Glucosylsphingosine is a highly sensitive and specific biomarker for primary diagnostic and follow-up monitoring in Gaucher disease in a non-Jewish, Caucasian cohort of Gaucher disease patients.
Gaucher disease (GD) is the most common lysosomal storage disorder (LSD). Based on a deficient β-glucocerebrosidase it leads to an accumulation of glucosylceramide. Standard diagnostic procedures include measurement of enzyme activity, genetic testing as well as analysis of chitotriosidase and CCL18/PARC as biomarkers. Even though chitotriosidase is the most well-established biomarker in GD, it is not specific for GD. Furthermore, it may be false negative in a significant percentage of GD patients due to mutation. Additionally, chitotriosidase reflects the changes in the course of the disease belatedly. This further enhances the need for a reliable biomarker, especially for the monitoring of the disease and the impact of potential treatments. Here, we evaluated the sensitivity and specificity of the previously reported biomarker Glucosylsphingosine with regard to different control groups (healthy control vs. GD carriers vs. other LSDs). Only GD patients displayed elevated levels of Glucosylsphingosine higher than 12 ng/ml whereas the comparison controls groups revealed concentrations below the pathological cut-off, verifying the specificity of Glucosylsphingosine as a biomarker for GD. In addition, we evaluated the biomarker before and during enzyme replacement therapy (ERT) in 19 patients, demonstrating a decrease in Glucosylsphingosine over time with the most pronounced reduction within the first 6 months of ERT. Furthermore, our data reveals a correlation between the medical consequence of specific mutations and Glucosylsphingosine. In summary, Glucosylsphingosine is a very promising, reliable and specific biomarker for GD.


Cross-sensory correspondences and cross talk between dimensions of connotative meaning: visual angularity is hard, high-pitched, and bright.
Higher-pitched sounds are judged to be, among other things, sharper, harder, and brighter than lower-pitched sounds. Following Karwoski, Odbert, and Osgood (Journal of General Psychology 26:199-222, 1942), such cross-sensory correspondences are proposed to have a semantic basis, reflecting extensive bidirectional cross-activation among dimensions of connotative meaning. On this basis, the same core set of correspondences should emerge whichever sensory feature is used to probe it. More angular (sharper) shapes should, for example, be higher-pitched and have the same cross-sensory features as higher-pitched sounds. Experiments 1-3 employed a speeded classification task designed to reveal cross-sensory correspondences having a semantic basis. With words as to-be-classified stimuli and with shapes varying in angularity as concurrent incidental stimuli, congruity effects between angularity and each of hardness, pitch, and brightness were confirmed. Correspondences with a semantic basis need not be cross-modality in nature. Experiment 4 confirmed this by reproducing the brightness-angularity congruity effect when contrasting values for both features were encoded nonverbally within the visual modality. The varying nature and origins of cross-sensory correspondences and the basis on which they induce congruity effects in speeded classification are explored.


Classroom Age Composition and Vocabulary Development Among At-Risk Preschoolers.
The purpose of this exploratory study was to examine the relationship between classroom age composition and preschoolers' vocabulary gains over an academic year and also to examine whether these relations were moderated by classroom quality. In this study (N = 130 children in 16 classrooms representing a subset of all children enrolled in these classrooms), results showed a significant cross-level interaction between classroom age composition and children's age, suggesting positive effects of greater variance in classroom age composition for younger but not older children. The interaction between behavior management (1 dimension of classroom quality) and classroom age composition was also significant, indicating that a wider distribution of classroom age composition was positively related to children's vocabulary gains within classrooms characterized by better behavior management. Findings underscore the importance of children's social interactions with more knowledgeable conversational partners in promoting their vocabulary development and signify the need to help teachers learn how to manage children's behaviors so as to provide a classroom that is optimal for child learning.


Phase Ib Trial To Evaluate the Safety and Pharmacokinetics of Multiple Ascending Doses of Filociclovir (MBX-400, Cyclopropavir) in Healthy Volunteers.
Filociclovir (MBX-400, cyclopropavir) is an antiviral agent with activity against cytomegalovirus (CMV). A phase 1, double-blind, randomized, placebo-controlled (3:1 ratio), single-center, multiple-ascending-dose trial was conducted to assess the safety, tolerability, and pharmacokinetics of filociclovir. Filociclovir (n = 18) or placebo (n = 6) was administered as a daily oral dose (100 mg, 350 mg, or 750 mg) for 7 days to normal healthy adults (ages, 25 to 65 years) who were monitored for 22 days. Safety assessments included clinical, laboratory, and electrocardiogram monitoring. Plasma and urine samplings were used to determine pharmacokinetic parameters. All study product-related adverse events were mild, most commonly gastrointestinal (17%), nervous system (11%), and skin and subcutaneous tissue (11%) disorders. One subject had reversible grade 3 elevation in serum creatinine and bilirubin, which was associated with an ∼1-log increase in plasma filociclovir exposure compared to levels for other subjects in the same (750-mg) cohort. No other serious adverse events were observed. Plasma exposures (area under the concentration-time curve from 0 to 24 h [AUC0-24]) on days 1 and 7 were similar, suggesting negligible dose accumulation. There was a sublinear increase in plasma exposure with dose, which plateaued at the daily dose of 350 mg. The amount of filociclovir recovered in the urine remained proportional to plasma exposure (AUC). Doses as low as 100 mg achieved plasma concentrations sufficient to inhibit CMV in vitro (This study has been registered at ClinicalTrials.gov under identifier NCT02454699.).


The ethics of sin taxes.
ABSTRACT The current global economic crisis is forcing governments to consider a variety of methods to generate funds for infrastructure. In the United States, smoking-related illness and an obesity epidemic are forcing public health institutions to consider a variety of methods to influence health behaviors of entire target groups. In this paper, the author uses a public health nursing model, the Public Health Code of Ethics (Public Health Leadership Society, 2002), the American Nurses' Association (ANA) Code of Ethics (2001), and other relevant ethical theory to weigh and balance the arguments for and against the use of sin taxes. A position advocating the limited use of sin taxes is supported as a reasonable stance for the public health professional.


Where do youth learn about suicides on the Internet, and what influence does this have on suicidal ideation?
Young people are susceptible to suicidal behavior as a result of learning about the suicidal behavior of others. This study was designed to determine whether Internet sites, such as online news and social networking websites, expose young people to suicide stories that might increase suicide ideation. We reinterviewed 719 young people ages 14 to 24 who had participated in a prior nationally representative survey. Respondents reported knowledge of persons they knew who had committed or attempted suicide as well as personal experiences of hopelessness and suicidal ideation on both occasions. On the second occasion one year later, they also reported use of various Internet platforms and how often they had been exposed to suicide stories on those sites, as well as from personal sources. Changes in ideation as a function of exposure to different sources of suicide stories were analyzed holding constant prior hopelessness and ideation. While traditional sources of information about suicide were most often cited (79% were from friends and family or newspapers), online sources were also quite common (59%). Social networking sites were frequently cited as sources, but these reports were not linked to increases in ideation. However, online discussion forums were both cited as sources and associated with increases in ideation. The Internet and especially social networking sites are important sources of suicide stories. However, discussion forums appear to be particularly associated with increases in suicidal ideation. Greater efforts should be undertaken to promote Internet sites directed to young people that enhance effective coping with hopelessness and suicidal ideation.


Developing and adapting a family-based diabetes program at the U.S.-Mexico border.
The prevalence of diabetes among Hispanics is more than twice that of non-Hispanic whites in communities along the U.S.-Mexico border. The University of Arizona and two community health agencies on the Arizona border, Campesinos Sin Fronteras and Mariposa Community Health Center, collaborated to design, pilot and assess the feasibility of a lay health-outreach worker- (promotora-) delivered diabetes education program for families. La Diabetes y La Unión Familiar was developed to build family support for patients with diabetes and to teach primary prevention behaviors to family members. Community and university partners designed a culturally appropriate program addressing family food choices and physical activity, behavior change, communication, and support behaviors. The program offers educational content and activities that can be presented in home visits or multifamily group sessions. Community partners led the implementation, and university partners guided the evaluation. Seventy-two families (249 total participants) including children and grandchildren participated. Preintervention and postintervention questionnaires completed by adults (n = 116) indicate a significant increase in knowledge of eight diabetes risk factors (P values for eight factors range from < 001 to .006) and a significant increase in family efficacy to change food (P < .001) and activity behaviors (P < .001). Interviews with participants highlight the program's positive psychosocial impact. Community and university collaboration involved building upon the promotoras' expertise in engaging the community and the university's expertise in program design and evaluation. A promotora-delivered family-based diabetes prevention program that emphasizes family support, communication, and health behaviors is feasible and can yield change in family knowledge, attitude, and behavior relative to diabetes risk factors.


A phase II study of adjuvant gemcitabine plus docetaxel followed by concurrent chemoradation in resected pancreaticobiliary carcinoma.
Adjuvant gemcitabine with or without chemoradiation is a standard therapeutic option for patients with resected pancreatic cancer. The feasibility and toxicity of gemcitabine with docetaxel before and after 5-fluorouracil (5FU)-based chemoradiation in the adjuvant pancreatic and biliary cancer setting were investigated. After a curative-intent resection, eligible patients with pancreaticobiliary cancers were treated with two cycles of gemcitabine and docetaxel followed by 5FU-based chemoradiation. Four weeks after completing chemoradiation, two cycles of gemcitabine and docetaxel were administered. The primary endpoint was the incidence of severe toxicities. Secondary endpoints included disease-free survival (DFS) and overall survival (OS). Fifty patients with pancreaticobiliary cancers were enrolled. Twenty-nine patients had pancreatic cancer whereas 21 patients had biliary tract or ampullary cancers. There was one death as a result of pneumonia, and 15% of patients experienced grade 3 or greater non-haematological toxicities. The median DFS and OS for patients with pancreatic cancer were 9.6 and 17 months, respectively, and for those with resected biliary tract cancer were 12 and 23 months, respectively. This combination of gemcitabine and docetaxel with chemoradiation is feasible and tolerable in the adjuvant setting. Future studies utilizing a different gemcitabine/taxane combination and schedule may be appropriate in the adjuvant treatment of both pancreatic cancer and biliary tumours.


