Surface-Enhanced Raman Spectroscopy Substrates: Plasmonic Metals to Graphene.
Surface-enhanced Raman spectroscopy (SERS), a marvel that uses surfaces to enhance conventional Raman signals, is proposed for a myriad of applications, such as diagnosis of diseases, pollutants, and many more. The substrates determine the SERS enhancement, and plasmonic metallic nanoparticles such as Au, Ag, and Cu have dominated the field. However, the last decades have failed to translate SERS prototypes into real-life applications. Irreproducibility on the SERS signal that stems from the roughened SERS substrates is the main causative factor for this observation. To mitigate irreproducibility several two-dimensional (2-D) substrates have been sought for use as possible alternatives. Application of 2-D graphene substrates in Raman renders graphene-enhanced Raman spectroscopy (GERS). This account used density functional theory (DFT) substantiated with experimental Raman to compare the enhancement capabilities of plasmonic Au nanoparticles (SERS), graphene substrate (GERS), and coupling of the two SERS and GERS substrates. The DFT also enabled the study of the SERS and GERS systems molecular orbital to gain insight into their mechanisms. The amalgamation of the SERS and GERS occurrence, i.e., graphene doped with plasmonic metallic substrates showed a pronounced enhancement and matched the Au-driven enhancement emanating from both electromagnetic and charge transfer SERS and GERS mechanisms.


Screening Obese Adolescents for Binge Eating Disorder in Primary Care: The Adolescent Binge Eating Scale.
To investigate the performance of a simple and developmentally appropriate 10-item questionnaire (Adolescent Binge Eating Scale) for the prediction of binge eating disorder (BED) diagnosis in adolescents seen for obesity. We evaluated the performance of the questionnaire in comparison with a clinical interview, in a population of adolescents being seen for obesity. The ?2 or Fisher exact tests were used. There were 94 adolescents aged 12-18 years (59.6% girls) who completed the study. The questionnaire demonstrated a good association with the clinical interview and distinguished different levels of risk for having a BED: participants who responded positively to questions 1 or 2 and had more than 6 positive answers to the 8 additional questions had a high risk of subclinical and clinical BED (83.3%); participants with 3 or fewer positive answers had a low risk of clinical BED (4%). The Adolescent Binge Eating Scale questionnaire is a potential screening tool to identify adolescents with obesity at high risk of BED and guide referral to a specialist to clarify the diagnosis and provide adequate care.


Differential responses to Ig and class II-mediated signals in splenic B cell subsets from normal and autoimmune mice.
B cells of mouse and human can be divided into distinct subpopulations, differing in distribution and phenotype. It is not known, however, whether B cell subsets respond similarly to signals mediated by cognate interactions with T cells, such as ligation of the B cell class II MHC molecule. Mouse splenic B cells proliferate in response to a combination of non-mitogenic anti-mu mAb, IL-4 and class II MHC-specific mAbs. In order to assess the response of B cell subpopulations to these signals, B cells were separated on the basis of CD23 expression. Previous studies have shown that CD23 expression is useful in distinguishing marginal zone from follicular B cells and peritoneal B1 from B2 B cells. B cells of both subsets responded to the combination of signals, but CD23- B cells showed a higher response. Splenic B cells were also purified from several strains of autoimmune mice, of interest because their disease features expansion of CD23- B cells and autoantibody production. While normal B cells showed no response to non-mitogenic anti-mu mAb alone, B cells from autoimmune mice showed a marked decrease in proliferation. Addition of IL-4 plus class II-specific mAbs restored increased proliferation. Again, responses were higher in CD23- than in CD23+ B cells. These findings suggest that CD23- B cells are especially responsive to signals delivered through class II and the IL-4 receptor. These signals may allow preferential rescue of CD23-B cells from antigen-mediated tolerance and result in their hyperexpansion in response to autoreactive T cells.


[Metoclopramide and neonatal methaemoglobinemia].
We report the case of a five-day-old newborn with cyanosis. After exclusion of pulmonary and cardiac illness, methaemoglobinemia was diagnosed. Cyanosis is the first symptom of methaemoglobinaemia. Numerous causes of methaemoglobinemia have been described, with congenital and acquired forms, which are the most frequent. We discuss here the clinical features, diagnosis, and treatment of acquired methaemoglobinaemia in newborns with special emphasis on forms secondary to metoclopramide toxicity.


Echocardiography of transposition of the great arteries.
The successful diagnosis, surgical planning, and long-term care of children with transposition of the great arteries require high-quality cardiac imaging with echocardiography. Echocardiography must identify the relevant anatomic variants of transposition of the great arteries, such as of ventricular septal defects and aortic arch anomalies. Methodical and detailed imaging of the coronary arteries is particularly important, as translocation of the coronary arteries is a critical component of the arterial switch procedure. Familiarity with the potential coronary artery variants and the ideal imaging planes is essential for an echocardiographer. Knowledge of both the early and late complications following the arterial switch procedure is essential to optimise post-operative echocardiography. These complications can include residual lesions leading to haemodynamic compromise or progressive late phenomena, such as aortic root dilatation and aortic insufficiency. Echocardiography will continue to be the cornerstone to the lifelong management of transposition of the great arteries, and improvements in technology and increased familiarity with modalities such as stress echocardiography will enhance the role of advanced imaging even further.


MicroRNA Promoter Identification in Arabidopsis Using Multiple Histone Markers.
A microRNA is a small noncoding RNA molecule, which functions in RNA silencing and posttranscriptional regulation of gene expression. To understand the mechanism of the activation of microRNA genes, the location of promoter regions driving their expression is required to be annotated precisely. Only a fraction of microRNA genes have confirmed transcription start sites (TSSs), which hinders our understanding of the transcription factor binding events. With the development of the next generation sequencing technology, the chromatin states can be inferred precisely by virtue of a combination of specific histone modifications. Using the genome-wide profiles of nine histone markers including H3K4me2, H3K4me3, H3K9Ac, H3K9me2, H3K18Ac, H3K27me1, H3K27me3, H3K36me2, and H3K36me3, we developed a computational strategy to identify the promoter regions of most microRNA genes in Arabidopsis, based upon the assumption that the distribution of histone markers around the TSSs of microRNA genes is similar to the TSSs of protein coding genes. Among 298 miRNA genes, our model identified 42 independent miRNA TSSs and 132 miRNA TSSs, which are located in the promoters of upstream genes. The identification of promoters will provide better understanding of microRNA regulation and can play an important role in the study of diseases at genetic level.


Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice.
Type 2 diabetes (T2D) is the most common form of diabetes in humans and is closely associated with dyslipidemia and obesity that magnifies the mortality and morbidity related to T2D. The genetic contribution to human T2D and related metabolic disorders is evident, and mostly follows polygenic inheritance. The TALLYHO/JngJ (TH) mice are a polygenic model for T2D characterized by obesity, hyperinsulinemia, impaired glucose uptake and tolerance, hyperlipidemia, and hyperglycemia. In order to determine the genetic factors that contribute to these T2D related characteristics in TH mice, we interbred TH mice with C57BL/6J (B6) mice. The parental, F1, and F2 mice were phenotyped at 8, 12, 16, 20, and 24 weeks of age for 4-hour fasting plasma triglyceride, cholesterol, insulin, and glucose levels and body, fat pad and carcass weights. The F2 mice were genotyped genome-wide and used for quantitative trait locus (QTL) mapping. We also applied a genetical genomic approach using a subset of the F2 mice to seek candidate genes underlying the QTLs. Major QTLs were detected on chromosomes (Chrs) 1, 11, 4, and 8 for hypertriglyceridemia, 1 and 3 for hypercholesterolemia, 4 for hyperglycemia, 11 and 1 for body weight, 1 for fat pad weight, and 11 and 14 for carcass weight. Most alleles, except for Chr 3 and 14 QTLs, increased phenotypic values when contributed by the TH strain. Fourteen pairs of interacting loci were detected, none of which overlapped the major QTLs. The QTL interval linked to hypercholesterolemia and hypertriglyceridemia on distal Chr 1 contains Apoa2 gene. Sequencing analysis revealed polymorphisms of Apoa2 in TH mice, suggesting Apoa2 as the candidate gene for the hyperlipidemia QTL. Gene expression analysis added novel information and aided in selection of candidates underlying the QTLs. We identified several genetic loci that affect the quantitative variations of plasma lipid and glucose levels and obesity traits in a TH × B6 intercross. Polymorphisms in Apoa2 gene are suggested to be responsible for the Chr 1 QTL linked to hypercholesterolemia and hypertriglyceridemia. Further, genetical genomic analysis led to potential candidate genes for the QTLs.


Immunosuppressive properties of alpha 1-microglobulin.
alpha 1-Microglobulin (alpha 1m), a serum glycoprotein (26,000 d), was found to impede the proliferative response of human lymphocytes to purified protein derivative (PPD) and tetanus toxoid. The data suggest that alpha 1m operates through an unstable suppressor mechanism, which no longer can function after 24 h of preculturing. This effect of alpha 1m on antigen stimulation did not seem to be due to binding of alpha 1m to PPD or cells, to altered kinetics of the PPD response, or to non-specific cytotoxicity. In contrast, PPD-induced leucocyte migration was not reversed by alpha 1m. alpha 1m did not cause significant inhibition in experiments in which lymphocytes were stimulated by the mitogens phytohaemagglutinin or concanavalin A. Finally, alpha 1m had its own leucocyte migration inhibitory effect.


A reconstruction algorithm for coherent scatter computed tomography based on filtered back-projection.
Coherent scatter computed tomography (CSCT) is a reconstructive x-ray imaging technique that yields the spatially resolved coherent-scatter form factor of the investigated object. Reconstruction from coherently scattered x-rays is commonly done using algebraic reconstruction techniques (ART). In this paper, we propose an alternative approach based on filtered back-projection. For the first time, a three-dimensional (3D) filtered back-projection technique using curved 3D back-projection lines is applied to two-dimensional coherent scatter projection data. The proposed algorithm is tested with simulated projection data as well as with projection data acquired with a demonstrator setup similar to a multi-line CT scanner geometry. While yielding comparable image quality as ART reconstruction, the modified 3D filtered back-projection algorithm is about two orders of magnitude faster. In contrast to iterative reconstruction schemes, it has the advantage that subfield-of-view reconstruction becomes feasible. This allows a selective reconstruction of the coherent-scatter form factor for a region of interest. The proposed modified 3D filtered back-projection algorithm is a powerful reconstruction technique to be implemented in a CSCT scanning system. This method gives coherent scatter CT the potential of becoming a competitive modality for medical imaging or nondestructive testing.


