The cytosolic class II chaperonin CCT recognizes delineated hydrophobic sequences in its target proteins.
The nonhomologous proteins actin and alpha- and beta-tubulin need the assistance of the cytosolic chaperonin containing TCP-1 (CCT) to reach their correct native state, and their folding requires a transient binary complex formation with CCT. We show that separate or combined deletion of three delineated hydrophobic sequences in actin disturbs the interaction with CCT. These sites are situated between residues 125-179, 244-285, and 340-375. Also, alpha- and beta-tubulin contain at least one recognition region, and intriguingly, it has a similar distribution of hydrophobic residues as region 244-285 in actin. Internal deletion of the sites in actin favor a model for cooperative binding of target proteins to CCT. Peptide mimetics, representing the binding regions, inhibit target polypeptide binding to CCT, suggesting that actin and tubulin contact similar CCT subunits. In addition, we show that actin recognition by class II chaperonins is different from that by class I.


Polymorphisms in the promoters of MMP-2 and TIMP-2 genes in patients with acne vulgaris.
Acne, a chronic inflammatory skin disease, can be seen at any age but it most often occurs in adolescents and young people. Several factors, including increased sebum production, abnormal cornification of the pilosebaceous units, proliferation of Propionibacterium acne, and extracellular matrix (ECM) remodeling, are thought to be associated with the pathogenesis of the acne. The remodeling of the ECM is regulated by a balance between matrix metalloproteinases (MMPs) and their inhibitors called tissue inhibitors of metalloproteinases (TIMPs). The current study investigated the potential association between MMP-2 (-1306 C/T) and TIMP-2 (-418 G/C) polymorphisms and the risk for acne in a Turkish population. The study was conducted with 85 subjects who presented to the Dermatology Department of Duzce University Hospital. DNA was isolated from 2 ml of peripheral blood taken from each subject, and their genotypes were analyzed with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The CC, CT, and TT genotypes for MMP-2 (-1306 C/T) polymorphism were similar between the patient and control group (24 [55.8%], 17 [39.5%], and 2 [4.7%], respectively, vs. 21 [50%], 18 [42.9%], and 3 [7.1%], respectively). However, the distribution of the GG, GC, and CC genotypes for TIMP-2 (-418 G/C) polymorphism were different between the patient and control group (30 [69.8%], 9 [14.8%] and 4 [9.3%], respectively, vs. 26 [61.9%], 14 [33.3%], and 2 [4.8%], respectively). The results demonstrated that the TIMP-2 (-418 CC) genotype was nearly two times more common in the patient group compared to the control group (p=0.686, OR=1.45). It may be possible that the TIMP-2 (-418 CC) genotype increases the tendency to develop acne vulgaris by disrupting the balance between MMPs and TIMPs. Further investigations are needed to clarify more precisely the relationship between acne and MMP-TIMP genes.


Highly shape- and size-tunable membrane nanopores made with DNA.
Membrane nanopores are key for molecular transport in biology, portable DNA sequencing1-4, label-free single-molecule analysis5-14 and nanomedicine5. Transport traditionally relies on barrel-like channels of a few nanometres width, but there is considerable scientific and technological interest for much wider structures of tunable shape. Yet, these nanopores do not exist in nature and are challenging to build using existing de novo routes for proteins10,15-17. Here, we show that rational design with DNA can drastically expand the structural and functional range of membrane nanopores. Our design strategy bundles DNA duplexes into pore subunits that modularly arrange to form tunable pore shapes and lumen widths of up to tens of nanometres. Functional units for recognition or signalling can be optionally attached. By dialling in essential parameters, we demonstrate the utility and potential of the custom-engineered nanopores by electrical direct single-molecule sensing of 10-nm-sized proteins using widely used research and hand-held analysis devices. The designer nanopores illustrate how DNA nanotechnology can deliver functional biomolecular structures to be used in synthetic biology, single-molecule enzymology and biophysical analysis, as well as portable diagnostics and environmental screening.


Anti-beta2-glycoprotein I autoantibodies and metabolic syndrome.
The metabolic syndrome (MetS) is a proatherogenic entity. Autoantibodies to phospholipid cofactors such as beta2-glycoprotein I (beta2-gpI) can influence atheroma appearance. Previous studies confirmed an association of IgA anti-beta2-gpI antibodies with cerebral ischemia, myocardial infarction, peripheral artery disease and carotid disease. This case-control study evaluates a possible association of anti-beta2-gpI and anticardiolipin (aCL) antibodies with non-complicated MetS. Cases comprised patients with MetS without history of vascular events; controls included individuals from the Orthopedic Infirmary admitted due to musculoskeletal disorders. Age, sex, race, history of hypertension, smoking, hypercholesterolemia and diabetes mellitus were evaluated as risk factors in both groups. IgG, IgM, and IgA anti-beta2-gpI and aCL antibodies were detected by enzymatic immunoassay. Sixty-eight patients with MetS and 82 controls were studied. Patients with MetS showed mean age higher than controls (P = 0.001), while males (P = 0.003; OR 0.31; 95%CI 0.15-0.16) and Caucasian ethnicity (P = 0.004; OR 0.25; 95%CI 0.10-0.60) predominated in controls. History of hypertension, hypercholesterolemia and diabetes mellitus were more prevalent in cases than in controls (P < 0.05). The frequency of aCL antibodies (all isotypes) and of IgG and IgM anti-beta2 gpI did not significantly differ in cases and controls. IgA anti-beta2-gpI antibodies were significantly more frequent in MetS patients (42.2%) than controls (10.9%) (P < 0.001). The adjusted OR for IgA anti-beta2-gpI antibodies was 3.60 (95%CI 1.55-8.37; P = 0.003). The current study shows that elevated levels of IgA autoantibodies to β2-gpI might be independently associated to MetS.


Miniature in vivo robot for laparoendoscopic single-site surgery.
The aim of this study was to develop a multidexterous robot capable of generating the required forces and speeds to perform surgical tasks intra-abdominally. Current laparoscopic surgical robots are expensive, bulky, and fundamentally constrained by a small entry incision. A new approach to minimally invasive surgery places the robot completely within the patient. Miniature in vivo robots may allow surgeons to overcome current laparoscopic constraints such as dexterity, orientation, and visualization. A collaborative research group from the Department of Surgery at the University of Nebraska Medical Center and the College of Engineering at the University of Nebraska-Lincoln designed and built a surgical robot prototype capable of performing specific surgical tasks within the peritoneal cavity. The basic robotic design consists of two arms each connected to a central body. Each arm has three degrees of freedom and rotational shoulder and elbow joints. This combination allows a surgeon to grasp, manipulate, cauterize, and perform intracorporeal suturing. The robot's workspace is a hollow hemisphere with an inner radius of 75 mm and an outer radius of 205 mm. Its versatility was demonstrated in four procedures performed in a porcine model: cholecystectomy, partial colectomy, abdominal exploration, and intracorporeal suturing. Miniature in vivo robots have the potential to address the limitations of using articulated instrumentation to perform advanced laparoscopic surgical procedures. Once inserted into the peritoneal cavity, the robot provides a stable platform for visualization with sufficient dexterity and speed to perform surgical tasks from multiple orientations and workspaces.


Long-Term Growth of the Neoaortic Root After Arterial Switch Operation.
The growth of the neoaortic root after the arterial switch operation for the transposition of the great arteries remains unclear. This study aimed to investigate the growth of the neoaortic root and identify risk factors for neoaortic root dilatation. Serial angiographic measurements of the neoaortic root for at least 10 years were evaluated in 145 patients. A total of 1,876 measurements of the sinuses of the Valsalva and the neoaortic annuli were obtained. A linear mixed effects model was used for z-score analysis, including evaluation of risk factors for neoaortic root dilatation. To assess changes in the time course of neoaortic root absolute diameters, a nonlinear mixed effects model with a growth curve model was used. The growth curve revealed progressive growth of the neoaortic root during somatic growth and stabilization in adulthood without normalization. The growth rates of the sinus and annulus were 0.0046 and 0.029 z-score per year, respectively. The sinus and annulus were estimated to grow up to 47 ± 1 mm and 31 ± 1 mm, respectively. Major risk factors for neoaortic root dilatation were double-outlet right ventricle (parameter estimate [PE] = 2.1, 95% confidence interval [CI] = 1.5 to 2.7, p < 0.0001 for sinus; PE = 1.2; 95% CI = 0.7 to 1.6, p < 0.0001 for annulus) and presence of neoaortic valve insufficiency (PE = 0.9; 95% CI = 0.4 to 1.5; p < 0.001 for sinus; PE = 1.6, 95% CI = 1.2 to 2.0, p < 0.0001 for annulus). The risk for neoaortic root dilatation was common. Long-term surveillance is mandatory, particularly in patients with double-outlet right ventricle and neoaortic valve insufficiency.


Awareness of deficits: emotional implications for persons with brain injury and their significant others.
The relationship between emotional distress and differing perceptions of the extent of deficits was investigated with fifty individuals with brain injury and their significant others. Participants completed questionnaires assessing their perceptions of the individual's deficits in various areas (Patient Competency Rating Scale, PCRS). Difference scores were used as markers for awareness of deficits. Emotional distress of the individuals with brain injury and their significant others was assessed with the Beck Depression Inventory (BDI) and the Beck Anxiety Inventory (BAI). Forty per cent of persons with brain injury and 34% of significant others reported symptoms suggestive of mild or greater depression, while 54% of persons with brain injury and 39% of significant others reported symptoms suggestive of experiencing mild or greater anxiety. Significant relationships were not found between the emotional distress of significant others and difference scores. Moderate-to-weak relationships were found between difference scores and the emotional distress of individuals with brain injury. The relationship between chronicity and awareness of deficits was in the opposite direction than predicted. The adjustment of significant others appears to be a function of the extent to which they perceive a resolution of deficits, time since injury, and other factors. Implications for rehabilitation and future research are discussed.


Significance and Functional Similarity for Identification of Disease Genes.
One of the most significant research issues in functional genomics is insilico identification of disease related genes. In this regard, the paper presents a new gene selection algorithm, termed as SiFS, for identification of disease genes. It integrates the information obtained from interaction network of proteins and gene expression profiles. The proposed SiFS algorithm culls out a subset of genes from microarray data as disease genes by maximizing both significance and functional similarity of the selected gene subset. Based on the gene expression profiles, the significance of a gene with respect to another gene is computed using mutual information. On the other hand, a new measure of similarity is introduced to compute the functional similarity between two genes. Information derived from the protein-protein interaction network forms the basis of the proposed SiFS algorithm. The performance of the proposed gene selection algorithm and new similarity measure, is compared with that of other related methods and similarity measures, using several cancer microarray data sets.