Vascular endothelium viability and function after total cardiopulmonary bypass in neonatal piglets.
Endothelium dysfunction with severe pulmonary hypertension may occur after total cardiopulmonary bypass (CPB) in infants as a result of a widespread inflammatory response. The aim of this study was to separate out the effects of lung ischemia-reperfusion from membrane oxygenator-induced activation of leukocytes on the function and viability of the pulmonary and systemic endothelia in neonatal piglets submitted to 90-min total CPB followed by 60-min reperfusion or in sham animals. Hemodynamics, gas exchange, endothelial-dependent relaxation in pulmonary and femoral arteries, and lung and skeletal muscle myeloperoxidase activity were assessed before, during, and after CPB, i.e., after reperfusion. Pulmonary and aortic endothelial cells and circulating leukocytes were harvested to assess reperfusion-induced changes in endothelial cells' viability and proliferation, and leukocyte-endothelial cell adhesion and cytotoxicity. Gas exchange worsened after reperfusion with pulmonary hypertension, increase in lung but not skeletal myeloperoxidase, and reduction of endothelial-dependent relaxation in pulmonary but not femoral arteries. After reperfusion, viabilities of pulmonary and aortic endothelial cells were reduced to 50%, endothelial cell growths were faster in pulmonary arteries than aorta, and leukocyte-pulmonary endothelial cell adhesion and cytotoxicity increased. These results suggest that in total CPB lung ischemia-reperfusion aggravates the inflammatory response and predisposes the lung endothelium to leukocyte-mediated injury.


Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 domain.
Ubiquitination of proteins is an abundant modification that controls numerous cellular processes. Many Ubiquitin (Ub) protein ligases (E3s) target both their substrates and themselves for degradation. However, the mechanisms regulating their catalytic activity are largely unknown. The C2-WW-HECT-domain E3 Smurf2 downregulates transforming growth factor-beta (TGF-beta) signaling by targeting itself, the adaptor protein Smad7, and TGF-beta receptor kinases for degradation. Here, we demonstrate that an intramolecular interaction between the C2 and HECT domains inhibits Smurf2 activity, stabilizes Smurf2 levels in cells, and similarly inhibits certain other C2-WW-HECT-domain E3s. Using NMR analysis the C2 domain was shown to bind in the vicinity of the catalytic cysteine, where it interferes with Ub thioester formation. The HECT-binding domain of Smad7, which activates Smurf2, antagonizes this inhibitory interaction. Thus, interactions between C2 and HECT domains autoinhibit a subset of HECT-type E3s to protect them and their substrates from futile degradation in cells.


The Rift Valley is a major barrier to dispersal of African clawed frogs (Xenopus) in Ethiopia.
The Ethiopian highlands - home to striking species diversity and endemism - are bisected by the Rift Valley, a zone of tectonic divergence. Using molecular data we examined the evolutionary history of two co-distributed species of African clawed frog (Xenopus clivii and X. largeni) that are endemic to this region. Our field collections substantially extend the known distribution of X. largeni, a species formerly known from highlands southeast of the Rift, but that also occurs to the northwest. In both species, analysis of mitochondrial DNA and 19 autosomal loci identifies significant population structure, suggests little or no recent migration across the Rift Valley, and provides divergence time estimates across the Rift of ∼1-3.5 million years. These results indicate that the Ethiopian Rift Valley is a major obstacle to dispersal of highland-adapted amphibians.


Mitigating with macrophytes: submersed plants reduce the toxicity of pesticide-contaminated water to zooplankton.
In ecotoxicology, appreciation is growing for the influence that ecological interactions have on the toxicity of contaminants, such as insecticides, to sensitive species. Most previous studies, however, have focused on factors that exacerbate insecticide effects on species, while factors that may mitigate these effects have been relatively ignored. In aquatic habitats, a small number of studies have shown that submersed macrophytes can remove some insecticides from the water column via sorption. Although examining sorption dynamics is important for understanding the environmental fate of insecticides, whether and to what extent macrophytes actually mitigate insecticide effects on aquatic species remains unknown. In the present study, the authors examined how much and how quickly several realistic densities of the macrophyte Elodea canadensis decreased the toxicity of the insecticide malathion to Daphnia magna, a keystone aquatic herbivore. To do this, the authors quantified Daphnia survival in outdoor test systems (0.95 L) exposed to a factorial combination of five Elodea densities crossed with five malathion concentrations. The authors discovered that malathion's lethality to Daphnia decreased with increasing Elodea density. Furthermore, the rate at which Elodea reduced malathion's toxicity in the water column increased with macrophyte density. These results provide strong evidence that submersed macrophytes can mitigate the ecological impacts of a popular insecticide and further support that ecological interactions can strongly influence contaminant environmental effects.


Bazhen decoction protects against acetaminophen induced acute liver injury by inhibiting oxidative stress, inflammation and apoptosis in mice.
Bazhen decoction is a widely used traditional Chinese medicinal decoction, but the scientific validation of its therapeutic potential is lacking. The objective of this study was to investigate corresponding anti-oxidative, anti-inflammatory and anti-apoptosis activities of Bazhen decoction, using acetaminophen-treated mice as a model system. A total of 48 mice were divided into four groups. Group I, negative control, treated with vehicle only. Group II, fed with 500 mg/kg/day Bazhen decoction for 10 continuous days. Group III, received a single dose of 900 mg/kg acetaminophen. Group IV, fed with 500 mg/kg/day Bazhen decoction for 10 continuous days and a single dose of 900 mg/kg acetaminophen 30 min before last Bazhen decoction administration. Bazhen decoction administration significantly decrease acetaminophen-induced serum ALT, AST, ALP, LDH, TNF-α, IL-1β, ROS, TBARS and protein carbonyl group levels, as well as GSH depletion and loss of MMP. Bazhen decoction restore SOD, CAT, GR and GPx activities and depress the expression of pro-inflammatory factors, such as iNOS, COX-2, TNF-α, NF-κB, IL-1β and IL-6, respectively. Moreover, Bazhen decoction down-regulate acetaminophen-induced Bax/Bcl-2 ratio, caspase 3, caspase 8 and caspase 9. These results suggest the anti-oxidative, anti-inflammatory and anti-apoptosis properties of Bazhen decoction towards acetaminophen-induced liver injury in mice.


Binary adaptive optics: atmospheric wave-front correction with a half-wave phase shifter.
We describe a binary approach to adaptive wave-front correction, especially suitable for narrow band applications, which would be simpler than conventional adaptive technology. Appropriate parts of the aberrant wave front are phase retarded by half a wavelength to ensure that none of the image-forming rays add together destructively. Simulations for monochromatic light show that the residual wave-front errors, in the absence of other errors, would result in Strehl ratios of ~40% with diffraction-limited widths at visible wavelengths. We simulate the imaging performance of such a system and describe a possible implementation that uses a ferroelectric liquid-crystal spatial light modulator.


Characterization of murine mannose-binding protein genes Mbl1 and Mbl2 reveals features common to other collectin genes.
Mannose-binding protein (MBP) is a member of a family of collagenous lectins (collectins), which are believed to play an important role in first-line host defense. In this study, the two genes encoding MBP in mice--Mbl1 and Mbl2--have been isolated and their exon-intron structure studied to understand their evolutionary relationship to the single human (MBL) and the two rat MBP genes. Mouse Mbl1 and Mbl2 have five and six exons, respectively. The structure of the mouse Mbl genes is similar to that of the rat and human MBP genes and shows homology to the other collectin genes, with the entire carbohydrate recognition domain being encoded in a single exon and all introns being in phase 1. The MBP encoded by mouse Mbl1 with three cysteines in the first coding exon, like the rat Mbl1 and human MBL, is capable of a higher degree of multimerization and has apparent ability to fix complement in the absence of antibody or C1q. However, the structural features of other exons, that is, the larger size of collagen domain region in the first coding exon (64 bp in Mbl2 vs 46 bp in Mbl1) and the smaller size of the exon encoding the trimerization domain (69 bp in Mbl2 vs 75 bp in Mbl1) reveal that the single human MBL gene is closely related to rodent Mbl2 rather than rodent Mbl1. The findings in this study suggest that in contrast to the evolution of another collectin gene--bovine surfactant protein-D--which duplicated in bovidae after divergence from humans, MBP gene most likely duplicated prior to human-rodent divergence, and that the human homolog to Mbl1 was perhaps lost during evolution.


