrogate marker for cefpodoxime among urinary tract isolates. The MicroScan system (Siemens) was used to determine susceptibility for cephalothin and cefuroxime on consecutive cultures with a colony count of ≥50 000 organisms. Simultaneously, an Etest (bioMérieux) for cefpodoxime was conducted. The cefpodoxime interpretation was compared to that of the other two agents, and the categorical agreement was calculated, defined as the percentage of identical susceptibility interpretations. Cefuroxime (83 %) had a significantly higher categorical agreement than cephalothin (63 %) among 300 isolates (P<0.01). The major error rate was 16 % for cephalothin and 3 % for cefuroxime. The very major error rate was 7 % for cephalothin and 14 % for cefuroxime among the 14 cefpodoxime-resistant isolates. For Escherichia coli, the major error rates were 15 % and 1 % for cephalothin and cefuroxime, respectively. Very major error rates were 9 % for both agents. Cefuroxime was a better predictor of cefpodoxime susceptibility than cephalothin, and appears to be the preferred surrogate agent for the MicroScan system, particularly for E. coli.


Nature of the bad metallic behavior of Fe1.06Te inferred from its evolution in the magnetic state.
We investigate with angle-resolved photoelectron spectroscopy the changes of the Fermi surface and the main bands from the paramagnetic state to the antiferromagnetic (AFM) state occurring below 72 K in Fe1.06Te. The evolution is completely different from that observed in Fe pnictides, as nesting is absent. The AFM state is a rather good metal, in agreement with our magnetic band structure calculation. On the other hand, the paramagnetic state is very anomalous with a large pseudogap of ~65 meV on the electron pocket that closes in the AFM state. We discuss this behavior in connection with spin fluctuations existing above the magnetic transition and the correlations predicted in the spin-freezing regime of the incoherent metallic state.


Protein adsorption modalities on polyelectrolyte multilayers.
Protein adsorption on polyelectrolyte multilayers (PEMUs) was evaluated using a combination of synthetic polyelectrolytes and proteins, including serum albumin, fibrinogen, and lysozyme. Variables such as surface and protein charge, polymer hydrophobicity, and hydrophilic repulsion were introduced to probe interaction mechanisms. Quantitative analysis with reflectance Fourier transform infrared spectroscopy, optical waveguiding, and UV-vis absorption, together with qualitative information from atomic force microscopy, provided a coordinated picture for what drives protein adsorption and how the molecules are disposed on the multilayer surface. It was found that multilayers bearing a particular surface charge sorbed biomolecules if they were of opposite charge, yielding significant loadings within the bulk PEMU. Adsorption of like-charged proteins, as surface aggregates, occurred to a much lower extent, driven by nonelectrostatic forces. A diblock copolymer comprising a hydrophilic poly(ethylene oxide) block was capable of further minimizing protein adsorption as a result of hydrophilic repulsion, although none of the surfaces tested defeated protein adsorption completely. However, poly(acrylic acid) homopolymer was quite effective in this respect. A composition gradient, formed during multilayer buildup, induced a gradient in hydrophilicity through the PEMU, which is an efficient and economical method of creating a protein-resistant surface.


Bifidobacterium pseudolongum are efficient indicators of animal fecal contamination in raw milk cheese industry.
The contamination of raw milk cheeses (St-Marcellin and Brie) from two plants in France was studied at several steps of production (raw milk, after addition of rennet - St-Marcellin - or after second maturation - Brie -, after removal from the mold and during ripening) using bifidobacteria as indicators of fecal contamination. Bifidobacterium semi-quantitative counts were compared using PCR-RFLP and real-time PCR. B. pseudolongum were detected in 77% (PCR-RFLP; 1.75 to 2.29 log cfu ml(-1)) and 68% (real-time PCR; 2.19 to 2.73 log cfu ml(-1)) of St-Marcellin samples and in 87% (PCR-RFLP; 1.17 to 2.40 log cfu ml(-1)) of Brie cheeses samples. Mean counts of B. pseudolongum remained stable along both processes. Two other populations of bifidobacteria were detected during the ripening stage of St-Marcellin, respectively in 61% and 18% of the samples (PCR-RFLP). The presence of these populations explains the increase in total bifidobacteria observed during ripening. Further characterization of these populations is currently under process. Forty-eight percents (St-Marcellin) and 70% (Brie) of the samples were B. pseudolongum positive/E. coli negative while only 10% (St-Marcellin) and 3% (Brie) were B. pseudolongum negative/E. coli positive. The increase of total bifidobacteria during ripening in Marcellin's process does not allow their use as fecal indicator. The presence of B. pseudolongum along the processes defined a contamination from animal origin since this species is predominant in cow dung and has never been isolated in human feces. B. pseudolongum was more sensitive as an indicator than E. coli along the two different cheese processes. B. pseudolongum should be used as fecal indicator rather than E. coli to assess the quality of raw milk and raw milk cheeses.


