Urinary mercury monitoring of university staff and students occasionally exposed to mercury vapor.
To monitor the exposure to mercury (Hg) vapor among university staff members and students who occasionally handle elemental Hg in laboratory experiments, urine samples were collected at health examinations conducted by the Health Service Center, University of Tokyo, for six years. Geometric mean of urinary Hg concentrations of 343 samples collected from 234 subjects was 1.61 micrograms Hg/g creatinine (Cr), with the range of 0.30 to 9.31 micrograms Hg/g Cr. Elevated urinary Hg levels, i.e. 3 micrograms Hg/g Cr or higher, were found only among the subjects who worked in several laboratories. This urinary Hg level is judged to correspond to 1-2 micrograms/m3 of air Hg concentration in working areas. The contribution of dental amalgam fillings to urinary Hg excretion, though it exists, was concluded to be small from the result of multiple regression analysis.


Cerebral microemboli during extracorporeal life support: a single-centre cohort study.
The aim of this study was to investigate the load and composition of cerebral microemboli in adult patients undergoing venoarterial extracorporeal life support (ECLS). Adult ECLS patients were investigated for the presence of cerebral microemboli and compared to critically ill, pressure-controlled ventilated controls and healthy volunteers. Cerebral microemboli were detected in both middle cerebral arteries for 30 min using transcranial Doppler ultrasound. Neurological outcome (ischaemic stroke, global brain ischaemia, intracerebral haemorrhage, seizure, metabolic encephalopathy, sensorimotor sequelae and neuropsychiatric disorders) was additionally evaluated. Twenty ECLS patients (cannulations: 15 femoro-femoral, 4 femoro-subclavian, 1 femoro-aortic), 20 critically ill controls and 20 healthy volunteers were analysed. ECLS patients had statistically significantly more cerebral microemboli than critically ill controls {123 (43-547) [median (interquartile range)] vs 35 (16-74), difference: 88 [95% confidence interval (CI) 19-320], P = 0.023} and healthy volunteers [11 (5-12), difference: 112 (95% CI 45-351), P < 0.0001]. In ECLS patients, 96.5% (7346/7613) of cerebral microemboli were of gaseous composition, while solid cerebral microemboli [1 (0-5)] were detected in 12 out of 20 patients. ECLS patients had more neurological complications than critically ill controls (12/20 vs 3/20, P = 0.003). In ECLS patients, a high microembolic rate (>100/30 min) tended to be associated with neurological complications including ischaemic stroke, neuropsychiatric disorders, sensorimotor sequelae and non-convulsive status epilepticus (odds ratio 4.5, 95% CI 0.46-66.62; P = 0.559). Our results indicate that adult ECLS patients are continuously exposed to many gaseous and, frequently, to few solid cerebral microemboli. Prolonged cerebral microemboli formation may contribute to neurological morbidity related to ECLS treatment. ClinicalTrials.gov, NCT02020759, https://clinicaltrials.gov/ct2/show/NCT02020759?term=erdoes&rank=1.


Pharmaceutical properties of two ethenzamide-gentisic acid cocrystal polymorphs: Drug release profiles, spectroscopic studies and theoretical calculations.
The aim of this study was to evaluate the stability and solubility of the polymorphic forms of the ethenzamide (ET) - gentisic acid (GA) cocrystals during standard technological processes leading to tablet formation, such as compression and excipient addition. In this work two polymorphic forms of pharmaceutical cocrystals (ETGA) were characterized by 13C and 15N solid-state nuclear magnetic resonance and Fourier transformed infrared spectroscopy. Spectroscopic studies were supported by gauge including projector augmented wave (GIPAW) calculations of chemical shielding constants.Polymorphs of cocrystals were easily identified and characterized on the basis of solid-state spectroscopic studies. ETGA cocrystals behaviour during direct compressionand tabletting with excipient addition were tested. In order to choose the best tablet composition with suitable properties for the pharmaceutical industry dissolution profile studies of tablets containing polymorphic forms of cocrystals with selected excipients were carried out.


Recommendations for followup of stage I and II seminoma: The Princess Margaret Cancer Centre approach.
Testicular seminoma most commonly affects young men and is associated with favourable prognosis. Various followup schedules and imaging protocols for testicular seminoma have been described without overall consensus. We reviewed the literature together with our experience at the Princess Margaret Cancer Centre and present an evidence-based followup approach for patients with stage I and II seminoma.


Lupus psychosis: differentiation from the steroid-induced state.
Steroid induced psychosis in SLE is rare but clinically important, and often difficult to distinguish from lupus cerebritis. We report a patient with SLE who became depressed following an increase in her steroid dosage. Based on her clinical presentation and high levels of antibodies to P ribosomal proteins (both in CSF and serum) a diagnosis of lupus cerebritis was made. Steroid dosage, time intervals, and the duration of mental changes may help in differentiating steroid psychosis from lupus cerebritis. No single laboratory test sufficient to establish a definitive diagnosis of lupus cerebritis is available at the present time. However, elevated levels of antibodies to P ribosomal proteins may assist in confirming the diagnosis of this condition.


[Effect of vitamin D supplementation on gestational diabetes mellitus:a Meta-analysis].
This Meta-analysis of randomized controlled trial( RCT) was conducted to summarize the preventive and therapeutic effects of vitamin D supplementation on gestational diabetes mellitus( GDM). The electronic database( CNKI, CBM, VIP, PubMed, Cochrane library, Web of Science) were systematically searched from inception to February 2018, using the keywords vitamin D and gestational diabetes to identify Meta-analysis. A total of 16 RCTs were included. A total of 6 RCTs were included for the prevention of GDM by vitamin D supplementation. Meta-analysis indicated that vitamin D supplementation significantly reduced the level of fasting plasma glucose( FPG)( SMD =-1. 87, 95% CI-3. 39--0. 35) and the incidence of GDM( OR = 0. 42, 95% CI 0. 30-0. 60) in pregnant women. Ten RCTs were included for the treatment of GDM by vitamin D supplementation. Meta-analysis indicated that vitamin D supplementation significantly reduced the level of fasting plasma glucose( FPG)( SMD =-0. 29, 95% CI-0. 56--0. 02) and Fasting Insulin( FINS)( SMD =-0. 42, 95% CI-0. 69--0. 15), also improved the homeostasis model of assessment-estimated insulin resistance( HOMA-IR)( SMD =-0. 53, 95% CI-0. 89--0. 17) and the homeostasis model of assessment-estimated B cell function( HOMA-β)( SMD =-0. 39, 95% CI-0. 61--0. 18), and increased the quantitative insulin sensitivity check index( QUICKI)( SMD = 0. 87, 95% CI 0. 41-1. 32) in GDM patients. supplementation may prevent and treat GDM by an improvement in HOMA-IR, HOMA-IR and QUICKI.


BMP signaling in development and diseases: a pharmacological perspective.
Bone morphogenetic protein (BMP) signaling has been implicated in several processes during embryonic development and in adult tissue homeostasis. Maintenance of many organs such as skin, intestinal villi, bones and bone marrow requires continuous regeneration and subsequent differentiation of stem cells in order to maintain organ shape and size necessary for proper functioning. Although BMPs were initially identified as osteogenic factors present in demineralized bone capable of inducing ectopic bone formation, it is now evident that BMPs perform several other functions during embryonic development as well as during the adult life of an organism. Many disorders have been linked to either the BMPs or the molecules functioning downstream of BMP signaling pathway. This review summarizes the existing literature describing the role of BMP signaling during embryonic development and in adult tissue homeostasis to provide a perspective on pharmacological interventions of BMP signaling pathway to mitigate several disease conditions.


Temporal regulation of transgene expression controlled by amino acid availability in human T cells.
T cell therapy strategies, from allogeneic stem cell transplantation toward genetically-modified T cells infusion, develop powerful anti-tumor effects but are often accompanied by side effects and their efficacy remains sometimes to be improved. It therefore appears important to provide a flexible and easily reversible gene expression regulation system to control T cells activity. We developed a gene expression regulation technology that exploits the physiological GCN2-ATF4 pathway's ability to induce gene expression in T cells in response to one essential amino acid deficiency. We first demonstrated the functionality of NUTRIREG in human T cells by transient expression of reporter genes. We then validated that NUTRIREG can be used in human T cells to transiently express a therapeutic gene such as IL-10. Overall, our results represent a solid basis for the promising use of NUTRIREG to regulate transgene expression in human T cells in a reversible way, and more generally for numerous preventive or curative therapeutic possibilities in cellular immunotherapy strategies.


Epidemiology of visceral mycoses in autopsy cases in Japan: the data from 1989 to 2009 in the Annual of Pathological Autopsy Cases in Japan.
To identify recent trends in the frequency of mycoses in autopsy cases, we analyzed, on a four-year basis, the 1989-2009 data in the Annual of Pathological Autopsy Cases in Japan. Of the 13,787 (9235 males) autopsies conducted in 2009, 4.5% (633/13,787) involved fungal infections and of the latter, 60.3% (368/633) were found to have severe clinical manifestations. Among the 610 (96.4%) cases involving a single etiologic angent, the predominant pathogens were Aspergillus (299 cases; 49%) and Candida (184 cases; 30.2%). However, it should be noted that the prevalence of severe aspergillosis and candidiasis has been decreasing. Although the frequency of cases involving zygomycetes seemed to be generally remaining stable from 1989-2009, we noted for the first time a peak in 2009 in such infections in patients less than one year old. Finally, deep-seated infections caused by unidentified fungi would appear to be decreasing over the time of the survey. Our finding, it is hoped, will encourage physicians to actively pursue viscerial fungal infections.


Synthesis and biological activities of neoechinulin A derivatives: new aspects of structure-activity relationships for neoechinulin A.
We synthesized a series of neoechinulin A derivatives and examined the structure-activity relationships in terms of their anti-nitration and anti-oxidant activities as well as their cytoprotective activity against peroxynitrite from SIN-1 (3-(4-morpholinyl)sydnonimine hydrochloride) using PC12 cells. Our results showed that the C-8/C-9 double bond, which constitutes a conjugate system with indole and diketopiperazine moieties of neoechinulin A is essential for anti-nitration and anti-oxidant activities as well as protection against SIN-1 cytotoxicity. The presence of an intact diketopiperazine moiety is an additional requirement for anti-nitration activity but not for the cytoprotective action. Our results suggest that the antioxidant activity or electrophilic nature of the C-8 carbon, both of which are afforded by the C-8/C-9 double bond, may play a role in the cytoprotective properties of this alkaloid.