Associations of Adiposity, Circulating Protein Biomarkers, and Risk of Major Vascular Diseases.
Obesity is associated with a higher risk of cardiovascular disease (CVD), but little is known about the role that circulating protein biomarkers play in this association. To examine the observational and genetic associations of adiposity with circulating protein biomarkers and the observational associations of proteins with incident CVD. This subcohort study included 628 participants from the prospective China Kadoorie Biobank who did not have a history of cancer at baseline. The Olink platform measured 92 protein markers in baseline plasma samples. Data were collected from June 2004 to January 2016 and analyzed from January 2019 to June 2020. Measured body mass index (BMI) obtained during the baseline survey and genetically instrumented BMI derived using 571 externally weighted single-nucleotide variants. Cross-sectional associations of adiposity with biomarkers were examined using linear regression. Associations of biomarkers with CVD risk were assessed using Cox regression among those without prior cancer or CVD at baseline. Mendelian randomization was conducted to derive genetically estimated associations of BMI with biomarkers. In observational analyses of 628 individuals (mean [SD] age, 52.2 [10.5] years; 385 women [61.3%]), BMI (mean [SD], 23.9 [3.6]) was positively associated with 27 proteins (per 1-SD higher BMI; eg, interleukin-6: 0.21 [95% CI, 0.12-0.29] SD; interleukin-18: 0.13 [95% CI, 0.05-0.21] SD; monocyte chemoattractant protein-1: 0.12 [95% CI, 0.04-0.20] SD; hepatocyte growth factor: 0.31 [95% CI, 0.24-0.39] SD), and inversely with 3 proteins (Fas ligand: -0.11 [95% CI, -0.19 to -0.03] SD; TNF-related weak inducer of apoptosis, -0.14 [95% CI, -0.23 to -0.06] SD; and carbonic anhydrase 9: (-0.14 [95% CI, -0.22 to -0.05] SD), with similar associations identified for other adiposity traits (eg, waist circumference [r = 0.96]). In mendelian randomization, the associations of genetically elevated BMI with specific proteins were directionally consistent with the observational associations. In meta-analyses of genetically elevated BMI with 8 proteins, combining present estimates with previous studies, the most robust associations were shown for interleukin-6 (per 1-SD higher BMI; 0.21 [95% CI, 0.13-0.29] SD), interleukin-18 (0.16 [95% CI, 0.06-0.26] SD), monocyte chemoattractant protein-1 (0.21 [95% CI, 0.11-0.30] SD), monocyte chemotactic protein-3 (0.12 [95% CI, 0.03-0.21] SD), TNF-related apoptosis-inducing ligand (0.23 [95% CI, 0.13-0.32] SD), and hepatocyte growth factor (0.14 [95% CI, 0.06-0.22] SD). Of the 30 BMI-associated biomarkers, 10 (including interleukin-6, interleukin-18, and hepatocyte growth factor) were nominally associated with incident CVD. Mendelian randomization shows adiposity to be associated with a range of protein biomarkers, with some biomarkers also showing association with CVD risk. Future studies are warranted to validate these findings and assess whether proteins may be mediators between adiposity and CVD.


Breast cancer screening in developing countries.
Developing countries have limited healthcare resources and use different strategies to diagnose breast cancer. Most of the population depends on the public healthcare system, which affects the diagnosis of the tumor. Thus, the indicators observed in developed countries cannot be directly compared with those observed in developing countries because the healthcare infrastructures in developing countries are deficient. The aim of this study was to evaluate breast cancer screening strategies and indicators in developing countries. A systematic review and the Population, Intervention, Comparison, Outcomes, Timing, and Setting methodology were performed to identify possible indicators of presentation at diagnosis and the methodologies used in developing countries. We searched PubMed for the terms "Breast Cancer" or "Breast Cancer Screening" and "Developing Country" or "Developing Countries". In all, 1,149 articles were identified. Of these articles, 45 full articles were selected, which allowed us to identify indicators related to epidemiology, diagnostic intervention (diagnostic strategy, diagnostic infrastructure, percentage of women undergoing mammography), quality of intervention (presentation of symptoms at diagnosis, time to diagnosis, early stage disease), comparisons (trend curves, subpopulations at risk) and survival among different countries. The identification of these indicators will improve the reporting of methodologies used in developing countries and will allow us to evaluate improvements in public health related to breast cancer.


Effects of Electroacupuncture on Chronic Unpredictable Mild Stress Rats Depression-Like Behavior and Expression of p-ERK/ERK and p-P38/P38.
We investigate the antidepressant-like effect and mechanism of electroacupuncture (EA) on a chronic unpredictable mild stress rats depression-like behavior. In our study, depression in rats was induced by unpredictable chronic mild stress (UCMS) and isolation for four weeks. Male Sprague-Dawley rats were randomly divided into four groups: Normal, Model, EA, and Sham EA. EA treatment was administered for two weeks, once a day for five days a week. Two acupoints, Yintang (EX-HN3) and Baihui (GV20), were selected. For sham EA, acupuncture needles were inserted shallowly into the acupoints: EX-HN3 and GV20. No electrostimulator was connected. The antidepressant-like effect of the electroacupuncture treatment was measured by sucrose intake test, open field test, and forced swimming test in rats. The protein levels of phosphorylated extracellular regulated protein kinases (p-ERK1/2)/ERK1/2 and p-P38/P38 in the hippocampus (HP) were examined by Western blot analysis. Our data demonstrate that EA treatment decreased the immobility time of forced swimming test and improved the sucrose solution intake in comparison to unpredictable chronic mild stress and placebo sham control. Electroacupuncture may act on depression by enhancing p-ERK1/2 and p-p38 in the hippocampus.


Highly persistent label-retaining cells in the hair follicles of mice and their fate following induction of anagen.
We have identified some unusually persistent label-retaining cells in the hair follicles of mice, and have investigated their role in hair growth. Three-dimensional reconstruction of dorsal underfur follicles from serial sections made 14 mo after complete labeling of epidermis and hair follicles in neonatal mice disclosed the presence of highly persistent label-retaining cells associated with the first-generation follicle involved in the production of the first wave of hairs, commonly called the bulge. The label-retaining cells were most often found on the ventral surface of the first-generation follicle, five cell positions from the base, near the attachment site of the arrector pilorum muscle. No label-retaining cells were found in the hair canal, sebaceous gland, or hair germ. These label-retaining cells remained in the follicle following induction of anagen by plucking of the hairs. Surprisingly, they were not part of the first wave of mitotic activity following plucking, but instead underwent mitosis beginning 42 h after plucking. Label-retaining cells or their labeled daughters were not found in the hair germs through 48 h following induction of anagen by plucking, but instead remained in their subsebaceous follicular location even upon completion of the hair growth cycle 21 d later. These label-retaining cells are, therefore, unlikely to contribute to the formation of a new anagen follicle.


SVM Classifier - a comprehensive java interface for support vector machine classification of microarray data.
Graphical user interface (GUI) software promotes novelty by allowing users to extend the functionality. SVM Classifier is a cross-platform graphical application that handles very large datasets well. The purpose of this study is to create a GUI application that allows SVM users to perform SVM training, classification and prediction. The GUI provides user-friendly access to state-of-the-art SVM methods embodied in the LIBSVM implementation of Support Vector Machine. We implemented the java interface using standard swing libraries. We used a sample data from a breast cancer study for testing classification accuracy. We achieved 100% accuracy in classification among the BRCA1-BRCA2 samples with RBF kernel of SVM. We have developed a java GUI application that allows SVM users to perform SVM training, classification and prediction. We have demonstrated that support vector machines can accurately classify genes into functional categories based upon expression data from DNA microarray hybridization experiments. Among the different kernel functions that we examined, the SVM that uses a radial basis kernel function provides the best performance. The SVM Classifier is available at http://mfgn.usm.edu/ebl/svm/.


Solution structure and function of YndB, an AHSA1 protein from Bacillus subtilis.
The solution structure of the Bacillus subtilis protein YndB has been solved using NMR to investigate proposed biological functions. The YndB structure exhibits the helix-grip fold, which consists of a β-sheet with two small and one long α-helix, forming a hydrophobic cavity that preferentially binds lipid-like molecules. Sequence and structure comparisons with proteins from eukaryotes, prokaryotes, and archaea suggest that YndB is very similar to the eukaryote protein Aha1, which binds to the middle domain of Hsp90 and induces ATPase activity. On the basis of these similarities, YndB has been classified as a member of the activator of Hsp90 ATPase homolog 1-like protein (AHSA1) family with a function that appears to be related to stress response. An in silico screen of a compound library of ∼ 18,500 lipids was used to identify classes of lipids that preferentially bind YndB. The in silico screen identified, in order of affinity, the chalcone/hydroxychalcone, flavanone, and flavone/flavonol classes of lipids, which was further verified by 2D (1) H-(15) N HSQC NMR titration experiments with trans-chalcone, flavanone, flavone, and flavonol. All of these compounds are typically found in plants as precursors to various flavonoid antibiotics and signaling molecules. The sum of the data suggests an involvement of YndB with the stress response of B. subtilis to chalcone-like flavonoids released by plants due to a pathogen infection. The observed binding of chalcone-like molecules by YndB is likely related to the symbiotic relationship between B. subtilis and plants.


SENP5 mediates breast cancer invasion via a TGFβRI SUMOylation cascade.
Identifying novel mechanisms, which are at the core of breast cancer biology, is of critical importance. Such mechanisms may explain response to treatment, reveal novel targets or drive detection assays. To uncover such novel mechanisms, we used survival analysis on gene expression datasets encompassing 1363 patients. By iterating over the compendia of genes, we screened for their significance as prognosis biomarkers and identified SUMO-specific protease 5 (SENP5) to significantly stratify patients into two survival groups across five unrelated tested datasets. According to these findings, low expression of SENP5 is associated with good prognosis among breast cancer patients. Following these findings, we analyzed SENP5 silencing and show it is followed by inhibition of anchorage-independence growth, proliferation, migration and invasion in breast cancer cell lines. We further show that these changes are conducted via regulation of TGFβRI levels. These data relate to recent reports about the SUMOylation of TGFβRI. Following TGFβRI changes in expression, we show that one of its target genes, MMP9, which plays a key role in degrading the extracellular matrix and contributes to TGFβ-induced invasion, is dramatically down regulated upon SENP5 silencing. This is the first report represents SENP5-TGFβ-MMP9 cascade and its mechanistic involvement in breast cancer.