Human papilloma virus infection in female kidney transplant recipients.
The objective of this study was to evaluate the incidence of genital human papilloma virus (HPV) infection and cervical intra-epithelial lesions in transplanted patients. Cervical Papanicolaou (Pap) smear/HPV test and colposcopic examinations were performed in 58 patients who were candidates for renal transplant surgery; these tests were repeated one year later. Their age range was 26-53 years (mean, 37.2 years). Hypertension was the most common cause of renal insufficiency (34.4%), while in 41.4% of the patients, the causative pathology was unknown. In 24.1% of the patients, there was no history of dialysis, i.e. they had pre-emptive transplantation. The mean duration of marriage (years since first intercourse) was 16.2 years (range, 1-35). Coitus interruptus was the most common contraceptive method used (37.9%), followed by tubal ligation and condom (10.3% and 6.9%, respectively). All patients had negative Pap tests and normal gynecologic exam before undergoing transplantation. The Pap test remained normal after transplant surgery, although the HPV test became positive in four patients (6.9%). There were five cases of white epithelium on colposcopy, but biopsy showed normal metaplasia. Two cases of extensive anogenital warts were treated by CO 2 laser, and one patient had recurrent warts, which responded well to second laser surgery. None of the study patients had squamous intra-epithelial lesions (SIL) or vulvar intra-epithelial neoplasia. Our study suggests that screening with HPV and Pap test should be performed before transplant surgery and should be repeated at regular intervals in order to avoid irreversible situations such as high-grade SILs, which are difficult to treat. Avoiding high-risk sexual relations in this group of patients is highly recommended.


Transforming growth factor-α enhances stem cell-mediated postischemic myocardial protection.
Transforming growth factor-α (TGF-α) has been shown to augment mesenchymal stem cell-mediated cardioprotection during acute ischemia and reperfusion in isolated heart models. To determine whether this pretreatment strategy would be effective in vivo, we hypothesized that the intramyocardial injection of mesenchymal stem cells pretreated with TGF-α after coronary artery ligation would confer greater preservation of cardiac function, reduction in infarct size, and reduction myocardial inflammation. Sprague-Dawley rats underwent left anterior descending coronary artery ligation. Ischemic border zones were injected 30 minutes later with vehicle (n = 11), 1 million mesenchymal stem cells (n = 9), or mesenchymal stem cells pretreated with TGF-α (250 ng/mL for 24 hours; n = 10). Cardiac function was assessed by echocardiography at 7 and 28 days after ligation. Infarct size was measured using triphenyltetrazolium chloride. Ischemic border zone cytokine expression was measured 30 days after infarction. Myocardial function after ligation was greatest in hearts injected with cells pretreated with TGF-α in association with reduced ventricular remodeling and infarct size compared with vehicle-injected hearts. Myocardial interleukin 1β, interleukin 6, and TNF-α concentrations were lower, and Bcl-2 expression was higher, in hearts injected with either cell type. Vascular endothelial growth factor and matrix metalloproteinase-2 expression were highest in hearts that received pretreated cells. Intramyocardial injection of mesenchymal stem cells pretreated with TGF-α further protects cardiac function and reduces infarct size compared with injection of untreated cells. Pretreating donor cells with TGF-α may be useful for enhancing cell-based therapies for myocardial ischemia.


S100A8/A9 induces autophagy and apoptosis via ROS-mediated cross-talk between mitochondria and lysosomes that involves BNIP3.
The complex formed by two members of the S100 calcium-binding protein family, S100A8/A9, exerts apoptosis-inducing activity in various cells of different origins. Here, we present evidence that the underlying molecular mechanisms involve both programmed cell death I (PCD I, apoptosis) and PCD II (autophagy)-like death. Treatment of cells with S100A8/A9 caused the increase of Beclin-1 expression as well as Atg12-Atg5 formation. S100A8/A9-induced cell death was partially inhibited by the specific PI3-kinase class III inhibitor, 3-methyladenine (3-MA), and by the vacuole H(+)-ATPase inhibitor, bafilomycin-A1 (Baf-A1). S100A8/A9 provoked the translocation of BNIP3, a BH3 only pro-apoptotic Bcl2 family member, to mitochondria. Consistent with this finding, DeltaTM-BNIP3 overexpression partially inhibited S100A8/A9-induced cell death, decreased reactive oxygen species (ROS) generation, and partially protected against the decrease in mitochondrial transmembrane potential in S100A8/A9-treated cells. In addition, either DeltaTM-BNIP3 overexpression or N-acetyl-L-cysteine co-treatment decreased lysosomal activation in cells treated with S100A8/A9. Our data indicate that S100A8/A9-promoted cell death occurs through the cross-talk of mitochondria and lysosomes via ROS and the process involves BNIP3.


Making a decision about trial participation: the feasibility of measuring deliberation during the informed consent process for clinical trials.
Informed consent of trial participants is both an ethical and a legal requirement. When facing a decision about trial participation, potential participants are provided with information about the trial and have the opportunity to have any questions answered before their degree of 'informed-ness' is assessed, usually subjectively, and before they are asked to sign a consent form. Currently, standardised methods for assessing informed consent have tended to be focused on aspects of understanding and associated outcomes, rather than on the process of consent and the steps associated with decision-making. Potential trial participants who were approached regarding participation in one of three randomised controlled trials were asked to complete a short questionnaire to measure their deliberation about trial participation. A total of 136 participants completed the 10-item questionnaire (DelibeRATE) before they made an explicit decision about trial participation (defined as signing the clinical trial consent form). Overall DelibeRATE scores were compared and investigated for differences between trial consenters and refusers. No differences in overall DelibeRATE scores were identified. In addition, there was no significant difference between overall score and the decision to participate, or not, in the parent trial. To our knowledge, this is the first study to prospectively measure the deliberation stage of the informed consent decision-making process of potential trial participants across different conditions and clinical areas. Although there were no differences detected in overall scores or scores of trial consenters and refusers, we did identify some interesting findings. These findings should be taken into consideration by those designing trials and others interested in developing and implementing measures of potential trial participants decision making during the informed consent process for research. International Standard Randomised Controlled Trial Number (ISRCTN) Register ISRCTN60695184 (date of registration: 13 May 2009), ISRCTN80061723 (date of registration: 8 March 2010), ISRCTN69423238 (date of registration: 18 November 2010).