Role of gut-associated lymphoreticular tissues in antigen-specific intestinal IgA immunity.
This study assessed the roles of the postnatal lymphotoxin-beta receptor (LTbetaR)-mediated signals in the gut-associated lymphoreticular tissues of mice for subsequent regulation of Ag-specific intestinal IgA responses. Blockade of LTbetaR-dependent events by postnatal administration of the fusion protein of LTbetaR and IgG Fc (LTbetaR-Ig) reduced both the size and numbers of Peyer's patches (PP) without influencing the PP microarchitecture. Interestingly, inhibition of LTbetaR-dependent signaling revealed significant reductions in the formation of follicular dendritic cell clusters in mesenteric lymph nodes (MLN). Furthermore, these postnatal signaling events controlled the development of isolated lymphoid follicles (ILF) because treatment with LTbetaR-Ig eliminated the formation of ILF. LTbetaR-Ig-treated mice with altered microarchitecture of MLN and lacking ILF were still able to produce significant Ag-specific mucosal IgA responses after oral immunization; however, the levels were significantly lower than those seen in control mice. These results imply the importance of ILF for Ag-specific intestinal immunity. However, mice treated with both TNFR55-Ig and LTbetaR-Ig in utero, which lack PP and MLN, but retain intact ILF, failed to induce Ag-specific IgA responses after oral immunization. These findings demonstrate that ILF are not essential for induction of intestinal IgA Ab responses to orally administered Ag. Furthermore, the induction of intestinal IgA Ab responses requires the proper maintenance of the MLN microarchitecture, including a follicular dendritic cell network.


The integrin alpha6beta1 modulation of PI3K and Cdc42 activities induces dynamic filopodium formation in human platelets.
Platelets are an ideal model for studying a rapid morphological change in response to various signal transduction systems. Morphological changes via the activation of integrin alphaIIbbeta3 in platelets have been investigated intensively. In contrast, activation via integrin alpha6beta1 is less well studied. Here, we provide the first biochemical evidence that integrins alpha6beta1 and alphaIIbbeta3 of platelets are associated with different membrane proteins. We also demonstrate that platelets activated by integrin alpha6beta1 show dynamic change by actively forming filopodia and never fully spreading over a period of more than an hour. In addition, platelets activated by integrin alpha6beta1 are different from those activated by integrin alphaIIbbeta3 in terms of cell-substrate contact and in their distribution pattern of actin, Arp2/3 and various phosphotyrosine proteins. The morphological appearance of platelets produced through integrin alpha6beta1 activation is highly dependent on PI3 kinase (PI3K) but less dependent on Src kinase. Suppression of PI3K activity in integrin alpha6beta1 activated platelets induces an increase in Cdc42 activity and more filopodium formation. However, both Cdc42 and PI3K activity are higher in platelets activated by integrin alpha6beta1 than in those activated by integrin alphaIIbbeta3. Taken together, this study demonstrates that the signals induced by integrin alpha6beta1 modulate at the level of PI3K and Cdc42 activity to allow platelets to actively form filopodia.


Trends in incidence, initial treatment and survival of myelodysplastic syndromes: a population-based study of 5144 patients diagnosed in the Netherlands from 2001 to 2010.
Studies with long-term follow-up of patients with myelodysplastic syndromes (MDS) based on data from nationwide population-based cancer registries are lacking. We conducted a nationwide population-based study to assess trends in incidence, initial treatment and survival in MDS patients diagnosed in the Netherlands from 2001 to 2010. We identified 5144 MDS patients (median age, 74 years) from the Netherlands Cancer Registry (NCR). The NCR only includes MDS cases that were confirmed by bone marrow examinations. Information regarding initial treatment decisions was available in the NCR. The age-standardised incidence rate of MDS was 2.3/100,000 in 2001-2005 and 2.8/100,000 in 2006-2010. The incidence increased with older age, with the highest incidence among those aged ≥80 years (32.1/100,000 in 2006-2010). Forty-nine percent of all MDS cases were unspecified. Of all patients, 89% receive no treatment or only supportive care and 8% were started on intensive therapy as initial treatment. Survival did not improve over time. The 5-year relative survival was 53%, 58%, 48%, 38% and 18% in patients with refractory anaemia (RA), RA with ringed sideroblasts, 5q-syndrome, refractory cytopenia with multilineage dysplasia, and RA with excess blasts, respectively. The incidence of MDS increased over time due to improved notification and better disease awareness, and has stabilised since 2007. The classification of MDS seems challenging as almost half of the pathologically confirmed cases were unspecified. The lack of improvement in survival might be explained by the limited availability of therapeutic agents. Therefore, ameliorated management and new treatment options are warranted.


Association of the Neutrophil-to-Lymphocyte Ratio with Lung Function and Exacerbations in Patients with Chronic Obstructive Pulmonary Disease.
The ratio of neutrophils to lymphocytes (NLR) is a widely available marker of inflammation. Several types of inflammatory cells and mediators have been found to be involved in the progression of chronic obstructive pulmonary disease (COPD). We sought to evaluate the association of the NLR with severity of airflow limitation and disease exacerbations in a COPD population. We analyzed 885 patients from the Korean COPD Subtype Study cohort that recruited subjects with COPD from 44 referral hospitals. We determined the relationship of NLR levels to severity of lung function using a linear regression model. In addition, we analyzed the experiences of COPD exacerbation according to the NLR quartiles. NLR levels were inversely associated with severity of airflow limitation as measured by FEV1% predicted and absolute values after adjustments for age, gender, body mass index, pack-years of smoking, and the use of inhaled corticosteroid (P<0.001, respectively). In the multivariate binary regression model, the NLR 4th quartile (vs. 1st quartile) was found to be a significant predictor of exacerbations during 1-year follow-up (OR = 2.05, 95% CI = 1.03 to 4.06, P = 0.041). Adding an NLR to FEV1 significantly improved prediction for exacerbations during 1-year follow-up as measured by the net reclassification improvement (NRI = 7.8%, P = 0.032) and the integrated discrimination improvement (IDI = 0.014, P = 0.021). The NLR showed a significant inverse relationship to airflow limitation and was a prognostic marker for future exacerbations in patients with COPD.


Complete plastid genome of Primula calliantha Franch. (Primulaceae): an alpine ornamental plant endemic to Hengduan Mountain, China.
Primula calliantha Franch. is an alpine species with an ornamental value that is endemic to the Hengduan Mountains of southwest China. Here, we sequenced and assembled its plastid complete genome, which is a circular molecule of 151,954 bp and contains a large single-copy (83,820 bp) and a small single-copy (17,814 bp) region, separated by a pair of inverted repeats (25,160 bp). There are 131 genes, 86 protein-coding, 37 tRNAs, and 8 rRNAs in the plastome, of which 114 genes, 80 CDSs, 30 tRNAs, and 4 rRNAs are unique, respectively. The P. calliantha plastid genome shows a high level of synteny with its close relatives, P. chionantha, P. purdomii, and P. woodwardii. Phylogenetic analysis based on 60 complete chloroplast genomes of Primulaceae confirmed its delimitation in Primula.


Effect of a group educational intervention on rural Chinese women's knowledge and attitudes about human papillomavirus (HPV) and HPV vaccines.
Statistics regarding HPV prevalence and cervical cancer rates in rural China are high, however, low levels of HPV awareness and HPV-related knowledge pose a great challenge for cervical cancer control. The authors conducted an educational intervention study, which was embedded in a cervical cancer screening project in Yangcheng county, Shanxi Province, China from October to December, 2011 and was designed to assess the short-term effectiveness of a hospital-based, brief, HPV-focused session on rural Chinese women's knowledge and attitudes. Student's t-test was used when comparing quantitative variables. Chi-squared test or Fisher's exact tests was used when comparing qualitative variables. We found that following the intervention, significant increases were detected in awareness regarding HPV (5.9 % vs. 59 %, p < 0.001) and cervical cancer (63.0 % vs. 89.2 %, p < 0.001). Changes were also observed regarding women's intention to vaccinate themselves (82.0 % vs. 89.0 %, p = 0.001) and their daughters (82.9 % vs. 88.0 %, p = 0.011), although the impact was more modest compared with the impact on change of awareness. Among women who were aware of HPV, 60.3 % knew that cervical cancer is related to HPV, while only 5.0 % knew the relationship between HPV and genital warts after the educational intervention. Educational campaigns, particularly those targeting women with limited education and poor access to public media or other educational channels are needed to improve knowledge regarding HPV in the general population.


DOES INCREASED MORTALITY FAVOR THE EVOLUTION OF MORE RAPID SENESCENCE?
It is widely believed (following the 1957 hypothesis of G. C. Williams) that greater rates of "extrinsic" (age- and condition-independent) mortality favor more rapid senescence. However, a recent analysis of mammalian life tables failed to find a significant correlation between minimum adult mortality rate and the rate of senescence. This article presents a simple theoretical analysis of how extrinsic mortality should affect the rate of senescence (i.e., the rate at which probability of mortality increases with age) under different evolutionary and population dynamical assumptions. If population dynamics are density independent, extrinsic mortality should not alter the senescence rate favored by natural selection. If population growth is density dependent and populations are stable, the effect of extrinsic mortality depends on the age specificity of the density dependence and on whether survival or reproduction (or both) are functions of density. It is possible that higher extrinsic mortality will increase the rate of senescence at all ages, decrease the rate at all ages, or increase it at some ages while decreasing it at others. Williams's hypothesis is most likely to be supported when density dependence acts primarily on fertility and does not differentially decrease the fertilities of older individuals. Patterns contrary to Williams's prediction are possible when density dependence acts primarily on the survival or fertility of later ages or when most variation in mortality rates is due to variation in nonextrinsic mortality.