On the nature of the intrinsic connectivity of the cat motor cortex: evidence for a recurrent neural network topology.
The details and functional significance of the intrinsic horizontal connections between neurons in the motor cortex (MCx) remain to be clarified. To further elucidate the nature of this intracortical connectivity pattern, experiments were done on the MCx of three cats. The anterograde tracer biocytin was ejected iontophoretically in layers II, III, and V. Some 30-50 neurons within a radius of approximately 250 microm were thus stained. The functional output of the motor cortical point at which biocytin was injected, and of the surrounding points, was identified by microstimulation and electromyographic recordings. The axonal arborizations of the stained neurons were traced under camera lucida. The axon collaterals were extensive, reaching distances of <or=7 mm from the injection site. More importantly, the axonal branches were studded all along their course with boutons. The vast majority of boutons formed synaptic contacts on the target cells as identified by electron microscopy. The majority of these boutons made asymmetric (type I, excitatory) synapses mainly on dendritic spines. The bouton density decreased approximately monotonically with distance from the center of the injection. Cluster analysis, lagged covariance analysis, and eigenvalue decomposition showed the bouton distribution map to be unimodal. Superposition of the synaptic bouton distribution map and the motor output map revealed that motor cortical neurons don't make point-to-point connections but rather bind together the representations of a variety of muscles within a large neighborhood. This recurrent-network type connectivity strongly supports the hypothesis that the MCx controls the musculature in an integrated manner.


Psychopathy and Sexual Aggression: Management Implications.
The current study explored the association between psychopathic traits and release suitability decisions and examined the role of Psychopathy Checklist-Revised (PCL-R) and Static-99 in predicting general and sexual recidivism. The sample included 207 adult male sex offenders involved in the long-term follow-up at the Massachusetts Treatment Center for Sexually Dangerous Persons (MTC) in Bridgewater, Massachusetts. Contrary to our expectations, PCL-R Factor 2 (Lifestyle/Antisocial) scores were positively associated with being selected for gradual release, whereas PCL-R Factor 1 (Interpersonal/Affective) scores were not related to parole boards' decisions. Additionally, the interaction between the two factors was a significant predictor, suggesting that the individuals with more pronounced Factor 1 traits were less likely to be released when their Factor 2 scores were high as well. Although Static-99 scores predicted both contact and non-contact sexual recidivism, psychopathy was not related to reoffending, possibly because offenders with child victims were over-represented in the sample.


Fog2 is critical for cardiac function and maintenance of coronary vasculature in the adult mouse heart.
Aberrant transcriptional regulation contributes to the pathogenesis of both congenital and adult forms of heart disease. While the transcriptional regulator friend of Gata 2 (FOG2) is known to be essential for heart morphogenesis and coronary development, its tissue-specific function has not been previously investigated. Additionally, little is known about the role of FOG2 in the adult heart. Here we used spatiotemporally regulated inactivation of Fog2 to delineate its function in both the embryonic and adult mouse heart. Early cardiomyocyte- restricted loss of Fog2 recapitulated the cardiac and coronary defects of the Fog2 germline murine knockouts. Later cardiomyocyte-restricted loss of Fog2 (Fog2MC) did not result in defects in cardiac structure or coronary vessel formation. However, Fog2MC adult mice had severely depressed ventricular function and died at 8-14 weeks. Fog2MC adult hearts displayed a paucity of coronary vessels, associated with myocardial hypoxia, increased cardiomyocyte apoptosis, and cardiac fibrosis. Induced inactivation of Fog2 in the adult mouse heart resulted in similar phenotypes, as did ablation of the FOG2 interaction with the transcription factor GATA4. Loss of the FOG2 or FOG2-GATA4 interaction altered the expression of a panel of angiogenesis-related genes. Collectively, our data indicate that FOG2 regulates adult heart function and coronary angiogenesis.


Are some QALYs more equal than others?
Including societal preferences in allocation decisions is an important challenge for the health care sector. Here, we present results of a phased discrete choice experiment investigating the impact of various attributes on respondents' preferences for distribution of health and health care. In addition to the renowned equity principles severity of illness (operationalized as initial health) and fair innings (operationalized as age), some characteristics of beneficiaries (culpability and having dependents) and the disease (rarity) were included in the choice experiment. We used a nested logit model to analyse the data. We found that all selected attributes significantly influenced respondents' choices. The phased inclusion showed that additional attributes affected respondents' preferences for previously-included attributes and reduced unobserved variance. Although not all these attributes may be considered relevant for decision making from a normative perspective, including them in choice experiments contributes to our understanding of societal preferences for each single attribute.


Clinical staging of prostate cancer: reproducibility and clarification of issues.
The American Joint Committee on Cancer (AJCC) staging system for prostate cancer adopted in 1992 is based on tumor-node-metastasis (TNM) designations. It has been widely accepted for use in local and advanced disease. The purpose of this study was to assess reproducibility of staging among observers and to help clarify staging issues. Twelve prostate cancer cases were sent to 20 physicians with special expertise in prostate cancer including eight urologists, eight radiation oncologists, and four medical oncologists. Physicians were asked to assign a stage based on the 1992 AJCC clinical staging. The most frequently reported stage assigned to each case was taken to be the consensus. Agreement was the percentage of physicians who reported that particular stage. Seventy-five percent of the physicians responded. The overall agreement for assignment of T stage was 63.9%. Differences were found by specialty for inclusion of available information in designating a T stage. The overall agreement for N stage was 73.8%. The most common designation was Nx regardless of availability of a computed tomography scan. The overall agreement for M stage was 76.6%. Without a bone scan the most common designation was Mx regardless of Gleason grade or prostate-specific antigen (PSA). A frequent comment was that PSA was more indicative of disease extent than current clinical staging. The reproducibility of the 1992 clinical AJCC staging is poor even among experts in the field. This problem arises primarily from disagreement regarding which studies are included in assigning a stage. Some of these difficulties are addressed in the 1997 revision. However, the clinical staging does not address the true biological significance of disease in many instances.


With no lysine L-WNK1 isoforms are negative regulators of the K+-Cl- cotransporters.
The K(+)-Cl(-) cotransporters (KCC1-KCC4) encompass a branch of the SLC12 family of electroneutral cation-coupled chloride cotransporters that translocate ions out of the cell to regulate various factors, including cell volume and intracellular chloride concentration, among others. L-WNK1 is an ubiquitously expressed kinase that is activated in response to osmotic stress and intracellular chloride depletion, and it is implicated in two distinct hereditary syndromes: the renal disease pseudohypoaldosteronism type II (PHAII) and the neurological disease hereditary sensory neuropathy 2 (HSN2). The effect of L-WNK1 on KCC activity is unknown. Using Xenopus laevis oocytes and HEK-293 cells, we show that the activation of KCCs by cell swelling was prevented by L-WNK1 coexpression. In contrast, the activity of the Na(+)-K(+)-2Cl(-) cotransporter NKCC1 was remarkably increased with L-WNK1 coexpression. The negative effect of L-WNK1 on the KCCs is kinase dependent. Elimination of the STE20 proline-alanine rich kinase (SPAK)/oxidative stress-responsive kinase (OSR1) binding site or the HQ motif required for the WNK-WNK interaction prevented the effect of L-WNK1 on KCCs, suggesting a required interaction between L-WNK1 molecules and SPAK. Together, our data support that NKCC1 and KCCs are coordinately regulated by L-WNK1 isoforms.


Varying oxygen coverage on Cu55 and its effect on CO oxidation.
Adsorption of molecular oxygen on a Cu55 cluster and the resulting oxidation effects have been investigated by spin-polarized density functional theory (DFT). The optimal structure for each Cu55O2N (N = 1-20) complex has been obtained via a sequential addition of O2 and systematic screening of the preferable adsorption sites. Upon structural optimization, several O2 molecules dissociate readily on Cu55 at different oxygen coverages, and further DFT molecular dynamics simulations at 300 K confirm the instability (small dissociation barrier) of the remaining O2 and a spontaneous movement of some oxygen atoms from the surface sites towards the cluster interior. The Cu55 cluster and its oxidized derivatives have been placed on a γ-Al2O3(100) surface to study the cluster-support interaction, and furthermore, CO oxidation reactions on both Cu55(O)2N and Cu55(O)2N/γ-Al2O3(100) have been studied as a function of oxygen coverage. The CO oxidation reaction barrier is rather insensitive to the oxygen coverage regardless of the support, indicating a small increase in activity with the number of surface oxygen atoms.


Integrating a health-related-quality-of-life module within electronic health records: a comparative case study assessing value added.
Health information technology (HIT) applications that incorporate point-of-care use of health-related quality of life (HRQL) assessments are believed to promote patient-centered interactions between seriously ill patients and physicians. However, it is unclear how willing primary care providers are to use such HRQL HIT applications. The specific aim of this study was to explore factors that providers consider when assessing the value added of an HRQL application for their geriatric patients. Three case studies were developed using the following data sources: baseline surveys with providers and staff, observations of staff and patients, audio recordings of patient-provider interactions, and semi-structured interviews with providers and staff. The primary factors providers considered when assessing value added were whether the HRQL information from the module was (1) duplicative of information gathered via other means during the encounter; (2) specific enough to be useful and/or acted upon, and; (3) useful for enough patients to warrant time spent reviewing it for all geriatric patients. Secondary considerations included level of integration of the HRQL and EHR, impact on nursing workflow, and patient reluctance to provide HRQL information. Health-related quality of life modules within electronic health record systems offer the potential benefit of improving patient centeredness and quality of care. However, the modules must provide benefits that are substantial and prominent in order for physicians to decide that they are worthwhile and sustainable. Implications of this study for future research include the identification of perceived "costs" as well as a foundation for operationalizing the concept of "usefulness" in the context of such modules. Finally, developers of these modules may need to make their products customizable for practices to account for variation in EHR capabilities and practice workflows.