A genetic portrait of the South-Eastern Carpathians based on autosomal short tandem repeats loci used in forensics.
This work aimed to describe the genetic landscape of the Balkan Peninsula, as revealed by STR markers commonly used in forensics and spatial methods specifically developed for genetic data. We generated and analyzed 16 short tandem repeats (STRs) autosomal genotypes in 287 subjects from ten administrative/geographical regions of Eastern Europe (Romania and the Republic of Moldova). We report estimates of the allele frequencies in these sub-populations, their fixation indexes, and use these results to complement previous spatial analyses of Southern Europe. In seven out of ten analyzed regional samples the heterozygosity, averaged across loci, was lower than expected. The average Fis was 0.011. Among the 16 loci, five returned a significant fixation index Fst. The composite Fst across the 16 loci, among the 10 regional samples, was 0.00417, a figure twice as large as that obtained with the same markers across the entire Northern Mediterranean. The first spatial principal component (sPC1) returned the picture of a Central-European pattern of frequencies for the Carpathians, which extended to the Southern boundary of the Balkan Peninsula. However, the 8 alleles extracted by sPC1 returned a picture of a strong reduction of the migration rate in the Carpathian region, mostly between the inner locations. Our results revealed an unexpected heterogeneity in the area. We believe that populations from some regions will require treatment as distinct entities when considered in forensic applications.


[Detection of uropathies in enuresis in children].
A protocol has been applied to all our patients consulting for nocturnal enuresis who also presented daytime wetting or urge to void, to rule out obstructive uropathies. Our protocol includes voiding cystourethrogram, IVP, cystometry and endoscopy. 64 females and 46 males, 4 to 14 year-old, were studied between 1980 and 1983. Obstructive urethral uropathy was ruled out in 37 females (58%) and 32 males (69%). The most common treatments in these patients were endoscopic resection (Bugbee) of posterior urethral valves in boys and resection of the distal ring in girls. All other associated diseases or malformations were treated according to their etiology. Results, analyzed through a questionnaire sent to parents, were good in 77% of the patients treated for obstruction. In conclusion we think that daytime wetting and urge to void are very frequently the emerging symptoms of a hidden uropathy, in most cases obstructing proximal or distal urethra. Surgical treatment can lead to a good cure rate.


Boosting the Peroxidase-Like Activity of Nanostructured Nickel by Inducing Its 3+ Oxidation State in LaNiO3 Perovskite and Its Application for Biomedical Assays.
Catalytic nanomaterials with intrinsic enzyme-like activities, called nanozymes, have recently attracted significant research interest due to their unique advantages relative to natural enzymes and conventional artificial enzymes. Among the nanozymes developed, particular interests have been devoted to nanozymes with peroxidase mimicking activities because of their promising applications in biosensing, bioimaging, biomedicine, etc. Till now, lots of functional nanomaterials have been used to mimic peroxidase. However, few studies have focused on the Ni-based nanomaterials for peroxidase mimics. In this work, we obtained the porous LaNiO3 nanocubes with high peroxidase-like activity by inducing its 3+ oxidation state in LaNiO3 perovskite and optimizing the morphology of LaNiO3 perovskite. The peroxidase mimicking activity of the porous LaNiO3 nanocubes with Ni3+ was about 58~fold and 22~fold higher than that of NiO with Ni2+ and Ni nanoparticles with Ni0. More, the porous LaNiO3 nanocubes exhibited about 2-fold higher activity when compared with LaNiO3 nanoparticles. Based on the superior peroxidase-like activity of porous LaNiO3 nanocubes, facile colorimetric assays for H2O2, glucose, and sarcosine detection were developed. Our present work not only demonstrates a useful strategy for modulating nanozymes' activities but also provides promising bioassays for clinical diagnostics.


Correction: Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea.
[This corrects the article DOI: 10.1371/journal.pmed.1001967.].


Perfluoroalkyl Acids Including Isomers in Tree Barks from a Chinese Fluorochemical Manufacturing Park: Implication for Airborne Transportation.
Measurement of airborne perfluoroalkyl acids (PFAAs) is challenging, but important for understanding their atmospheric transport. Tree bark is good media for monitoring semivolatile compounds in the atmosphere. Whether it could work as an indicator of airborne PFAAs was first examined in this study. Bark and leaf samples collected around a Chinese fluorochemical manufacturing park (FMP) were analyzed for PFAAs and their branched isomers. Total PFAA concentrations (∑PFAAs) in the bark (mean, 279 ng/g dw) and leaf (250 ng/g dw) samples were comparable. ∑PFAAs in the barks collected within the boundaries of the FMP were significantly (p < 0.05) higher than those outside the FMP, and displayed a decreasing spatial trend as the distance from the FMP increased. However, such spatial difference and trend were not observed for the leaves. PFAA compositional profiles in most of the tree barks were consistent with each other, but different from those in tree leaves. These results indicated that tree barks mainly accumulated airborne PFAAs, while uptake from soil and translocation could make partial contribution to those in leaves. Perfluorooctanoate and perfluorooctanesulfonate in barks had strictly consistent isomeric compositions with their electrochemical fluorination products. Overall, these results indicated that the bark could be a good indicator of airborne PFAAs with respect to their occurrence, isomeric signature, and atmospheric transport.


Genes with linkage or association with type 2 diabetes mellitus.
Complex diseases, such as type 2 diabetes mellitus (T2DM), arise from metabolic disruptions with genetic and environmental components. Multiple genes are responsible for the genetic susceptibility to T2DM. The contribution of these genes to the diabetic phenotype may be modest, variable among different populations, and dependent on interactions with other genes and the environment. The methods of genetic dissection based on linkage, allele sharing, and linkage disequilibrium may lack the statistical power to detect weak associations in heterogeneous populations. Nevertheless, genes involved in insulin signaling, insulin secretion, insulin resistance, glucose metabolism, obesity, diabetes comorbidity and the hormone processing protease genes have been associated with T2DM. New research strategies are improving the methods of genetic dissection and include genomic sequence information to characterize profiles of sequence variants that predispose to T2DM.


Efficacy of intra-arterial fibrinolysis for acute ischemic stroke: meta-analysis of randomized controlled trials.
Although intra-arterial (IA) fibrinolysis for acute ischemic stroke has been clinically available for many years, it is not a therapy approved by the US Food and Drug Administration. Single, randomized, clinical trials (RCTs) have suggested beneficial effects, but no single RCT has demonstrated that IA fibrinolysis yields increases in both good (modified Rankin Scale score 0 to 2) and excellent (modified Rankin Scale score 0 to 1) outcomes when compared with the control group. Relatively few participants and inadequate statistical power in single RCTs may have contributed to this difficulty. Method- We performed a systematic literature search to identified RCTs of IA fibrinolysis in acute ischemic stroke. Multiple outcomes were analyzed, with emphasis on good and excellent outcomes at 90 days or at trial end point. The systematic search identified 5 RCTs with 395 participants comparing IA fibrinolysis and control. IA fibrinolysis was associated with increased good (odds ratio=2.05; 95% CI, 1.33 to 3.14; P=0.001) and excellent (odds ratio=2.14; 95% CI, 1.31 to 3.51; P=0.003) outcomes. For additional end points, IA fibrinolysis was associated with increased frequencies of minimal neurologic deficit (National Institutes of Health Stroke Scale score 0 to 1), minimal impairment of activities of daily living (Barthel Index 90 to 100 or 95 to 100), and recanalization. IA fibrinolysis was associated with increased radiological and symptomatic intracerebral hemorrhage. However, there was no difference in mortality between groups. Formal meta-analysis suggests that IA fibrinolysis substantially increases recanalization rates and good and excellent clinical outcomes in acute ischemic stroke. Increased hemorrhage frequencies are not associated with any increase in mortality.


Early Socioemotional Intervention Mediates Long-Term Effects of Atypical Rearing on Structural Covariation in Gray Matter in Adult Chimpanzees.
Atypical rearing has deleterious effects on chimpanzee behavior during development, some of which can be ameliorated with a responsive care intervention (RCI). Here, we obtained in vivo magnetic resonance images of adult brains of 27 chimpanzees given institutional care, with and without RCI, and compared them with those of 16 chimpanzees mother-reared from birth. We found significant long-term rearing effects on structural covariation and gray matter volume, specifically in the basal forebrain (i.e., caudate, putamen, nucleus accumbens, rectus gyrus, and orbital prefrontal cortex), indicating that RCI prevented brain changes due to atypical rearing. A significant correlation between covariation in these brain areas and caregiver nurturing, experienced in the first month of life, suggests a possible developmental mechanism for the effect of early experience on brain networks. We identified an early intervention that prevents changes in the basal forebrain that otherwise emerge as a consequence of institutionalized rearing without species-typical socioemotional experiences.


Arterial ischemic stroke in children: risk factors and etiologies.
Stroke is increasingly recognized as a significant cause of morbidity and mortality in children, and as a financial burden for families and society. Recent studies have identified and confirmed presumptive risk factors, and have identified novel associations with childhood arterial ischemic stroke. A better understanding of risk factors for stroke in children, which differ from the atherosclerotic risk factors in adults, is the first step needed to improve strategies for stroke prevention and intervention, and ultimately minimize the physical, mental, and financial burden of arterial ischemic stroke. Here, we discuss recent advances in research for selected childhood stroke risk factors, highlighting the progress made in our understanding of etiologic mechanisms and pathophysiology, and address the future directions for acute and long-term treatment strategies for pediatric stroke.


Normal Percentile Reference Curves and Correlation of Acetabular Index and Acetabular Depth Ratio in Children.
Radiographic surveillance of the hip is vital in the diagnosis and treatment of developmental dysplasia of the hip (DDH) in children. The acetabular index (AI) and the acetabular depth ratio (ADR) are radiographic parameters for evaluation of acetabular morphology. Normal reference curves for these parameters that allow for serial evaluation of acetabular development in a manner that is independent of age are necessary and clinically useful. The purpose of this study was (1) to establish normal values of AI and ADR in the normally developing pediatric hip up to age 14, (2) to generate percentile reference curves of both parameters, (3) to determine the extent of correlation between AI and ADR, and (4) to assess intrarater and interrater reliability of AI measurement. We identified 1734 patients who underwent anterior-posterior pelvic radiography between 2004 and 2014. A total of 1152 patients (age range, 0.15 to 13.97 y; 2304 hips) were identified as radiographically normal in the radiology report, signed by the attending pediatric radiologist on the basis of the absence of structural deformity of the hip and previously established reference values for DDH assessment. A review of the medical records confirmed that patients had no diagnosis of DDH or any other orthopaedic hip pathology. The AI and ADR were measured in all radiographs. Normal values and fully parametric percentile curves were generated from birth to skeletal maturity. Correlation between AI and ADR was assessed using linear regression analysis. Normal AI decreased, and ADR increased, with age. Percentile curves were generated for AI and ADR. Using the provided equations, measured values can be converted to age-appropriate percentile and Z-score. The 2 parameters exhibited strong correlation (Pearson correlation=-0.789, P<0.001). For every unit increase in ADR, AI decreased by 0.94 degrees. We present updated normative values of AI that expand up to age 14, and novel reference values for ADR. The reference curves allow for the easy conversion of measured values to percentile and Z-score. Using the presented method during surveillance of the pathologic hip, change in acetabular development can now be assessed in a manner that is independent of age and the natural development of the acetabulum. Level IV-case series.