Expression and regulation of the proton-coupled oligopeptide transporter PhT2 by LPS in macrophages and mouse spleen.
Membrane transporter PhT2 (SLC15A3), which belongs to the proton-coupled oligopeptide transporter family, mediates the transport of di/tripeptides and histidine utilizing an inwardly directed proton gradient and negative membrane potential. The aim of this study was to elucidate the molecular expression of PhT2 in macrophages and mouse tissues and to explore the regulation of PhT2 by lipopolysaccharide (LPS). The results showed relatively high expression of PhT2 in J774A.1 and THP-1 macrophage cells, mouse spleen, and lung. Using an LPS-induced inflammatory cell model, we found that hPhT2 mRNA expression was up-regulated in THP-1 cells and that the up-regulation was suppressed by pyrrolidine dithiocarbamate, a specific inhibitor of NF-κB. Similar results were observed in mouse spleen during LPS-induced acute inflammation. Using dual-labeling immunofluorescence and confocal laser scanning microscopy, we confirmed that mPhT2 was colocalizing with lysosome-associated membrane protein 1 in transfected HEK293 cells. These results suggested that PhT2, a lysosomal membrane transporter, was up-regulated by LPS via the NF-κB signaling pathway.


Isolation of a gene encoding a novel spectinomycin phosphotransferase from Legionella pneumophila.
A gene capable of conferring spectinomycin resistance was isolated from Legionella pneumophila, the agent of Legionnaires' disease. The gene (aph) encoded a 36-kDa protein which has similarity to aminoglycoside phosphotransferases. Biochemical analysis confirmed that aph encodes a phosphotransferase which modifies spectinomycin but not hygromycin, kanamycin, or streptomycin. The strain that was the source of aph demonstrated resistance to spectinomycin, and Southern hybridizations determined that aph also exists in other legionellae.


Pregabalin in Chronic Post-thoracotomy Pain.
Chronic post-thoracotomy pain (CPP) has very high incidence and therefore it needs attention. Usually, it is burning, dysaesthetic and aching in nature and it displays many features of neuropathic pain. No one technique of thoracotomy has been shown to reduce the incidence of chronic post thoracotomy pain. To evaluate the efficacy and safety of pregabalin in patients with chronic post-thoracotomy pain. This prospective, randomized study was conducted on 50 consenting patients who underwent posterolateral thoracotomy. 25 patients were given pregabalin for 21 days (Group A). Another 25 were given diclofenac sodium (Group B) on demand and they escaped treatment. Visual Analogue Scale (VAS) scoring was performed on days 0, 1 and 7, then follow up was done at 3, 6, 12 and 24 weeks. The data was analyzed by using t-test and Chi- square test for various variables. The pain VAS scores in Group A were significantly low at all observation points except on day 0, day 1 and day 7 post-operatively, when the difference in pain scores in both the groups were comparable. The overall pain scores of Group A were comparable at day 0, day 1 and at day 7 as compared to those of Group B (p>0.9). Pain was significantly low at three weeks (p<0.05). Pain scores of Group A were significantly low at 6 weeks,12 weeks and 24 weeks as compared to those of Group B (p<0.001) and the difference was statistically significant. No significant adverse reactions were observed during study period. Pregabalin is a safe and an effective adjuvant which is used for reducing the chronic post thoracotomy pain, which has no side effects and a high patient compliance. These results should be supported with multidisciplinary studies with larger sample sizes and longer follow-ups.


Potentiation of opiate action in neuroblastoma N18TG2 cells by lipid incorporation.
The effect of cerebroside sulfate, phosphatidylserine, and other phospholipids on opiate receptor function in neuroblastoma N18TG2 cells was studied by incorporation of lipids into the membrane bilayer of viable cells. A concentration- and time-dependent incorporation of sulfatide by N18TG2 cells was observed. The incorporated lipid was not metabolized during the incubation period of up to 48 hr at 37 degrees. Optimal conditions for lipid incorporation were determined to be 4 days after the cell seeding and in 1% fetal calf serum. The incorporated lipid was established to be associated with the plasma membrane fraction of the crude cell homogenate. Furthermore, increases in Vmax but not Km values of the adenylate cyclase for Mg2+, ATP, and prostaglandin E1 were observed in neuroblastoma N18TG2 cells exposed to cerebroside sulfate for 4--6 hr. The incorporation of cerebroside sulfate or phosphatidylserine by N18TG2 cells did not increase the number of opiate binding sites in this cell line as determined by [3H]naloxone, [3H]etorphine, or 3H-labeled D-Ala2-Met5-enkephalinamide binding. Although there was an increase in the affinity of [3H]naloxone binding, linear correlation between the amount of cerebroside sulfate incorporated and the quantity of binding increase was not observed. However, augmentation of both the potencies and the efficacies (maximal inhibitory level) of morphine and enkephalin to regulate adenylate cyclase activity was observed after sulfatide incorporation. At the maximal concentration of cerebroside sulfate used (67 microM) the opiate receptor activity in N18TG2 cells approached that of NG108-15 cells. Identical treatment of N18TG2 cells with cerebroside or psychosine sulfate did not produce any potentiation of the opiate inhibition of adenylate cyclase. Of all of the phospholipids tested--phosphatidylserine, phosphatidylinositol, and phosphatidylcholine--only phosphatidylcholine produced a potentiation of the opiate effect. Both synthetic dipalmitoyl phosphatidylcholine or brain phosphatidylcholine could elicit the potentiation.


Translational mini-review series on vaccines: The Edward Jenner Museum and the history of vaccination.
Edward Jenner's discovery of vaccination must rank as one of the most important medical advances of all time and is a prominent example of the power of rational enquiry being brought to bear during the Age of Enlightenment in 18th century Europe. In the modern era many millions of lives are saved each year by vaccines that work essentially on the same principles that were established by Edward Jenner more than 200 years ago. His country home in Berkeley, Gloucestershire, is where he carried out his work and where he spent most of his life. The building is now a museum in which the life and times of Jenner are commemorated including not only the discovery of smallpox vaccination but also his other important scientific contributions to natural history and medicine. The trustees of the Edward Jenner museum are committed to promoting the museum as a real and "virtual" educational centre that is both entertaining and informative.


Re-assessment of YAP1 and MCR1 contributions to inhibitor tolerance in robust engineered Saccharomyces cerevisiae fermenting undetoxified lignocellulosic hydrolysate.
Development of robust yeast strains that can efficiently ferment lignocellulose-based feedstocks is one of the requirements for achieving economically feasible bioethanol production processes. With this goal, several genes have been identified as promising candidates to confer improved tolerance to S. cerevisiae. In most of the cases, however, the evaluation of the genetic modification was performed only in laboratory strains, that is, in strains that are known to be quite sensitive to various types of stresses. In the present study, we evaluated the effects of overexpressing genes encoding the transcription factor (YAP1) and the mitochondrial NADH-cytochrome b5 reductase (MCR1), either alone or in combination, in an already robust and xylose-consuming industrial strain of S. cerevisiae and evaluated the effect during the fermentation of undiluted and undetoxified spruce hydrolysate. Overexpression of either gene resulted in faster hexose catabolism, but no cumulative effect was observed with the simultaneous overexpression. The improved phenotype of MCR1 overexpression appeared to be related, at least in part, to a faster furaldehyde reduction capacity, indicating that this reductase may have a wider substrate range than previously reported. Unexpectedly a decreased xylose fermentation rate was also observed in YAP1 overexpressing strains and possible reasons behind this phenotype are discussed.


[Instructions for aggregated evidence: About reviews, systematic reviews and meta-analyses (part 2)].
Valid systematic reviews are essential for a safe navigation through the existing literature on a specific clinical topic. In the second part of our training to "Reviews, systematic reviews and meta-analyses", we explain how the results of systematic reviews and meta-analyses should be presented and how they should be interpreted. We describe the forest plot, with which you can get a quick overview of the results of numerous studies, the funnel plot, which can be useful for identifying a publication bias, and report on sensitivity and subgroup analyses, which are of great importance to discover the source of heterogeneity between individual studies. Finally, at the end of our article series, we hopefully convinced you of the importance to make up your own mind about the interpretation of the results of aggregated evidence.


Cardiovascular exercise training extends influenza vaccine seroprotection in sedentary older adults: the immune function intervention trial.
To determine whether cardiovascular exercise training resulted in improved antibody responses to influenza vaccination in sedentary elderly people who exhibited poor vaccine responses. Single-site randomized parallel-arm 10-month controlled trial. University of Illinois at Urbana-Champaign. One hundred forty-four sedentary, healthy older (69.9 +/- 0.4) adults. Moderate (60-70% maximal oxygen uptake) cardiovascular exercise was compared with flexibility and balance training. The primary outcome was influenza vaccine response, as measured according to hemagglutination inhibition (HI) anti-influenza antibody titer and seroprotective responses (HI titer > or =40). Secondary measures included cardiovascular fitness and body composition. Of the 160 participants enrolled, 144 (90%) completed the 10-month intervention with excellent compliance ( approximately 83%). Cardiovascular, but not flexibility, exercise intervention resulted in improvements in indices of cardiovascular fitness, including maximal oxygen uptake. Although not affecting peak (e.g., 3 and 6 weeks) postvaccine anti-influenza HI titers, cardiovascular exercise resulted in a significant increase in seroprotection 24 weeks after vaccination (30-100% dependent on vaccine variant), whereas flexibility training did not. Participants randomized to cardiovascular exercise experienced improvements in influenza seroprotection throughout the entire influenza season, whereas those in the balance and flexibility intervention did not. Although there were no differences in reported respiratory tract infections, the exercise group exhibited reduced overall illness severity and sleep disturbance. These data support the hypothesis that regular endurance exercise improves influenza vaccine responses.