Prediction of the oxygen cost of the deadlift exercise.
The purpose of this study was to examine the relationship between total estimated work, bar load and total oxygen consumption (TVO2) during the deadlift exercise. Forty-two observations of TVO2 during a wide range of deadlifting bouts were made on a heterogeneous sample of 10 males and 14 females. TVO2 was measured by standard open-circuit spirometry. An R of 0.912 for work and TVO2 indicated that total estimated work during deadlifting can be used to predict oxygen cost accurately. The calculated regression equation was TVO2 (litres of O2) = 2.63 + 0.80 work (kJ) with a S.E.E. of 1.50 litres O2. An R of 0.909 for bar load and TVO2 indicated essentially the same predictability using bar load as the independent variable. The calculated regression equation was TVO2 (litres O2) = 2.88 + 0.005 bar load (kg) with a S.E.E. of 1.5 litres O2. Care should be taken when converting oxygen cost to energy expenditure values using non-protein R equivalents, since underestimations are likely, due to the heavy glycolytic involvement.


Effect of attractive interactions on the water-like anomalies of a core-softened model potential.
It is now well established that water-like anomalies can be reproduced by a spherically symmetric potential with two length scales, popularly known as core-softened potential. In the present study we aim to investigate the effect of attractive interactions among the particles in a model fluid interacting with core-softened potential on the existence and location of various water-like anomalies in the temperature-pressure plane. We employ extensive molecular dynamic simulations to study anomalous nature of various order parameters and properties under isothermal compression. Order map analyses have also been done for all the potentials. We observe that all the systems with varying depth of attractive wells show structural, dynamic, and thermodynamic anomalies. As many of the previous studies involving model water and a class of core softened potentials have concluded that the structural anomaly region encloses the diffusion anomaly region, which in turn, encloses the density anomaly region, the same pattern has also been observed in the present study for the systems with less depth of attractive well. For the systems with deeper attractive well, we observe that the diffusion anomaly region shifts toward higher densities and is not always enclosed by the structural anomaly region. Also, density anomaly region is not completely enclosed by diffusion anomaly region in this case.


Florida's undeclared epidemic: malignant melanoma.
Contrary to the trend of early diagnosis observed in other parts of the world, in Florida melanoma is still being discovered in the more advanced stages. This is characterized by thicker lesions at diagnosis, which are hallmarked by bleeding, itching, ulceration, and increased vertical growth. In a study of 1,626 cutaneous melanoma patients at the H. Lee Moffitt Cancer Center in Florida, three prognostic factors, tumor thickness, Clark level, and presence of ulceration in the primary tumor, have remained relatively constant over an eight-year period (1987-1994). Despite the lack of change in tumor thickness in the last four years, mortality rate is decreasing, possibly due to more effective treatments. Regardless of these apparent improvements in mortality rates, definite progress must be made in the early detection of malignant melanoma through the initiation of statewide programs of lay public and professional education. In addition, it is proposed that the establishment of statewide screening programs of the Caucasian population with skin phenotypes 1 and 2 will also facilitate the early diagnosis of melanoma in the future, improve the outlook for these patients, and begin to address a major public health problem in the state of Florida.


How to Prevent Workplace Incivility?: Nurses' Perspective.
Many articles have studied workplace incivility and its influence on outcomes, but very few have been conducted to assess how to prevent this issue. In this study, we aimed to determine how to prevent workplace incivility from the nurses' perspective. This was a qualitative study which was based on a conventional content analysis approach. Thirty four nurses (25 to 52 years old) from seven training hospitals in Tabriz, Iran were selected through purposive sampling. Thirty six semi-structured interviews and eight field notes were analyzed. The data analysis revealed 417 codes, ten categories, three subthemes and one theme, that is, A Need for a Comprehensive Attempt. Attempt of organization, nurses, and public as subthemes are needed to prevent workplace incivility. The findings of the study indicated that a comprehensive and systematic attempt was needed to prevent incivility. Nurses should try to improve their skills; officials should try to show the real image and position of nurses and hospitals to the community.


Heterologous expression of equine CYP3A94 and investigation of a tunable system to regulate co-expressed NADPH P450 oxidoreductase levels.
The activity of cytochrome P450 enzymes depends on the enzyme NADPH P450 oxidoreductase (POR). The aim of this study was to investigate the activity of the equine CYP3A94 using a system that allows to regulate the POR protein levels in mammalian cells. CYP3A94 and the equine POR were heterologously expressed in V79 cells. In the system used, the POR protein regulation is based on a destabilizing domain (DD) that transfers its instability to a fused protein. The resulting fusion protein is therefore degraded by the ubiquitin-proteasome system (UPS). Addition of "Shield-1" prevents the DD fusion protein from degradation. The change of POR levels at different Shield-1 concentrations was demonstrated by cytochrome c reduction, Western immunoblot analysis, and immunocytochemistry. The alteration of CYP3A94 activity was investigated using a substrate (BFC) known to detect CYP3A4 activity. Equine CYP3A94 was demonstrated to be metabolically active and its activity could be significantly elevated by co-expression of POR. Cytochrome c reduction was significantly increased in V79-CYP3A94/DD-POR cells compared to V79-CYP3A94 cells. Surprisingly, incubation with different Shield-1 concentrations resulted in a decrease in POR protein shown by Western immunoblot analysis. Cytochrome c reduction did not change significantly, but the CYP3A94 activity decreased more than 4-fold after incubation with 500 nM and 1 µM Shield-1 for 24 hours. No differences were obtained when V79-CYP3A94 POR cells with and without Shield-1 were compared. The basal activity levels of V79-CYP3A94/DD-POR cells were unexpectedly high, indicating that DD/POR is not degraded without Shield-1. Shield-1 decreased POR protein levels and CYP3A94 activity suggesting that Shield-1 might impair POR activity by an unknown mechanism. Although regulation of POR with the pPTuner system could not be obtained, the cell line V79-CYP3A94/DD-POR system can be used for further experiments to characterize the equine CYP3A94 since the CYP activity was significantly enhanced with co-expressed POR.


Treated wastewater phytotoxicity assessment using Lactuca sativa: Focus on germination and root elongation test parameters.
Sensitive and simple ecotoxicological bioassays like seed germination and root elongation tests are commonly used to evaluate the phytotoxicity of waste and industrial discharge waters. Although the tests are performed following national and international standards, various parameters such as the number of seeds per dish, the test duration or the type of support used remain variable. To be able to make a correct comparison of results from different studies, it is crucial to know which parameter(s) could affect ecotoxicological diagnosis. We tested four different control waters and three seed densities. No significant differences on either germination rate or root elongation endpoints were shown. Nevertheless, we found that the four lettuce cultivars (Appia, batavia dorée de printemps, grosse blonde paresseuse, and Kinemontepas) showed significantly different responses when watered with the same and different metal-loaded industrial discharge water. From the comparison, it is clear that a differential sensitivity scale occurs among not just species but cultivars.


Determination of the backbone mobility of ribonuclease T1 and its 2'GMP complex using molecular dynamics simulations and NMR relaxation data.
The results of 1-nanosecond molecular dynamics simulations of the enzyme ribonuclease T1 and its 2'GMP complex in water are presented. A classification of the angular reorientations of the backbone amide groups is achieved via a transformation of NH-vector trajectories into several coordinate frames, thus unravelling contributions of NH-bond librations and backbone dihedral angle fluctuations. The former turned out to be similar for all amides, as characterized by correlation times of librational motions in a subpicosecond scale, angular amplitudes of about 10-12 degrees for out-of-peptide-plane displacements of the NH-bond and 3-5 degrees for the in-plane displacements, whereas the contributions of much slower backbone dihedral angle fluctuations strongly depend on the secondary structure. Correlation functions relevant for NMR were obtained and analyzed utilizing the 'model-free' approach (Lipari, G. and Szabo, A. (1982) J. Am. Chem. Soc. 104, 4546-4559, 4559-4570; Clore et al., (1990) J. Am. Chem. Soc. 112, 4989-4991). The dependence of the amplitude of local motion on the residue location in the backbone is in good agreement with the results of NMR relaxation measurements and X-ray data. The protein dynamics is characterized by a highly restricted local motion of those parts of the backbone with defined secondary structure as well as by a high flexibility in loop regions. The comparison of results derived from different periods of the trajectory (of 50 ps and 1 ns duration, 1000 points sampled) reveals a dependence of the observed dynamic picture on the characteristic time scale of the experimental method used. Comparison of the MD data for the free and liganded enzyme clearly indicates a restriction of the mobility within certain regions of the backbone upon inhibitor binding.


Thirty years of turnstiles and transport.
To characterize transport in a deterministic dynamical system is to compute exit time distributions from regions or transition time distributions between regions in phase space. This paper surveys the considerable progress on this problem over the past thirty years. Primary measures of transport for volume-preserving maps include the exiting and incoming fluxes to a region. For area-preserving maps, transport is impeded by curves formed from invariant manifolds that form partial barriers, e.g., stable and unstable manifolds bounding a resonance zone or cantori, the remnants of destroyed invariant tori. When the map is exact volume preserving, a Lagrangian differential form can be used to reduce the computation of fluxes to finding a difference between the actions of certain key orbits, such as homoclinic orbits to a saddle or to a cantorus. Given a partition of phase space into regions bounded by partial barriers, a Markov tree model of transport explains key observations, such as the algebraic decay of exit and recurrence distributions.


Research on Channel Characteristics and Electrode Electrical Performance of Earth Current Field Information Transmission Technology.
Starting from the need for emergency rescue information transmission in tunnel engineering accidents, this article focuses on researching and solving the technical problems of information transmission between rescue personnel and trapped personnel after tunnel engineering collapse accidents, before and during the rescue process. The research objects are the information transmission channel and grounding electrode in the earth current field information transmission technology, and the electromagnetic characteristics of the earth medium and the electrical performance of the grounding electrode are studied and analyzed using the electromagnetic simulation software Maxwell based on finite element algorithm, establish a three-dimensional model based on the transmission of current field information of the ground electrode, analyze the effects of the electrode array, electrode depth, and radius on impedance. Research has shown that the impedance of the earth is related to the resistivity of the medium and is not a human-controllable factor. To reduce the contact impedance of an electric dipole antenna, one should start with the contact impedance of the earth electrode. The impedance of the transmitting end is an important factor affecting the efficiency of information transmission; parallel connection of multiple grounding electrodes, increasing the depth of grounding electrode penetration into the soil layer, and increasing the radius between grounding electrode pairs are all effective methods to reduce the contact impedance of electric dipole antennas, thereby improving information transmission capacity. To achieve wireless information transmission through the stratum, by appropriately selecting the operating frequency of electromagnetic waves, a certain distance of signal transmission can be achieved.


Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric cancer models in the pediatric preclinical testing program.
Inhibitors of PARP, an enzyme involved in base excision repair, have demonstrated single-agent activity against tumors deficient in homologous repair processes. Ewing sarcoma cells are also sensitive to PARP inhibitors, although the mechanism is not understood. Here, we evaluated the stereo-selective PARP inhibitor, talazoparib (BMN 673), combined with temozolomide or topotecan. Talazoparib was tested in vitro in combination with temozolomide (0.3-1,000 μmol/L) or topotecan (0.03-100 nmol/L) and in vivo at a dose of 0.1 mg/kg administered twice daily for 5 days combined with temozolomide (30 mg/kg/daily x 5; combination A) or 0.25 mg/kg administered twice daily for 5 days combined with temozolomide (12 mg/kg/daily x 5; combination B). Pharmacodynamic studies were undertaken after 1 or 5 days of treatment. In vitro talazoparib potentiated the toxicity of temozolomide up to 85-fold, with marked potentiation in Ewing sarcoma and leukemia lines (30-50-fold). There was less potentiation for topotecan. In vivo, talazoparib potentiated the toxicity of temozolomide, and combination A and combination B represent the MTDs when combined with low-dose or high-dose talazoparib, respectively. Both combinations demonstrated significant synergism against 5 of 10 Ewing sarcoma xenografts. The combination demonstrated modest activity against most other xenograft models. Pharmacodynamic studies showed a treatment-induced complete loss of PARP only in tumor models sensitive to either talazoparib alone or talazoparib plus temozolomide. The high level of activity observed for talazoparib plus temozolomide in Ewing sarcoma xenografts makes this an interesting combination to consider for pediatric evaluation.


Tobramycin-Treated Pseudomonas aeruginosa PA14 Enhances Streptococcus constellatus 7155 Biofilm Formation in a Cystic Fibrosis Model System.
Cystic fibrosis (CF) is a human genetic disorder which results in a lung environment that is highly conducive to chronic microbial infection. Over the past decade, deep-sequencing studies have demonstrated that the CF lung can harbor a highly diverse polymicrobial community. We expanded our existing in vitro model of Pseudomonas aeruginosa biofilm formation on CF-derived airway cells to include this broader set of CF airway colonizers to investigate their contributions to CF lung disease, particularly as they relate to the antibiotic response of the population. Using this system, we identified an interspecies interaction between P. aeruginosa, a bacterium associated with declining lung function and worsening disease, and Streptococcus constellatus, a bacterium correlated with the onset of pulmonary exacerbations in CF patients. The growth rate and cytotoxicity of S. constellatus 7155 and P. aeruginosa PA14 were unchanged when grown together as mixed biofilms in the absence of antibiotics. However, the addition of tobramycin, the frontline maintenance therapy antibiotic for individuals with CF, to a mixed biofilm of S. constellatus 7155 and P. aeruginosa PA14 resulted in enhanced S. constellatus biofilm formation. Through a candidate genetic approach, we showed that P. aeruginosa rhamnolipids were reduced upon tobramycin exposure, allowing for S. constellatus 7155 biofilm enhancement, and monorhamnolipids were sufficient to reduce S. constellatus 7155 biofilm viability in the absence of tobramycin. While the findings presented here are specific to a biofilm of S. constellatus 7155 and P. aeruginosa PA14, they highlight the potential of polymicrobial interactions to impact antibiotic tolerance in unanticipated ways. Deep-sequencing studies have demonstrated that the CF lung can harbor a diverse polymicrobial community. By recapitulating the polymicrobial communities observed in the CF lung and identifying mechanisms of interspecies interactions, we have the potential to select the best therapy for a given bacterial community and reveal potential opportunities for novel therapeutic interventions. Using an in vitro model of bacterial infection on CF airway cells, we tested how a particular polymicrobial community grows, damages human cells, and responds to antibiotics in single and mixed infections. We describe here the mechanism of an interspecies interaction between two pathogens in the CF lung, P. aeruginosa and S. constellatus, which is potentiated by a commonly prescribed antibiotic, tobramycin.


Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer's disease.
Characterized as a peripheral metabolic disorder and a degenerative disease of the central nervous system respectively, it is now widely recognized that type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) share several common abnormalities including impaired glucose metabolism, increased oxidative stress, insulin resistance and amyloidogenesis. Several recent studies suggest that this is not an epiphenomenon, but rather these two diseases disrupt common molecular pathways and each disease compounds the progression of the other. For instance, in AD the accumulation of the amyloid-beta peptide (Abeta), which characterizes the disease and is thought to participate in the neurodegenerative process, may also induce neuronal insulin resistance. Conversely, disrupting normal glucose metabolism in transgenic animal models of AD that over-express the human amyloid precursor protein (hAPP) promotes amyloid-peptide aggregation and accelerates the disease progression. Studying these processes at a cellular level suggests that insulin resistance and Abeta aggregation may not only be the consequence of excitotoxicity, aberrant Ca(2+) signals, and proinflammatory cytokines such as TNF-alpha, but may also promote these pathological effectors. At the molecular level, insulin resistance and Abeta disrupt common signal transduction cascades including the insulin receptor family/PI3 kinase/Akt/GSK3 pathway. Thus both disease processes contribute to overlapping pathology, thereby compounding disease symptoms and progression.


A case of paroxysmal kinesigenic dyskinesia suspected to be reflex epilepsy.
An 11-year-old male patient developed weakness or right arm elevation after sudden movement at the age of eight. Reflex epilepsy was initially suspected; however, magnetic resonance imaging and electroencephalography (EEG) revealed no abnormality. Video-EEG monitoring was performed, but no change was noted during attacks of weakness. He was diagnosed with paroxysmal kinesigenic dyskinesia (PKD) and carbamazepine has stopped his attacks. PKD is a rare neurological disorder characterized by brief attacks of involuntary movement triggered by sudden voluntary movements, which may be confused with reflex epilepsy. PKD should be considered as a differential diagnosis of reflex epilepsy.


[DNA extraction using Chelex resin for oncogenic amplification analysis in head and neck tumours].
DNA extraction from tissues can be the most laborious and complex step in amplifying DNA by PCR when phenol-choroform procedure is used. We compare this lengthy, slow and expensive extraction method with other two based in the use of Chelex-100 resin. This chelating resin has been applied for extracting DNA from different tissues to use with the PCR. These procedures are simple, rapid and do not require multiple steps. In this study we compared DNA extraction from 30 head and neck squamous cell carcinomas (HNSCC) using organic solvent precipitation, Chelex 100 resin with and without proteinase K pretreatment. The results show that proteinase K-Chelex 100 procedure is as efficient as the phenol-chloroform one.


The SH3 domain in the fucosyltransferase FUT8 controls FUT8 activity and localization and is essential for core fucosylation.
Core fucose is an N-glycan structure synthesized by α1,6-fucosyltransferase 8 (FUT8) localized to the Golgi apparatus and critically regulates the functions of various glycoproteins. However, how FUT8 activity is regulated in cells remains largely unclear. At the luminal side and uncommon for Golgi proteins, FUT8 has an Src homology 3 (SH3) domain, which is usually found in cytosolic signal transduction molecules and generally mediates protein-protein interactions in the cytosol. However, the SH3 domain has not been identified in other glycosyltransferases, suggesting that FUT8's functions are selectively regulated by this domain. In this study, using truncated FUT8 constructs, immunofluorescence staining, FACS analysis, cell-surface biotinylation, proteomics, and LC-electrospray ionization MS analyses, we reveal that the SH3 domain is essential for FUT8 activity both in cells and in vitro and identified His-535 in the SH3 domain as the critical residue for enzymatic activity of FUT8. Furthermore, we found that although FUT8 is mainly localized to the Golgi, it also partially localizes to the cell surface in an SH3-dependent manner, indicating that the SH3 domain is also involved in FUT8 trafficking. Finally, we identified ribophorin I (RPN1), a subunit of the oligosaccharyltransferase complex, as an SH3-dependent binding protein of FUT8. RPN1 knockdown decreased both FUT8 activity and core fucose levels, indicating that RPN1 stimulates FUT8 activity. Our findings indicate that the SH3 domain critically controls FUT8 catalytic activity and localization and is required for binding by RPN1, which promotes FUT8 activity and core fucosylation.


INFLIXIMAB and ADALIMUMAB in Uveitic Macular Edema.
To compare the efficacy of infliximab and adalimumab in patients with refractory uveitis-related macular edema (ME). A retrospective study was conducted in all patients with refractory uveitis-related ME treated with infliximab or adalimumab in Pitié-Salpêtrière hospital between January 1, 2006 and January 1, 2016. All patients underwent a complete ophthalmologic examination, OCT and retinal angiography at baseline, and 6 (M6) and 24 months (M24) after treatment initiation. Main outcome was a decrease in central foveal thickness (CFT) on OCT. Twenty-five patients were included: 12 treated with adalimumab and 13 treated with infliximab. The median baseline CFT was 381 μm (Q1 = 254; Q3 = 470) in the adalimumab group and 469 μm (307; 539) in the infliximab group. At M6, 6/12 adalimumab-treated patients (50%) and 8/13 infliximab-treated patients (61%) were responders. The median CFT decrease from baseline was 61 μm (17-136) and 66 μm (-59-119) respectively at M6 and M24 in the adalimumab group versus 92 μm (9-165) and 52 μm (33-130) respectively at M6 and M24 in the infliximab group (all p > 0.05). No significant difference in efficacy was observed between infliximab and adalimumab at M6 and M24.


Reconstitution of Vanadium Haloperoxidase's Catalytic Activity by Boric Acid-Towards a Potential Biocatalytic Role of Boron.
Boron's unusual properties inspired major advances in chemistry. In nature, the existence and importance of boron has been fairly explored (e.g. bacterial signaling, plant development) but its role as biological catalyst was never reported. Here, we show that boric acid [B(OH)3 ] can restore chloroperoxidase activity of Curvularia inaequalis recombinant apo-haloperoxidase's (HPO) in the presence of hydrogen peroxide and chloride ions. Molecular modeling and semi-empirical PM7 calculations support a thermodynamically highly favored (bio)catalytic mechanism similarly to vanadium haloperoxidases (V-HPO) in which [B(OH)3 ] is assumedly located in apo-HPO's active site and a monoperoxyborate [B(OH)3 (OOH)- ] intermediate is formed and stabilized by interaction with specific active site amino acids leading ultimately to the formation of HOCl. Thus, B(OH)3 -HPO provides the first evidence towards the future exploitation of boron's role in biological systems.