Analgesic consumption in nursing homes: observational study about 99 nursing homes.
Few analgesics' studies in nursing homes are available. Quantitative and qualitative analgesic consumption evaluation in nursing homes in 2012. Multicenter, descriptive, retrospective and observational study about French Korian Nursing homes' residents, using Medissimo solution, and under at least one analgesic treatment during 2012. We considered as chronic prescription a duration greater than or equal to 28 days and as short prescription a duration less than 28 days. Population studied is 10.818 residents. 62% consumed at least one analgesic, 51% had a chronic analgesic consumption, 11% had a short analgesic consumption and 25% had an analgesic consumption both short and chronic. 47% residents under analgesic treatment received at least one prescription of painkillers "when require". Short prescription represents 19% of analgesic prescriptions: 57% are level 1 only, 20% are level 3 only and 16% are level 2 only. Chronic prescription represents 81% of analgesic prescriptions: 68% are level 1 only, 13% are level 2 only and 5% are level 3 only. 18 INNs were prescribed in nursing homes: paracetamol in 74% of cases, tramadol in 13% of cases, opioids and NSAIDs in 8% of cases. Our study reveals an analgesic consumption sometimes inappropriate with respect to paracetamol, tramadol and NSAIDs consumptions in addition to an overuse of fentanyl patch consumption. Residents in nursing homes are high analgesics consumers, often chronic. Paracetamol is the reference molecule.


Arsenic exposure during pregnancy and size at birth: a prospective cohort study in Bangladesh.
The authors evaluated the association of prenatal arsenic exposure with size at birth (birth weight, birth length, head and chest circumferences). This prospective cohort study, based on 1,578 mother-infant pairs, was conducted in Matlab, Bangladesh, in 2002-2003. Arsenic exposure was assessed by analysis of arsenic in urine collected at around gestational weeks 8 and 30. The association of arsenic exposure with size at birth was assessed by linear regression analyses. In analysis over the full range of exposure (6-978 microg/L), no dose-effect association was found with birth size. However, significant negative dose effects were found with birth weight and head and chest circumferences at a low level of arsenic exposure (<100 microg/L in urine). In this range of exposure, birth weight decreased by 1.68 (standard error (SE), 0.62) g for each 1-microg/L increase of arsenic in urine. For head and chest circumferences, the corresponding reductions were 0.05 (SE, 0.03) mm and 0.14 (SE, 0.03) mm per 1 microg/L, respectively. No further negative effects were shown at higher levels of arsenic exposure. The indicated negative effect on birth size at a low level of arsenic exposure warrants further investigation.


Alpha2-chimaerin interacts with EphA4 and regulates EphA4-dependent growth cone collapse.
EphA4-dependent growth cone collapse requires reorganization of actin cytoskeleton through coordinated activation of Rho family GTPases. Whereas various guanine exchange factors have recently been identified to be involved in EphA4-mediated regulation of Rho GTPases and growth cone collapse, the functional roles of GTPase-activating proteins in the process are largely unknown. Here we report that EphA4 interacts with alpha2-chimaerin through its Src homology 2 domain. Activated EphA4 induces a rapid increase of tyrosine phosphorylation of alpha2-chimaerin and enhances its GTPase-activating protein activity toward Rac1. More importantly, alpha2-chimaerin regulates the action of EphA4 in growth cone collapse through modulation of Rac1 activity. Our findings have therefore identified a new alpha2-chimaerin-dependent signaling mechanism through which EphA4 transduces its signals to the actin cytoskeleton and modulates growth cone morphology.


Efficacy and Safety of Figure-of-Eight Suture for Hemostasis After Radiofrequency Catheter Ablation for Atrial Fibrillation.
This study evaluated the safety and efficacy of venous figure-of-eight (FoE) suture to achieve femoral venous hemostasis after radiofrequency (RF) catheter ablation (CA) for atrial fibrillation (AF).Methods and Results:We retrospectively examined 517 consecutive patients undergoing RFCA for AF. The control group (n=247) underwent manual compression for femoral venous hemostasis after sheath removal with 6 h of bed rest. The FoE group (n=270) underwent FoE suture technique with 4 h of bed rest. All patients achieved successful hemostasis within 24 h after CA. Although the incidence of hematoma was similar between the groups, the incidence of rebleeding was lower in the FoE group than in the control group (FoE vs. control, 3.7% vs. 18.6%, P<0.001). The post-procedural use of analgesic and/or anti-emetic agents was less frequent in the FoE group (19.3% vs. 32.0%, P<0.001). On multiple logistic regression analysis after adjustment for age and sex, the use of a vitamin K antagonist (OR, 2.42; 95% CI: 1.18-4.99, P=0.02) and the FoE suture technique (OR, 0.17; 95% CI: 0.08-0.35, P<0.001) were independent predictors of rebleeding after CA. FoE suture technique effectively achieved femoral venous hemostasis after RFCA for AF. It reduced the risk of rebleeding, shortened bed rest duration, and relieved patient discomfort.


Characterisation of qnr plasmid-mediated quinolone resistance in Enterobacteriaceae from Italy: association of the qnrB19 allele with the integron element ISCR1 in Escherichia coli.
The spread of plasmid-mediated quinolone resistance determinants (qnr-like determinants) was evaluated in a collection of 232 ciprofloxacin-resistant or extended-spectrum beta-lactamase (ESBL)-producing enterobacterial isolates recovered between November 2007 and May 2008 at Padua University Hospital, Italy. qnr genes were mainly found in Klebsiella pneumoniae (68%) and to a lesser extent in Escherichia coli (5.1%). Among the qnrA1, qnrS1 and qnrB19 alleles found, the latter was by far the most frequent. Genetic environment analysis revealed that one qnrB19 gene in E. coli was embedded in an ISCR1 complex class 1 integron. All other qnrB19 genes were flanked by an ISEcp1C region as part of the Tn2012 transposon. qnrA1- and qnrS1-containing strains were not clonally related. Both topoisomerase II mutations and ESBL (mainly SHV-12, TEM-1 and TEM-150 types) were present in most of the qnr-positive strains. qnrB19 is extremely frequent in K. pneumoniae isolates from Italy. In addition, association of qnrB19 with the ISCR1 mobile element in E. coli suggests a broad distribution of this resistance gene in the near future.


Cohesin: a guardian of genome integrity.
Ability to reproduce is one of the hallmark features of all life forms by which new organisms are produced from their progenitors. During this process each cell duplicates its genome and passes a copy of its genome to the daughter cells along with the cellular matrix. Unlike bacteria, in eukaryotes there is a definite time gap between when the genome is duplicated and when it is physically separated. Therefore, for precise halving of the duplicated genome into two, it is required that each pair of duplicated chromosomes, termed sister chromatids, should be paired together in a binary fashion from the moment they are generated. This pairing function between the duplicated genome is primarily provided by a multimeric protein complex, called cohesin. Thus, genome integrity largely depends on cohesin as it ensures faithful chromosome segregation by holding the sister chromatids glued together from S phase to anaphase. In this review, we have discussed the life cycle of cohesin during both mitotic and meiotic cell divisions including the structure and architecture of cohesin complex, relevance of cohesin associated proteins, mechanism of cohesin loading onto the chromatin, cohesion establishment and the mechanism of cohesin disassembly during anaphase to separate the sister chromatids. We have also focused on the role of posttranslational modifications in cohesin biology. For better understanding of the complexity of the cohesin regulatory network to the readers, we have presented an interactome profiling of cohesin core subunits in budding yeast during mitosis and meiosis.


The photocatalytic reduction of U(VI) by Ag-doped SnS2 materials under visible light.
Efficient degradation of uranium(VI) (U(VI)) in wastewater is an urgent problem because of the chemical toxicity and radiotoxicity. In this study, the Agx-SnS2 photocatalysts were compounded by a simple hydrothermal method, effectively removing U(VI) under visible light in water. Compared with SnS2, the results indicated that Agx-SnS2 would decrease the crystallinity without destroying the crystal structure. Moreover, it has excellent photocatalytic performance on the degradation rate of U(VI). Ag0.5-SnS2 exhibited a prominent photocatalytic reduction efficiency of UO22+ of about 86.4% under optical light for 75 min. This was attributed to Ag-doped catalysts, which can narrow the band gap and enhance absorption in visible light. Meanwhile, the doping of Ag promoted the separation of photoinduced carriers, so that more photogenerated charges participated in the photocatalytic reaction. The stability and reusability were verified by the cycle test and the potential photocatalytic mechanism was analyzed based on the experiment.


[The role of nitric oxide in pathogenesis of essential hypertension].
It is known that NO is involved in a variety of physiological functions including the regulation of blood pressure. Dysregulation of L-arginine/NOS/NO biological activity occurs in blood hypertension. The present review will focus on a significance of NO in pathogenesis of essential hypertension.


Risk Factors for Lymph Node Metastasis in Undifferentiated-Type Gastric Carcinoma.
Undifferentiated-type carcinoma has a high incidence of lymph node metastasis. The independent risk factors for lymph node metastasis in undifferentiated-type carcinoma are invasion depth, tumor size, lymphovascular invasion, and presence of ulcer. In the cases that meet the curative resection criteria, no lymph node metastasis was observed in the Japanese studies, but some metastases were observed in Korean studies. After performing curative endoscopic submucosal dissection, the survival rate is similar to that of gastrectomy. The discrepancy between endoscopy and pathology is high in undifferentiated-type carcinoma. The tumor size in endoscopy is a significant risk factor for non-curative resection, and when the tumor size is small, the non-curative resection rate is significantly reduced. Lymphovascular invasion can be assessed in pathologic examination and D2-40 stain is helpful. The presence of ulcer should be determined by pathology, but ulcer's omission in pathology report makes the analysis difficult. Undifferentiatedtype carcinomas with differentiated-type components show higher lymph node metastasis rate than that of pure undifferentiatedtype carcinomas. The lymph node metastasis rate of signet ring cell type is lower than that of other undifferentiated-type carcinomas and is similar to differentiated-type carcinomas. The application of these additional histologic findings may improve the indication of endoscopic submucosal dissection.