R-COMP 21 for frail elderly patients with aggressive B-cell non-Hodgkin lymphoma: a pilot study.
We evaluated the toxicity and efficacy of nonpegylated liposomal doxorubicin (Myocet) when substituted for conventional doxorubicin in the CHOP-21 regimen in the treatment of frail elderly patients with aggressive non-Hodgkin lymphoma. Twenty frail patients (median age, 73 years), as defined by Balducci et al., with diffuse large B cell or grade IIIb follicular lymphoma, either at diagnosis (15 patients) or relapsed (five patients), were prospectively enrolled. Nine out of 20 (45%) had a World Health Organisation (WHO) performance status > or =2. Fifteen out of 20 patients (75%) had an International Prognostic Index (IPI) score > or =3. Thirteen out of 20 (65%) evaluable patients obtained a complete response. Five additional patients (25%) achieved a partial response. With a median follow-up of 24 months (range 18-27), 15/18 responding patients (83%) are alive and disease free, as well as 3/18 are alive with active disease. Toxicity was mainly hematological with grade 3/4 neutropenia in 26% of cycles and febrile neutropenia in 5%. However, 3/20 patients presented a grade III-IV WHO toxicity (one fatal pulmonary embolism, one congestive, and one ischemic heart failure) while receiving R-COMP chemotherapy. In conclusion, R-COMP-21 is an effective regimen with promising response rates for frail and elderly patients with aggressive non-Hodgkin lymphoma.


Chemometric characterization of the cypriot spirit "zivania".
In 42 alcoholic beverages produced in Cyprus and other countries, 26 chemical and physical-chemical variables were determined by HPLC and GC chromatography, (1)H NMR and ICP spectroscopy, and other techniques. Data were processed using multivariate chemometric techniques, involving principal component analysis, cluster analysis, regularized discriminant analysis, and classification and regression trees. Zivania can be differentiated from beverages from other countries. Using 2- and 3-methyl-butanol, 2-methyl-propanol, furfural, methanol, and the alcoholic grade and the chemical shift of -CH(3) in (1)H NMR spectra as features, a nearly correct classification for zivania was achieved. The reasons for diversions are given.


[20alpha- and 20beta-reduction of steroids by immobilized enzyme preparations and Bacillus megaterium cells].
Cells of Bacillus megaterium immobilized due to incorporation into polyacrylamide gel retained their viability. They differed significantly in their enzymic activity from free cells: 20alpha- and 20beta-hydroxysteroid dehydrogenase activites were substantially decreased and they also showed the capacity to synthesize significant quantities of a new derivative and to destruct steroids. Immobolized protein fractions maintained 20alpha-hydroxysteroid dehydrogenase and 20beta-hydroxysteroid dehydrogenase activities but their specific activites were lower than those of native protein fractions. It is suggested that the synthesis of new compounds was induced by acrylamide that was bound during polymerization.


High-resolution mapping and characterization of open chromatin across the genome.
Mapping DNase I hypersensitive (HS) sites is an accurate method of identifying the location of genetic regulatory elements, including promoters, enhancers, silencers, insulators, and locus control regions. We employed high-throughput sequencing and whole-genome tiled array strategies to identify DNase I HS sites within human primary CD4+ T cells. Combining these two technologies, we have created a comprehensive and accurate genome-wide open chromatin map. Surprisingly, only 16%-21% of the identified 94,925 DNase I HS sites are found in promoters or first exons of known genes, but nearly half of the most open sites are in these regions. In conjunction with expression, motif, and chromatin immunoprecipitation data, we find evidence of cell-type-specific characteristics, including the ability to identify transcription start sites and locations of different chromatin marks utilized in these cells. In addition, and unexpectedly, our analyses have uncovered detailed features of nucleosome structure.


Population pharmacokinetics and pharmacodynamics of rivaroxaban--an oral, direct factor Xa inhibitor--in patients undergoing major orthopaedic surgery.
There is a clinical need for novel oral anticoagulants with predictable pharmacokinetics and pharmacodynamics. Rivaroxaban is an oral direct Factor Xa (FXa) inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. This analysis was performed to characterize the population pharmacokinetics and pharmacodynamics of rivaroxaban in patients participating in two phase II, double-blind, randomized, active-comparator-controlled studies of twice-daily rivaroxaban for the prevention of venous thromboembolism after total hip- or knee-replacement surgery. Sparse blood samples were taken from all patients participating in the studies (n = 1009). In addition, a subset of patients in the hip study (n = 36) underwent full profiling. Rivaroxaban plasma concentrations, FXa activity and the prothrombin time were determined. Nonlinear mixed-effects modelling was used to model the population pharmacokinetics and pharmacodynamics of rivaroxaban. An oral one-compartment model described the population pharmacokinetics of rivaroxaban well. On the first postoperative day only, categorization of patients as slow or fast absorbers as a tool to address variability in absorption improved the fit of the model. Clearance of rivaroxaban was lower and more variable on the first postoperative day, and so time was factored into the model. Overall, the only major difference between the models for the hip study and the knee study was that clearance was 26% lower in the knee study, resulting in approximately 30% higher exposure. Residual variability in the models was moderate (37% and 34% in the hip and knee studies, respectively). Plasma concentrations of rivaroxaban increased dose dependently. Pharmacokinetic parameters that were estimated using the models agreed closely with results from full-profile patients in the hip study, demonstrating that rivaroxaban pharmacokinetics are predictable. The pharmacokinetics of rivaroxaban were affected by expected covariates: age affected clearance in the hip study only, haematocrit (on the first postoperative day only) and gender affected clearance in the knee study only, and renal function affected clearance in both studies. Bodyweight affected the volume of distribution in both studies. However, the effects of covariates on the pharmacokinetics of rivaroxaban were generally small, and predictions of 'extreme' case scenarios suggested that fixed dosing of rivaroxaban was likely to be possible. FXa activity and the prothrombin time were both affected by surgery, probably because of perioperative bleeding and intravenous administration of fluids; therefore, time was included in the pharmacodynamic models. In both studies, FXa activity correlated with rivaroxaban plasma concentrations following a maximum effect model, whereas prothrombin time prolongation correlated following a linear model with intercept. The slope of the prothrombin time prolongation correlation was 3.2 seconds/(100 microg/L) in the hip study and 4.2 seconds/(100 microg/L) in the knee study. Both pharmacodynamic models in both studies demonstrated low residual variability of approximately 10%. This population analysis in patients undergoing major orthopaedic surgery demonstrated that rivaroxaban has predictable, dose-dependent pharmacokinetics that were well described by an oral one-compartment model and affected by expected covariates. Rivaroxaban exposure could be assessed using the prothrombin time, if necessary, but not the international normalized ratio. The findings suggested that fixed dosing of rivaroxaban may be possible in patients undergoing major orthopaedic surgery.


Error rates and powers in genome-scale RNAi screens.
For hit selection in genome-scale RNAi research, we do not want to miss small interfering RNAs (siRNAs) with large effects; meanwhile, we do not want to include siRNAs with small or no effects in the list of selected hits. There is a strong need to control both the false-negative rate (FNR), in which the siRNAs with large effects are not selected as hits, and the restricted false-positive rate (RFPR), in which the siRNAs with no or small effects are selected as hits. An error control method based on strictly standardized mean difference (SSMD) has been proposed to maintain a flexible and balanced control of FNR and RFPR. In this article, the authors illustrate how to maintain a balanced control of both FNR and RFPR using the plot of error rate versus SSMD as well as how to keep high powers using the plot of power versus SSMD in RNAi high-throughput screening experiments. There are relationships among FNR, RFPR, Type I and II errors, and power. Understanding the differences and links among these concepts is essential for people to use statistical terminology correctly and effectively for data analysis in genome-scale RNAi screens. Here the authors explore these differences and links.


Predictors of Food and Water Stockpiling During the COVID-19 Pandemic Among Latinos and Non-Latino Black People.
The study examined factors associated with food and water stockpiling (FWS) during the COVID-19 pandemic. A secondary analysis of online survey data collected in two waves: April 2020 (wave 1) and June/July 2020 (wave 2), was conducted through REDCap web application. A total of 2,271 Non-Latino Black and Latino adults (mean age: 36.8 years (SD = 16.0); 64.3% female) living in Illinois were recruited. Participants self-reported if they stockpiled food and/or water (FWS) seven days prior to survey completion because of the pandemic. Logistic regression was used to determine if each variable was associated with the odds of reporting FWS. Nearly a quarter (23.3%) of participants reported FWS. The adjusted model revealed that odds of FWS increase as the number of household members increased (OR: 1.21; 95% CI: 1.05-1.41). Odds of FWS were lower among participants who were not self-quarantining compared to those self-quarantining all the time (OR: 0.32; 95% CI: 0.17 - 0.62). Furthermore, individuals with lower levels of concern about COVID-19 had lower odds of FWS than those extremely concerned. Household size, self-quarantine status, and concern about COVID-19 were significantly associated with FWS. These findings highlight the need to address the concerns of marginalized individuals to promote healthy behaviors.


Processing of the T-DNA of Agrobacterium tumefaciens generates border nicks and linear, single-stranded T-DNA.
Transfer and integration of a defined region (T-DNA) of the tumor-inducing (Ti) plasmid of Agrobacterium tumefaciens is essential for tumor formation. We used a physical assay to study structural changes induced in Agrobacterium T-DNA by cocultivation with plant cells. We show that nicks are introduced at unique, identical locations in each of the 24-base-pair imperfect direct repeats which flank the T-DNA and present evidence that a linear, single-stranded molecule is generated. We propose that these changes result from processing of the T-DNA for transfer and that they occur by a mechanism similar to DNA processing during conjugative DNA transfer between bacteria.


Niche space of corals along the Florida reef tract.
Over the last three decades corals have declined precipitously in the Florida Keys. Their population decline has prompted restoration effort. Yet, little effort has been invested in understanding the contemporary niche spaces of coral species, which could assist in prioritizing conservation habitats. We sought to predict the probability of occurrence of 23 coral species, including the critically endangered Acropora cervicornis, using observations at 985 sites from 2011-2015. We ran boosted regression trees to evaluate the relationship between the presence of these corals and eight potential environmental predictors: (i) bathymetry (m), (ii) mean of daily sea surface temperature (SST) (°C), (iii) variance of SST (°C), (iv) range of SST (°C), (v) chlorophyll-a concentration (mg m3), (vi) turbidity (m-1), (vii) wave energy (kJ m-2), and (viii) distance from coast (km). The Marquesas and the lower and upper Florida Keys were predicted to support the most suitable habitats for the 23 coral species examined. A. cervicornis had one of the smallest areas of suitable habitat, which was limited to the lower and upper Florida Keys, the Dry Tortugas, and nearshore Broward-Miami reefs. The best environmental predictors of site occupancy of A. cervicornis were SST range (4-5°C) and turbidity (K490 between 0.15-0.25 m-1). Historically A. cervicornis was reported in clear oligotrophic waters, although the present results find the coral species surviving in nearshore turbid conditions. Nearshore, turbid reefs may shade corals during high-temperature events, and therefore nearshore reefs in south Florida may become important refuges for corals as the ocean temperatures continue to increase.