Influence of fiber Bragg grating spectrum degradation on the performance of sensor interrogation algorithms.
The working principle of fiber Bragg grating (FBG) sensors is mostly based on the tracking of the Bragg wavelength shift. To accomplish this task, different algorithms have been proposed, from conventional maximum and centroid detection algorithms to more recently-developed correlation-based techniques. Several studies regarding the performance of these algorithms have been conducted, but they did not take into account spectral distortions, which appear in many practical applications. This paper addresses this issue and analyzes the performance of four different wavelength tracking algorithms (maximum detection, centroid detection, cross-correlation and fast phase-correlation) when applied to distorted FBG spectra used for measuring dynamic loads. Both simulations and experiments are used for the analyses. The dynamic behavior of distorted FBG spectra is simulated using the transfer-matrix approach, and the amount of distortion of the spectra is quantified using dedicated distortion indices. The algorithms are compared in terms of achievable precision and accuracy. To corroborate the simulation results, experiments were conducted using three FBG sensors glued on a steel plate and subjected to a combination of transverse force and vibration loads. The analysis of the results showed that the fast phase-correlation algorithm guarantees the best combination of versatility, precision and accuracy.


Effect of shear stress on attachment of corneal endothelial cells in association with corneal endothelial cell loss after laser iridotomy.
Laser iridotomy often causes bullous keratopathy; however, the mechanism is unclear. We investigated whether changes in aqueous humor hydrodynamics after laser iridotomy have any role in corneal endothelial cell loss. Porcine corneal endothelial cells were plated onto glass slides. Following 1 or 3 hours for adhesion, the endothelial cells were exposed to shear stresses (0.1-10 dyne/cm) for 15 minutes, and the number of detached cells was counted. In addition, the pressure and shear stress on corneal endothelial layer were calculated in a virtual model of laser iridotomy. The number of detached corneal endothelial cells increased with shear stresses in a dose-dependent manner. Significant increase of rate of detached corneal endothelial cells was observed at >0.3 dyne/cm after 1-hour attachment and at 1 dyne/cm after 3-hour attachment. The maximum pressure on corneal endothelial layer was 0.007 mm Hg, which is negligible compared with intraocular pressure. However, the maximum shear stress on the corneal endothelial layer could be> dyne/cm in some conditions of laser iridotomy. The resistance of corneal endothelial cell loss to shear stress is time dependent. Shear stress could be a cause of corneal endothelial cell loss in some conditions of laser iridotomy.


Onychomycosis--treatment, relapse and re-infection.
The treatment of onychomycosis has improved considerably following the introduction of the oral antifungals terbinafine and itraconazole. The pharmacokinetic characteristics of both these drugs has made short treatment times effective. Patients with a culture-proven dermatophyte infection of the toe-nails, receiving terbinafine 250 mg daily for 12 weeks, have a 70% chance of cure. The risk of relapse is probably less than 10%, and this may be prevented by a further course of terbinafine should the expected increasing length of unaffected nail growth stall or cultures become positive. Once cured, the regular and prophylactic use of an effective topical antifungal may help to prevent a recurrence of tinea pedis and onychomycosis.


Wnt Signaling in Kidney Development and Disease.
Wnt signal cascade is an evolutionarily conserved, developmental pathway that regulates embryogenesis, injury repair, and pathogenesis of human diseases. It is well established that Wnt ligands transmit their signal via canonical, β-catenin-dependent and noncanonical, β-catenin-independent mechanisms. Mounting evidence has revealed that Wnt signaling plays a key role in controlling early nephrogenesis and is implicated in the development of various kidney disorders. Dysregulations of Wnt expression cause a variety of developmental abnormalities and human diseases, such as congenital anomalies of the kidney and urinary tract, cystic kidney, and renal carcinoma. Multiple Wnt ligands, their receptors, and transcriptional targets are upregulated during nephron formation, which is crucial for mediating the reciprocal interaction between primordial tissues of ureteric bud and metanephric mesenchyme. Renal cysts are also associated with disrupted Wnt signaling. In addition, Wnt components are important players in renal tumorigenesis. Activation of Wnt/β-catenin is instrumental for tubular repair and regeneration after acute kidney injury. However, sustained activation of this signal cascade is linked to chronic kidney diseases and renal fibrosis in patients and experimental animal models. Mechanistically, Wnt signaling controls a diverse array of biologic processes, such as cell cycle progression, cell polarity and migration, cilia biology, and activation of renin-angiotensin system. In this chapter, we have reviewed recent findings that implicate Wnt signaling in kidney development and diseases. Targeting this signaling may hold promise for future treatment of kidney disorders in patients.


The enteral vs parenteral nutrition debate revisited.
Many trials and several meta-analyses have been devoted to comparing enteral with parenteral nutrition support. In this review, these studies are subjected to critical analysis with particular emphasis on their methodology and clinical relevance. Evidence is produced to suggest that the heterogeneous patient populations of the studies and the rigid approach taken to comparing different nutrition therapies inter alia render their conclusions highly questionable and of very doubtful clinical significance. An alternative approach to nutrition research is suggested in which strategies of nutrition support rather than fixed menus are compared. It is suggested that objective measures of intestinal function be evaluated more fully in patients requiring nonvolitional nutrition support, and these are briefly reviewed. In addition, a more scientific approach to evaluating the physiological effects of nutrition support, including chemical tagging and evaluation of muscle function, is recommended.


Psychometric Properties of the Impact of Events Scale-Revised (IES-R) Among General Iranian Population During the COVID-19 Pandemic.
Objective: The aim of this study was to translate and evaluate the validity and reliability of the Impact of Events Scale-Revised (IES-R) among the Iranian general population during the coronavirus disease 2019 (COVID-19) pandemic. Method: This study was methodological cross-sectional. It was conducted on an Iranian public population from April to July 2020 which was during the COVID-19 pandemic. Construct validity was determined through exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) with a total of 500 adults recruited via online data gathering. Reliability was checked through the average inter-item correlation (AIC), Cronbach's alpha, and McDonald's omega. Convergent and divergent validity was determined using Fornell and Larcker's approach. Results: The results showed that the Persian version of IES-R had three factors, including intrusion (six items), avoidance (seven items), and hyperarousal (five items), that explained 59.22% of the total variance of the IES-R. The CFA findings indicated that all goodness-of-fit indices confirmed the model fit. The Cronbach's alpha, McDonald's omega, composite reliability (CR), and maximal reliability were excellent, and the three factors have good convergent validity. Conclusion: The findings of this study indicated that the Persian version of the IES-R scale is efficient and useful to assess post-traumatic stress disorder among Iran general population in the COVID-19 outbreak.


Photon energy dependence of Kerr rotation in GeTe/Sb2Te3 chalcogenide superlattices.
We report on pump-probe based helicity dependent time-resolved Kerr measurements under infrared excitation of chalcogenide superlattices, consisting of alternately stacked GeTe and Sb2Te3 layers. The Kerr rotation signal consists of the specular inverse Faraday effect (SIFE) and the specular optical Kerr effect (SOKE), both of which are found to monotonically increase with decreasing photon energy over a sub-eV energy range. Although the dependence of the SIFE can be attributed to the response function of direct third-order nonlinear susceptibility, the magnitude of the SOKE reflects cascading second-order nonlinear susceptibility resulting from electronic transitions between bulk valence/conduction bands and interface-originating Dirac states of the superlattice.


Three stories, three outcomes.
Physicians who care for older patients may find themselves being asked to make a judgment about whether a person is able to continue driving. Discussing this topic is rarely easy for the physician or the patient. One option for physicians who find themselves in this situation is referring the patient for an evaluation by a driver rehabilitation specialist. This article describes what this entails and how such an evaluation might help clarify whether a patient can safely remain behind the wheel.


[The effect of oxyfedrine on cardiac performance in coronary patients. Tests using electrocardiographic and metabolic parameters in atrial stimulation].
In 17 patients with coronary heart disease the effects of the beta-active agent L-3-(beta-hydroxy-alpha-methyl-phenethyl-amino)-3'-methoxy-propiophenone (oxyfedrine, Ildamen) were proved at rest and during atrial pacing by measurements of coronary venous O2-saturation, myocardial lactate extraction, angina threshold and ST-segment depression. In 88% oxyfedrine had antianginal effectivity with rise in angina threshold (+11%), reduction of ST-segment depression (--48%) and reduction of lactate production(--63%). The rise in coronary venous O2-saturation ("35%) and the electrocardiographic and metabolic reduction of hypoxic reaction indicate the improvement of nutritional coronary flow. Therefore improvement of myocardial O2-balance is derived from the reduced energy requirement by decrease of heart size and ventricular wall tension and the rise of myocardial O2-supply by coronary dilation in spite of the increased energy requirement by ascending contractility. Conclusively the application of oxyfedrine is preferred in coronary heart disease with simultaneous congestive heart failure.


Robust Quality Infrastructure is Key to Safe and Effective Delivery of Immune Effector Cells: How FACT-Finding Can Help.
Immune effector cells (IEC) include a broad range of immune cells capable of modulating several disease states including malignant and non-malignant conditions. The growth in use of IECs as both investigational and commercially available products has required medical institutions to develop workflows/processes to safely implement and deliver this transformative therapy. Adding to the complexity of this therapy is the variety of targets, diseases, sources, and unique toxicities that a patient experiences following IEC therapy. For over 25 years the Foundation for the Accreditation of Cellular Therapy (FACT) has established the standard for use of cellular therapy, initially with hematopoietic cell transplant (HCT) and more recently with their development of standards to encompass IEC products such as chimeric antigen receptor (CAR) T cells. To date, IEC therapy has challenged the bandwidth and infrastructure of institutions offering this therapy. To address these challenges FACT has established a programmatic framework to improve the delivery of IEC therapy. In this manuscript we outline the current state of IEC program development, accreditation, and solutions to the challenges that programs face as they expand their application of novel IEC therapy.


Disentangling effects of structure and knowledge in perceiving partly occluded shapes: An ERP study.
Using event-related potentials (ERPs) we investigated the influence of object knowledge on perceiving partly occluded shapes. We created stimuli based on well-known objects of which the middle part was occluded. Object completions that were compatible with structure consisted of the connection of the visible fragments by smoothly extending their contours. In contrast, object completions that were incompatible with structure consisted of separate disconnected completions of the fragments. Furthermore, object completions could be in line with, or conflict with expectations based on knowledge. We measured ERPs when hidden parts were revealed by removing the occluder, and observed an early positive ERP peaking around 115-140ms at occipital sites, presumably triggered by physical differences. Most importantly, we observed a positive ERP peaking around 300-400ms at parieto-occipital sites that could be related to influences of both structure and knowledge. An additional analysis controlling for differential stimulus characteristics revealed similar conclusions. All in all, we demonstrate that the interpretation of partly occluded shapes is not solely driven by stimulus structure, but that it can also be influenced by knowledge of objects.