Amino Assets: How Amino Acids Support Immunity.
Amino acids are fundamental building blocks supporting life. Their role in protein synthesis is well defined, but they contribute to a host of other intracellular metabolic pathways, including ATP generation, nucleotide synthesis, and redox balance, to support cellular and organismal function. Immune cells critically depend on such pathways to acquire energy and biomass and to reprogram their metabolism upon activation to support growth, proliferation, and effector functions. Amino acid metabolism plays a key role in this metabolic rewiring, and it supports various immune cell functions beyond increased protein synthesis. Here, we review the mechanisms by which amino acid metabolism promotes immune cell function, and how these processes could be targeted to improve immunity in pathological conditions.


Physical exercise interventions for improving performance-based measures of physical function in community-dwelling, frail older adults: a systematic review and meta-analysis.
To conduct a systematic review to determine the efficacy of exercise-based interventions on improving performance-based measures of physical function and markers of physical frailty in community-dwelling, frail older people. Comprehensive bibliographic searches in MEDLINE, the Cochrane Library, PEDro, and CINAHL databases were conducted (April 2013). Randomized controlled trials of community-dwelling older adults, defined as frail according to physical function and physical difficulties in activities of daily living (ADL). Included trials had to compare an exercise intervention with a control or another exercise intervention, and assess performance-based measures of physical function such as mobility and gait, or disability in ADL. Two review authors independently screened the search results and performed data extraction and risk of bias assessment. Nineteen trials were included, 12 of them comparing exercise with an inactive control. Most exercise programs were multicomponent. Meta-analysis was performed for the comparison of exercise versus control with the inverse variance method under the random-effects models. When compared with control interventions, exercise was shown to improve normal gait speed (mean difference [MD]=.07m/s; 95% confidence interval [CI], .04-.09), fast gait speed (MD=.08m/s; 95% CI, .02-.14), and the Short Physical Performance Battery (MD=2.18; 95% CI, 1.56-2.80). Results are inconclusive for endurance outcomes, and no consistent effect was observed on balance and the ADL functional mobility. The evidence comparing different modalities of exercise is scarce and heterogeneous. Exercise has some benefits in frail older people, although uncertainty still exists with regard to which exercise characteristics (type, frequency, duration) are most effective.


Trabecular Metal Versus Non-Trabecular Metal Acetabular Components and the Risk of Re-Revision Following Revision Total Hip Arthroplasty: A Propensity Score-Matched Study from the National Joint Registry for England and Wales.
Studies have suggested that Trabecular Metal (TM)-coated acetabular components may reduce implant failure following revision total hip arthroplasty. However, these studies have predominantly been limited to small, single-center cohorts, with many lacking a comparator group. Using National Joint Registry data from England and Wales, we compared re-revision rates following revision total hip arthroplasty between TM and non-TM-coated acetabular components from 1 manufacturer. This retrospective observational study included all revision total hip arthroplasties performed with use of 1 of 4 cementless acetabular components produced by the same manufacturer (Zimmer Biomet). The acetabular components either had a TM surface coating (TM Modular and Continuum designs) or a non-TM surface coating (Trilogy and Trilogy IT designs). Revision total hip arthroplasties with TM and non-TM implants were matched for multiple potential patient and surgical confounding factors using propensity scores. Outcomes following revision total hip arthroplasty (re-revision for all acetabular indications, aseptic acetabular loosening, or infection) were compared between matched groups using competing risk regression analysis. Analyses were repeated in a subgroup initially revised for infection. Of 3,862 matched revision total hip arthroplasties (1,931 in the TM group and 1,931 in the non-TM group), the overall prevalence of acetabular re-revision (2.7%; 95% confidence interval [CI] = 2.1% to 3.2%), re-revision for aseptic acetabular loosening (0.96%; 95% CI = 0.68% to 1.3%), and re-revision for infection (1.4%; 95% CI = 1.0% to 1.8%) were low. Six-year rates of re-revision for all causes (subhazard ratio [SHR] = 0.91; 95% CI = 0.61 to 1.35; p = 0.636), aseptic acetabular loosening (SHR = 1.32; 95% CI = 0.68 to 2.53; p = 0.410), and infection (SHR = 0.68; 95% CI = 0.39 to 1.20; p = 0.165) were similar between revision total hip arthroplasties with TM and non-TM coatings. Of 247 total hip arthroplasties initially revised for infection (116 TM and 131 non-TM), the rates of re-revision for all causes (SHR = 0.48; 95% CI = 0.15 to 1.56; p = 0.225), aseptic acetabular loosening (SHR = 0.54; 95% CI = 0.05 to 5.74; p = 0.608), and infection (SHR = 0.82; 95% CI = 0.28 to 2.36; p = 0.706) were similar between the TM and non-TM groups. Following revision total hip arthroplasty, TM-coated acetabular components had a low risk of both aseptic and septic re-revision, with rates that were comparable with those of non-TM components. Extended follow-up of large revision total hip arthroplasty cohorts will establish whether TM components have any clinical benefit over non-TM designs when used in patients with similar acetabular bone stock. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Association of glutathione-S-transferase polymorphisms with atopic dermatitis risk in preschool age children.
Glutathione S-transferase (GST) enzymes are critical for detoxifying reactive oxygen species (ROS) and their products which have been implicated in the pathology of inflammatory diseases such as atopic dermatitis (AD). We investigated the effects of genetic polymorphisms of GST on the risk of AD in preschool age children. Biomarkers for oxidative stress were also evaluated with respect to GST genotype. The GSTP1 Val105 allele was significantly associated with an increased risk of AD [odds ratio (OR)=1.62, p<0.05]. The combination of the GSTP1 Val105 allele and the GSTT1 null genotype further increased this risk by 2.3-fold (p<0.01). No association was observed for the GSTM1 null or GSTT1 null genotype alone. In children with AD, blood total antioxidant capacity was significantly less (p<0.001), while malondialdehyde was higher (p=0.12). Children with the GSTP1 Val105 allele had significantly lower concentrations of erythrocyte glutathione compared to GSTP1 ILE/ILE homozygotes (P=0.03). Our study suggests that the GSTP1 Val105 allele is an important determinant of susceptibility to AD in preschool age children and increased oxidative stress may play a role in the pathogenesis of AD.