Contaminants in the southern tip of South America: Analysis of organochlorine compounds in feathers of avian scavengers from Argentinean Patagonia.
The aim of this study was to assess the exposure to organochlorine compounds (OC) in 91 primary wing feathers of avian scavengers, Turkey vulture (Cathartes aura), American black vulture (Coragyps atratus) and Southern crested caracaras (Polyborus plancus) from the southern tip of South America, in the Argentinean Patagonia. We analyzed for a series of OC including hexachlorocyclohexane (HCH) isomers, endosulfan, aldrin, dieldrin, endrin, dichlorodiphenyltrichloroethane (p,p'-DDT), dichlorodiphenyldichloroethane (p,p'-DDD), dichlorodiphenyldichloroethylene (p,p'-DDE), heptachlor and heptachlor-epoxide. This is the first study on OC in feathers of three terrestrial top carnivores from South America. OC concentrations found in the studied species were much higher than those found in feathers of raptors from Europe and Asia, which likely indicate their high use in the region, specifically in agriculture, and other possible uses of OC in this area. ∑HCH had the highest median concentration, followed by ∑Drins, ∑DDT, ∑Heptachlor, and ∑Endosulfan, similar to those reported in several food samples in Argentina. On the other hand, differences in OC profiles between species and areas may be related to feeding and migratory habits, as well as the molt period. Three individuals showed ∑DDT (DDT, DDD and DDE) concentrations in feathers related to sublethal effects. However, this comparison should be used with caution due to problems with extrapolating such data across tissues and species.


Detection of the equilibrium folding intermediate of beta-lactoglobulin in the presence of trifluoroethanol by mass spectrometry.
Nano-electrospray ionization mass spectrometry (nano-ESI-MS) was used to monitor the effect of trifluoroethanol (TFE) on the conformational properties of beta-lactoglobulin (BLG). TFE stabilizes protein secondary structure, particularly alpha-helices. However, it also acts as a denaturant above critical concentrations. In the case of BLG, TFE at low concentrations is known to induce formation of an equilibrium intermediate that contains non-native helical structure. Such an intermediate is thought to form also under physiological conditions, playing a role in BLG folding in vivo by preventing aggregation. This well-characterized system was chosen in order to test species distributions obtained by nano-ESI-MS. BLG spectra at increasing concentrations of TFE at pH 2 indicate transient accumulation of a conformer whose charge-state distribution (CSD) falls between that of the native and that of the denatured protein, indicating that the TFE-induced, partially folded form can be selectively monitored by this technique. The condition of its maximum accumulation corresponds to 16% TFE, in excellent agreement with results from solution experiments. In contrast, titrations with methanol or acetonitrile (ACN) reveal apparent two-state transitions from native to fully unfolded BLG. At 10% TFE, the protein appears to be still fully folded at room temperature but, if unfolding is elicited by the combination with other denaturing agents, e.g. heat or low concentrations of ACN, it proceeds via formation of the intermediate. Thus, TFE can also induce formation of the BLG intermediate in synergism with generic denaturing agents. This study indicates good agreement between ESI-MS and other biophysical methods monitoring protein conformational transitions in the presence of TFE.


'It's the system working for the system': carers' experiences of learning disability services in Ireland.
The aim of this article is to examine the experiences of families with young adults with learning disabilities trying to access services. The landscape of disability services for this group is made up of day care, special vocational training and respite places. It aims to identify the extent of an implementation gap between government rhetoric and the degree to which services are characterised as being non-supportive interactions on the ground. Using Ireland as a case study, during a time when the economy is booming and government rhetoric claims unparalleled developments in allocating resources and extra respite 'places', this article identifies the main challenges faced by family carers associated with accessing appropriate services for their disabled adult child, in their attempt to achieve greater independence. This article reports the findings of a qualitative study in which individual semistructured interviews were held with family carers (n = 25) and representatives from national carer organisations (n = 6) in Ireland. These were people caring for an adult (18-30 years) with a learning disability and their experiences were also useful in cross-checking the carer organisation interviews. The findings show that there is limited flexibility, choice and availability in meeting the preferences of the service-users, and throughout the study, services were characterised as being non-supportive interactions. This is not simply symptomatic of a lack of resources. Despite improved funding, supportive attitudes and flexibility are still crucial in meeting user requirements at the level of delivery; thus highlighting that often the system works for the system, not for the user.


Is there ever a single best answer (SBA): assessment driving certainty in the uncertain world of GP?
Uncertainty is inherent in all areas of medical practice, not least in primary care, which is defined by its acceptance of uncertainty and complexity. Single best answer (SBA) questions are a ubiquitous assessment tool in undergraduate medical assessments; however clinical practice, particularly in primary care, challenges the supposition that a single best answer exists for all clinical encounters and dilemmas. In this article, we seek to highlight several aspects of the relationship between this assessment format and clinical uncertainty by considering its influence on medical students' views of uncertainty in the contexts of their medical education, personal epistemology, and clinical expectations.


Structural and functional changes of faba bean legumin during super-limited tryptic hydrolysis.
The influence of a super-limited tryptic hydrolysis on physicochemical and surface functional properties of faba bean legumin has been studied using size-exclusion HPLC, SDS-PAGE, UV and fluorescence spectroscopy, fluorescence probe techniques, surface tension measurements as well as determination of emulsifying activity index (EAI) and emulsion droplets diameter (D). The extent of legumin hydrolysis comprised the range between about 14 and 60 split peptide bonds per molecule resulting in a stepwise decrease of legumin molecular weight to 240 kDa (legumin-T) via discrete intermediates with characteristic subunit patterns. These changes are accompanied by an increase in the surface hydrophobicity and the exposure of aromatic chromophores. No differences were found in the surface tension between the variously hydrolyzed legumin samples. Best emulsifying properties (highest EAI and lowest D values) were attained after a rather low tryptic hydrolysis (about 30 split peptide bonds per mol). Further hydrolysis impaired the emulsifying parameter which were, however, higher (EAI) or lower (D) than those for native legumin.


Supraclavicular node biopsy in staging of testicular carcinoma.
The supraclavicular lymph nodes are known as a potential site for metastatic disease of the gastrointestinal and genitourinary cancers. The values of supraclavicular node biopsy in patients undergoing staging for testicular cancer were studied prospectively. Of 108 patients with testicular cancer undergoing therapy, 26 had supraclavicular node biopsy as part of their staging procedure. Evidence of metastatic disease to the supraclavicular nodes was found in 36% (10/26) of the patients. Ten of these patients had abnormal examinations of the supraclavicular fossa and nine of them (90%) had histologic evidence of metastatic disease. However, of the 16 patients with normal examination of the supraclavicular fossa, only one patient (6.3%) presented with clinically inapparent metastatic disease. The low yield for detection of clinically inapparent metastatic disease mitigates against indiscriminate supraclavicular node biopsy in the staging of testicular carcinoma.


Angiotensin II receptor subtypes and biological responses in the adrenal cortex and medulla.
Angiotensin II (AII) receptor subtypes and their potential coupling mechanisms were studied using recently developed peptide and nonpeptide antagonists in rat and bovine adrenal zona glomerulosa cells, as well as in membranes prepared from rat and bovine adrenal cortex and medulla. Comparison of the potencies of these novel antagonists to displace 125I-[Sar1,Ile8]AII from its binding sites revealed two distinct AII binding sites in membranes prepared from rat adrenal capsules (zona glomerulosa) and from rat adrenal inner zones containing the medulla. About 85% of the binding sites of the glomerulosa zone and 30% of those of the inner zones were of the AT1 subtype, with relative affinities for the nonpeptide antagonists Dup 753 and PD 123177 and the peptide antagonist CGP 42112A in the order of Dup 753 much greater than CGP 42112A greater than PD 123177. In contrast, the relative binding potencies for the other (AT2) population of binding sites were CGP 42112A greater than PD 123177 much greater than Dup 753. Neither AII nor its peptide antagonist [Sar1,Ile8]AII could distinguish between the two sets of binding sites. The effects of the new antagonists on functional responses of rat adrenal glomerulosa cells demonstrated that both AII-stimulated aldosterone production and the AII-induced inhibition of adrenocorticotropic hormone-stimulated cAMP formation were mediated by the AT1 receptor subtype. In bovine adrenals, only AT1 receptors were detected in membranes prepared from the cortex and the medulla, as well as in cultured glomerulosa cells. The relative inhibitory potency of Dup 753 was lower by an order of magnitude at bovine than at rat AT1 receptors. The inhibition of AII-induced aldosterone production by the various antagonists was closely correlated with their inhibitory potencies on 125I-[Sar1,Ile8]AII binding to bovine glomerulosa cells. These data suggest that the known effects of AII in adrenal glomerulosa cells are mediated through the AT1 receptor subtype and that the distribution and/or specificity of the AT2 receptors shows marked species variations.


Short Form of Weinstein Noise Sensitivity Scale (NSS-SF): Reliability, Validity and Gender Invariance among Chinese Individuals.
Independent from noise exposure, noise sensitivity plays a pivotal role in people's noise annoyance perception and concomitant health deteriorations. The present study empirically investigated the psychometric properties of the Chinese version of the Weinstein Noise Sensitivity Scale-Short Form (CNSS-SF), the widely used inventory measuring individual differences in noise perception. In total, 373 Chinese participants (age = 21.41 ± 3.36) completed the online, anonymous questionnaire package. Examination of the CNSS-SF's reliability (internal consistency), factorial validity through validation and cross-validation, nomological validity and measurement invariance across gender groups were undertaken. The Cronbach alpha coefficients and composite reliabilities indicated sufficient reliability of the CNSS-SF. Two confirmatory factor analyses (CFA), in two randomly partitioned groups of participants, substantiated the factorial validity of the scale. The nomological validity of the scale was also corroborated by the significant positive association of its score with the trait anxiety score. Measurement invariance of the CNSS-SF was also found across genders via multi-group CFA. Though not without limitations, findings from the present research provide promising evidence for the utility of the scale in measuring noise sensitivity among the Chinese population. The availability of the CNSS-SF can promote research related to environmental noise and health in China, as well as facilitate cross-cultural comparisons.