Synthesis, structure, magnetism, and high temperature thermoelectric properties of Ge doped Yb14MnSb11.
The Zintl phase Yb(14)MnSb(11) was successfully doped with Ge utilizing a tin flux technique. The stoichiometry was determined by microprobe analysis to be Yb(13.99(14))Mn(1.05(5))Sb(10.89(16))Ge(0.06(3)). This was the maximum amount of Ge that could be incorporated into the structure via flux synthesis regardless of the amount included in the reaction. Single crystal X-ray diffraction could not unambiguously determine the site occupancy for Ge. Bond lengths varied by about 1% or less, compared with the undoped structure, suggesting that the small amount of Ge dopant does not significantly perturb the structure. Differential scanning calorimetry/thermogravimetry (DSC/TG) show that the doped compound's melting point is greater than 1200 K. The electrical resistivity and magnetism are virtually unchanged from the parent material, suggesting that Yb is present as Yb(2+) and that the Ge dopant has little effect on the magnetic structure. At 900 K the resistivity and Seebeck coefficient decrease resulting in a zT of 0.45 at 1100 K, significantly lower than the undoped compound.


Processing speed in perceptual visual crowding.
In this study, a perceptual visual crowding paradigm was designed to quantitatively assess the detection speed of (un)crowded meaningful visual targets using eye-movement responses. This paradigm was tested in individuals with dyslexia and age-matched controls. Trials were shown on a monitor with an integrated eye tracker to 25 control and 11 dyslexic subjects without any known ocular problems. Each trial started with fixation of a central target. Next, four peripheral targets were shown (left, right, top, bottom), one being a duplicate of the central target. The duplicate was either surrounded by flankers (crowding trials) or shown in isolation (reference trials). The timing of the primary saccades were obtained as a measure for detection speed. The performance of the reference trials was significantly higher compared to the crowding trials (p < 0.05) and a 54% increase in saccadic reaction time (SRT) was found for the crowding trials. The linear mixed model revealed a significant effect of critical spacing and chart type. For the reference trials, no significant differences in SRT were found between dyslexic and control subjects. However, for the crowding trials, a significant increase of ∼13% in SRT was found in the dyslexic subjects. A first application of this paradigm showed that dyslexic subjects perform equally well in identifying visual targets in crowded as well as uncrowded scenes compared to controls. However, they seem to need more time to identify targets in crowded scenes, which might be related to the reading difficulties that they experience in general.


Automatic, semi-automatic and manual validation of urban drainage data.
Advances in sensor technology and the possibility of automated long distance data transmission have made continuous measurements the preferable way of monitoring urban drainage processes. Usually, the collected data have to be processed by an expert in order to detect and mark the wrong data, remove them and replace them with interpolated data. In general, the first step in detecting the wrong, anomaly data is called the data quality assessment or data validation. Data validation consists of three parts: data preparation, validation scores generation and scores interpretation. This paper will present the overall framework for the data quality improvement system, suitable for automatic, semi-automatic or manual operation. The first two steps of the validation process are explained in more detail, using several validation methods on the same set of real-case data from the Belgrade sewer system. The final part of the validation process, which is the scores interpretation, needs to be further investigated on the developed system.


Propagation of narrow-band-high-frequency clicks: measured and modeled transmission loss of porpoise-like clicks in porpoise habitats.
Estimating the range at which harbor porpoises can detect prey items and environmental objects is integral to understanding their biosonar. Understanding the ranges at which they can use echolocation to detect and avoid obstacles is particularly important for strategies to reduce bycatch. Transmission loss (TL) during acoustic propagation is an important determinant of those detection ranges, and it also influences animal detection functions used in passive acoustic monitoring. However, common assumptions regarding TL have rarely been tested. Here, TL of synthetic porpoise clicks was measured in porpoise habitats in Canada and Denmark, and field data were compared with spherical spreading law and ray-trace (Bellhop) model predictions. Both models matched mean observations quite well in most cases, indicating that a spherical spreading law can usually provide an accurate first-order estimate of TL for porpoise sounds in porpoise habitat. However, TL varied significantly (+/-10 dB) between sites and over time in response to variability in seafloor characteristics, sound-speed profiles, and other short-timescale environmental fluctuations. Such variability should be taken into account in estimates of the ranges at which porpoises can communicate acoustically, detect echolocation targets, and be detected via passive acoustic monitoring.


Lower artemether, dihydroartemisinin and lumefantrine concentrations during rifampicin-based tuberculosis treatment.
To investigate the pharmacokinetics of artemether, dihydroartemisinin and lumefantrine during rifampicin intake and after stopping rifampicin. An open-label, two-phase, longitudinal drug interaction study with patients serving as their own controls. We recruited HIV-1-seropositive Ugandan adults who were receiving rifampicin-based tuberculosis treatment and who did not have malaria. Pharmacokinetic sampling after six doses of artemether-lumefantrine was performed during rifampicin-based tuberculosis treatment (phase 1) and repeated at least 3 weeks after stopping rifampicin-based tuberculosis treatment (phase 2). Six and five patients completed phases 1 and 2, respectively. Median age and weight were 30 years and 64 kg. Artemether and dihydroartemisinin area under the concentration-time curve (AUC(0-12h)) were significantly lower by 89% [geometric mean ratio (GMR) 90% confidence interval (CI) 0.11, 0.05-0.26] and 85% (0.15, 0.10-0.23), respectively, during rifampicin-based treatment when compared to AUC(0-12h) after stopping rifampicin intake. Similarly, artemether and dihydroartemisinin C(max) were 83% (0.17, 0.08-0.39) and 78% (0.22, 0.15-0.33) lower, respectively, during rifampicin treatment. For artemether, mean (±SD) C(12) was 0.5(±1.0) and 5.9(±2.5) ng/ml in phases 1 and 2, respectively. Corresponding values for dihydroartemisinin (DHA) were 0.3(±0.4) and 4.7(±2.0) ng/ml, respectively. Day 8 lumefantrine concentration was significantly lower by 84% (GMR 90% CI 0.16, 0.09-0.27), and AUC(Day3-Day25) was significantly lower by 68% (GMR 90% CI 0.32, 0.21-0.49) during rifampicin-based treatment when compared to exposure values after stopping rifampicin. Pharmacokinetic parameters for artemether-lumefantrine were markedly lower during rifampicin-based tuberculosis treatment. Artemether-lumefantrine should not be co-administered with rifampicin.


The long time follow-up of craniovertebral junction fixation in patients with rheumatoid arthritis.
Rheumatoid arthritis (RA) can have very destructive effects, especially in the cervical spine. Bone quality is poor in these patients. The purpose of this study is to evaluate the feasibility of fusion and accuracy of fluoroscopy in cervical transpedicular fixation (CPF) in a standardized clinical protocol for RA patients. 96 pedicles of 15 patients operated between January 2000 and ay 2010 due to atlanto-axial and subaxial cervical subluxation were investigated for post-operative malposition of the transpedicular screws. Three-dimensional computed tomography was used as a useful tool in preoperative planning and in transarticular or transpedicular screw placement with the free hand technique in the cervical spine of RA patients. Fixation and reduction with fusion was performed in all of the patients, and autogrefts from iliac wing were used for fusion. Ranawat's and Nurick scales were used to assess the results. All screws were evaluated by Kast's criteria. Fusion or stability was evaluated on plain radiographs taken 3 weeks and 6, 12 and 60 months after the surgery. Female to male ratio was 6/9. The mean age at the time of surgery was 57.4 years (range 44-72 years). Five of the patients were operated for both C1-2 and subaxial subluxation. Two of the 15 patients had only C1-2 subluxation and the remaining eight patients had only subaxial cervical subluxation. The screws were at their correct places in 84 pedicles (87.5.%) while minor breach was detected in 9 (10.9%). According to Ranawat's criteria, seven patients remained the same, and eight patients showed improvement. Instrumentation failure, loss of reduction or non-union was not observed at the final follow-up (average 31.5 months; range 24-60 months). CPF provides a very strong three column stabilization and solid fusion in the osteoporotic vertebrae, but also carries a risk of vascular injury without nerve damage or in the RA patients, but the risk is low in experienced hands.


Young Thai People's Exposure to Alcohol Portrayals in Society and the Media: A Qualitative Study for Policy Implications.
Although previous quantitative studies have documented the association between exposure to alcohol portrayals and drinking attitudes in Western countries, few qualitative studies have explored this matter in Thailand. A better understanding of the association in young Thais is required for a more efficient alcohol policy development. This study aims to explore the information young Thais have learnt from exposure to alcohol portrayals in society and the media, examine how this exposure shapes their drinking attitudes, and investigate the alignment of policy-makers' views on drinking with those of young people. Two qualitative research methods were employed. Seventy-two university students (38 men, 34 women) aged 20-24 participated in focus groups conducted on campus. Semi-structured interviews were conducted with academia, civil society and representatives from government who were involved in alcohol policy. Recorded data were transcribed verbatim, systematically coded and analysed using content analysis. Young Thais were regularly exposed to alcohol portrayals, particularly on social media and in their social environment. Being increasingly exposed to alcohol portrayals, particularly on social media, and the role of the alcohol industry emerged as concerning matters to the academia and civil society sectors. In response to the concerns, the government social media monitoring and alcohol censorship had become more challenging. This study reflects the growing concerns from academia and civil society sectors of the impacts of increased alcohol exposure and the role that the industry may have on young people's drinking attitudes. It highlights the need for response to significant policy challenges to reduce these impacts.