Quantifying estrogen metabolism: an evaluation of the reproducibility and validity of enzyme immunoassays for 2-hydroxyestrone and 16alpha-hydroxyestrone in urine.
Rapid and simple enzyme immunoassays (EIAs) were recently developed to measure 2-hydroxyestrone and 16alpha-hydroxyestrone in unextracted urine. The balance between these competing estrogen metabolism pathways may serve as a biomarker of breast cancer risk. Before testing these assays in epidemiologic studies, we evaluated their reproducibility, and validity relative to gas chromatography-mass spectroscopy (GC-MS). Overnight 12-hr urine collections from five midfollicular premenopausal women, five midluteal premenopausal women, and five postmenopausal women were aliquoted and stored at -70 degrees C. Two aliquots from each woman were assayed with the EIAs in a random, blinded order, monthly over 4 months and 1 year later. Reproducibility over 4 months was good for both metabolites in premenopausal women (coefficient of variation = 8-14%) and satisfactory in postmenopausal women (approximately 19%). Reproducibility over 12 months remained good in premenopausal women, but was poor in postmenopausal women, with mean readings increasing 50 to 100%. Wide variation in estrogen metabolite levels enabled a single EIA measurement to characterize individual differences among premenopausal women in midfollicular (intraclass correlation coefficient = 98-99%) and midluteal phase (85-91%). A narrower range in metabolite levels among postmenopausal women reduced discrimination (78-82%). The correlation between EIA and GC-MS measurement was excellent for both metabolites (r>0.9), except for 2-hydroxyestrone in postmenopausal women (r=0.6). Analysis of absolute agreement suggested that both EIAs were less sensitive than GC-MS, and each detected nonspecific background. The low concentration of estrogen metabolites in urine from postmenopausal women may explain the problems with reproducibility and validity in this menstrual group. Accordingly, more sensitive EIAs have been developed and are now being evaluated.


Chief Dental Officers for England and the development of dental services in the United Kingdom.
The United Kingdom currently holds the Presidency of the European Union. The Department of Health for England has taken the opportunity to support a history of the development of dental services in the UK, focusing in particular on the role played by its chief dental officers. Emeritus professor Stanley Gelbier was asked to undertake the project. Until December 2002 he was professor of dental public health at the Guy's, King's and St Thomas' Dental Institute of King's College London. For many years Professor Gelbier has been interested in the history of dentistry. He has served as deputy and then curator of the Museum of the British Dental Association since 1983 and has researched and written widely on dental history especially in relation to the development of community and public health services.


An enzyme-linked immunosorbent assay for detecting antibodies to Pasteurella multocida in chickens.
An enzyme-linked immunosorbent assay (ELISA) was developed to detect the humoral antibody response in chickens receiving subcutaneous injections of the CU vaccine strain of Pasteurella multocida. Serum samples were collected twice weekly for 3 weeks, and chicken antibody responses were monitored using ELISA. The positive/negative ratio method of analysis was used to determine the antibody titer of vaccinated chickens. After a loge transformation of the ELISA titer, a linear relationship was confirmed between ELISA titer and positive/negative ratio. Regression analysis was used to construct a standard curve and derive an equation from this relationship. Using this equation, only one dilution was needed to determine the antibody titer of any unknown serum sample. The ELISA technique was used to monitor the mean antibody titer of vaccinated chickens over the 3-week period. A classic primary response curve occurred when titer was plotted against time.


Intramolecular and intermolecular perturbation on electronic state of FAD free in solution and bound to flavoproteins: FTIR spectroscopic study by using the C = O stretching vibrations as probes.
The intramolecular and intermolecular perturbation on the electronic state of FAD was investigated by FTIR spectroscopy by using the C=O stretching vibrations as probes in D(2)O solution. Natural and artificial FADs, i.e. 8-CN-, 8-Cl-, 8-H-, 8-OCH(3)-, and 8-NH(2)-FAD labelled by 2-(13)C, (18)O=C(2), or 4,10a-(13)C(2) were used for band assignments. The C(2)=O and C(4)=O stretching vibrations of oxidized FAD were shifted systematically by the substitution at the 8-position, i.e. the stronger the electron-donating ability (NH(2) > OCH(3) > CH(3) > H > Cl > CN) of the substituent, the lower the wavenumber region where both the C(2)=O and C(4)=O bands appear. In contrast, the C(4)=O band of anionic reduced FAD scarcely shifted. The 1,645-cm(-1) band containing C(2)=O stretching vibration shifted to 1,630 cm(-1) in the medium-chain acyl-CoA dehydrogenase (MCAD)-bound state, which can be explained by hydrogen bonds at C(2)=O of the flavin ring. The band was observed at 1,607 cm(-1) in the complex of MCAD with 3-thiaoctanoyl-CoA. The 23 cm(-1) shift was explained by the charge-transfer interaction between oxidized flavin and the anionic acyl-CoA. In the case of electron-transferring flavoprotein, two bands associated with the C(4)=O stretching vibration were obtained at 1,712 and 1,686 cm(-1), providing evidence for the multiple conformations of the protein.


Computer simulation of wound closure in epithelial tissues: cell-basal-lamina adhesion.
The mechanism of wound closure in epithelial tissues, i.e., cell monolayer sheets, is investigated through computer simulations. A wound means an area in which some cells have been removed from the normal tissue. The vertex dynamics cell model [T. Nagai and H. Honda, Philos. Mag. B 81, 699 (2001)], which describes morphogenesis of epithelial tissues using the concepts of statistical physics, is modified and applied to the closure of small wounds without mitosis. It is shown that cell-basal-lamina adhesion governs the wound closure competing with cell-cell adhesion and cell elasticity. The simulation results reproduce the actual wound closure process qualitatively and partly quantitatively. The closing proceeds with the translation of the edges of wound polygons toward the wound center and the intermittent reduction in the number of polygon edges. Over time, the process leads to an exponential decrease in the wound area. A shape factor is introduced to describe the wound shape quantitatively and is used to examine the time variation thereof. A method for determining model parameters by comparison with the experiments is given.


Effect of MPS1 Inhibition on Genotoxic Stress Responses in Murine Tumour Cells.
The monopolar spindle 1 (MPS1) is a serine/threonine kinase that plays an important role in spindle assembly checkpoint signaling. To determine the possible relationship between MPS1 inhibition and genotoxic stress responses, herein we examined whether MPS1 inhibition influences cellular susceptibility towards two genotoxic treatments, etoposide and ionizing radiation (IR). Two murine tumour cell lines, SCCVII and EMT6, were used. The effect of genotoxic treatments with or without two novel MPS1 inhibitors, NMS-P715 and AZ3146, on cellular survival, cell-cycle distribution, centrosome status and mitotic catastrophe (MC) was evaluated. MPS1 inhibition sensitized murine tumour cells to etoposide but not to IR. In addition, MPS1 inhibition altered cell-cycle progression and exacerbated centrosome abnormalities, resulting in enhanced MC induced by etoposide but not by IR. MPS1 inhibition promotes the etoposide-induced aberrant mitosis and, consequently, the induction of tumour cell death.


Prevalence and Risk Factors of Abuse among Community Dwelling Elderly of Guwahati City, Assam.
In spite of tremendous impact on health, elder abuse is still an underreported and unrecognized issue. To assess the prevalence of abuse among community dwelling elderly and to identify the various risk factors. This community-based cross-sectional study was conducted in 10 randomly selected wards of Guwahati city. A total of 331 elderly (60 years and above) were interviewed. Abuse was screened by Hwalek-Sengstock Elder Abuse Screening Test (H-S EAST). The study revealed 9.31% prevalence. Neglect was the most common type of abuse reported. Age, sex, socioeconomic status, living status, and functional status were found to be significantly associated with abuse. Abuse is prevalent among elderly population.


A pilot study on phosphate and nitrate removal from secondary wastewater effluent using a selective ion exchange process.
A pilot study was conducted at a wastewater treatment plant (WWTP) in Easton, Pennsylvania, for the removal of varying concentrations of phosphate (HPO4(2-)) and nitrate NO3- using a newly developed ion exchange material referred to as Polymeric Ligand Exchanger (PLE). The PLE was prepared by immobilizing copper (II) ions onto a commercially available chelating resin, DOW-3N. The loaded copper ions act as ligand exchanger sites that selectively bind with target ligands such as phosphate and nitrate. This pilot study was the final experimental testing phase of the PLE toward the full process development for the selective removal of both phosphate and nitrate using secondary effluent from a fully operational WWTP. In order to establish the effectiveness of the PLE, a commercially available activated alumina (AA) was also tested for comparison. Effluent phosphorus and nitrate concentration of less than 0.1 mg l(-1) were achieved for up to 500 bed volumes; phosphorous was reduced from an average concentration of 4.0 mg l(-1) and nitrate from average concentration of 16.4 mg l(-1). In accord with prior laboratory observations, the pilot test results showed that the PLE could selectively remove phosphate from secondary municipal wastewater effluent under normal conditions (pH, ionic strength, dissolved organic carbon content). In addition, the pilot study provided new evidence that nitrate could be removed from secondary municipal wastewater effluent and concurrently with phosphate. The selective ion exchange process provides an alternative for concurrent removal of the eutrophic-enhancing nutrients, phosphate and nitrate.


Perceived and real barriers for men entering nursing: implications for gender diversity.
The objective of this literature review is to describe the perceived or real barriers to men seeking a career in nursing, and to suggest strategies for ameliorating barriers. A literature search exploring barriers existing for men pursuing nursing was conducted. Although the literature underscored the structure of nursing has changed substantially over the last fifty years, these changes have not always provoked a change in the public's perception of nursing. Barriers for men entering nursing still exist. Implications for gender diversity in nursing are discussed. Strategies for decreasing barriers experienced by males entering nursing are warranted.


Proteomics for the analysis of the Candida albicans biofilm lifestyle.
Candida albicans is an opportunistic pathogenic fungus capable of causing infections in immunocompromised patients. Candidiasis is often associated with the formation of biofilms on the surface of inert or biological materials. Biofilms are structured microbial communities attached to a surface and encased within a matrix of exopolymeric substance (EPS). At present, very little is known about the changes in protein profiles that occur during the transition from the planktonic to the biofilm mode of growth. Here, we report the use of proteomics for the comparative analysis of subcellular fractions obtained from C. albicans biofilm and planktonic cultures, including cell surface-associated proteins and secreted components present in liquid culture supernatants (for planktonic cultures) and EPS (for biofilms). The analysis revealed a high degree of similarity between the protein profiles associated with the planktonic and biofilm extracts, and led to the identification of several differentially expressed protein spots. Among the differentially expressed proteins, there was a preponderance of metabolic enzymes that have been described as cell surface proteins and immunodominant antigens. Proteins found in the biofilm matrix included a few predicted to form part of the secretome, and also many secretion-signal-less proteins. These observations contribute to our understanding of the C. albicans biofilm lifestyle.