Gain of chromosome 3q is an early and consistent genetic aberration in carcinomas of the vulva.
The aim was to determine whether specific gains of chromosome 3q and laminin-5gamma2-chain expression can improve early detection of invasive capacity in precancerous and squamous cell carcinoma of the vulva (VSCC). Six VSCC and three precancerous lesions were studied. Multicolor fluorescence in situ hybridization (FISH) probe sets were applied to nuclei suspensions prepared from archival material using the Hedley method. The probe panel consists of the centromers of chromosome 7, chromosome 3, and the TERC gene residing on the long arm of chromosome 3. Laminin-5gamma2-chain immunohistochemical analysis was performed on corresponding specimens and was expressed only in the VSCC. The genome-specific FISH analysis revealed 3q amplification in 43% of the nuclei analyzed for the VSCC and 22% of the nuclei for the precancerous lesions. Low-level 3q amplifications were found in precancerous lesions with an average fold increase of 1.15 for 3q. The invasive lesions showed higher average fold increases for 3q, averaging 1.32. Laminin-5gamma2-chain protein was expressed only in VSCC, whereas 3q gains were observed both in precancerous lesions and in VSCC, indicating that gain of chromosome 3q is an early and consistent event during carcinogenesis of VSCC.


Survival of Escherichia coli O157:H7 and non-pathogenic E. coli on irradiated and non-irradiated beef surfaces.
This study examined changes in numbers of pathogenic (PEC) and non-pathogenic (NPEC) Escherichia coli during storage at 10°C on the surfaces of irradiated (IR) and non-irradiated (NIR) meat pieces excised from the neck, brisket and rump of beef carcasses and in Brain Heart Infusion Broth (BHI) and Maximum Recovery Diluent (MRD). On irradiated meat pieces, there were significant differences between mean PEC and NPEC counts at all sites. Differences in counts were also observed between IR and NIR surfaces and among the three meat sites for both E. coli types. These differences occurred only on IR samples, suggesting that the irradiation associated reductions in normal beef surface flora influenced survival of both E. coli types. PEC and NPEC counts increased during storage in BHI, but only NPEC counts increased in MRD. The results of this study highlight the impact of meat surface type and the presence/absence of the normal beef carcass surface flora on E. coli survival and/or growth during meat storage. Such previously unreported effects, and their precise mechanisms, have direct implications in the development and application of accurate models for the prediction of the safety and shelf life of stored meat.


Integrin alpha1beta1 regulates epidermal growth factor receptor activation by controlling peroxisome proliferator-activated receptor gamma-dependent caveolin-1 expression.
Integrin alpha1beta1 negatively regulates the generation of profibrotic reactive oxygen species (ROS) by inhibiting epidermal growth factor receptor (EGFR) activation; however, the mechanism by which it does this is unknown. In this study, we show that caveolin-1 (Cav-1), a scaffolding protein that binds integrins and controls growth factor receptor signaling, participates in integrin alpha1beta1-mediated EGFR activation. Integrin alpha1-null mesangial cells (MCs) have reduced Cav-1 levels, and reexpression of the integrin alpha1 subunit increases Cav-1 levels, decreases EGFR activation, and reduces ROS production. Downregulation of Cav-1 in wild-type MCs increases EGFR phosphorylation and ROS synthesis, while overexpression of Cav-1 in the integrin alpha1-null MCs decreases EGFR-mediated ROS production. We further show that integrin alpha1-null MCs have increased levels of activated extracellular signal-regulated kinase (ERK), which leads to reduced activation of peroxisome proliferator-activated receptor gamma (PPARgamma), a transcription factor that positively regulates Cav-1 expression. Moreover, activation of PPARgamma or inhibition of ERK increases Cav-1 levels in the integrin alpha1-null MCs. Finally, we show that glomeruli of integrin alpha1-null mice have reduced levels of Cav-1 and activated PPARgamma but increased levels of phosphorylated EGFR both at baseline and following injury. Thus, integrin alpha1beta1 negatively regulates EGFR activation by positively controlling Cav-1 levels, and the ERK/PPARgamma axis plays a key role in regulating integrin alpha1beta1-dependent Cav-1 expression and consequent EGFR-mediated ROS production.