Gold coast seaway smartrelease decision support system: optimising recycled water release in a sub tropical estuarine environment.
Gold Coast Water is responsible for the management of the water, recycled water and wastewater assets of the City of the Gold Coast on Australia's east coast. Excess treated recycled water is released at the Gold Coast Seaway, a man-made channel connecting the Broadwater Estuary with the Pacific Ocean, on an outgoing tide in order for the recycled water to be dispersed before the tide changes and re-enters the Broadwater estuary. Rapid population growth has placed increasing demands on the city's recycled water release system and an investigation of the capacity of the Broadwater to assimilate a greater volume of recycled water over a longer release period was undertaken in 2007. As an outcome, Gold Coast Water was granted an extension of the existing release licence from 10.5 hours per day to 13.3 hours per day from the Coombabah wastewater treatment plant (WWTP). The Seaway SmartRelease Project has been designed to optimise the release of the recycled water from the Coombabah WWTP in order to minimise the impact to the receiving estuarine water quality and maximise the cost efficiency of pumping. In order achieve this; an optimisation study that involves intensive hydrodynamic and water quality monitoring, numerical modelling and a web-based decision support system is underway. An intensive monitoring campaign provided information on water levels, currents, winds, waves, nutrients and bacterial levels within the Broadwater. This data was then used to calibrate and verify numerical models using the MIKE by DHI suite of software. The Decision Support System will then collect continually measured data such as water levels, interact with the WWTP SCADA system, run the numerical models and provide the optimal time window to release the required amount of recycled water from the WWTP within the licence specifications.


The Effect of Obesity on Revision Discectomy After Singlelevel Lumbar Discectomy.
The prevalence of obesity has been rising, creating a major public health concern. While several studies have shown obesity to increase the risk of surgical complications, few have analyzed its effects on reoperation, specifically after singlelevel lumbar discectomy. Data was obtained using the commercially available Explorys software that houses deidentified data for several major healthcare systems. A database search was used to find all patients who had undergone a lumbar discectomy. Scoliosis, spondylolisthesis, smoking history and depression were excluded as possible confounding variables, after which 25,960 patients remained. Of them, 690 were found to have undergone a revision discectomy within 2 years. Those who were obese were found to have a relative risk of 1.64 for revision discectomy compared to those who were nonobese, 95% confidence interval (95%CI) 1.322.03, p 0.0001. These findings contribute to the importance of modifiable risk factor assessment preoperatively and their effects on surgical complications. (Journal of Surgical Orthopaedic Advances 29(1):1012, 2020).


Brain signatures of meaning access in action word recognition.
The brain basis of action words may be neuron ensembles binding language- and action-related information that are dispersed over both language- and action-related cortical areas. This predicts fast spreading of neuronal activity from language areas to specific sensorimotor areas when action words semantically related to different parts of the body are being perceived. To test this, fast neurophysiological imaging was applied to reveal spatiotemporal activity patterns elicited by words with different action-related meaning. Spoken words referring to actions involving the face or leg were presented while subjects engaged in a distraction task and their brain activity was recorded using high-density magnetoencephalography. Shortly after the words could be recognized as unique lexical items, objective source localization using minimum norm current estimates revealed activation in superior temporal (130 msec) and inferior frontocentral areas (142-146 msec). Face-word stimuli activated inferior frontocentral areas more strongly than leg words, whereas the reverse was found at superior central sites (170 msec), thus reflecting the cortical somatotopy of motor actions signified by the words. Significant correlations were found between local source strengths in the frontocentral cortex calculated for all participants and their semantic ratings of the stimulus words, thus further establishing a close relationship between word meaning access and neurophysiology. These results show that meaning access in action word recognition is an early automatic process ref lected by spatiotemporal signatures of word-evoked activity. Word-related distributed neuronal assemblies with specific cortical topographies can explain the observed spatiotemporal dynamics reflecting word meaning access.


Asymmetrical effects of adaptation to left- and right-shifting prisms depends on pre-existing attentional biases.
Proposals that adaptation with left-shifting prisms induces neglect-like symptoms in normal individuals rely on a dissociation between the postadaptation performance of individuals trained with left- versus right-shifting prisms (e.g., Colent, Pisella, & Rossetti, 2000). A potential problem with this evidence is that normal young adults have an a priori leftward bias (e.g., Jewell & McCourt, 2000). In Experiment 1, we compared the line bisection performance of young adults to that of aged adults, who as a group may lack a leftward bias in line bisection. Participants trained with both left- and right-shifting prisms. Consistent with our hypothesis, while young adults demonstrated aftereffects for left, but not right prisms, aged adults demonstrated reliable aftereffects for both prisms. In Experiment 2, we recruited a larger sample of young adults, some of whom were right-biased at baseline. We observed an interaction between baseline bias and prism-shift, consistent with the results of Experiment 1: Left-biased individuals showed a reduced aftereffect when training with right-shifting prisms and right-biased individuals showed a reduced aftereffect when training with left-shifting prisms. These results suggest that previous failures to find generalizable aftereffects with right-shifting prisms may be driven by participants' baseline biases rather than specific effects of the prism itself.


Performance assessment of urine flow cytometry (UFC) to screen urines to reflex to culture in immunocompetent and immunosuppressed hosts.
Urine flow cytometry (UFC) is an automated method to quantify bacterial and white blood cell (WBC) counts. We aimed to determine whether a threshold for these parameters can be set to use UFC as a sensitive screen to predict which urine samples will subsequently grow in culture. Urines submitted to our microbiology laboratory at a tertiary care centre from 22 July 2015-17 February 2016 underwent UFC (Sysmex UF-1000i) analysis, regular urinalysis and urine culture. Positive urine cultures were defined as growth ≥104 c.f.u. ml-1 of organisms associated with urinary tract infections. The correlation of UFC bacterial and WBC counts with urine culture was assessed using receiver operating characteristics curves. The sensitivity (SN), specificity (SP), negative predictive values (NPVs), positive predictive values (PPVs) and false negative rate (FNR) were calculated at various thresholds in immunocompetent and immunosuppressed patients. A total of 15 046 urine specimens were submitted, of which 14 908 were analysable in the study. The average time to UFC result from receipt in the laboratory was 0.76 h (+/-1.04). The test performance at a set threshold of UFC bacteria ≥20 or WBC >5 was: SN=96.0 %, SP=39.2 %, PPV=47.0 %, NPV=94.5 % and FNR=4.0 %. This threshold eliminates 26 % of urine cultures. Immunosuppressed hosts had a lower sensitivity of 90.6 % and a higher FNR of 9.4 %. UFC is a rapid and sensitive method to screen out urine samples that will subsequently be negative and to reflex urines to culture that will subsequently grow. UFC results are available within 1 h from receipt and enable the elimination of culture when the set threshold is not met.


Excited-state intramolecular hydrogen transfer (ESIHT) of 1,8-dihydroxy-9,10-anthraquinone (DHAQ) characterized by ultrafast electronic and vibrational spectroscopy and computational modeling.
We combine ultrafast electronic and vibrational spectroscopy and computational modeling to investigate the photoinduced excited-state intramolecular hydrogen-transfer dynamics in 1,8-dihydroxy-9,10-anthraquinone (DHAQ) in tetrachloroethene, acetonitrile, dimethyl sulfoxide, and methanol. We analyze the electronic excited states of DHAQ with various possible hydrogen-bonding schemes and provide a general description of the electronic excited-state dynamics based on a systematic analysis of femtosecond UV/vis and UV/IR pump-probe spectroscopic data. Upon photoabsorption at 400 nm, the S2 electronic excited state is initially populated, followed by a rapid equilibration within 150 fs through population transfer to the S1 state where DHAQ exhibits ESIHT dynamics. In this equilibration process, the excited-state population is distributed between the 9,10-quinone (S2) and 1,10-quinone (S1) states while undergoing vibrational energy redistribution, vibrational cooling, and solvation dynamics on the 0.1-50 ps time scale. Transient UV/vis pump-probe data in methanol also suggest additional relaxation dynamics on the subnanosecond time scale, which we tentatively ascribe to hydrogen bond dynamics of DHAQ with the protic solvent, affecting the equilibrium population dynamics within the S2 and S1 electronic excited states. Ultimately, the two excited singlet states decay with a solvent-dependent time constant ranging from 139 to 210 ps. The concomitant electronic ground-state recovery is, however, only partial because a large fraction of the population relaxes to the first triplet state. From the similarity of the time scales involved, we conjecture that the solvent plays a crucial role in breaking the intramolecular hydrogen bond of DHAQ during the S2/S1 relaxation to either the ground or triplet state.


Freezing and thawing or freezing, thawing, and aging effects on beef tenderness.
The objective of this study was to determine the effect of freezing and thawing or freezing and thawing with an additional aging period after frozen storage on the tenderness of longissimus lumborum (LL) and semitendinosus (ST) steaks relative to aged, fresh steaks. Left-side LL and ST (n = 35 each) were obtained from U.S. Select carcasses classified at the grading stand by the U.S. Meat Animal Research Center visible and near-infrared spectroscopy tenderness system to have predicted slice shear force greater than 16.5 kg at 14 d postmortem. At 2 d postmortem, 2.54 cm thick steaks were cut from each muscle and assigned to 1 of the following treatments: 2 d fresh (2FRESH), 2 d freeze + thaw (2FREEZE), 2 d freeze + thaw + 12 d age (2FREEZE+12AGE), 14 d fresh (14FRESH), 14 d freeze + thaw (14FREEZE), 14 d freeze + thaw + 14 d age (14FREEZE+14AGE), and 28 d fresh (28FRESH). Steaks assigned to a freezing treatment were frozen at -26°C for 30 d before thawing/cooking or thawing with an additional aging period at 2°C. Slice shear force for LL and ST was lower (P < 0.01) for 2FREEZE (27.4 and 24.5 kg) and 14FREEZE (22.4 and 22.4 kg) compared to 2FRESH (33.0 and 29.2 kg) and 14FRESH (25.3 and 25.5 kg), respectively. Slice shear force for LL and ST was lower (P < 0.01) for 2FREEZE+12AGE (17.8 and 20.8 kg) and 14FREEZE+14AGE (14.6 and 19.0 kg) compared to 14FRESH (25.3 and 25.5 kg) and 28FRESH (18.7 and 21.7 kg), respectively. Desmin degradation for LL was not different (P > 0.05) between 2FREEZE (21.0%) and 2FRESH (14.6%) or between 14FREEZE (40.4%) and 14FRESH (38.4%); however, desmin degradation was higher (P < 0.06) in 2FREEZE+12AGE (46.7%) and 14FREEZE+14AGE (71.1%) when compared to 14FRESH (38.4%) and 28FRESH (60.5%), respectively. Cooking loss for LL was higher (P < 0.01) in 2FREEZE+12AGE (15.2%) compared to 14FRESH (14.0%) but was not different (P > 0.05) between 14FREEZE+14AGE (15.0%) and 28FRESH (14.3%). Freezing and thawing or a combination of freezing, thawing, and aging resulted in increased tenderness for LL and ST steaks when compared to fresh steaks with the same aging time. These results indicate freezing could be incorporated into normal commercial product distribution processes to improve the consistency of meat tenderness. Researchers who freeze steaks before tenderness assessment should be aware and acknowledge that freezing affects tenderness data.