Endothelial lipase modulates pressure overload-induced heart failure through alternative pathway for fatty acid uptake.
Lipoprotein lipase has been considered as the only enzyme capable of generating lipid-derived fatty acids for cardiac energy. Endothelial lipase is another member of the triglyceride lipase family and hydrolyzes high-density lipoproteins. Although endothelial lipase is expressed in the heart, its function remains unclear. We assessed the role of endothelial lipase in the genesis of heart failure. Pressure overload-induced cardiac hypertrophy was generated in endothelial lipase(-/-) and wild-type mice by ascending aortic banding. Endothelial lipase expression in cardiac tissues was markedly elevated in the early phase of cardiac hypertrophy in wild-type mice, whereas lipoprotein lipase expression was significantly reduced. Endothelial lipase(-/-) mice showed more severe systolic dysfunction with left-ventricular dilatation compared with wild-type mice in response to pressure overload. The expression of mitochondrial fatty acid oxidation-related genes, such as carnitine palmitoyltransferase-1 and medium-chain acyl coenzyme A dehydrogenase, was significantly lower in the heart of endothelial lipase(-/-) mice than in wild-type mice. Also, endothelial lipase(-/-) mice had lower myocardial adenosine triphosphate levels than wild-type mice after aortic banding. In cultured cardiomyocytes, endothelial lipase was upregulated by inflammatory stimuli, whereas lipoprotein lipase was downregulated. Endothelial lipase-overexpression in cardiomyocytes resulted in an upregulation of fatty acid oxidation-related enzymes and intracellular adenosine triphosphate accumulation in the presence of high-density lipoprotein. Endothelial lipase may act as an alternative candidate to provide fatty acids to the heart and regulate cardiac function. This effect seemed relevant particularly in the diseased heart, where lipoprotein lipase action is downregulated.


Modeling Parkinson's disease with induced pluripotent stem cells harboring α-synuclein mutations.
Parkinson's disease (PD) is a common neurodegenerative condition affecting more than 8 million people worldwide. Although, the majority of PD cases are sporadic in nature, there are a growing number of monogenic mutations identified to cause PD in a highly penetrant manner. Many of these familial mutations give rise to a condition that is clinically and neuropathologically similar, if not identical, to sporadic PD. Mutations in genes such as SNCA cause PD in an autosomal dominant manner and patients have motor and non-motor symptoms that are typical for sporadic PD. With the advent of reprogramming technology it is now possible to capture these mutations in induced pluripotent stem cells (iPSCs) to establish models of PD in a dish. There are multiple neuronal subtypes affected in PD including the midbrain dopaminergic (mDA) neurons of the substantia nigra. Robust neuronal differentiation into mDA or other relevant neural cell types are critical to accurately model the disease and ensure the findings are relevant to understanding the disease process. Another challenge for establishing accurate models of PD is being met by the generation of isogenic control iPSC lines with precise correction of mutations using advanced gene editing technology. The contributions of ageing and environmental factors present further challenges to this field, but significant progress is being made in these areas to establish highly relevant and robust models of PD. These human neuronal models, used in conjunction with other model systems, will vastly improve our understanding of the early stages of the PD, which will be key to identifying disease-modifying and preventative treatments.


In vitro and in vivo fitness of respiratory syncytial virus monoclonal antibody escape mutants.
Respiratory syncytial virus (RSV) is the only infectious disease for which a monoclonal antibody (MAb) is used in humans. Palivizumab (PZ) is a humanized murine MAb to the F protein of RSV. PZ-resistant viruses appear after in vitro and in vivo growth of RSV in the presence of PZ. Fitness for replication could be a determinant of the likelihood of dissemination of resistant viruses. We assessed the fitness of two PZ-resistant viruses (F212 and MP4). F212 grew less well in cell culture than the parent A2 virus and was predicted to be less fit than A2. Equal amounts of F212 and A2 were mixed and passaged in cell culture. F212 disappeared from the viral population, indicating it was less fit than the A2 virus. The MP4 virus grew as well as A2 in culture and in cotton rats. A2/MP4 virus input ratios of 1:1, 10:1, 100:1, and 1,000:1 were compared in competitive replication. For all input ratios except 1,000:1, the MP4 virus became dominant, supplanting the A2 virus. The MP4 virus also dominated the A2 virus during growth in cotton rats. Thus, the mutant MP4 virus was more fit than A2 virus in both in vitro and in vivo competitive replication. Whether this fitness difference was due to the identified nucleotide substitutions in the F gene or to mutations elsewhere in the genome is unknown. Understanding the mechanisms by which mutant virus fitness increased or decreased could prove useful for consideration in attenuated vaccine design efforts.


Surgery for Young Adults With Aortic Valve Disease not Amenable to Repair.
Aortic valve replacement is the gold standard for the management of patients with severe aortic stenosis or mixed pathology that is not amenable to repair according to currently available guidelines. Such a simplified approach may be suitable for many patients, but it is far from ideal for young adults considering emerging evidence demonstrating that conventional valve replacement in this cohort of patients is associated with inferior long-term survival when compared to the general population. Moreover; the utilisation of mechanical and bioprosthetic valves can significantly impact on quality and is linked to increased rates of morbidities. Other available options such as stentless valve, homografts, valve reconstruction and Ross operation can be an appealing alternative to conventional valve replacement. Young patients should be fully informed about all the options available - shared decision making is now part of modern informed consent. This can be achieved when referring physicians have a better understanding of the short and long term outcomes associated with every intervention, in terms of survival and quality of life. This review presents up to date evidence for available surgical options for young adults with aortic stenosis and mixed disease not amenable to repair.


Pain from the lumbar zygapophysial joints: a test of two models.
One hundred seventy-six consecutive patients with chronic low-back pain and no history of previous lumbar surgery were studied to test the clinical criteria of Fairbank et al. and Helbig and Lee for zygapophysial joint pain. All patients underwent a history, examination, and a series of zygapophysial joint injections or blocks of the medial branches of the dorsal ramus with lignocaine. Those patients responding to the first series of blocks were given confirmatory blocks using bupivacaine. None of the clinical features tested was found to be associated with response to the confirmatory block. The Fairbank et al. and Helbig and Lee criteria were shown to be unreliable in distinguishing pain of zygapophysial joint origin from pain of other origins.


Bridging HIV-1 cellular latency and clinical long-term non-progressor: an interactomic view.
Development of an effective HIV management is enticed by the fact that long-term non-progressors (LTNP) restrict viral replication spontaneously, but is hindered by HIV-1 latency. Given that the most overlapping characteristics found between HIV-1 LTNP and latency, detailed analysis of the difference would disclose the essentials of latency. In this study, microarray data from our previous study was combined with HIV-1 latency and LTNP data obtained from NCBI GEO database. Principal variance component analysis and hierarchical clustering verified the removal of batch effect across platform. The analysis revealed a total of 456 differential expressed genes with >2-fold change and B-statistic >0. Bayesian inference was used to reconstitute the transcriptional network of HIV-1 latency or LTNP, respectively. Gene regulation was reprogrammed under different disease condition. By network interference, KPNA2 and ATP5G3 were identified as the hubs in latency network which mediate nuclear export and RNA processing. These data offer comparative insights into HIV-1 latency, which will facilitate the understanding of the genetic basis of HIV-1 latency in vivo and serve as a clue for future treatment dealing with key targets in HIV-1 latency.


What causes itch in atopic dermatitis?
Itch, the hallmark of atopic dermatitis, has a significant impact on quality of life for patients with this disease. Various central and peripheral mediators have been suggested to play a role in the pathophysiology of atopic eczema itch. Significant cross-talk occurs among stratum corneum, keratinocytes, immune cells, and nerve fibers, which are in close proximity to one another and induce itch. The impaired barrier function associated with the itch-scratch cycle further augments this vicious cycle. Recent advances in our understanding of itch pathophysiology shed light on peripheral and central neural sensitization of nerve fibers that contribute significantly to itch in atopic dermatitis. Recently, several new mediators have been described as associated with itch in atopic dermatitis, including serine proteases, interleukin 31, and nerve growth factor. This review covers the peripheral and central mechanisms and mediators involved in pathogenesis of itch in atopic dermatitis.


Posterior drug delivery via periocular route: challenges and opportunities.
Drug delivery to the posterior segment via the periocular route is a promising route for delivery of a range of formulations. In this review, we have highlighted the challenges and opportunities of posterior segment drug delivery via the periocular route. Consequently, we have discussed different types of periocular routes, physiological barriers that limit effective drug delivery, practical challenges regarding patient compliance and acceptability and recent advances in developing innovative strategies to enhance periocular drug delivery. We conclude with a perspective on how we envisage the importance of understanding complex barrier functions so as to continue to develop innovative drug-delivery systems.


Egr family members regulate nonlymphoid expression of Fas ligand, TRAIL, and tumor necrosis factor during immune responses.
The Fas ligand (FasL)/Fas pathway is crucial for homeostasis of the immune system and peripheral tolerance. Peripheral lymphocyte deletion involves FasL/Fas in at least two ways: coexpression of both Fas and its ligand on T cells, leading to activation-induced cell death, and expression of FasL by nonlymphoid cells, such as intestinal epithelial cells (IEC), that kill Fas-positive T cells. We demonstrate here that superantigen Staphylococcus enterotoxin B (SEB) induced a dramatic upregulation of FasL, TRAIL, and TNF mRNA expression and function in IEC from BALB/c and C57BL/6 mice. Using adoptive transfer in which CD4(+) T cells from OT-2 T-cell receptor transgenic mice were transferred into recipients, we observed an induction in IEC of FasL, TRAIL, and TNF mRNA after administration of antigen. Specific Egr-binding sites have been identified in the 5' promoter region of the FasL gene, and Egr-1, Egr-2, and Egr-3 mRNA in IEC from mice treated with SEB and from transgenic OT-2 mice after administration of antigen was upregulated. Overexpression of Egr-2 and Egr-3 induced endogenous ligand upregulation that was inhibited by overexpression of Egr-specific inhibitor Nab1. These results support a role for Egr family members in nonlymphoid expression of FasL, TRAIL, and TNF.