Zinc-mediated dimerization and its effect on activity and conformation of staphylococcal enterotoxin type C.
Staphylococcal enterotoxins are superantigen exotoxins that mediate food poisoning and toxic shock syndrome in humans. Despite their structural and functional similarities, superantigens display subtle differences in biological properties and modes of receptor binding as a result of zinc atoms bound differently in their crystal structures. For example, the crystal structures of the staphylococcal enterotoxins in the type C serogroup (SECs) contain a zinc atom coordinated by one aspartate and two histidine residues from one molecule and another aspartate residue from the next molecule, thus forming a dimer. This type of zinc ligation and zinc-mediated dimerization occurs in several SECs, but not in most other staphylococcal enterotoxin serogroups. This prompted us to investigate the potential importance of zinc in SEC-mediated pathogenesis. Site-directed mutagenesis was used to replace SEC zinc binding ligands with alanine. SEC mutants unable to bind zinc did not have major conformational alterations although they failed to form dimers. Zinc binding was not essential for T cell stimulation, emesis, or lethality although in general the mutants were less pyrogenic. Thus the zinc atom in SECs might represent a non-functional heavy atom in an exotoxin group that has diverged from related bacterial toxins containing crucial zinc atoms.


Plasticity in oligodendrocyte lineage progression: An OPC puzzle on our nerves.
Myelin deposition in the central nervous system has been shown to be responsive to experience, with sensory enrichment increasing myelination and sensory or social deprivation decreasing myelination. This process is referred to as "adaptive myelination" or "myelin plasticity" and signifies an essential component of new learning. However, whether these experience-driven adaptations are driven by (a) underlying changes in the generation of myelinating cells, (b) altered interactions between myelin sheath and axon, or (c) a combination of the above remains unclear. It has been suggested that myelination largely follows an "innate" and automatic programme, allowing for a predictable pattern of central nervous system myelin deposition over time. Adaptive myelination is thought to account for more nuanced alterations that do not dramatically shift this pattern, but ultimately drive functional responses. This makes the study of myelin plasticity particularly difficult, as it necessitates being able to clearly and specifically draw boundaries between the innate and adaptive programme. Thus, the field requires a holistic understanding of the remit of innate myelin development, prior to investigation of adaptive myelination. This review will collate literature regarding different aspects of oligodendrocyte and myelin development (namely, oligodendrocyte proliferation, differentiation, death and myelin sheath formation) in an innate context, before discussing how these parameters are proposed to change under adaptive conditions. It is the hope that this review will highlight the need for a comprehensive and integrated approach towards studying both innate and adaptive forms of myelination.


Branching patterns of rabbit oculomotor and trochlear nerves demonstrated by Sihler's stain technique.
A modified Sihler's stain technique was used to visualize the branching patterns of oculomotor and trochlear nerves. The levator palpebrae, superior rectus, inferior rectus, medial rectus, inferior oblique, superior oblique and tensor trochlea muscles were isolated from the eyes of normal rabbits and processed using modified Sihler's technique. The distributions and terminal ramifications of the oculomotor and trochlear nerves were observed. Two distinct divisions and terminal branches of the oculomotor nerve were shown in detail together with the trochlear nerve distribution. The application of Sihler's technique enables researchers to trace nerve branching within relatively transparent muscles, whereas the nerve fibers are counterstained and clearly visible. This technique could be useful for detailed studies of the motor control of extraocular muscles.


A locus on 2p12 containing the co-regulated MRPL19 and C2ORF3 genes is associated to dyslexia.
DYX3, a locus for dyslexia, resides on chromosome 2p11-p15. We have refined its location on 2p12 to a 157 kb region in two rounds of linkage disequilibrium (LD) mapping in a set of Finnish families. The observed association was replicated in an independent set of 251 German families. Two overlapping risk haplotypes spanning 16 kb were identified in both sample sets separately as well as in a joint analysis. In the German sample set, the odds ratio for the most significantly associated haplotype increased with dyslexia severity from 2.2 to 5.2. The risk haplotypes are located in an intergenic region between FLJ13391 and MRPL19/C2ORF3. As no novel genes could be cloned from this region, we hypothesized that the risk haplotypes might affect long-distance regulatory elements and characterized the three known genes. MRPL19 and C2ORF3 are in strong LD and were highly co-expressed across a panel of tissues from regions of adult human brain. The expression of MRPL19 and C2ORF3, but not FLJ13391, were also correlated with the four dyslexia candidate genes identified so far (DYX1C1, ROBO1, DCDC2 and KIAA0319). Although several non-synonymous changes were identified in MRPL19 and C2ORF3, none of them significantly associated with dyslexia. However, heterozygous carriers of the risk haplotype showed significantly attenuated expression of both MRPL19 and C2ORF3, as compared with non-carriers. Analysis of C2ORF3 orthologues in four non-human primates suggested different evolutionary rates for primates when compared with the out-group. In conclusion, our data support MRPL19 and C2ORF3 as candidate susceptibility genes for DYX3.


Double core hole creation and subsequent Auger decay in NH3 and CH4 molecules.
Energies of the hollow molecules CH(4)(2+) and NH(3)(2+) with double vacancies in the 1s shells have been measured using an efficient coincidence technique combined with synchrotron radiation. The energies of these states have been determined accurately by high level electronic structure calculations and can be well understood on the basis of a simple theoretical model. Their major decay pathway, successive Auger emissions, leads first to a new form of triply charged ion with a core hole and two valence vacancies; experimental evidence for such a state is presented with its theoretical interpretation. Preedge 2-hole-1-particle (2h-1p) states at energies below the double core-hole states are located in the same experiments and their decay pathways are also identified.


Detection of hemizygosity in Hermansky-Pudlak syndrome by quantitative real-time PCR.
Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism, a bleeding diathesis and, in some patients, pulmonary fibrosis or granulomatous colitis. HPS is associated with biosynthesis defects of melanosomes, platelet-dense bodies, and lysosomes. There are seven genetic HPS subtypes; HPS-1 is the most common. We used a real-time quantitative PCR (qPCR) approach to investigate six HPS-1 patients, previously assigned as having homozygous mutations in the HPS1 gene. HPS1 gene copy numbers, calculated by use of a comparative Ct method, revealed that one patient was in fact hemizygous for her c.1189delC (S396delC) HPS1 mutation. The causative deletion/insertion was 13,966 bp in size, with defined breakpoints, and involved an adjacent gene (C10orf33). A mechanism of formation is proposed for the deletion/insertion, and both multiplex and qPCR indicated that the deletion/insertion was present in the patient, her brother, and her father. qPCR amplification is valuable for detecting deletions too small to be identified by fluorescence in situ hybridization. This demonstration of hemizygosity, performed using genomic DNA, can eliminate concerns about non-paternity and can verify the diagnosis of an autosomal recessive disorder when a DNA alteration appears to be homozygous by standard PCR and sequencing methods, and its pathogenicity is in doubt.


Knock-in of Cx46 partially rescues fiber defects in lenses lacking Cx50.
Connexins 46 (Cx46) and 50 (Cx50) support lens development and homeostasis. Knockout (KO) of Cx50, but not Cx46, causes defects in lens fiber organization, F-actin enrichment, gap junction (GJ) size, ball-and-socket (BS) maturation, and GJ-associated protein distributions. To further determine the unique roles of Cx50 and Cx46, we investigated whether these defects persisted in Cx46 knock-in (Ki) lenses. Ki mice had Cx46 knocked-in to their Cx50 loci, where it was expressed under endogenous Cx50 promoters. Fiber cell morphology and the distribution of lens membrane/cytoskeleton proteins from wild-type (WT), Ki, and Cx50 KO mice were visualized by immunofluorescent labeling and confocal microscopy. Cx46 Ki partially rescued Cx50 KO lens fiber defects. Three-week-old Ki lens fibers had typical F-actin distributions but were nonuniformly sized and disorganized. The Cx-associated proteins zonula occludens-1 (ZO-1) and β-dystroglycan (βDys) no longer localized to the nuclei but remained absent from GJs. BS formed, but this occurred with lower than WT frequency. BS appeared with greater frequency in 8-week-old Ki lenses, but so did aberrant balloon-like structures similar to those in Cx50 KO lenses. Unexpectedly, 8-week-old Cx50 KO and Ki cortical lens fibers were no longer disorganized. Cx identity is important for some aspects of fiber development (organization, Cx association with ZO-1 and βDys) but not others (F-actin enrichment). Either Cx supports BS maturation, but the sparsity of BS and presence of balloon-like structures in Ki lenses suggest that Cx50 is more capable of doing so. The partial rescue of BS structures may support the rapid growth of cortical fibers to the improved growth of Ki lenses compared to Cx50 KO lenses at young ages. Neither absence of Cx50 nor presence of Ki Cx46 affects cortical fiber cell organization by the age of 8 weeks.


Transcranial magnetic stimulation reduces masseter motoneuron pool excitability throughout the cortical silent period.
To evaluate the time-course of changes in masseter motoneuron pool excitability following transcranial magnetic stimulation of motor cortex, and relate this to the duration of the masseter cortical silent period (CSP). Surface EMG was recorded bilaterally from masseter and digastric muscles in 13 subjects. Focal TMS was applied at 1.3x active motor threshold (AMT) to motor cortex of one hemisphere to elicit a muscle evoked potential (MEP) and silent period bilaterally in masseter as subjects maintained an isometric bite at approximately 10% maximum. With jaw muscles relaxed, a servo-controlled stretcher evoked a stretch reflex in masseter which was conditioned by TMS (1.3x AMT) at 14 different conditioning-testing intervals. There were 20 trials at each interval, in random order. TMS evoked no MEP in resting masseter, but often produced a small MEP in digastric. Mean (+/-SE) masseter CSP was 67+/-3ms. The masseter stretch reflex was facilitated when stretch preceded TMS by 8 and 10ms, which we attribute to spatial summation of corticobulbar and Ia-afferent excitatory inputs to masseter. Masseter stretch reflex amplitude was reduced when TMS was given up to 75ms before stretch, and for up to 2ms afterwards. We conclude that descending corticobulbar activity evoked by TMS acts bilaterally on brainstem interneurons that either inhibit masseter motoneurons or increase pre-synaptic inhibition of Ia-afferent terminals for up to 75ms after TMS. The reduction of masseter motoneuron pool excitability following TMS has a similar time-course to the CSP. In contrast to the situation for spinal and facial (CN VII) muscles, the masseter CSP appears to have no component that can be attributed exclusively to cortical mechanisms. Abnormalities in the masseter cortical silent period observed in neurological conditions may be due to pathophysiological changes at cortical and/or sub-cortical levels.