Chemiluminescent identification and quantification of artemisinin and relevant sesquiterpene lactone derivatives.
A simple, sensitive, and rapid chemiluminescence method was developed for the detection and quantification of selected derivatives of artemisinin. It was found that the chemiluminescence (CL) signal resulting from the alkaline luminol reaction of the artemisinin derivatives in the presence of hematin was linear over a wide concentration range. We report results that suggest that a visual test or a test involving digital image capture may be used in addition to a field-ready instrumental approach to combat drug counterfeiting of malarial therapies.


First-line medication dosing in pediatric refractory status epilepticus.
To identify factors associated with low benzodiazepine (BZD) dosing in patients with refractory status epilepticus (RSE) and to assess the impact of BZD treatment variability on seizure cessation. This was a retrospective study with prospectively collected data of children with convulsive RSE admitted between June 2011 and January 2019. We analyzed the initial and total BZD dose within 10 minutes of treatment initiation. We used logistic regression modeling to evaluate predictors of low BZD dosing and multivariate Cox regression analysis to assess the impact of low BZD dosing on time to seizure cessation. We included 289 patients (55.7% male) with a median age of 4.3 (1.3-9.5) years. BZDs were the initial medication in 278 (96.2%). Of those, 161 patients (57.9%) received a low initial dose. Low initial BZD doses occurred in both out-of-hospital (57 of 106; 53.8%) and in-hospital (104 of 172; 60.5%) settings. One hundred three patients (37.1%) received low total BZD dose. Male sex (odds ratio [OR] 2, 95% confidence interval [CI] 1.18-3.49; p = 0.012), older age (OR 1.1, 95% CI 1.05-1.17; p < 0.001), no prior diagnosis of epilepsy (OR 2.1, 95% CI 1.23-3.69; p = 0.008), and delayed BZD treatment (OR 2.2, 95% CI 1.24-3.94; p = 0.007) were associated with low total BZD dose. Patients who received low total BZD dosing were less likely to achieve seizure cessation (hazard ratio 0.7, 95% CI 0.57-0.95). BZD doses were lower than recommended in both out-of-hospital and in-hospital settings. Factors associated with low total BZD dose included male sex, older age, no prior epilepsy diagnosis, and delayed BZD treatment. Low total BZD dosing was associated with decreased likelihood of Seizure cessation. This study provides Class III evidence that patients with RSE who present with male sex, older age, no prior diagnosis of epilepsy, and delayed BZD treatment are more likely to receive low total BZD doses. This study provides Class III evidence that in pediatric RSE low total BZD dose decreases the likelihood of seizure cessation.


The influence of first near-spectacle reading correction on accommodation and its interaction with convergence.
Accommodation and convergence can adapt to blur and disparity stimuli and to age-related changes in accommodative amplitude. Does this ability decline with age? The authors investigated short-term adaptation to first near-spectacle reading correction on the accommodative-stimulus response (ASR) function, accommodative amplitude (AA), AC/A, and CA/C ratios in a pre-presbyopic and an incipient presbyopic population and determined whether changes in these functions recovered after discontinuation of the use of near spectacles. Thirty subjects with normal vision participated; their ages ranged from 21 to 30 years (n = 15) and 38 to 44 years (n = 15). Oculomotor functions were measured before and after single-vision reading spectacles were worn for near tasks over a 2-month period and then 2 months after the use of near spectacles was discontinued. The slope of the ASR function and the AC/A and CA/C ratios did not change significantly after near spectacles were worn. There was a hyperopic shift of the ASR function that significantly reduced the near point of accommodation (NPA) and lowered the far-point refraction. These changes were age invariant and did not recover after 2 months of discontinuation of near spectacle wear. These results imply that the NPA may be enhanced normally by tonic bias of accommodation that elevates the entire ASR function and produces myopic refraction bias. When this bias relaxes after reading spectacles are worn, there is a hyperopic shift of the refractive state and a reduction of the NPA, specified from optical infinity.


Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial.
Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension. To establish preclinical proof of concept, we developed two independent rat models of cirrhosis that were characterized by progressive reduction in renal blood flow and glomerular filtration rate and showed evidence of renal endothelial dysfunction. We then set out to further explore and validate our hypothesis in a phase 2 randomized open-label parallel-group study in male and female patients with alcohol-related cirrhosis and portal hypertension. Forty patients were randomized 1:1 to treatment with serelaxin intravenous (i.v.) infusion (for 60 min at 80 μg/kg/d and then 60 min at 30 μg/kg/d) or terlipressin (single 2-mg i.v. bolus), and the regional hemodynamic effects were quantified by phase contrast magnetic resonance angiography at baseline and after 120 min. The primary endpoint was the change from baseline in total renal artery blood flow. Therapeutic targeting of renal vasoconstriction with serelaxin in the rat models increased kidney perfusion, oxygenation, and function through reduction in renal vascular resistance, reversal of endothelial dysfunction, and increased activation of the AKT/eNOS/NO signaling pathway in the kidney. In the randomized clinical study, infusion of serelaxin for 120 min increased total renal arterial blood flow by 65% (95% CI 40%, 95%; p < 0.001) from baseline. Administration of serelaxin was safe and well tolerated, with no detrimental effect on systemic blood pressure or hepatic perfusion. The clinical study's main limitations were the relatively small sample size and stable, well-compensated population. Our mechanistic findings in rat models and exploratory study in human cirrhosis suggest the therapeutic potential of selective renal vasodilation using serelaxin as a new treatment for renal dysfunction in cirrhosis, although further validation in patients with more advanced cirrhosis and renal dysfunction is required. ClinicalTrials.gov NCT01640964.