PIKfyve controls fluid phase endocytosis but not recycling/degradation of endocytosed receptors or sorting of procathepsin D by regulating multivesicular body morphogenesis.
The mammalian phosphatidylinositol (PtdIns) 5-P/PtdIns 3,5-P2-producing kinase PIKfyve has been implicated in maintaining endomembrane homeostasis in mammalian cells. To address the role of PIKfyve in trafficking processes, we examined the functioning of the biosynthetic, endocytic, and recycling pathways in stable human embryonic kidney 293 cell lines inducibly expressing the wild-type or kinase-defective dominant-negative form. PIKfyveWT or PIKfyveK1831E expression did not affect the processing and lysosomal targeting of newly synthesized procathepsin D. Likewise the rates of transferrin uptake/recycling or epidermal growth factor receptor degradation were not altered upon expression of either protein. In contrast, PIKfyveK1831E but not PIKfyveWT expression markedly impaired the late uptake of fluid phase marker horseradish peroxidase. Inspection of the organelle morphology by confocal microscopy with specific markers in COS cells transiently expressing PIKfyveK1831E showed the Golgi apparatus, end lysosomes, and the recycling compartment indistinguishable from nontransfected cells, despite the dramatic PIKfyveK1831E-induced endomembrane vacuolation. In contrast, we observed a striking effect on the late endocytic compartment, marked by disruption of the dextran-labeled perinuclear endosomal compartment and formation of dispersed enlarged vesicles. Electron microscopy identified the cytoplasmic vacuoles in the PIKfyveK1831E-expressing human embryonic kidney 293 cells as enlarged multivesicular body-like structures with substantially lower number of internal vesicles and membrane whorls. Together, these data indicate that PIKfyve selectively regulates the sorting and traffic of peripheral endosomes containing lysosomaly directed fluid phase cargo through controlling the morphogenesis and function of multivesicular bodies.


A CAD system for B-mode fatty liver ultrasound images using texture features.
The present study proposes a computer-aided diagnosis (CAD) system for the diagnosis of grades of fatty liver disease, namely mild, moderate and severe fatty liver along with normal liver tissue. Fifty-three B-mode ultrasound images consisting of 12 normal, 14 mild, 14 moderate and 13 severe fatty liver images are used. Based on the visual interpretations by the radiologists, region of interests (ROIs) from within the liver and one ROI from the diaphragm region are considered from each image. The texture features of these ROIs are combined in three ways to form ratio features, inverse ratio features and additive features. The sub-sets of optimal features are obtained by a differential evolution feature selection (DEFS) algorithm and a support vector machine (SVM) has been used for the classification task. The Laws ratio features have shown better performance with an average accuracy and standard deviation of 84.9±3.2. Hence, the CAD system could be useful to the radiologists in diagnosing grades of fatty liver disease.


Application of monolithic supports to online extraction and LC-MS analysis of benzodiazepines in whole blood samples.
A column-switching (CS) LC-MS method allowing high-speed determination of benzodiazepines (BZDs) in whole blood is presented. After protein precipitation with ACN followed by evaporation and reconstitution with the loading mobile phase, the online sample clean-up was carried out using a CS device. Two extractive precolumns were evaluated: a conventional restricted access material (RAM) sorbent and a monolithic silica support. Separation was achieved using a Chromolith Performance RP-18e (100 mmx4.6 mm id) monolithic silica column, and detection was performed by atmospheric pressure chemical ionization (APCI) MS. The method with both supports has been fully validated according to an accuracy profile approach. Finally, the monolithic silica column, demonstrating better validation data and a higher robustness than the RAM sorbent, was used for the analysis of several real forensic cases.


Mesoporous Silica Nanoparticles as Drug Delivery Vehicles in Cancer.
Even though cancer treatment has improved over the recent decades, still more specific and effective treatment concepts are mandatory. Surgical removal is not always possible, metastases are challenging and chemo- and radiotherapy can not only have severe side-effects but also resistances may occur. To cope with these challenges more efficient therapies with fewer side-effects are required. One promising approach is the use of drug delivery vehicles. Here, mesoporous silica nanoparticles (MSN) are discussed as biodegradable drug carrier to improve efficacy and reduce side-effects. MSN excellently fulfill the criteria for nanoparticulate carriers: their distinct structure allows high loading capacity and a plethora of surface modifications. MSN synthesis permits fine-tuning of particle and pore sizes. Moreover, drug release can be tailored through various gatekeeper systems which are for example pH-sensitive or redox-sensitive. Furthermore, MSN can either enter tumors passively by the enhanced permeability and retention effect or can be actively targeted by various ligands. PEGylation prolongs circulation time and availability. A huge advantage of MSN is their explicitly low toxic profile in vivo. Yet, clinical translation remains challenging. Overall, mesoporous silica nanoparticles are a promising tool for innovative, more efficient and safer cancer therapies.


Tako-Tsubo Cardiomyopathy (TTC) is an acute, reversible disease of the myocardium. It seems to be caused by an excess of epinephrine, norepinephrine and dopamine. Psychological or physiological stress is considered as a risk factor. Several cases of Tako-Tsubo cardiomyopathy in the context of seizures and electroconvulsive therapy have been reported. We describe the case of a 63-year-old patient who developed TTC during a second series of ECT applications with etomidate anaesthesia and continued antidepressant medication with tranylcypromine. Potential pathophysiological correlations are discussed on the basis of the available literature. Given the increased risk of TTC recurrence, the question on reinitiation of ECT treatment after remission of the heart disease is also addressed. At least in theory, depressive disorders, ECT applications with seizures, the application of the anaesthetic etomidate, as well as tranylcypromine treatment may all be causally related to the development of TTC. Etomidate is known to interfere with cortisol synthesis, resulting in sympathomimetic and pro-inflammatory effects. To date, 19 cases of TTC in conjunction with ECT applications have been published. As in our patient, ECT was reinitiated successfully without complications in eight of them. ECT-related TTC seems to be caused by multiple factors. Circumstantial evidence in our case as well as published data does not support the conclusion that a single risk factor can be held responsible for the development of TTC. Based on theoretical considerations and preliminary findings on a potential role of a relative cortisol deficit, future studies should be encouraged to provide relevant evidence. If careful risk-benefit considerations are done and specific precautions are taken, previous TTC does not exclude reinitiation of ECT.


Investigation of X-ray fluorescence computed tomography (XFCT) and K-edge imaging.
This work provides a comprehensive Monte Carlo study of X-ray fluorescence computed tomography (XFCT) and K-edge imaging system, including the system design, the influence of various imaging components, the sensitivity and resolution under various conditions. We modified the widely used EGSnrc/DOSXYZnrc code to simulate XFCT images of two acrylic phantoms loaded with various concentrations of gold nanoparticles and Cisplatin for a number of XFCT geometries. In particular, reconstructed signal as a function of the width of the detector ring, its angular coverage and energy resolution were studied. We found that XFCT imaging sensitivity of the modeled systems consisting of a conventional X-ray tube and a full 2-cm-wide energy-resolving detector ring was 0.061% and 0.042% for gold nanoparticles and Cisplatin, respectively, for a dose of ∼ 10 cGy. Contrast-to-noise ratio (CNR) of XFCT images of the simulated acrylic phantoms was higher than that of transmission K-edge images for contrast concentrations below 0.4%.


Treatment of infertility with hypogonadotropic hypogonadism: 10-year experience in Auckland, New Zealand.
Infertility in idiopathic or acquired hypogonadotropic hypogonadism (HH) was managed with exogenous gonadotropins and artificial reproduction as needed, in Auckland, New Zealand, from 2000 to 2010. Of eight men seeking conception, 2/2 with acquired HH but only 2/6 with congenital HH achieved clinical pregnancy with exogenous gonadotropins, whereas 12/14 women (86%) achieved one or more live births. Current gonadotropin treatment does not seem to be optimal for men with congenital HH.


Barriers and facilitators to the management of mental health complications after mild traumatic brain injury.
Clinical practice guidelines for mild traumatic brain injury (mTBI) management call on family physicians to proactively screen and initiate treatment for mental health complications, but evidence suggests that this does not happen consistently. The authors aimed to identify physician-perceived barriers and facilitators to early management of mental health complications following mTBI. Semi-structured interviews based on the Theoretical Domains Framework (TDF) were conducted with 11 family physicians. Interview transcripts were analyzed using directed content analysis. Factors influencing management of mental health post-mTBI were identified along five TDF domains. Family physicians could benefit from accessible and easily implemented resources to manage post-mTBI mental health conditions, having a better defined role in this process, and formalization of referrals to mental health specialists.


Identification and Characterization of Canine Ligament Progenitor Cells and Their Extracellular Matrix Niche.
Ligaments are prone to injury and degeneration in humans and animals, however the healing potential of ligament is poor and current treatment options ineffective. Stem cell-based therapies hold potential for treatment of ligament injuries. This study aimed to characterize a ligament progenitor cell (LPC) population and to identify specific niche components which could promote the survival and function of LPCs. LPCs were isolated from canine cranial cruciate ligament and characterized for clonogenicity, multipotency and marker expression. The extracellular matrix (ECM) composition was characterized by the novel application of a metabolic labeling and mass spectrometry technique. LPCs demonstrated clonogenicity, multipotency, and stem cell marker expression. A number of different collagens, glycoproteins, and proteoglycans were identified in the LPC niche using proteomics. Metabolic labeling of cells demonstrated unique turnover profiles for distinct ECM protein groups, indicating the importance of certain niche components for LPC survival and function. The newly synthesized niche components identified in this study could be exploited to aid identification of LPCs and to promote their survival and function for potential ligament repair strategies.


Fatal case of pneumonia caused by a nonhemolytic strain of Streptococcus pyogenes.
We report a case of pneumonia with a fatal outcome caused by a nonhemolytic strain of Streptococcus pyogenes. This strain was isolated in pure growth from blood cultures and was fully identified biochemically. Such strains will be difficult to recognize and isolate from sites with heavy growth of normal flora. This phenomenon has been reported sporadically before, and it is unknown how common such strains may be in pharyngeal samples.


The Subcutaneous ICD: A Review of the UNTOUCHED and PRAETORIAN Trials.
The ICD is an important part of the treatment and prevention of sudden cardiac death in many high-risk populations. Traditional transvenous ICDs (TV-ICDs) are associated with certain short- and long- term risks. The subcutaneous ICD (S-ICD) was developed in order to avoid these risks and complications. However, this system is associated with its own set of limitations and complications. First, patient selection is important, as S-ICDs do not provide pacing therapy currently. Second, pre-procedural screening is important to minimise T wave and myopotential oversensing. Finally, until recently, the S-ICD was primarily used in younger patients with fewer co-morbidities and less structural heart disease, limiting the general applicability of the device. S-ICDs achieve excellent rates of arrhythmia conversion and have demonstrated noninferiority to TV-ICDs in terms of complication rates in real-world studies. The objective of this review is to discuss the latest literature, including the UNTOUCHED and PRAETORIAN trials, and to address the risk of inappropriate shocks.