Serum vitamin D levels among patients in a clinical oncology practice compared to primary care patients in the same community: a case-control study.
Objectives Low serum vitamin D levels have been associated with risk for certain malignancies, but studies have not directly analysed levels between community oncology and primary care practices. The purpose of this study was to compare serum vitamin D levels in patients at a community oncology practice with non-cancer patients at a primary care practice. Design Retrospective case-control study. 25-Hydroxyvitamin D levels were ordered for screening in both cancer and non-cancer patients. Levels were compared in univariate and multivariate analyses adjusted for age, body mass index and season of blood draw. Setting A community-based radiation oncology centre and a community-based primary care practice: both located in Northeastern Pennsylvania, USA. Participants 170 newly diagnosed cancer patients referred for initial consultation at the community oncology centre from 21 November 2008 to 18 May 2010, and 170 non-cancer patients of the primary care practice who underwent screening for hypovitaminosis D for the first time from 1 January 2009 to 31 December 2009. Primary and secondary outcome measures The primary outcome measure was mean serum vitamin D level, and the secondary outcome measures were frequencies of patients with vitamin D levels <20 ng/ml and levels <30 ng/ml. Results The oncology patients had a significantly lower mean serum vitamin D level (24.9 ng/ml) relative to a cohort of non-cancer primary care patients (30.6 ng/ml, p<0.001) from the same geographical region. The relationship retained significance after adjustment for age, body mass index and season of blood draw in multivariate analysis (p=0.001). Levels <20 and <30 ng/ml were more frequent in the oncology patients (OR (95% CI)=2.59 (1.44 to 4.67) and 2.04 (1.20 to 3.46), respectively) in multivariate analysis. Conclusions Cancer patients were found to have low vitamin D levels relative to a similar cohort of non-cancer primary care patients from the same geographical region.


Education and training to support the use of clinical telehealth: A review of the literature.
Introduction Despite a growing literature base, substantial investment, and policy changes within governments, the integration of telehealth into routine clinical care has been limited. The availability of appropriate systematic education and training for practitioners has been highlighted as necessary for strong adoption. However, the availability and nature of telehealth-related education and training for practitioners is not understood. By reviewing the literature, we aimed to describe the delivery of education and training in telehealth, with particular focus on content, modes of delivery, types of institutions, and target clinician groups. Methods We performed searches using PubMed, Scopus, Embase, Web of Science, PsycINFO, the Cochrane Library, and ERIC. We included studies that were focused on the delivery of telehealth-related academic or vocational education and training. We extracted information pertaining to country, programs and their participants, and tabulated the results. Results Altogether 388 articles were identified, of which nine studies were selected for final review. Programs from five countries were represented and articles were spread across telemedicine and clinically oriented journals. Education and training in telehealth has been provided as both university level and vocational courses using conventional classroom based delivery methods and e-learning. Reported curriculum items included terminology, clinical applications, the evidence-base, and technological aspects. Conclusions Published evidence in peer-reviewed literature on telehealth education and training is limited. According to this review, a number of topics relating to telehealth have been covered by existing education programs both within tertiary and professional development levels.


[Cooperation and networking in early prevention and intervention and child protection: the importance of evidence-based methods].
Prevention, intervention and child protection in early childhood essentially need well-established interdisciplinary systematic networking. Individual, heterogeneous and complex needs of families cannot be met by one profession alone. Successful cooperation of various institutions and professions is based on fixed arrangements and cooperation pathways. Networking has to be systematically established in everyday routine to be able to work in difficult emergency cases of child protection. Only well established cooperation is experienced as a support for the participants of the network and not as an additional complication. Prerequisite for such a development of favorable conditions is an evidence-based knowledge of the impact of different structures of cooperation, relations and conditions. This requires data collection with the aim of further empirically based development of local network structures. Three tools for such surveys have been developed and tested in the field.


Common pathways and communication between the brain and heart: connecting post-traumatic stress disorder and heart failure.
Psychiatric illnesses and cardiovascular disease (CVD) contribute to significant overall morbidity, mortality, and health care costs, and are predicted to reach epidemic proportions with the aging population. Within the Veterans Administration (VA) health care system, psychiatric illnesses such as post-traumatic stress disorder (PTSD) and CVD such as heart failure (HF), are leading causes of hospital admissions, prolonged hospital stays, and resource utilization. Numerous studies have demonstrated associations between PTSD symptoms and CVD endpoints, particularly in the Veteran population. Not only does PTSD increase the risk of HF, but this relationship is bi-directional. Accordingly, a VA-sponsored conference entitled "Cardiovascular Comorbidities in PTSD: The Brain-Heart Consortium" was convened to explore potential relationships and common biological pathways between PTSD and HF. The conference was framed around the hypothesis that specific common systems are dysregulated in both PTSD and HF, resulting in a synergistic acceleration and amplification of both disease processes. The conference was not intended to identify all independent pathways that give rise to PTSD and HF, but rather identify shared systems, pathways, and biological mediators that would be modifiable in both disease processes. The results from this conference identified specific endocrine, autonomic, immune, structural, genetic, and physiological changes that may contribute to shared PTSD-CVD pathophysiology and could represent unique opportunities to develop therapies for both PTSD and HF. Some recommendations from the group for future research opportunities are provided.


Down-regulation and change in subcellular distribution of receptors for luteinizing hormone-releasing hormone in OV-1063 human epithelial ovarian cancers during therapy with LH-RH antagonist Cetrorelix.
The inhibition of growth of various hormone-dependent cancers by analogs of luteinizing hormone-releasing hormone (LH-RH) may be exerted in part through receptors for LH-RH present on tumor cells, but the direct mode of action of LH-RH agonists and antagonists is still not completely understood. The aim of this study was to investigate the effects of agonist [D-Trp6]LH-RH and antagonist Cetrorelix, administered s.c. at a dose of 100 microg/day for 3 weeks on the binding characteristics and subcellular localization of receptors for LH-RH in OV-1063 human epithelial ovarian cancers xenografted into nude mice. Using radioligand binding studies, following in vitro desaturation, we demonstrated the presence of specific, high affinity binding sites for LH-RH in both cell membrane and nuclear fraction of OV-1063 tumors. Treatment with Cetrorelix, but not [D-Trp6]LH-RH, caused about 60% reduction (p<0. 01) in tumor volume and weight. [D-Trp6]LH-RH decreased the number of LH-RH receptors on OV-1063 tumor membranes by 44% after 14 days (p<0.01), and the concentration of receptors remained at that level on day 21. The maximal binding capacity of receptors for LH-RH in the nuclei was significantly higher (p<0.05) after 3 weeks of treatment with [D-Trp6]LH-RH. Cetrorelix decreased the concentration of membrane receptors for LH-RH by 53% (p<0.01) after 14 days and the levels on day 21 were even lower, showing a 70% reduction (p<0. 01). In contrast, the number of LH-RH binding sites in the nuclear pellet was significantly increased (p<0.01) by Cetrorelix at that time. Our results demonstrate for the first time that the down-regulation of LH-RH receptors on the cell membranes of OV-1063 human ovarian cancers after therapy with antagonist Cetrorelix or agonist [D-Trp6]LH-RH is associated with an increase in receptor concentration in the nuclei. These phenomena could be related to the internalization and subcellular translocation of receptors in these tumor cells.


Long-term evaluation of endothelial cell loss after phacoemulsification.
To check whether three months' follow-up is sufficient to determine endothelial cell loss after cataract surgery and whether this value depends on preoperative central endothelial cell density. A two-year prospective assessment of central endothelial cell density was done in 60 eyes after phacoemulsification. In 30 eyes a 3.5 mm corneal incision closed with a single crossed suture was made, and the other 30 had a 3.5 mm scleral tunnel no-stitch incision. Central endothelial cell density was measured before surgery and 1, 3, 6 months and 2 years after. The mean rate of endothelial cell loss even two years after surgery was significantly higher than the physiological rate, amounting to 0.9% per year. There was no correlation between preoperative central endothelial cell density and postoperative cell loss. Even two years' follow-up is not sufficient to establish the total endothelial cell loss after cataract surgery. The amount of cell loss does not depend on the preoperative density.


Alternative transient states and slow plant community responses after changed flooding regimes.
Climate change will have large consequences for flooding frequencies in freshwater systems. In interaction with anthropogenic activities (flow regulation, channel restoration and catchment land-use) this will both increase flooding and drought across the world. Like in many other ecosystems facing changed environmental conditions, it remains difficult to predict the rate and trajectory of vegetation responses to changed conditions. Given that critical ecosystem services (e.g. bank stabilization, carbon subsidies to aquatic communities or water purification) depend on riparian vegetation composition, it is important to understand how and how fast riparian vegetation responds to changing flooding regimes. We studied vegetation changes over 19 growing seasons in turfs that were transplanted in a full-factorial design between three riparian elevations with different flooding frequencies. We found that (a) some transplanted communities may have developed into an alternative stable state and were still different from the target community, and (b) pathways of vegetation change were highly directional but alternative trajectories did occur, (c) changes were rather linear but faster when flooding frequencies increased than when they decreased, and (d) we observed fastest changes in turfs when proxies for mortality and colonization were highest. These results provide rare examples of alternative transient trajectories and stable states under field conditions, which is an important step towards understanding their drivers and their frequency in a changing world.


Potential impact of soil microbiomes on the leaf metabolome and on herbivore feeding behavior.
It is known that environmental factors can affect the biosynthesis of leaf metabolites. Similarly, specific pairwise plant-microbe interactions modulate the plant's metabolome by stimulating production of phytoalexins and other defense-related compounds. However, there is no information about how different soil microbiomes could affect the plant growth and the leaf metabolome. We analyzed experimentally how diverse soil microbiomes applied to the roots of Arabidopsis thaliana were able to modulate plant growth and the leaf metabolome, as assessed by GC-MS analyses. Further, we determined the effects of soil microbiome-driven changes in leaf metabolomics on the feeding behavior of Trichopulsia ni larvae. Soil microbiomes differentially impacted plant growth patterns as well as leaf metabolome composition. Similarly, most microbiome-treated plants showed inhibition to larvae feeding, compared with unamended control plants. Pyrosequencing analysis was conducted to determine the soil microbial composition and diversity of the soils used in this study. Correlation analyses were performed to determine relationships between various factors (soil microbial taxa, leaf chemical components, plant growth patterns and insect feeding behavior) and revealed that leaf amino acid content was positively correlated with both microbiome composition and insect feeding behavior.