Uranium isotopes distinguish two geochemically distinct stages during the later Cambrian SPICE event.
Anoxic marine zones were common in early Paleozoic oceans (542-400 Ma), and present a potential link to atmospheric pO2 via feedbacks linking global marine phosphorous recycling, primary production and organic carbon burial. Uranium (U) isotopes in carbonate rocks track the extent of ocean anoxia, whereas carbon (C) and sulfur (S) isotopes track the burial of organic carbon and pyrite sulfur (primary long-term sources of atmospheric oxygen). In combination, these proxies therefore reveal the comparative dynamics of ocean anoxia and oxygen liberation to the atmosphere over million-year time scales. Here we report high-precision uranium isotopic data in marine carbonates deposited during the Late Cambrian 'SPICE' event, at ca. 499 Ma, documenting a well-defined -0.18‰ negative δ238U excursion that occurs at the onset of the SPICE event's positive δ13C and δ34S excursions, but peaks (and tails off) before them. Dynamic modelling shows that the different response of the U reservoir cannot be attributed solely to differences in residence times or reservoir sizes - suggesting that two chemically distinct ocean states occurred within the SPICE event. The first ocean stage involved a global expansion of euxinic waters, triggering the spike in U burial, and peaking in conjunction with a well-known trilobite extinction event. During the second stage widespread euxinia waned, causing U removal to tail off, but enhanced organic carbon and pyrite burial continued, coinciding with evidence for severe sulfate depletion in the oceans (Gill et al., 2011). We discuss scenarios for how an interval of elevated pyrite and organic carbon burial could have been sustained without widespread euxinia in the water column (both non-sulfidic anoxia and/or a more oxygenated ocean state are possibilities). Either way, the SPICE event encompasses two different stages of elevated organic carbon and pyrite burial maintained by high nutrient fluxes to the ocean, and potentially sustained by internal marine geochemical feedbacks.


A microRNA-129-5p/Rbfox crosstalk coordinates homeostatic downscaling of excitatory synapses.
Synaptic downscaling is a homeostatic mechanism that allows neurons to reduce firing rates during chronically elevated network activity. Although synaptic downscaling is important in neural circuit development and epilepsy, the underlying mechanisms are poorly described. We performed small RNA profiling in picrotoxin (PTX)-treated hippocampal neurons, a model of synaptic downscaling. Thereby, we identified eight microRNAs (miRNAs) that were increased in response to PTX, including miR-129-5p, whose inhibition blocked synaptic downscaling in vitro and reduced epileptic seizure severity in vivo Using transcriptome, proteome, and bioinformatic analysis, we identified the calcium pump Atp2b4 and doublecortin (Dcx) as miR-129-5p targets. Restoring Atp2b4 and Dcx expression was sufficient to prevent synaptic downscaling in PTX-treated neurons. Furthermore, we characterized a functional crosstalk between miR-129-5p and the RNA-binding protein (RBP) Rbfox1. In the absence of PTX, Rbfox1 promoted the expression of Atp2b4 and Dcx. Upon PTX treatment, Rbfox1 expression was downregulated by miR-129-5p, thereby allowing the repression of Atp2b4 and Dcx. We therefore identified a novel activity-dependent miRNA/RBP crosstalk during synaptic scaling, with potential implications for neural network homeostasis and epileptogenesis.


Differential regulation of epaxial and hypaxial muscle development by paraxis.
In vertebrates, skeletal muscle is derived from progenitor cell populations located in the epithelial dermomyotome compartment of the each somite. These cells become committed to the myogenic lineage upon delamination from the dorsomedial and dorsolateral lips of the dermomyotome and entry into the myotome or dispersal into the periphery. Paraxis is a developmentally regulated transcription factor that is required to direct and maintain the epithelial characteristic of the dermomyotome. Therefore, we hypothesized that Paraxis acts as an important regulator of early events in myogenesis. Expression of the muscle-specific myogenin-lacZ transgene was used to examine the formation of the myotome in the paraxis-/- background. Two distinct types of defects were observed that mirrored the different origins of myoblasts in the myotome. In the medial myotome, where the expression of the myogenic factor Myf5 is required for commitment of myoblasts, the migration pattern of committed myoblasts was altered in the absence of Paraxis. In contrast, in the lateral myotome and migratory somitic cells, which require the expression of MyoD, expression of the myogenin-lacZ transgene was delayed by several days. This delay correlated with an absence of MyoD expression in these regions, indicating that Paraxis is required for commitment of cells from the dorsolateral dermomyotome to the myogenic lineage. In paraxis-/-/myf5-/- neonates, dramatic losses were observed in the epaxial and hypaxial trunk muscles that are proximal to the vertebrae in the compound mutant, but not those at the ventral midline or the non-segmented muscles of the limb and tongue. In this genetic background, myoblasts derived from the medial (epaxial) myotome are not present to compensate for deficiencies of the lateral (hypaxial) myotome. Our data demonstrate that Paraxis is an important regulator of a subset of the myogenic progenitor cells from the dorsolateral dermomyotome that are fated to form the non-migratory hypaxial muscles.