Interactions between the ABI1 and the ectopically expressed ABI3 genes in controlling abscisic acid responses in Arabidopsis vegetative tissues.
In Arabidopsis, the abscisic acid (ABA)-Insensitive ABI1 and ABI3 genes have been proposed to act in separate ABA signalling cascades. Recessive mutations in ABI3 alter various physiological processes during seed development, whereas the dominant abi1 mutation inhibits ABA responses largely in vegetative tissues. The seed-specific ABI3 gene was ectopically expressed in the vegetative tissues of transgenic Arabidopsis plants carrying a transcriptional fusion between the CaMV 35S promoter and the ABI3 cDNA. Genetic interactions between the ectopically expressed ABI3 and endogenous ABI1 genes were investigated by monitoring diverse ABA responses in vegetative tissues. Ectopic expression of ABI3 conferred to plantlets the ability to accumulate the seed-specific At2S33 and AtEm1 mRNAs in response to ABA, and the abi1 mutation inhibited this ABI3-dependent induction of AtEm1 by ABA. Furthermore, ectopic expression of ABI3 also influenced ABI1-dependent responses that occur in wild-type vegetative tissues. Expression of ABI3 increased ABA induction of the Rab18 mRNA and ABA inhibition of root growth, and both responses were sensitive to the abi1 mutation in the presence as in the absence of ABI3. Finally, although ABI3 is thought to be a transcription activator and stomatal regulation is not known to involve transcriptional events, the ectopically expressed ABI3 gene suppressed the effect of the abi1 mutation on stomatal regulation. The present data demonstrate that ABI1 and ABI3 genetically interact in controlling diverse ABA responses in transgenic vegetative tissues. The possibility that the endogenous ABI1 and ABI3 genes may similarly act in a common ABA signalling pathway in seed is discussed with previous phenotypic studies of the abi1 and abi3 mutants.


Oxygen tension changes the rate of migration of human skin keratinocytes in an age-related manner.
Migration of keratinocytes to re-epithelialize wounds is a key step in dermal wound healing. In aged human skin, wound healing rates decrease and cellular damage by reactive oxygen species (ROS) accumulates. The relationship between age, ROS and human skin keratinocyte migration is not clearly understood. In this study, 4% and 21% oxygen tensions were used to modify levels of ROS produced by metabolism to model low and high oxidative stress conditions. When migration of keratinocytes from young and old primary skin was compared using an in vitro scratch assay, old keratinocytes migrated faster in high oxygen tension than did young keratinocytes, whereas young keratinocytes migrated faster in low oxygen tension. Although all young and old cells at the scratch margins showed intense increases in dihydroethidium oxidation immediately after scratching, the old keratinocytes grown at 21% oxygen demonstrated a greater decrease in the DHE oxidation following scratching and migrated the fastest. These results show that old and young keratinocytes respond to oxygen tension differently and support the hypothesis that keratinocyte migration is affected by the capacity to remove ROS.


Assessment of dyspnea and dynamic hyperinflation in male patients with chronic obstructive pulmonary disease during a six minute walk test and an incremental treadmill cardiorespiratory exercise test.
The six minute walk test (6MWT) is a standardized test that provides information on exercise capacity in patients with COPD. It is considered a submaximal test in opposition to incremental cardiopulmonary exercise tests (CPET) that provide valuable information on all the systems involved in exercise. 1. To compare the perceptive, physiological responses and degree of dynamic hyperinflation during two exercise tests: the 6MWT and the incremental CPET on a treadmill. 2. To evaluate how dyspnea is related to dynamic hyperinflation (DH) and other functional parameters in both tests. 29 stable COPD male patients, age 68±5.8 years, mean post-bronchodilator FEV1 57±11%, were recruited. To evaluate dynamic hyperinflation, inspiratory capacity (IC) was measured at rest and upon completing each one of the tests. At the same time, perceived dyspnea and leg discomfort were rated on specific modified Borg scales. The mean walk distance in 6MWT was 494±88m. The Borg scale rating for shortness of breath upon completing the test was 4.7±2, whilst 2.9±2 for leg discomfort. IC changed from 2.53±0.63l before to 2.34±0.60l after completion of the test. In the treadmill CPET, maximal oxygen consumption (V˙O2max) was 21.8±5mL/kg/min with 6.6±2 dyspnea and 4.3±2 leg discomfort on Borg scales. IC changed from 2.17±0.53l to 1.20±0.43l. Dynamic hyperinflation occurs in male COPD patients during submaximal exercise such as the 6MWT. This phenomenon is more pronounced after incremental CPET on a treadmill. Despite being dyspnea the dominant limiting symptom for both tests, we observed different physiological responses.


Bioaccumulation of PCBs in aquatic biota from a tidal freshwater marsh ecosystem.
Water, sediments, and aquatic biota were sampled in a tidal river-marsh on the Potomac River near Washington, DC (USA) to assess baseline concentrations of polychlorinated biphenyls (PCBs) and bioaccumulation in finish species. The mean sediment total-PCB concentration in the wetland was 50 ng/g dry weight, and mean concentrations in biota ranged from 150 ng/g to 450 ng/g wet weight. The highest PCB concentrations were observed in channel catfish. The median biota-sediment accumulation factor (BSAF) estimated in all finfish species for total-PCBs was 2.9. However, some of the individual and co-eluting PCB congeners had median BSAFs that were substantially greater (e.g., congener numbers 42, 74, 182/187/128, and 171) or lower (e.g., congener numbers 18/15, 45, 185, and 208) than the total-PCB average. Apparent bioaccumulation factors (biota/water PCB concentration ratios) for PCB congeners showed a parabolic relation with n-octanol/water partition coefficients, confirming some previous investigations. There was no clear trend between apparent bioaccumulation factors and trophic level. Organic-carbon-normalized sediment distribution constants (sediment/water PCB concentration ratios) were linearly related to the apparent bioaccumulation factors for all the finfish species investigated.


Fast transformations between configuration state function and Slater determinant bases for direct configuration interaction.
A hybrid configuration state function (CSF) and Slater determinant (SD) basis full configuration interaction (CI) program was developed to simultaneously take advantage of fast SD basis algorithms for σ = Hc formation and the smaller CI vector length and more robust convergence offered by a CSF basis. Graphical processing unit acceleration of the direct CSF-SD and SD-CSF basis transformation algorithms ensures that the combined transformation time per iteration relative to σ formation is small (∼15%). In addition to the obvious benefits of reducing the memory footprint of the CI vector, additional computational savings are demonstrated that rely directly on the size of the CI basis, in one particular case reducing the CI time-to-solution of a HF-CAS-(16,16)-CI/6-31G calculation of ethylene from 1954.79 s to 956 s by using a CSF basis, a 2.0× speedup.


Clostridium difficile infection in solid organ transplant recipients.
Clostridium difficile infection (CDI) is a major healthcare-associated infection that causes significant morbidity and an economic impact in the United States. In this review, we provide an overview of Clostridium difficile infection in solid organ transplant recipients with an emphasis on recent literature. C. difficile in solid organ transplant population has unique risk factors. Fecal microbiota transplantation has shown favorable results in treatment of recurrent C. difficile in this population. Preliminary data from animal studies suggests excellent efficacy with immunization against C. difficile toxins. Over the last decade, number of individuals receiving solid organ transplants has increased exponentially making peri-transplant complications a common occurrence.C. difficile is a frequent cause of morbidity in solid organ transplant recipients. Early and accurate diagnosis of C. difficile requires a stepwise approach. Differentiating between asymptomatic carriage and infection is a diagnostic challenge. Microbial diversity is inversely proportional to risk of C. difficile infection. Antimicrobial stewardship programs help to retain microbial diversity in individuals susceptible to CDI. Recurrent or relapsing C. difficile infection require fecal microbiota transplantation for definitive cure.


The risk of residual or recurring adenoma after piecemeal endoscopic mucosal resection of large non-pedunculated colorectal polyps is predictable.
Piecemeal endoscopic mucosal resection is a safe and effective procedure for the management of large non-pedunculated colorectal polyps. Its major limitation is the possibility of residual or recurrent adenoma and the consequent need for scheduled surveillance colonoscopies, with the implied burden for the patient and health systems. We aimed to evaluate if the Size/Morphology/Site/Access (SMSA) and Sydney EMR Recurrence Tool (SERT) scores are effective in predicting residual/recurrent adenoma after piecemeal endoscopic resection of large non-pedunculated colorectal polyps. Prospective observational cohort study of piecemeal endoscopic mucosal resection of large non-pedunculated colonic polyps performed in a tertiary center. SMSA and SERT scores were calculated in the index colonoscopy and evaluated regarding the ability to predict residual/recurrent adenoma. One hundred fifty-eight procedures were included. Lesions mean size was 31.6 ± 10.1 mm. 65.8% were flat and 61.4% were located in the right colon. Residual/recurrent adenoma was present in 17 (10.8%) cases. SMSA 2 and SERT 0 lesions had 0.0% and 5.7% of residual/recurrent adenoma rate at 6 months, respectively, while SMSA 3-4 and SERT 1-4 lesions had a 11.5% and 14.8% rate, respectively, at 6 months. SMSA grade 2 and SERT grade 0 had a negative predictive value of 100% and 94%, respectively, for residual/recurrent adenoma. SMSA score had an area under the receiver-operating characteristics curve of 0.732 (P = 0.003), while SERT score had a value of 0.730 (P = 0.002) for residual/recurrent adenoma. SMSA and SERT scores are effective tools to identify lesions with a low risk of residual/recurrent adenoma.


Effects of non-steroidal antiallergic eyedrops on the complement-mediated histamine release from human cells.
Leukocytes from ten allergic patients (five allergic to dust-mites and five allergic to pollen) were treated with N-acetyl aspartyl glutamic acid (NAAGA) 4.9%, disodium cromoglycate (DSCG) 2%, lodoxamide (LODO) 1%, and levocabastine (LEVO) 0.5% (concentrations representing the pharmaceutical eyedrop preparations) for 20 minutes. Degranulation was then induced with Complement (rHu5Ca). Histamine was measured in the supernatant with ELISA. LODO and LEVO were inactive in blocking histamine released from human cells, and paradoxical unexpected effects were found with these two agents. They both induced significant histamine release in almost 100% of the samples. DSCG was able to block histamine release in seven patients out of nine (ranging between 5 and 34%). NAAGA was the most active agent on human cells and was able to block basophil degranulation in nine patients out of nine (inhibition ranging between 4 and 66% of total histamine pool).