T-cell autoreactivity to citrullinated autoantigenic peptides in rheumatoid arthritis patients carrying HLA-DRB1 shared epitope alleles.
Anti-citrullinated peptide antibodies are found in rheumatoid arthritis (RA) patients with HLA-DRβ chains encoding the shared epitope (SE) sequence. Citrullination increases self-antigen immunogenicity, through increased binding affinity to SE-containing HLA-DR molecules. To characterise T-cell autoreactivity towards citrullinated self-epitopes, we profiled responses of SE+ healthy controls and RA patients to citrullinated and unmodified epitopes of four autoantigens. We compared T-cell proliferative and cytokine responses to citrullinated and native type II collagen 1,237 to 1,249, vimentin 66 to 78, aggrecan 84 to 103 and fibrinogen 79 to 91 in six SE+ healthy controls and in 21 RA patients with varying disease duration. Cytokine-producing cells were stained after incubation with peptide in the presence of Brefeldin-A. Although proliferative responses were low, IL-6, IL-17 and TNF were secreted by CD4+ T cells of SE+ RA patients and healthy controls, as well as IFNγ and IL-10 secreted by RA patients, in response to citrullinated peptides. Of the epitopes tested, citrullinated aggrecan was most immunogenic. Patients with early RA were more likely to produce IL-6 in response to no epitope or to citrullinated aggrecan, while patients with longstanding RA were more likely to produce IL-6 to more than one epitope. Cytokine-producing CD4+ T cells included the CD45RO+ and CD45RO- and the CD28+ and CD28- subsets in RA patients. Proinflammatory cytokines were produced by CD4+ T cells in SE+ individuals in response to citrullinated self-epitopes, of which citrullinated aggrecan was most immunogenic. Our data suggest that the T-cell response to citrullinated self-epitopes matures and diversifies with development of RA.


Alteration in the modulatory role of respiratory epithelium after exposure of guinea pigs to respirable cotton dust.
Chest tightness may occur after inhalation of cotton dust. To understand the origins of this symptom of byssinosis, we exposed guinea pigs to respirable cotton dust and determined whether the resulting pulmonary obstruction was associated with alterations in the in vitro reactivity of the trachea to methacholine. The isolated, perfused trachea preparation was utilized because it allows a comparison of airway smooth muscle responses to drugs after they are applied separately to the mucosal or serosal surfaces. In epithelium-containing control tracheae, mucosally applied methacholine was less potent and elicited smaller maximum contractile responses than those obtained when it was applied to the serosal compartment. After a 6-h inhalation exposure to 30 mg/m3 respirable cotton dust, the mucosal maximum response to methacholine was substantially increased immediately (0 h) after the end of the exposure, but it was decreased 18 h postexposure. A dust level of 10 mg/m3 produced modest increases in the mucosal maximum responses at both postexposure periods, elevating them to the magnitude of the extraluminal maximum response. The potency of serosally applied methacholine was not affected by any cotton dust exposure. Mechanical epithelium removal increased mucosal reactivity to the serosal level in both control and cotton (30 mg/m3)-exposed groups, and abolished the effects of dust on mucosal reactivity to methacholine. Our findings suggest that the modulatory effect of the epithelium may be inhibitory or excitatory. The balance between the two influences may be altered by inhaled cotton dust.


Stat3 regulates microtubules by antagonizing the depolymerization activity of stathmin.
Stat3 is a member of the signal transducer and activator of transcription family, which is important in cytokine signaling. Gene ablation studies have revealed a requirement for Stat3 in diverse biological processes (Akira, S. 2000. Oncogene. 19: 2607-2611; Levy, D.E., and C.K. Lee. 2002. J. Clin. Invest. 109:1143-1148). Previously, the function of Stat3 had been attributed exclusively to its transcriptional activity in the nucleus. In this study, we reveal an interaction between Stat3 and the microtubule (MT)-destabilizing protein stathmin. Stathmin did not overtly affect ligand-stimulated Stat3 activation. In contrast, the expression of Stat3 is required for the stabilization of MTs and cell migration. We further demonstrate that Stat3-containing cells are resistant to the MT-destabilizing effect of stathmin overexpression. In addition, down-regulation of stathmin protein levels in Stat3-deficient cells partially reversed the MT and migration deficiencies. Recombinant Stat3 was also capable of reversing stathmin inhibition of tubulin polymerization in vitro. Our results indicate that Stat3 modulates the MT network by binding to the COOH-terminal tubulin-interacting domain of stathmin and antagonizing its MT destabilization activity.


Prevalence and Correlates of Penile HPV Infection in a Clinic-Based Sample of Hispanic Males.
The aim of this manuscript is to describe the prevalence, genotypic distribution of penile HPV infection and the behavioral risk factors associated with penile HPV infection (any HPV type, high-oncogenic-risk [HR] types, low-oncogenic-risk [LR] types, and of multiple HPV types) in a group of sexually active males who went to an STI clinic in San Juan, Puerto Rico. After providing informed consent, the participants, underwent a detailed behavioral interview and a clinical examination. Frequency distributions and descriptive statistics were used to characterize the study samples. Prevalence estimates and 95% confidence intervals (CI) were calculated for any type of HPV, HR types, LR types, or multiple types. Logistic regression analyses was performed to determine factors associated with each of the HPV types. Two hundred and six participants were enrolled in this study. The mean age of the participants was 37.8±13.1 years. Close to 80% of the sample were infected with at least one HPV type; 73.5% were infected with one or more LR-HPV types; 32.4%, with one or more HR-HPV types; and 46.0%, with multiple HPV types. The most prevalent HR types were HPV-35, -31, and -16; the most prevalent LR types were HPV 6/11, and -84. After adjusting for age, having a high number of lifetime female sexual partners was highly associated with having multiple types of HPV infection (estimated OR=2.86; 95% CI=1.41, 5.80). HPV infection is common among sexually active males frequenting this STI clinic. HPV types not covered by the current quadrivalent HPV vaccine were identified. Multiple HPV types in the penis are significantly related to the lifetime number of female sexual partners. The high prevalence of HPV at this particular STI clinic evidences that males need to be targeted in primary care settings if the available vaccine is to be effectively promoted. In addition, opportunities for secondary prevention of HPV in STI settings are recommended, because of the burden of anal and penile cancer documented in the island.


Applications of Nanotechnology in the Diagnosis and Therapy of Stroke.
Stroke is a leading cause of death and disability worldwide. The classification of stroke subtypes is difficult but critical for the prediction of clinical course and patient management, and limited treatment options are available. There is an urgent need for improvements in both diagnosis and therapy. Strokes have rapidly evolving phases of damage involving unique compartments of the brain, which imposes severe limitations for current diagnostic and treatment procedures. The rapid development of nanotechnology in other areas of modern medicine has ignited a widespread interest in its potential for the field of stroke. An important feature of nanoparticles is the relative ease in which their structures and surface chemistries can be modified for specific and potentially multiple, simultaneous purposes. Nanoparticles can be synthesized to carry and deliver therapeutics to specific cellular or subcellular compartments; they can be engineered to provide enhanced contrast for imaging based on the detection of changes in the blood flow; or possess ligand-specific chemistries which can facilitate diagnosis and monitor the treatment response. More specifically for a stroke, nanoparticles can be engineered to release their payload in response to the distinct extracellular processes occurring around the clot and in the ischemic penumbra, as well as aid in the detection of pathological hallmarks present at various stages of stroke progression. These capacities allow targeted release of disease-modifying agents in the affected brain tissue, increasing treatment efficacy, and limiting unwanted side effects. While nanospheres, liposomes, and mesoporous nanostructures all emerge as future prospects for stroke treatment and diagnosis, much of this potential is yet to be clinically realized. This review outlines aspects of nanotechnology identified as having potential to revolutionize the field of stroke.