[Parkinson's Disease: Clinical Review and Update].
Parkinson's disease is the second most common neurodegenerative disorder, and a significant increase in its prevalence in the past three decades has been documented. Environmental and genetic factors contribute to the pathophysiology of this disease, and 5% - 10% of cases have a monogenic cause. The diagnosis relies on clinical findings, supported by adequate testing. There is no absolute method to diagnose Parkinson's disease in vivo, except for genetic testing in specific circumstances, whose usefulness is limited to a minority of cases. New diagnostic criteria have been recently proposed with the aim of improving diagnostic accuracy, emphasizing findings that might point to other causes of parkinsonism. The available therapeutic options are clinically useful, as they improve the symptoms as well as the quality of life of patients. After the introduction of levodopa, deep brain stimulation emerged as the second therapy with an important symptomatic impact in the treatment of Parkinson's disease. Non-motor symptoms and motor complications are responsible for a large proportion of disability, so these should be identified and treated. Current scientific research is focused on the identification of disease biomarkers allowing correct and timely diagnosis, and on creating more effective therapies, thus fulfilling current clinical unmet needs. This paper presents an updated review on Parkinson's disease, guiding the readership through current concepts, and allowing their application to daily clinical practice.


Including historical data in the analysis of clinical trials: Is it worth the effort?
Data of previous trials with a similar setting are often available in the analysis of clinical trials. Several Bayesian methods have been proposed for including historical data as prior information in the analysis of the current trial, such as the (modified) power prior, the (robust) meta-analytic-predictive prior, the commensurate prior and methods proposed by Pocock and Murray et al. We compared these methods and illustrated their use in a practical setting, including an assessment of the comparability of the current and the historical data. The motivating data set consists of randomised controlled trials for acute myeloid leukaemia. A simulation study was used to compare the methods in terms of bias, precision, power and type I error rate. Methods that estimate parameters for the between-trial heterogeneity generally offer the best trade-off of power, precision and type I error, with the meta-analytic-predictive prior being the most promising method. The results show that it can be feasible to include historical data in the analysis of clinical trials, if an appropriate method is used to estimate the heterogeneity between trials, and the historical data satisfy criteria for comparability.


Chaotic communication in radio-over-fiber transmission based on optoelectronic feedback semiconductor lasers.
Performance of chaotic communication in radio-over-fiber (ROF) transmission based on optoelectronic feedback semiconductor lasers is studied numerically. The chaotic carrier is generated by optoelectronic feedback semiconductor lasers, where chaotic communication is realized by synchronizing a receiver laser with a transmitter laser. Transmission quality of different message encoding schemes, including additive chaos modulation (ACM) and on-off shift keying (OOSK), are investigated and compared. In this study, the dispersion and nonlinearity effects in the fiber transmission module and the amplified spontaneous emission noise from the optical amplifiers are considered. In the wireless channel, effects of additive white Gaussian noise, multipath, and path loss are included. To quantitatively study the performance of this chaotic communication system in the ROF transmission, bit-error-rates (BER) of different transmission lengths, message bit-rates, and signal-to-noise ratios are studied. The optimal launched power and message strength that minimize the BER while assuring effective communication security are discussed. While the ACM scheme is shown to perform better in a fiber only configuration, the OOSK scheme shows better immunity to the random effects and waveform distortions presented in the wireless channel.


Plasma IL-6, its soluble receptors and F2-isoprostanes at rest and during exercise in chronic fatigue syndrome.
The aim of the current study was to investigate the levels of interleukin-6 (IL-6), its soluble receptors (sIL-6R and sgp130) and F(2)-isoprostanes, at rest and during exercise, in patients with chronic fatigue syndrome (CFS). Six male CFS patients and six healthy controls performed an incremental exercise test to exhaustion and a submaximal exercise bout to exhaustion. Blood samples taken in the submaximal test at rest, immediately post-exercise and 24 h post-exercise were analyzed for IL-6, sIL-6R, sgp130 and F(2)-isoprostanes. A further 33 CFS and 33 healthy control participants gave a resting blood sample for IL-6 and sIL-6R measurement. During the incremental exercise test only power output at the lactate threshold was lower (P<0.05) in the CFS group. F(2)-isoprostanes were higher (P<0.05) in CFS patients at rest and this difference persisted immediately and 24 h post-exercise. The exercise study found no differences in IL-6, sIL-6R or sgp130 at any time point between groups. In the larger resting group, there were no differences in IL-6 and sIL-6R between CFS and control groups. This investigation has demonstrated that patients with CFS do not have altered plasma levels of IL-6, sIL-6R or sgp130 either at rest or following exercise. F(2)-isoprostanes, however, were consistently higher in CFS patients.