Development of an Electronic Medical Record for Extracorporeal Membrane Oxygenation and Its Role in a Multidisciplinary Team.
As the extracorporeal membrane oxygenation (ECMO) program at our institution has grown and our staffing model has evolved into a multidisciplinary team, our method of ECMO charting has also evolved, using an electronic medical record (EMR) with electronic checklists, progress notes, and remote access. Using our EPIC charting platform, version 1 of our EMR was implemented in 2015. It has been revised three times, and remote access deemed necessary to properly support our staff and patients. Our current, yet still evolving, remotely accessible, ECMO EMR incorporates hourly charting and protocol-based checklists for procedures such as initiation of support, shift handoffs, circuit checks, and patient transport. Perfusionists are required to fill out thrice daily progress notes, notes for bedside/operating room procedures, and patient transport. We present a format for centers looking to implement a comprehensive EMR for ECMO patients. An expanding ECMO program required a change to our staffing model, and an EMR with electronic checklists and remote access facilitated the transition to a multidisciplinary team. Protocol-based checklists ensure consistency during procedures, transports, and shift changes. The remote access and required progress notes create a safer team approach and keep our perfusionists engaged when specialists are sitting ECMO.


Solvent mediated interactions in the structure of the nucleosome core particle at 1.9 a resolution.
Solvent binding in the nucleosome core particle containing a 147 base pair, defined-sequence DNA is characterized from the X-ray crystal structure at 1.9 A resolution. A single-base-pair increase in DNA length over that used previously results in substantially improved clarity of the electron density and accuracy for the histone protein and DNA atomic coordinates. The reduced disorder has allowed for the first time extensive modeling of water molecules and ions. Over 3000 water molecules and 18 ions have been identified. Water molecules acting as hydrogen-bond bridges between protein and DNA are approximately equal in number to the direct hydrogen bonds between these components. Bridging water molecules have a dual role in promoting histone-DNA association not only by providing further stability to direct protein-DNA interactions, but also by enabling formation of many additional interactions between more distantly related elements. Water molecules residing in the minor groove play an important role in facilitating insertion of arginine side-chains. Water structure at the interface of the histones and DNA provides a means of accommodating intrinsic DNA conformational variation, thus limiting the sequence dependency of nucleosome positioning while enhancing mobility. Monovalent anions are bound near the N termini of histone alpha-helices that are not occluded by DNA phosphate groups. Their location in proximity to the DNA phosphodiester backbone suggests that they damp the electrostatic interaction between the histone proteins and the DNA. Divalent cations are bound at specific sites in the nucleosome core particle and contribute to histone-histone and histone-DNA interparticle interactions. These interactions may be relevant to nucleosome association in arrays.


Barriers and Facilitators to Effective Inpatient Palliative Care Consultations: A Qualitative Analysis of Interviews With Palliative Care and Nonpalliative Care Providers.
To identify factors that hinder or facilitate the palliative care consultation team's (PCCT) successful collaboration with other providers from the perspectives of both PCCT and nonpalliative specialists. Qualitative study, including semistructured interviews with PCCT and nonpalliative care providers from various specialties at 4 Midwestern hospitals. Interviews were audio-recorded and transcribed into written text documents for thematic analysis. Palliative care consultation team (n = 19) and nonpalliative care providers (n = 29) were interviewed at their respective hospital sites or via telephone. Palliative care consultation team providers included physicians, nurse practitioners, registered nurses, social workers, and one chaplain. Specialists included critical care physicians, surgeons, hospitalists, nephrologists, oncologists, and cardiologists. Six themes emerged reflecting barriers to and facilitators of successful collaboration between the PCCT and other providers. Primary barriers included attitudes about palliative care, lack of knowledge about the role of the PCCT, and patient and family resistance. Facilitators included marketing of the palliative care service and education about the expertise of the PCCT. In order to engage in more effective collaboration with other specialty providers, the PCCT may consider strategies including structured educational interventions, increased visibility in the hospital, and active marketing of the utility of palliative care across disciplines.


Unimolecular reactivity of strong metal-cation complexes in the gas phase: ethylenediamine-Cu(+).
The gas-phase reactions between ethylenediamine (en) and Cu(+) have been investigated by means of mass spectrometry techniques. The MIKE spectrum reveals that the adduct ions [Cu(+)(H(2)NCH(2)CH(2)NH(2))] spontaneously decompose by loosing H(2), NH(3) and HCu, the loss of hydrogen being clearly dominant. The spectra of the fully C-deuterated species show the loss of HD, NH(3) and CuD but no losses of H(2), D(2), NH(2)D, NHD(2), ND(3) or CuH are observed. This clearly excludes hydrogen exchange between the methylene and the amino groups as possible mechanisms for the loss of ammonia. Conversely, methylene hydrogen atoms are clearly involved in the loss of molecular hydrogen. The structures and bonding characteristics of the Cu(+)(en) complexes as well as the different stationary points of the corresponding potential energy surface (PES) have been theoretically studied by DFT calculations carried out at B3LYP/6-311+G(2df,2p)//B3LYP/6-311G(d,p) level. Based on the topology of this PES the most plausible mechanisms for the aforementioned unimolecular fragmentations are proposed. Our theoretical estimates indicate that Cu(+) strongly binds to en, by forming a chelated structure in which Cu(+) is bridging between both amino groups. The binding energy is quite high (84 kcal mol(-1)), but also the products of the unimolecular decomposition of Cu(+)(en) complexes are strongly bound Cu(+)-complexes.


Imaging work-up and endovascular treatment options for aorto-enteric fistula.
Aorto-enteric fistula (AEF) is a rare life-threatening condition. Early recognition and diagnosis are of paramount importance to improve outcome. In this article four cases of AEF with relevant pre- and post-procedural images are presented to demonstrate the utility of cross-sectional imaging in the work-up of AEF. The literature is reviewed to describe the typical presentation of AEF, the diagnostic work-up of AEF, and the different methods used to treat AEF. Endovascular repair of AEF is gaining increasing attention due to its decreased short-term mortality compared to open surgical techniques.


Bombesin-like peptides: candidates as diagnostic and therapeutic tools.
Bombesin (BBS) is proved to have a wide variety of the pharmacologic effects, including effects on the release of gastrointestinal hormones and control of gastrointestinal motility. More recently, the role of BBS in tumor growth, cellular proliferation and inflammation has attracted attention. There is evidence that increased BBS receptor expression may be considered as a specific marker for small-cell lung cancer, colorectal adenocarcinoma, gastric and pancreatic cancer, prostate, ovarian and breast cancer, neuroblastoma, renal cell carcinoma, malignant melanoma and thyroid carcinoma. BBS expression was found to be correlated with the histological grade of the tumor. Similarly, BBS treatment significantly improves the healing of chronic gastric ulcers and ameliorates the severity of burn- or colitis-induced gut injury. Although there is much complexity still to be elucidated to understand fully the physiologic and pathologic roles of BBS-like peptides several clinical or experimental trials have addressed that circulating or tissue levels of BBS-like peptides or their receptor expression may be used as diagnostic or prognostic markers of neoplastic disease, and incorporation of BBS receptor antagonists in the treatment of human cancer could provide substantial benefit to the cancer patients. Moreover, trophic, anti-ulcerogenic and anti-inflammatory actions of exogenous BBS make this peptide a potential supplement in minimizing or reversing tissue damage against several injurious challenges. In conclusion, based on the evidence summarized herein, related to the mitogenic and anti-inflammatory effects of BBS-like peptides, further investigations are needed to derive the benefit of BBS-like peptides in pharmacologic strategies.


Refractory ceramic fiber (RCF) toxicity and epidemiology: a review.
This paper provides a review of the relevant literature on refractory ceramic fibers (RCFs), summarizing relevant data and information on the manufacture, processing, applications, potential occupational exposure, toxicology, epidemiology, risk analysis, and risk management. RCFs are amorphous fibers used for high-temperature insulation applications. RCFs are less durable/biopersistent than amphibole asbestos, but more durable/biopersistent than many other synthetic vitreous fibers (SVFs). Moreover, as produced/used, some RCFs are respirable. Toxicology studies with rodents using various exposure methods have shown that RCFs can cause fibrosis, lung cancer, and mesothelioma. Interpretation of these animal studies is difficult for various reasons (e.g., overload in chronic inhalation bioassays). Epidemiological studies of occupationally exposed cohorts in Europe and the United States have demonstrated measurable effects (e.g., mild respiratory symptoms and pleural plaques) but no disease (i.e., no interstitial fibrosis, no excess lung cancer, and no mesothelioma) to date. The RCF industry, working cooperatively with various government agencies in the United States, has developed a comprehensive product stewardship program (PSP) to identify and control risks associated with occupational exposure. One provision of the PSP is the adoption of a voluntary recommended exposure guideline (REG) of 0.5 fibers/milliliter (f/ml). Selected on the basis of prudence and demonstrated feasibility, compliance with the REG should reduce risks to levels between 0.073/1000 and 1.2/1000, based on extrapolations from chronic animal inhalation studies.


Apolipoprotein E gene polymorphism and serum lipids in patients with superficial fungal disease.
Superficial mycosis, including dermatophytic infections, tinea versicolor, and cutaneous candidiasis is mostly limited to the outer layers of the skin, nails, and mucous membranes. In this study, Apolipoprotein E (ApoE) polymorphism and lipoprotein cholesterol concentrations were compared between 42 patients with superficial fungal disease and 27 control subjects. Both the patients and controls were found to be normolipemic. The patients with superficial fungal disease had significantly higher concentrations of high-density cholesterol (HDL) compared to the control group (p=0.0462). However, there was no difference in the serum triglyceride, low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) cholesterol concentrations. A significantly higher incidence of heterozygosity E2/3 was found in the patients (p=0.0228), and significantly lower incidence of homozygosity E3/3 in all patients, and those with candidiasis and dermatophytosis (p=0.0139, 0.0194 and 0.0337, respectively) compared to the control group. The E3/4 genotype differences between patients and controls were not statistically significant. There were slight differences in the allele frequencies between the two groups, but these did not reach statistically significant levels. It was concluded that the presence of apoE2/3 genotype, high HDL-cholesterol levels and the absence of apoE3/3 genotype can be regarded as risk factors for superficial fungal disease, especially dermatophytosis.