Comparison of mothers' understanding of two child growth charts in Lesotho.
Reported are the results of a study that compared mothers' understanding of two growth monitoring charts in Lesotho, which was carried out to assist the government in selecting a national growth chart. The study was conducted over 4 months in nine primary health care (PHC) clinics, where 1221 mothers were enrolled. Mothers were assigned to one of the following chart groups: "road-to-health" (RTH), "growth surveillance" (GS), or no chart (controls). Mothers in the first two groups received instruction on their respective chart during monthly growth monitoring sessions and were tested on their knowledge of this chart before and after the follow-up period. The mothers in the control group were tested on the RTH and GS charts at the beginning and at the end of the study. The results indicated that mothers who received training on either chart markedly improved their understanding compared with the control group and that the RTH group understood their chart better than the GS group did theirs.


Basal cell carcinoma associated with erythema ab igne.
Erythema ab igne is a skin condition mainly caused by heat exposure. Erythema ab igne usually follows a favorable prognosis. However, it may increase the risk of developing cutaneous malignancy in the involved skin. Being familiar with the type of cutaneous malignancies that may arise in the site of erythema ab igne is considerably important. To our knowledge, this letter presents the first case that shows the association between erythema ab igne and basal cell carcinoma.


A method for modelling GP practice level deprivation scores using GIS.
A measure of general practice level socioeconomic deprivation can be used to explore the association between deprivation and other practice characteristics. An area-based categorisation is commonly chosen as the basis for such a deprivation measure. Ideally a practice population-weighted area-based deprivation score would be calculated using individual level spatially referenced data. However, these data are often unavailable. One approach is to link the practice postcode to an area-based deprivation score, but this method has limitations. This study aimed to develop a Geographical Information Systems (GIS) based model that could better predict a practice population-weighted deprivation score in the absence of patient level data than simple practice postcode linkage. We calculated predicted practice level Index of Multiple Deprivation (IMD) 2004 deprivation scores using two methods that did not require patient level data. Firstly we linked the practice postcode to an IMD 2004 score, and secondly we used a GIS model derived using data from Rotherham, UK. We compared our two sets of predicted scores to "gold standard" practice population-weighted scores for practices in Doncaster, Havering and Warrington. Overall, the practice postcode linkage method overestimated "gold standard" IMD scores by 2.54 points (95% CI 0.94, 4.14), whereas our modelling method showed no such bias (mean difference 0.36, 95% CI -0.30, 1.02). The postcode-linked method systematically underestimated the gold standard score in less deprived areas, and overestimated it in more deprived areas. Our modelling method showed a small underestimation in scores at higher levels of deprivation in Havering, but showed no bias in Doncaster or Warrington. The postcode-linked method showed more variability when predicting scores than did the GIS modelling method. A GIS based model can be used to predict a practice population-weighted area-based deprivation measure in the absence of patient level data. Our modelled measure generally had better agreement with the population-weighted measure than did a postcode-linked measure. Our model may also avoid an underestimation of IMD scores in less deprived areas, and overestimation of scores in more deprived areas, seen when using postcode linked scores. The proposed method may be of use to researchers who do not have access to patient level spatially referenced data.


Commented review of the Colombian legislation regarding the ethics of health research.
The scope of ethics in health research transcends its legal framework and the regulations established in Resolution 8430 of 1993. These norms represent a fundamental tool to determine the minimum protection standards for research subjects, and, therefore, they should be known, applied properly, and reflect upon by all researchers in the field.Here I present and discuss from an analytical point of view the regulations that guide research in health. In this framework, health is understood as a multidimensional process, and research in health as a multidisciplinary exercise involving basic, clinical and public health research, collective health, and other related sciences.The main analytical categories are related to the principles and actors involved in research (regulatory authorities, ethical committees, and special or vulnerable subjects and populations), and to professional ethics codes, in addition to informed consents and data management.Despite the contribution of this legislation to the qualification of health research, my conclusion is that the national legislation in ethics for health research requires updating regarding technological and scientific developments, as well as specifications from the multiple types of health studies.


Gender differences in stroke recognition among stroke survivors.
Studies suggest that gender differences exist in the recognition of stroke warning signs. Poor recognition of stroke warning signs has been attributed to negative treatment-seeking behaviors, which can result in poor outcomes. The aim of this study was to examine gender differences in the recognition of traditional early warning signs of stroke and first action to initiate treatment in a sample of stroke survivors. We collected survey data to examine recognition of traditional stroke warning signs and appropriate first action to initiate treatment along with demographic (age, stroke age, education, usual source of care, and insurance) and clinical (health literacy and stroke knowledge) variables. Seventy-one stroke survivors participated in this pilot study. Women in the sample were significantly older than men at time of stroke (62 years old vs. 55 years old; p < .05). The two groups did not differ in clinical variables. Recognition of traditional individual stroke warning signs ranged from approximately 60% to 90%. There were no significant gender differences in the recognition of individual warning signs. Women were more likely to recognize all five traditional warning signs compared with men (67% vs. 42%; p = .04). Similarly, 58% of female participants recognized all five traditional stroke warning signs collectively and would call 9-1-1 as a first action compared with only 29% of men (p = .02). Although women recognized traditional stroke warning signs more often than men, educational programs should emphasize both traditional and nontraditional stroke warning signs among women and address these differences with their healthcare providers.


HnRNPH1/H2, U1 snRNP, and U11 snRNP cooperate to regulate the stability of the U11-48K pre-mRNA.
Alternative splicing (AS) is a major contributor to proteome diversity, but it also regulates gene expression by introducing premature termination codons (PTCs) that destabilize transcripts, typically via the nonsense-mediated decay (NMD) pathway. Such AS events often take place within long, conserved sequence elements, particularly in genes encoding various RNA binding proteins. AS-NMD is often activated by the protein encoded by the same gene, leading to a self-regulating feedback loop that maintains constant protein levels. However, cross-regulation between different RNA binding proteins is also common, giving rise to finely tuned regulatory networks. Recently, we described a feedback mechanism regulating two protein components of the U12-dependent spliceosome (U11-48K and U11/U12-65K) through a highly conserved sequence element. These elements contain a U11 snRNP-binding splicing enhancer (USSE), which, through the U11 snRNP, activates an upstream U2-type 3'ss, resulting in the degradation of the U11-48K mRNA by AS-NMD. Through phylogenetic analysis, we now identify a G-rich sequence element that is conserved in fishes as well as mammals. We show that this element binds hnRNPF/H proteins in vitro. Knockdown of hnRNPH1/H2 or mutations in the G-run both lead to enhanced activation of the 3'ss in vivo, suggesting that hnRNPH1/H2 proteins counteract the 3'ss activation. Furthermore, we provide evidence that U1 binding immediately downstream from the G-run similarly counteracts the U11-mediated activation of the alternative 3'ss. Thus, our results elucidate the mechanism in which snRNPs from both spliceosomes together with hnRNPH1/H2 proteins regulate the recognition and activation of the highly conserved alternative splice sites within the U11-48K pre-mRNA.


Cerebellopontine angle lipoma.
A case of a cerebellopontine angle lipoma is presented with a typical clinical, audiometric and radiological features of an acoustic neuroma. The correct pre-operative diagnosis was elusive even with the aid of magnetic resonance imaging.


Defective dystrophin in Duchenne and Becker dystrophy myotubes in cell culture.
We examined normal and dystrophic human myotubes in cell culture for expression of dystrophin, the protein product of the Duchenne muscular dystrophy locus. Dystrophin levels in developing myotubes detected by Western blotting increased after 24 hours and reached maximum levels after 10 days in fusion medium. We did not detect dystrophin in myotubes cultured from Duchenne myoblasts (7 cases). Myotubes from a Becker muscular dystrophy patient's biopsy produced a lower molecular weight (approximately 408 kd) dystrophin, which was the same size in a whole muscle preparation from the same biopsy. This 408-kd dystrophin was the expected size for this Becker patient whose DNA was deleted for exons 45-48 of the Duchenne gene. This cell culture system will allow a detailed analysis of the effects of potential pharmacologic agents on steady-state dystrophin levels.


[West Nile virus; ecology and epidemiology of an emerging pathogen in Colombia].
West Nile virus (WNV) has an enzootic mosquito-bird-mosquito cycle in nature, Culex sp mosquitoes being the main vectors. Birds are the main amplifying hosts. Humans and horses are incidental dead-end hosts. It produces a flu-like or a self-limited febrile disease in most humans. It can cause encephalitis, meningitis or meningoencephalitis in cases of neurological disease, having greater incidence and mortality from encephalitis in older people and immune-compromised patients. Outbreaks have been reported in Africa, the Middle-east, Europe and Asia. WNV first appeared in North-America in 1999 and its circulation has been documented in Mexico, the Caiman islands, Jamaica, the Dominican Republic, Martinique, Guadalupe, Cuba, Puerto Rico, El Salvador and more recently in Colombia. The public health concern regarding WNV if it becomes introduced into Middle- and South-America will depend upon the interaction of several factors. The prevailing conditions in Colombia are apt for its spread and development. There are two main hypotheses; the virus could become enzootic and endemic and cause limited human disease, or it could become epidemic and cause annual outbreaks affecting large numbers of humans and animals. It will depend upon Colombian birds' susceptibility to the virus because of biological differences and intra-specific geographical variations in mosquitoe species' vector competence and the environmental effects on its ability to transmit the virus; such factors are determinant in the primary amplifying cycle.


How to manage patients with cardiopulmonary disease?
Systemic lupus erythematosus (SLE) is a connective tissue disease characterized by the formation of autoantibodies and immune complexes. The heart and lungs are among the organ systems commonly affected in SLE. Pericarditis, premature coronary atherosclerosis, pleuritis and pulmonary infections are the most prevalent cardiopulmonary manifestations. Other rare associations include myocarditis, coronary arteritis, acute lupus pneumonitis/pulmonary haemorrhage, acute reversible hypoxaemia and 'shrinking lung' syndrome. Current imaging modalities may provide earlier detection of subclinical disease, which may aid in preventing these potentially fatal complications. The response to treatment varies, depending on the presentation of disease. In this chapter we address the frequency, diagnosis and monitoring, and treatment regimens of cardiac and pulmonary involvement in patients with SLE.