The role of corticosteroids in the treatment of cerebral schistosomiasis caused by Schistosoma mansoni: case report and discussion.
A 26-year-old Brazilian man was admitted to The Toronto Hospital with a headache and visual scintillation. His last travel to Brazil was five years previously. A computed tomography (CT) scan of the head showed an occipital mass with surrounding vasogenic edema. Occipital brain biopsy revealed Schistosoma mansoni eggs. The patient was treated with two doses of praziquantel (20 mg/kg) and dexamethasone (10 mg). His symptoms and occipital mass resolved. Cerebral schistosomiasis is, in part, caused by the host's inflammatory response to Schistosoma. Modes of treatment have included surgical resection, the antiparasitic drugs oxamniquine or praziquantel, and corticosteroids. Corticosteroids may diminish granulomatous inflammation, thereby preventing further tissue destruction, and there is evidence that they also reduce ova deposition. Our review of the literature supports prompt medical therapy in patients with cerebral schistosomiasis. While the minimally or asymptomatic individual may be treated with praziquantel alone, clinicians should consider adjunctive therapy with corticosteroids for patients with prominent neurologic signs or symptoms or mass lesions with evidence of surrounding edema on a CT scan or by magnetic resonance imaging.


Differential effects of estradiol on drinking by ovariectomized rats in response to hypertonic NaCl or isoproterenol: Implications for hyper- vs. hypo-osmotic stimuli for water intake.
We examined the effects of estradiol on behavioral responses to osmotic challenges in ovariectomized (OVX) rats to test the hypothesis that estradiol enhances sensitivity to gradual changes in plasma osmolality (pOsm) in stimulating water intake. Despite comparably elevated pOsm after a slow infusion of 2 M NaCl, the latency to begin water intake was significantly less in estradiol-treated OVX rats compared to that in oil vehicle-treated rats. Other groups of OVX rats were injected with isoproterenol, which increases circulating angiotensin II. These rats then were given 0.15 M NaCl to drink instead of water, to prevent decreased pOsm associated with water ingestion. Isoproterenol stimulated 0.15 M NaCl intake by both groups; however, estradiol-treated rats consumed less 0.15 M NaCl than did oil-treated rats, findings that are similar to those reported when estradiol-treated rats consumed water. The estradiol enhancement of sensitivity to increased, but not to decreased, pOsm suggests that estradiol has directionally-specific effects on osmoregulatory drinking. Moreover, the estradiol attenuation of 0.15 M NaCl intake after isoproterenol suggests that estradiol effects on osmoregulatory drinking are independent of those on volume regulatory drinking.


Effects of laser etching on shear bond strengths of brackets bonded to fluorosed enamel.
To evaluate the effects of laser etching on the shear bond strengths (SBS) and failure modes of brackets bonded to fluorosed enamel. This in vitro study included 34 fluorosed and 34 nonfluorosed teeth. Teeth were divided into four subgroups according to the etching procedure: Group (A) normal enamel etched with 37% phosphoric acid for 15 s, Group (B) nonfluorosed enamel etched with erbium:yttrium aluminum garnet (Er: YAG) laser for 15 s, Group (C) fluorosed enamel etched with 37% phosphoric acid for 30 s, Group (D) fluorosed enamel etched with Er: YAG laser for 30 s. After bonding of the premolar metal brackets, specimens were subjected to the thermal cycles. After SBS test, modified adhesive remnant index (ARI) by using stereomicroscope and failure modes with a scanning electron microscope (SEM) was determined. After bonding, one specimen from each group was examined under SEM to identify enamel-resin interfaces. ANOVA and Tukey post-hoc tests were used to compare the SBS values. The Kruskal-Wallis and Chi-square tests were used to analyze the distribution of ARI scores and failure modes of groups. The highest mean SBS value (17.56 ± 1.05 MPa) was found in Group A, while the lowest (12.25 ± 0.96 MPa) in Group D. Significant differences were found in the SBS test and failure modes among all groups. The differences between ARI scores of the groups were not significant. According to our findings, laser etching reduced the SBS of brackets bonded to fluorosed teeth, but provided clinically acceptable SBS values.


Class of compound dissipative solitons as a result of collisions in one and two spatial dimensions.
We study the interaction of quasi-one-dimensional (quasi-1D) dissipative solitons (DSs). Starting with quasi-1D solutions of the cubic-quintic complex Ginzburg-Landau (CGL) equation in their temporally asymptotic state as the initial condition, we find, as a function of the approach velocity and the real part of the cubic interaction of the two counterpropagating envelopes: interpenetration, one compound state made of both envelopes or two compound states. For the latter class both envelopes show DSs superposed at two different locations. The stability of this class of compound states is traced back to the quasilinear growth rate associated with the coupled system. We show that this mechanism also works for 1D coupled cubic-quintic CGL equations. For quasi-1D states that are not in their asymptotic state before the collision, a breakup along the crest can be observed, leading to nonunique results after the collision of quasi-1D states.


Active ignoring in early visual cortex.
Selective attention is critical for controlling the input to mental processes. Attentional mechanisms act not only to select relevant stimuli but also to exclude irrelevant stimuli. There is evidence that we can actively ignore irrelevant information. We measured neural activity relating to successfully ignoring distracters (using preview search) and found increases in both the precuneus and primary visual cortex during preparation to ignore distracters. We also found reductions in activity in fronto-parietal regions while previewing distracters and a reduction in activity in early visual cortex during search when a subset of items was successfully excluded from search, both associated with precuneus activity. These results are consistent with the proposal that actively excluding distractions has two components: an initial stage where distracters are encoded, and a subsequent stage where further processing of these items is inhibited. Our findings suggest that it is the precuneus that controls this process and can modulate activity in visual cortex as early as V1.