Are laboratory investigations recommended in current medical practice guidelines supported by available evidence?
It has been suggested that evidence-based laboratory medicine (EBLM) could help to improve the pertinence and accuracy of medical guidelines. In order to demonstrate this, we have used an EBLM approach (i.e. a systematic review) to examine three recently published guidelines that gave quite conflicting recommendations regarding the use of laboratory variables in the management of primary non-small cell lung cancer patients. In recommending the routine measurement of serum albumin, and, to a lesser extent, that of serum calcium in the pre-therapeutic prognostic evaluation of the advanced disease, the American Thoracic Society and the European Respiratory Society were probably correct with regard to calcium but perhaps mistaken regarding albumin. Some of the recommendations of the European Group on Tumour Markers regarding the usefulness of routine measurements of tumour markers (carcinoembryonic antigen (CEA), cancer antigen 125 (CA 125), tissue-polypeptide antigen (TPA)) in the pre- and/or post-therapeutic prognostic evaluation can also be criticised. In addition, the latter society as well as the Société de Pneumologie de Langue Française did not even try to list laboratory variables, others than tumour markers, that would be useful to stratify patients participating in clinical trials (i.e. lactate dehydrogenase (LDH), albumin, calcium, blood cell count, etc.), and the laboratory variables listed by the two former societies were probably not the right ones in this context: in particular LDH and tumour markers (fragments of cytokeratin 19 (Cyfra 21-1), tissue-polypeptide-specific antigen (TPS), neuron-specific enolase (NSE)) were not mentioned. Most, if not all of these discrepancies in the current medical practice guidelines might have been avoided had an EBLM approach been used by the authors.


Association of field dependence and color-coding to male students' achievement.
This study concerned the relationship of field dependence and differentially color-coded materials (black-and-white and colored) with 56 male students' achievement. Significant differences were found in favor of the 21 field-independent men on the Total Criterion Test. Nonsignificant differences were found on the color-coding variable. A surprising and unexpected result was that the field-dependent men who viewed the black and white materials scored significantly higher than the 4 who viewed the color-coded materials.


The Predictive Role of a Novel Risk Index in Patients Undergoing Carotid Artery Stenting: Systemic Immune-Inflammation Index.
Inflammatory mechanisms play an important role in both atherosclerosis and stroke. There are several inflammatory peripheral blood count markers associated with carotid artery stenosis degree, symptomatic carotid artery lesions and carotid artery stent restenosis that reported in previous studies. However, the prognostic role of the blood cell counts and their ratios in predicting in-hospital and long-term outcomes in patients undergoing carotid artery stenting (CAS) has not been comprehensively investigated. Systemic immune-inflammation index (SII) proved its' efficiency in patients with solid tumors and its' role was rarely examined in cardiovascular disorders and stroke. The current study evaluated the effect of this novel risk index on in-hospital and long-term outcomes in a large patient population who underwent CAS. A total of 732 patients with carotid artery stenosis who underwent CAS were enrolled to the study. SII was calculated using the following formula: neutrophil-to-lymphocyte ratio × total platelet count in the peripheral blood (per mm3) and the patients were stratified accordingly: T1, T2 and T3. In-hospital and 5-year outcomes were compared between the tertiles of SII. During the hospitalization, major stroke, ipsilateral stoke, myocardial infarction, death and major adverse cardiovascular events (MACE) rates were significantly higher in high SII level (T3) compared to SII levels (T1 and 2). In long-term outcomes, ipsilateral stroke, major stroke, transient ischemic attack, death, and MACE were significantly higher in the patients with higher SII level (T3). The 5-year Kaplan-Meier overall survival for T1, T2, and T3 were 97.5%, 96.7% and 86.0% respectively. In-hospital and 5-year regression analyses demonstrated that high SII was independently associated with MACE and mortality. SII was independently associated with in-hospital and long-term clinical outcomes in patients undergoing CAS. Immune and inflammation status, as assessed easily and quickly using SII, has a good discriminative value in these patients.


Electromagnetically induced absorption in detuned stub waveguides: a simple analytical and experimental model.
We give an analytical and experimental demonstration of a classical analogue of the electromagnetic induced absorption (EIA) in a simple photonic device consisting of two stubs of lengths d1 and d2 grafted at the same site along a waveguide. By detuning the lengths of the two stubs (i.e. δ = d(2) - d(1)) we show that: (i) the amplitudes of the electromagnetic waves in the two stubs can be written following the two resonators model where each stub plays the role of a radiative resonator with low Q factor. The destructive interference between the waves in the two stubs may give rise to a sharp resonance peak with high Q factor in the transmission as well as in the absorption. (ii) The transmission coefficient around the resonance induced by the stubs can be written following a Fano-like form. In particular, we give an explicit expression of the position, width and Fano parameter of the resonances as a function of δ. (iii) By taking into account the loss in the waveguides, we show that at the transmission resonance, the transmission (reflection) increases (decreases) as a function of δ. Whereas the absorption goes through a maximum around 0.5 for a threshold value δth which depends on the attenuation in the system and then falls to zero. (iv) We give a comparison between the phase of the determinant of the scattering matrix, the so-called Friedel phase and the phase of the transmission amplitude. (v) The effect of the boundary conditions at the end of the resonators on the EIA resonance is also discussed. The analytical results are obtained by means of the Green's function method, whereas the experiments are carried out using coaxial cables in the radio-frequency regime. These results should have important consequences for designing integrated devices such as narrow-frequency optical or microwave filters and high-speed switches.


Sustained response versus relapse: the pharmacotherapeutic goal for obsessive-compulsive disorder.
Convincing evidence from placebo-referenced randomized controlled trials supports efficacy for clomipramine and selective serotonin reuptake inhibitors for acute treatment of obsessive-compulsive disorder. It remains less conclusively understood whether these agents maintain efficacy over the longer term. This paper systematically reviews long-term medication studies in obsessive-compulsive disorder. Studies of clomipramine, fluoxetine and sertraline investigated 'responders' from acute treatment trials and extended treatment up to 12 months versus placebo. Responses to medication were sustained. A 24-week placebo-controlled trial of escitalopram (10 mg or 20 mg/day) and paroxetine (40 mg/day) demonstrated ongoing efficacy for all three treatments. Studies that randomized treated cases to placebo demonstrated reemergence of symptoms in the placebo-treated cohort. Six relapse prevention trials were found by systematic search. Some, but not all, revealed significant advantages for remaining on medication. Paroxetine (20-60 mg/day) and escitalopram (10 or 20 mg/day) were each found to outperform placebo in preventing relapse during 24 weeks of double-blind, randomized follow-up. Meta-analysis, using Review Manager software (4.2.8), detected overall superiority of selective serotonin reuptake inhibitors to placebo in preventing relapse among adult treatment-responders. Worsening by five Yale-Brown Obsessive Compulsive Scale points emerged from the review as a suggested threshold for relapse. Viewed collectively, these results suggest that selective serotonin reuptake inhibitors are effective long-term treatments and relapse prevention represents the treatment target for obsessive-compulsive disorder.


Small Bowel Obstruction Caused by Spontaneous Transomental Hernia: A Case Report.
An internal hernia is a protrusion of visceral contents through a defect in the mesentery or peritoneum. Small bowel obstruction is a common clinical presentation of internal hernias, accounting for 4.1% of all intestinal obstructions. Transomental hernia is a rare type of internal hernia (1-4% of internal hernias), with non-specific symptoms, making its preoperative diagnosis difficult. It is strangulated more frequently, and the postoperative mortality rate is high (30%). Therefore, early diagnosis and management are crucial. We report a case of a 77-year-old female who presented with small bowel obstruction, and a suspected incarcerated internal hernia on abdomen-pelvis CT. A spontaneous transomental hernia was confirmed on emergency laparotomy.


The molecular basis of essential fatty acid limitation in Daphnia magna: A transcriptomic approach.
It is widely accepted that in many food webs, the trophic transfer efficiency among primary producers and herbivores is determined by the nutritional value of primary producers. In pelagic freshwater and marine ecosystems, secondary production by herbivorous crustacean zooplankton is often limited by the seston's content of essential ω3 polyunsaturated fatty acids (ω3 PUFAs). However, little is known about the genetic network behind the positive relationship between phytoplankton ω3 PUFA content and zooplankton growth and reproduction. In our experimental study, we analysed gene expression changes of the freshwater cladoceran Daphnia magna under different food regimes differing in their ω3 PUFA composition. To disentangle ω3 PUFA effects from other factors, we fed D. magna with different pure phytoplankton cultures (i.e., algal and cyanobacterial diets) with or without supplementing the essential ω3 PUFA eicosapentaenoic acid (EPA). As hypothesized, we observed enhanced growth on diets supplemented with EPA. We applied an Illumina RNA-seq approach to D. magna from different diet treatments to find and monitor genes that are regulated dependent on EPA availability. Of 26,646 potential protein products (mapped to the D. magna genome), we identified transcriptomic signatures driven by the different food sources. Further analyses revealed specific candidate genes involved in EPA metabolism, irrespective of the basal food source. This allows a first functional annotation of previously uncharacterized genes involved in the EPA-specific response of D. magna and may finally provide a link to molecular processes connected to ω3 PUFA metabolism and conversion and thus trophic transfer efficiency in pelagic food webs.


Cost-effectiveness of anastrozole compared to tamoxifen in hormone receptor-positive early breast cancer. Analysis based on the ATAC trial.
The 5-year completed treatment analysis of the Anastrozole and Tamoxifen-Alone or in Combination (ATAC) trial showed the superiority of anastrozole over tamoxifen for reduction of disease progression in patients with hormone receptor-positive (HR+) early breast cancer (EBC). The objective was to evaluate the cost-effectiveness of anastrozole versus tamoxifen in this setting. A health economic model was developed comparing the natural history of EBC patients treated with anastrozole or tamoxifen. The perspective of the Belgian health care system was taken. Disease progression from EBC was obtained from the ATAC trial and further progression beyond the clinical trial from published literature. Resource use data were obtained from the ATAC study and from published local retrospective data. Anastrozole was cost-effective versus tamoxifen, provided that a time horizon of at least 9 years is taken. This sensitivity to time horizon is inherently associated with the adjuvant setting due to the different evolution of costs and outcomes over time. Costs are incurred solely during the first 5 years, whereas outcomes are cumulated beyond adjuvant treatment. In conclusion, provided that a sufficient time horizon is taken and that long-term model predictions are confirmed from further follow-up from the ATAC study, anastrozole is a highly cost-effective adjuvant therapy compared to tamoxifen.