Imaging for evaluation of cholesteatoma: current concepts and future directions.
To examine the rationale and utility of imaging in patients with known or suspected cholesteatoma, with emphasis on high-resolution computed tomography (HRCT) and diffusion-weighted MRI (DW-MRI). The initial diagnosis of cholesteatoma is largely based on patient history and clinical findings. HRCT scan can be a useful adjunct to define the presence of pathologic soft tissue in the temporal bone, and the extent of bony erosion, and inform the otologic surgeon about expected findings at the time of surgery. Although MRI has not traditionally been used in the evaluation of cholesteatoma given its poor resolution of bone anatomy, recent advances in DW-MRI sequences allow for high sensitivity and specificity in identifying the presence of cholesteatoma. More specifically, non-echo-planar DW-MRI is superior in the detection of residual or recurrent cholesteatoma compared to delayed-contrast MRI and echo-planar DW-MRI. HRCT and DW-MRI offer complementary anatomic information that can be used effectively in the management of cholesteatoma. DW-MRI imaging has proven to be a reliable method for detecting residual or recurrent cholesteatomas down to 3 mm in size, and allows radiologic differentiation between cholesteatoma and other soft tissue. As more centers implement DW-MRI imaging for detecting residual or recurrent cholesteatoma, there will likely be less need for second-look surgery, thereby potentially decreasing associated morbidity and surgical costs.


A Possible Role for LTBP2 in the Etiology of Primary Angle Closure Glaucoma.
To assess the association of LTBP2 mutations with primary angle closure glaucoma (PACG). We studied 54 unrelated patients with PACG and one individual with pseudoexfoliation accompanied with angle closure glaucoma; these consisted of 28 female and 27 male subjects aged 27 to 82 (mean, 63) years. The 36 exons and flanking intronic sequences of LTBP2 in all patients were amplified by PCR and sequenced by the Sanger protocol. The sequences were compared to LTBP2 reference sequences. A total of 100 to 400 controls aged at least 60 years old were screened for various variations. Out of 24 observed sequence variations, ten were in amino acid coding regions; of these four created synonymous codons while six caused amino acid changes. Based on allele frequencies, biochemical parameters, absence in control individuals, evolutionary conservation of affected amino acids, and bioinformatic predictions on the effects on protein function, it was concluded that only two mutations causing p. Gln1417Arg and p. Gly1660Trp may contribute to PACG. The p. Gly1660Trp mutation was observed in a patient with both PACG and PEX syndrome. P. Gln1417Arg had previously been reported only in a subject with POAG. LTBP2 may contribute to PACG. This finding emphasizes that there may be an overlap in the etiology of various forms of glaucoma and the overlaps likely contribute to common features in various forms of glaucoma.


Intra- and postoperative myocardial ischemia without significant coronary artery stenosis.
A 73-year-old man without a history of coronary artery disease had two episodes of significant ST-segment elevation indicative of inferior myocardial ischemia during the resection of an abdominal aortic aneurysm. During the further course, sudden ST-segment elevations occurred and resolved spontaneously without preceding hemodynamic instability. The patient sustained two episodes of cardiac arrest due to ventricular fibrillation and intermittent third-degree atrioventricular block with ventricular asystole. On cardiac catheterization, coronary arteries had a right dominant pattern. The right coronary artery was entirely patent on multiple injections. Thus, right coronary artery spasm is the only possible explanation for these observations.


[Molecular mechanism at the presynaptic active zone].
Our higher brain functions such as learning and memory, emotion, and consciousness depend on the precise regulation of complicated neural networks in the brain. Neurons communicate with each other through the synapse, which comprise 3 regions: the presynapse, synaptic cleft, and postsynapse. The active zone (AZ) beneath the presynaptic membrane is the principal site for Ca2+ -dependent neurotransmitter release: AZ is involved in determining the site for docking and synaptic vesicle fusion. Presently, the full molecular composition of AZ is unclear, but it is known to contain several AZ-specific proteins, including cytomatrix of the active zone-associated protein (CAST)/ERC2, ELKS, RIM1, Munc13-1, Piccolo/Aczonin, and Bassoon. CAST and ELKS are novel active zone proteins that directly bind to Rab3-interacting molecules (RIMs), Bassoon, and Piccolo, and are thought to play a role in neurotransmitter release by binding these to AZ proteins. In this review, current advances in studies on AZ structure and function have been summarized, and the focus is mainly on protein-protein interactions among the AZ proteins.


Lattice Boltzmann model for predicting frosting process on surfaces considering wettability.
The process of frosting is a multiscale problem, which leads to challenges of proposing accurate numerical methods. In this study, a lattice Boltzmann model for predicting frost formation and growth on surfaces of various wettabilities is proposed based on the heterogeneous nucleation and dendrite growth theories. Three lattice Boltzmann equations are used to calculate the velocity, humidity, and temperature distributions. Furthermore, the heterogeneous nucleation theory and dendrite growth theory are used to construct the equations that govern ice production during the frosting process, so that the surface wettability can be considered. After experimental validation, the model was used in the analysis of frosting behaviors on plates and in microchannels with different wettabilities. The effects of the intrinsic contact angles and roughness on the frost layer properties were evaluated. This study will likely facilitate a better understanding of frosting on the mesoscopic level.


Spectroscopic and computational studies of nitrite reductase: proton induced electron transfer and backbonding contributions to reactivity.
A combination of spectroscopy and DFT calculations has been used to define the geometric and electronic structure of the nitrite bound type 2 (T2) copper site at high and low pH in nitrite reductase from Rhodobacter sphaeroides. At high pH there is no electron transfer from reduced type 1 (T1) to the nitrite bound T2 copper, while protonation triggers T1 --> T2 electron transfer and generation of NO. The DFT calculated reaction coordinate for the N-O bond cleavage in nitrite reduction by the reduced T2 copper suggests that the process is best described as proton transfer triggering electron transfer. Bidentate nitrite binding to copper is calculated to play a major role in activating the reductive cleavage of the nitrite bond through backbonding combined with stabilization of the (-)OH product by coordination to the Cu(2+).


CKS1B promotes the progression of hepatocellular carcinoma by activating JAK/STAT3 signal pathway.
Hepatocellular carcinoma (HCC) is a malignancy of considerable concern due to its continuous increase in morbidity and mortality. This study attempts to identify the molecules that play a key role in the progression of HCC, explore its potential mechanism, and provide more target choices for targeted therapy. Using overexpression plasmid and shRNA, CKS1B was respectively overexpressed and knocked down to explore its biological function roles in HCC progression and development. MTT and colony formation assays showed that knockdown of CKS1B inhibited the survival and proliferation of HCC cell lines (Hep3B and Huh7). The flow cytometry and western blot analysis showed that knockdown of CKS1B significantly induced the apoptosis of Hep3B and Huh7 cells. The wound healing and transwell invasion assays showed that knockdown of CKS1B had a significant inhibitory effect on the migration and invasion of Hep3B and Huh7 cells. These functional tests confirmed that CKS1B acts as an oncogene that regulates the malignant progression of HCC. Moreover, this study also demonstrated that knockdown of CKS1B inhibited the activation of JAK/STAT3 pathway, evidenced by the significantly downregulated p-STAT3 protein expression. Furthermore, knockdown of CKS1B also downregulated STAT3 target genes TIMP-1, Bcl-2 and VEGF, which were involved in controlling cell apoptosis and migration. On the contrary, overexpression of CKS1B caused the completely opposite results. Taken together, CKS1B acts as an oncogene to promote the proliferation and metastasis of HCC cells by activating JAK/STAT3 signaling pathway.


Reactive Myelopoiesis Triggered by Lymphodepleting Chemotherapy Limits the Efficacy of Adoptive T Cell Therapy.
Adoptive T cell therapy (ACT) in combination with lymphodepleting chemotherapy is an effective strategy to induce the eradication of tumors, providing long-term regression in cancer patients. Despite that lymphodepleting regimens condition the host for optimal engraftment and expansion of adoptively transferred T cells, lymphodepletion concomitantly promotes immunosuppression during the course of endogenous immune recovery. In this study, we have identified that lymphodepleting chemotherapy initiates the mobilization of hematopoietic progenitor cells that differentiate to immunosuppressive myeloid cells, leading to a dramatic increase of peripheral myeloid-derived suppressor cells (MDSCs). In melanoma and lung cancer patients, MDSCs rapidly expanded in the periphery within 1 week after completion of a lymphodepleting regimen and infusion of autologous tumor-infiltrating lymphocytes (TILs). This expansion was associated with disease progression, poor survival, and reduced TIL persistence in melanoma patients. We demonstrated that the interleukin 6 (IL-6)-driven differentiation of mobilized hematopoietic progenitor cells promoted the survival and immunosuppressive capacity of post-lymphodepletion MDSCs. Furthermore, the genetic abrogation or therapeutic inhibition of IL-6 in mouse models enhanced host survival and reduced tumor growth in mice that received ACT. Thus, the expansion of MDSCs in response to lymphodepleting chemotherapy may contribute to ACT failure, and targeting myeloid-mediated immunosuppression may support anti-tumor immune responses.


Effects of linear ablation at the isthmus between the tricuspid annulus and inferior vena cava for atrial flutter on autonomic nervous activity: analysis of heart rate variability.
Heart rate is largely affected by the autonomic nervous system. However, little is known about the anatomic pathway of autonomic nerve fibers innervating the sinus node. The present study: (1) evaluates the effects of cavotricuspid isthmus ablation for common atrial flutter (AFL) on autonomic nervous function by using heart rate variability analysis, and (2) investigates the distribution of autonomic nerve pathways innervating the sinus node. Twelve patients with paroxysmal common atrial flutter who maintained sinus rhythm both before and after radiofrequency ablation were selected for the study. Holter ambulatory recordings were performed before and after (2.3 +/- 1.0 days) radiofrequency ablation of cavotricuspid isthmus. Heart rate and time domain (SDANN, rMSSD, pNN50) and frequency domain (low frequency (LF), high frequency (HF), LF/HF) analysis of heart rate variability were compared before and after ablation. Mean heart rate did not change significantly after ablation (59 +/- 6 vs 61 +/- 9 beats/min); parasympathetic indices of heart rate variability (SDANN, rMSSD, pNN50, HF) did not change significantly (110 +/- 37 vs 117 +/- 20 ms; 32 +/- 21 vs 28 +/- 9 ms; 4.8 +/- 0.9 vs 4.7 +/- 0.71n(ms2)); and sympathetic indices of heart rate variability (LF/HF) did not change significantly (1.1 +/- 0.2 vs 1.2 +/- 0.1). Cavotricuspid isthmus ablation for atrial flutter did not significantly change heart rate and heart rate variability because parasympathetic and sympathetic fibers innervating the sinus node are scarce in this region.