Toxin profiles of five geographical isolates of Dinophysis spp. from North and South America.
Marine dinoflagellates of the genus Dinophysis can produce toxins of the okadaic acid (OA) and pectenotoxin (PTX) groups. These lipophilic toxins accumulate in filter-feeding shellfish and cause an illness in consumers called diarrhetic shellfish poisoning (DSP). In 2008, a bloom of Dinophysis led to the closure of shellfish harvesting areas along the Texas coast, one of the first DSP-related closures in the U.S. This event resulted in a broad study of toxin production in isolates of Dinophysis spp. from U.S. waters. In the present study, we compared toxin profiles in geographical isolates of Dinophysis collected in the U.S. (Eel Pond, Woods Hole MA; Martha's Vineyard, MA; and Port Aransas Bay, Texas), and in those from Canada (Blacks Harbour, Bay of Fundy) and Chile (Reloncavi Estuary), when cultured in the laboratory under the same conditions. For each isolate, the mitochondrial cox1 gene was sequenced to assist in species identification. Strains from the northeastern U.S. and Canada were all assigned to Dinophysis acuminata, while those from Chile and Texas were most likely within the D. acuminata complex whereas precise species designation could not be made with this marker. Toxins were detected in all Dinophysis isolates and each isolate had a different profile. Toxin profiles of isolates from Eel Pond, Martha's Vineyard, and Bay of Fundy were most similar, in that they all contained OA, DTX1, and PTX2. The Eel Pond isolate also contained OA-D8 and DTX1-D7, and low levels (unconfirmed structurally) of DTX1-D8 and DTX1-D9. D. acuminata from Martha's Vineyard produced DTX1-D7, along with OA, DTX1, and PTX2, as identified in both the cells and the culture medium. D. acuminata from the Bay of Fundy produced DTX1 and PTX2, as found in both cells and culture medium, while only trace amounts of OA were detected in the medium. The Dinophysis strain from Texas only produced OA, and the one from Chile only PTX2, as confirmed in both cells and culture medium.


Clinical and microbiological characteristics of peritoneal dialysis-related peritonitis caused by Escherichia coli in southern Taiwan.
Peritonitis is a serious complication and major cause of treatment failure in patients undergoing peritoneal dialysis (PD). Escherichia coli is the major pathogen in extraintestinal Gram-negative infections, including PD-related peritonitis. The outcomes of E. coli peritonitis in PD varied from relatively favorable outcomes to a higher incidence of treatment failure. The aim of this study was to investigate the impact of bacterial virulence and host characteristics on the outcomes of PD-related peritonitis caused by E. coli. From January 2000 to June 2016, a total of 47 episodes of monomicrobial and 10 episodes of polymicrobial E. coli PD-related peritonitis, as well as 89 episodes of monomicrobial Gram-positive (56 Staphylococcus spp. and 33 Streptococcus spp.) PD-related peritonitis cases, were retrospectively enrolled. Clinical features, E. coli bacterial virulence, and outcomes were analyzed. Compared to Streptococcus spp. peritonitis, E. coli peritonitis had a higher peritoneal catheter removal rate (38 versus 12%; P = 0.0115). Compared to the monomicrobial group, patients in polymicrobial group were older and had higher peritoneal catheter removal rate (80 versus 38%; P = 0.0324). Treatment failure of E. coli peritonitis was associated with more polymicrobial peritonitis and immunocompromised comorbidity, longer duration of PD therapy, and more antimicrobial resistance. E. coli isolates with more iron-related genes had higher prevalence of phylogenetic group B2 and papG II, iha, ompT, and usp genes. This study demonstrates the important roles of clinical and bacterial characteristics in the outcomes of monomicrobial and polymicrobial E. coli PD-related peritonitis.


Novel pathological predictive factors for extranodal extension in oral squamous cell carcinoma: a retrospective cohort study based on tumor budding, desmoplastic reaction, tumor-infiltrating lymphocytes, and depth of invasion.
Extranodal extension (ENE) is a poor prognostic factor for oral squamous cell carcinoma (OSCC). Identifying ENE by clinical and/or radiological examination is difficult, thereby leading to unnecessary neck dissections. Currently, no definitive predictors are available for ENE. Thus, we aimed to determine the histological predictors of ENE by routine histopathological examination using biopsy and surgically resected specimens. This retrospective study included 186 surgically resected OSCC and 83 matched biopsy specimens. Clinical features associated with the tumor microenvironment, including desmoplastic reaction (DR), tumor budding (TB), and tumor-infiltrating lymphocytes (TILs), were evaluated using hematoxylin and eosin-stained primary OSCC and neck dissection specimens. These histological features were divided into two groups: DR-immature (DR-I) and DR-mature (DR-M); TB-high (TB-H) and TB-low (TB-L); and TILs-low (TILs-L) and TILs-high (TILs-H). Clinical depth of invasion (cDOI) and pathological DOI (pDOI) were adapted for biopsies and resections, respectively; DOI was evaluated as DOI > 10 mm and DOI ≤ 10 mm. The clinicopathological relationships between these histopathological features and ENE and the independent risk factors for ENE were analyzed. The histological predictors of ENE were evaluated. The histological status of DR, TILs, and TB present in biopsy and resection specimens showed high accuracy with that of ENE. DR-I, TILs-L, and TB-H were significantly associated with lymph node metastasis, cDOI, and pDOI. Bivariate and multivariate analyses revealed that TB-H and pDOI > 10 mm in resections were independent factors for the presence of ENE (ENE +). The combination of TB-H/pDOI > 10 mm in resection specimens showed high specificity (91%) and accuracy (83%) regarding ENE + . Although there proved to be no independent factors in biopsies, DR-I and TILs-L were significantly associated with ENE + (p < 0.001). The combination of DR-I/TILs-L/cDOI > 10 mm in biopsies exhibited high sensitivity and specificity with ENE + (70% and 77%, respectively, p < 0.001). These histological predictors could detect even minor ENE (< 2 mm). The tumor microenvironment status in primary OSCC was significantly associated with that of ENE, and TB-H was an independent risk factor for ENE. The histological status of DR-I/TILs-L/cDOI > 10 mm in biopsy specimens and TB-H/pDOI > 10 mm in resection specimens is a useful predictor of ENE.


Prevalence of asthma, rhinitis and eczema in children from the Bangkok area using the ISAAC (International Study for Asthma and Allergy in Children) questionnaires.
Within the past three decades, there has been a rising trend for prevalences of asthma and allergic diseases worldwide, particularly from developed and industrializing countries. In Thailand, limited studies on epidemiology of atopic diseases have indicated relatively low prevalences of these conditions among the Thais. Recently, a standardized phase I questionnaire of the International Study of Asthma and Allergies in Childhood (ISAAC) has been developed to study and to compare geographical and temporal trend for prevalences of asthma, allergic rhinitis and eczema in children. The objectives of phase I ISAAC study in Thailand are to study prevalence of the three most common allergic diseases i.e. asthma, allergic rhinitis and eczema among Thai children of the two age groups (i.e., 6-7 and 13-14 years) living in the Bangkok metropolitan area and to collect basic epidemiologic data of these diseases among these children. The Thai translated version of phase I ISAAC questionnaires was administered to Thai children of the two age groups as above. Questionnaires were answered by parents of younger children, whereas, they were self-administered by 13-14 years old children. In addition, the validated international video questionnaires were used with older children. Fourteen primary schools and 13 secondary schools were randomly selected to cover the entire Bangkok metropolitan area. A total of 7341 questionnaires were eligible for the analysis (3628 from the younger age group and 3713 from the older age group). Data were entered and analysed by the Epi-Info program. The cumulative and 12 month period prevalences of the three conditions for all children were as follows; wheezing, 18.3 per cent, 12.7 per cent; rhinitis, 44.2 per cent, 38.7 per cent; and eczema, 15.4 per cent, 14.0 per cent, respectively. The period prevalence of wheezing for older children (13.6%) was higher than for younger children (11.7%). Prevalences of severe wheeze and exercise wheeze were more common among older children (4.0% and 15.7%). Both age groups reported high percentages for night cough (23.6% and 28.6%). A significantly large number of children from both groups reported symptoms of rhinitis with the majority indicating that symptoms were severe enough to limit their daily activities. Nevertheless, when confined only to those with eye symptoms, the prevalence decreased to 13.1 per cent. Eczema, in contrast to the other two conditions, occurred more frequently among younger children than among older children (period prevalence of 16% vs 9.1%). The rash was of a relatively mild nature since 77 per cent of children reporting symptoms indicated that the rash had cleared within the past 12 months. Allergic conditions are very common among children residing in Bangkok. Compared to the last survey in 1990, the period prevalence of wheezing has increased 4 fold, allergic rhinitis has increased nearly 3 fold whereas, eczema has remained stable. A large number of children in Bangkok are suffering from rhinitis symptoms. Results of this phase I ISAAC study indicate that allergic diseases are perhaps the most common childhood diseases in Thailand and could lead to a substantial economical loss for the country. There is an urgent need for an in-depth study to define epidemiological factors responsible for this increase.


Kinetics of an acid-base catalyzed reaction (aspartame degradation) as affected by polyol-induced changes in buffer pH and pK values.
The kinetics of an acid-base catalyzed reaction, aspartame degradation, were examined as affected by the changes in pH and pK(a) values caused by adding polyols (sucrose, glycerol) to phosphate buffer. Sucrose-containing phosphate buffer solutions had a lower pH than that of phosphate buffer alone, which contributed, in part, to reduced aspartame reactivity. A kinetic model was introduced for aspartame degradation that encompassed pH and buffer salt concentrations, both of which change with a shift in the apparent pK(a) value. Aspartame degradation rate constants in sucrose-containing solutions were successfully predicted using this model when corrections (that is, lower pH, lower apparent pK(a) value, buffer dilution from the polyol) were applied. The change in buffer properties (pH, pK(a)) from adding sucrose to phosphate buffer does impact food chemical stability. These effects can be successfully incorporated into predictive kinetic models. Therefore, pH and pK(a) changes from adding polyols to buffer should be considered during food product development.


Radiographers' knowledge of aging.
A Facts on Aging Quiz (FAQ) was given to a survey group of radiographers and students. As a group, radiographers were found to be as well educated as any other group of health care professionals. A progression was seen from student to graduate radiographer; the contention is made that early clinical experience may be responsible for much of the knowledge radiographers have about aging.