Simultaneous glottic and supraglottic laryngeal webs: report of a case.
In a rare case of simultaneous glottic and supraglottic webbing a tantalum keel, as described by McNaught, and a silcone elastomer keel, as described by Montgomery, were placed simultaneously via laryngofissure. Use of different materials appeared to have no bearing on the final, successful outcome.


The choices we make as teachers.
"She wasn't like you...wasn't like any politician I've ever known." Ethan Kanin, Secretary of State about US president Allison Taylor in the US serial, 24. When an ethical dilemma arises, the choices we make decide our ethical concerns and moral position in a given situation. In the TV serial, 24, the US president faces such an ethical dilemma when she has to either cover up for her daughter's crime or get her arrested. She is torn between the role of a mother and that of a President. She chooses her sworn duty to protect the country and has her daughter arrested. She gives precedence to her duty as the President of a country over her mother's role.


Ectopic liver and hepatocarcinogenesis: report of three cases with four years' follow-up.
Hepatocellular carcinoma (HCC) may arise in ectopic livers, which are autonomous islands of normal liver parenchyma located in the abdomen or thorax. The majority of HCCs in ectopic livers are reported in oriental patients. We describe here three new cases of HCC in Caucasian patients. The clinical presentation varied from dull epigastric pain in one patient, to abrupt onset with signs and symptoms of acute abdomen caused by intra-abdominal bleeding in another patient, to an unexplained progressive increase of alpha-fetoprotein serum levels in a third patient. None had risk factors for HCC or liver disease. One of the patients developed HCC at age 34 years; she is the youngest patient ever described to develop HCC in ectopic liver. Our data further strengthen the hypothesis that ectopic livers are particularly predisposed to developing HCC. The patients were followed up for 4 years after surgery: two remain free of disease, suggesting that the unique localisation and growth pattern may render these tumours particularly susceptible to curative resection.


Allopurinol as a cardioprotectant during coronary artery bypass graft surgery.
To examine the role of allopurinol as a cardioprotectant during coronary artery bypass graft (CABG) surgery. A search of MEDLINE (1966-October 2002) was performed using the following terms: allopurinol, xanthine oxidase, oxygen free radical, and coronary artery bypass. References evaluated were limited to English-language and human studies, yielding 41 citations, 13 of which were found suitable. The 5 largest studies are discussed. Multiple studies with various doses have evaluated the effects of allopurinol on outcomes in CABG patients. These studies found that allopurinol can reduce in hospital mortality, improve cardiac performance, reduce incidence of arrhythmias, reduce markers of ischemia and free-radical generation, and reduce the need for inotropic support. However, these findings were not consistent between all studies. Allopurinol may reduce the incidence of CABG complications. Although the optimal dose has not been determined, reviewed literature suggests that patients should receive at least 600 mg one day prior to surgery, as well as at least 600 mg on the day of surgery.


A parametrized two-domain thermodynamic model explains diverse mutational effects on protein allostery.
New experimental findings continue to challenge our understanding of protein allostery. Recent deep mutational scanning study showed that allosteric hotspots in the tetracycline repressor (TetR) and its homologous transcriptional factors are broadly distributed rather than spanning well-defined structural pathways as often assumed. Moreover, hotspot mutation-induced allostery loss was rescued by distributed additional mutations in a degenerate fashion. Here, we develop a two-domain thermodynamic model for TetR, which readily rationalizes these intriguing observations. The model accurately captures the in vivo activities of various mutants with changes in physically transparent parameters, allowing the data-based quantification of mutational effects using statistical inference. Our analysis reveals the intrinsic connection of intra- and inter-domain properties for allosteric regulation and illustrate epistatic interactions that are consistent with structural features of the protein. The insights gained from this study into the nature of two-domain allostery are expected to have broader implications for other multidomain allosteric proteins.


Gaussian basis sets for accurate calculations on molecular systems in gas and condensed phases.
We present a library of Gaussian basis sets that has been specifically optimized to perform accurate molecular calculations based on density functional theory. It targets a wide range of chemical environments, including the gas phase, interfaces, and the condensed phase. These generally contracted basis sets, which include diffuse primitives, are obtained minimizing a linear combination of the total energy and the condition number of the overlap matrix for a set of molecules with respect to the exponents and contraction coefficients of the full basis. Typically, for a given accuracy in the total energy, significantly fewer basis functions are needed in this scheme than in the usual split valence scheme, leading to a speedup for systems where the computational cost is dominated by diagonalization. More importantly, binding energies of hydrogen bonded complexes are of similar quality as the ones obtained with augmented basis sets, i.e., have a small (down to 0.2 kcal/mol) basis set superposition error, and the monomers have dipoles within 0.1 D of the basis set limit. However, contrary to typical augmented basis sets, there are no near linear dependencies in the basis, so that the overlap matrix is always well conditioned, also, in the condensed phase. The basis can therefore be used in first principles molecular dynamics simulations and is well suited for linear scaling calculations.


Radiofrequency catheter ablation versus balloon cryoablation of atrial fibrillation: markers of myocardial damage, inflammation, and thrombogenesis.
Evidence from animal and human studies suggests that cryoablation might be associated with a lesser inflammatory response and activation of coagulation compared with radiofrequency ablation. The study was aimed at comparing the effect of cryoballoon and radiofrequency catheter ablation of paroxysmal atrial fibrillation on markers of myocardial damage, inflammation, and activation of coagulation. Forty-one patients received either cryoballoon (n = 23) or radiofrequency (n = 18) ablation of atrial fibrillation. We measured troponin I, high-sensitivity CRP, and interleukin 6 at baseline from the cubital vein, and from the right and left atrium before and after ablation, and from the cubital vein the following day. Prothrombin fragments 1 + 2, soluble P‑selectin, and D‑dimer were measured before and after ablation from both atria. We observed higher troponin I release in the cryoballoon than in the radiofrequency group (7.01 mcg/l (interquartile range [IQR]: 5.30-9.09) vs 2.32 mcg/l (IQR: 1.45-2.98), p < 0.001). The levels of inflammatory markers (high-sensitivity CRP and interleukin 6) in the two groups were comparable, as were the levels of markers of coagulation activation. Procedure duration, fluoroscopy times, and mid-term success (23 months, IQR 7-32) of the two groups were also comparable. Cryoballoon ablation of atrial fibrillation causes more significant myocardial damage, that is, more extensive ablation lesions, compared with radiofrequency catheter ablation. However, no major differences between these two ablation techniques with regard to the inflammatory response and activation of the coagulation system were observed.


[Takotsubo Cardiomyopathy and Neurogenic Pulmonary Edema Following Fibrinolytic Therapy for Embolic Stroke:A Case Report].
A 79-year-old man presented with left hemiparesis and disturbance of consciousness. Brain magnetic resonance(MR)imaging revealed an infarction in the right insular cortex. MR angiography showed a defect in the inferior trunk of the right middle cerebral artery. The patient was treated with alteplase about 2.5 h after onset. Immediately after the intravenous alteplase administration, the hemiparesis improved. However, his respiratory condition unexpectedly worsened 10 h after onset. Chest radiography demonstrated an infiltrative shadow in both lung fields. Transthoracic echocardiogram showed a dysfunction in the left ventricle and no contraction at the apex of the heart, consistent with a type of cardiomyopathy, known as takotsubo cardiomyopathy(TCM). Gradually, the patient's respiratory and cardiac function improved. Here, we describe a very rare case of TCM and neurogenic pulmonary edema(NPE)following an acute cerebral infarction, which was treated with alteplase intravenous administration. TCM and NPE have a poor prognosis, therefore diagnosis, management, and treatment in the acute phase is required.


New mechanism for glomerular injury. Myeloperoxidase-hydrogen peroxide-halide system.
Reactive oxygen species, particularly hydrogen peroxide (H2O2), participate in neutrophil-mediated glomerulonephritis. However, the mechanism of H2O2 neptrotoxicity is unknown. Myeloperoxidase (MPO), a neutrophil cationic enzyme that localizes in glomeruli, can react with H2O2 and halides to form highly reactive products. We tested the hypothesis that the MPO-H2O2-halide system may induce glomerular injury by infusing MPO followed by H2O2 in a chloride-containing solution into the renal artery of rats. Controls received MPO or H2O2 alone. MPO-H2O2-perfused rats developed significant proteinuria, endothelial cell swelling, and epithelial cell foot process effacement, whereas control kidneys were normal. In the presence of free 125I, MPO-H2O2-perfused rats incorporated large amounts of 125I, localized to the glomerular basement membrane and mesangium by autoradiography, into glomeruli. Glomerular iodination was greatly decreased or absent in controls. The MPO-H2O2-halide system causes glomerular injury and may be important in neutrophil-mediated glomerulonephritis.


A predictive study of obsessive-compulsive disorder response to clomipramine.
Studies on predictive factors of the obsessive-compulsive disorder response to pharmacologic treatment, specifically clomipramine, are relatively scarce. Forty-five patients treated for a mean period of 18.6 months were classified as having poor response, intermediate response and excellent response, defined by change scores on the Yale-Brown Obsessive-Compulsive Scale. Poor and intermediate response patients were grouped together and compared with the excellent response subgroup. Univariate analysis showed length of illness, family history (siblings), initial compulsiveness score, and cleaning rituals as significant predictors. Two multiple regression analyses with these as independent or predictive variables showed higher initial scores on the Yale-Brown Obsessive-Compulsive Scale associated with poorer response to treatment but, most importantly, cleaning rituals as a predictor of poor or modest response to clomipramine. It may be important for the clinician to assess cleaning habits separately from the more frequently mentioned obsessive-compulsive symptom, hand washing. This distinction may have important clinical, therapeutic, and prognostic implications.