TD-DFT study of the light-induced spin crossover of Fe(III) complexes.
Two light-induced spin-crossover Fe(III) compounds have been studied with time-dependent density functional theory (TD-DFT) to investigate the deactivation mechanism and the role of the ligand-field states as intermediates in this process. The B3LYP* functional has previously shown its ability to accurately describe (light-induced) spin-crossover in Fe(II) complexes. Here, we establish its performance for Fe(III) systems using [Fe(qsal)2](+) (Hqsal = 2-[(8-quinolinylimino)methyl]phenol) and [Fe(pap)2](+) (Hpap = 2-(2-pyridylmethyleneamino)phenol) as test cases comparing the B3LYP* results to experimental information and to multiconfigurational wave function results. In addition to rather accurate high spin (HS) and low spin (LS) state geometries, B3LYP* also predicts ligand-to-metal charge transfer (LMCT) states with large oscillator strength in the energy range where the UV-VIS spectrum shows an intense absorption band, whereas optically allowed π-π* excitations on the ligands were calculated at higher energy. Subsequently, we have generated a two-dimensional potential energy surface of the HS and LS states varying the Fe-N and Fe-O distances. LMCT and metal centered (MC) excited states were followed along the approximate minimal energy path that connects the minima of the HS and LS on this surface. The (2)LMCT state has a minimum in the same region as the initial LS state, where we also observe a crossing with the intermediate spin (IS) state. Upon the expansion of the coordination sphere of the Fe(III) ion, the IS state crosses with the HS state and further expansion of the coordination sphere leads to the excited spin state trapping as observed in experiment. The calculation of the intersystem crossing rates reveals that the deactivation from (2)LMCT → IS → HS competes with the (2)LMCT → IS → LS pathway, in line with the low efficiency encountered in experiments.


Dissociable effects of self-reported daily sleep duration on high-level cognitive abilities.
Most people will at some point experience not getting enough sleep over a period of days, weeks, or months. However, the effects of this kind of everyday sleep restriction on high-level cognitive abilities-such as the ability to store and recall information in memory, solve problems, and communicate-remain poorly understood. In a global sample of over 10000 people, we demonstrated that cognitive performance, measured using a set of 12 well-established tests, is impaired in people who reported typically sleeping less, or more, than 7-8 hours per night-which was roughly half the sample. Crucially, performance was not impaired evenly across all cognitive domains. Typical sleep duration had no bearing on short-term memory performance, unlike reasoning and verbal skills, which were impaired by too little, or too much, sleep. In terms of overall cognition, a self-reported typical sleep duration of 4 hours per night was equivalent to aging 8 years. Also, sleeping more than usual the night before testing (closer to the optimal amount) was associated with better performance, suggesting that a single night's sleep can benefit cognition. The relationship between sleep and cognition was invariant with respect to age, suggesting that the optimal amount of sleep is similar for all adult age groups, and that sleep-related impairments in cognition affect all ages equally. These findings have significant real-world implications, because many people, including those in positions of responsibility, operate on very little sleep and may suffer from impaired reasoning, problem-solving, and communications skills on a daily basis.


Spontaneous Helical Structure Formation in Laminin Nanofibers.
Laminin is a cross-shaped heterotrimer composed of three polypeptides chains that assembles into an insoluble extracellular matrix (ECM) network as part of the basement membrane, serving a vital role in many processes such as embryonic development, differentiation, and muscle and nerve regeneration. Here we engineered monodisperse laminin nanofibers using a surface-initiated assembly technique in order to investigate how changes in protein composition affect formation and structure of the network. Specifically, we compared laminin 111 with varying degrees of purity and with and without entactin to determine whether these changes alter biophysical properties. All the laminin types were reproducibly patterned as 200 μm long, 20 μm wide nanofibers that were successfuly released during surface-initiated assembly into solution. All nanofibers contracted upon release, and while initial lengths were identical, lengths of released fibers depended on the laminin type. Uniquely, the laminin 111 at high purity (>95%) and without entactin spontaneouly formed helical nanofibers at greater than 90%. Atomic force microscopy revealed that the nanofiber contraction was associated with a change in nanostructure from fibrillar to nodular, suggestive of refolding of laminin molecules into a globular-like conformation. Further, for the high purity laminin that formed helices, the density of the laminin at the edges of the nanofiber was higher than in the middle, providing a possible origin for the differential pre-stress driving the helix formation. Together, these results show that variation in the purity of laminin 111 and presence of entactin can have significant impact on the biophysical properties of the assembled protein networks. This highlights the fact that our understanding of protein assembly and function is still incomplete and that cell-free, in vitro assays can provide unique insights into the ECM.


Prevalence of Trachoma in Bauchi State, Nigeria: Results of 20 Local Government Area-Level Surveys.
To determine the prevalence of trachomatous inflammation - follicular (TF) and trichiasis in each of the 20 local government areas (LGAs) of Bauchi State, Nigeria. We undertook a population-based prevalence survey in each LGA in Bauchi State, employing the Global Trachoma Mapping Project methodology. We used a 2-stage, systematic and quasi-random sampling strategy. Using probability proportional to size, we selected 25 clusters, in each of which 25 households were selected by random walk. All residents of selected households 1 year and older were examined for TF, trachomatous inflammation - intense, and trichiasis, using the World Health Organization simplified grading scheme. Only two LGAs in Bauchi State had TF prevalences in 1-9-year-olds over 5%, with none having TF prevalences of 10% or greater. Only one LGA had a trichiasis prevalence in adults below the elimination threshold; all the others had trichiasis at levels suggestive of public health significance. In all 20 LGAs, more than 60% of households were within 1 km of an improved source of water for hygiene. Efforts need to be made in Bauchi State to provide trichiasis surgery in order to avert trachomatous blindness. Water supplies needs to be sustained and good personal hygiene practices assured so that elimination of trachoma as a public health problem will be achieved and sustained.


SCN10A/Nav1.8 modulation of peak and late sodium currents in patients with early onset atrial fibrillation.
To test the hypothesis that vulnerability to atrial fibrillation (AF) is associated with rare coding sequence variation in the SCN10A gene, which encodes the voltage-gated sodium channel isoform NaV1.8 found primarily in peripheral nerves and to identify potentially disease-related mechanisms in high-priority rare variants using in-vitro electrophysiology. We re-sequenced SCN10A in 274 patients with early onset AF from the Vanderbilt AF Registry to identify rare coding variants. Engineered variants were transiently expressed in ND7/23 cells and whole-cell voltage clamp experiments were conducted to elucidate their functional properties. Resequencing SCN10A identified 18 heterozygous rare coding variants (minor allele frequency ≤1%) in 18 (6.6%) AF probands. Four probands were carriers of two rare variants each and 14 were carriers of one coding variant. Based on evidence of co-segregation, initial assessment of functional importance, and presence in ≥1 AF proband, three variants (417delK, A1886V, and the compound variant Y158D-R814H) were selected for functional studies. The 417delK variant displayed near absent current while A1886V and Y158D-R814H exhibited enhanced peak and late (INa-L) sodium currents; both Y158D and R818H individually contributed to this phenotype. Rare SCN10A variants encoding Nav1.8 were identified in 6.6% of patients with early onset AF. In-vitro electrophysiological studies demonstrated profoundly altered function in 3/3 high-priority variants. Collectively, these data strongly support the hypothesis that rare SCN10A variants may contribute to AF susceptibility.


Separate cortical stages in amodal completion revealed by functional magnetic resonance adaptation.
Objects in our environment are often partly occluded, yet we effortlessly perceive them as whole and complete. This phenomenon is called visual amodal completion. Psychophysical investigations suggest that the process of completion starts from a representation of the (visible) physical features of the stimulus and ends with a completed representation of the stimulus. The goal of our study was to investigate both stages of the completion process by localizing both brain regions involved in processing the physical features of the stimulus as well as brain regions representing the completed stimulus. Using fMRI adaptation we reveal clearly distinct regions in the visual cortex of humans involved in processing of amodal completion: early visual cortex - presumably V1 -processes the local contour information of the stimulus whereas regions in the inferior temporal cortex represent the completed shape. Furthermore, our data suggest that at the level of inferior temporal cortex information regarding the original local contour information is not preserved but replaced by the representation of the amodally completed percept. These findings provide neuroimaging evidence for a multiple step theory of amodal completion and further insights into the neuronal correlates of visual perception.


Diagnostic accuracy of 64-slice multidetector CT for detection of in-stent restenosis in an unselected, consecutive patient population.
To investigate the diagnostic accuracy of 64-slice multidetector computed tomography (64-CT) for detection of in-stent restenosis (ISR) in an unselected, consecutive patient population. Detection of in-stent restenosis by cardiac CT would be a major advance for the evaluation of patients suspected of having ISR. However, the diagnostic accuracy of current generation 64-CT in this context is not fully established. We conducted a prospective study on patients with stable angina or acute coronary syndrome with no prior history of coronary artery disease. Six months after percutaneous coronary intervention (PCI) with stent placement they underwent a 64-CT scan (Toshiba Multi-Slice Aquilion 64) and consequently a repeat coronary angiography for comparison. Cardiac CT data sets were analyzed for the presence of in-stent restenosis by two independent expert readers blinded to the coronary angiographic data. Ninety-three patients with a total of 140 stents were evaluated. Males comprised 82% of the study group and the mean age was 63±10 years. The mean time from PCI to the repeat coronary angiography was 208±37 days and the mean time from 64-CT to repeat coronary angiography was 3.7±4.9 days. The restenosis rate according to coronary angiography was 26%. Stent diameter, strut thickness, heart rate and body mass index (BMI) significantly affected image quality. The sensitivity, specificity, positive and negative predictive values of 64-CT for detection of in-stent restenosis were 27%, 95%, 67% and 78%, respectively. Current generation, 64-slice CT, remains limited in its ability to accurately detect in-stent restenosis.


Psychometric characteristics of the WHOQOL-SRPB Scale in a population of stroke survivors and caregivers.
Studies have shown that spirituality plays an important role in enhancing the quality of life of stroke survivors and their caregivers. Spirituality has been associated with positive patient and caregiver outcomes, so a valid, reliable measure of spirituality is important. It has not been tested with stroke survivors and their caregivers, so the aim of this study was to evaluate the validity and reliability of the World Health Organization Quality of Life Spiritual Religious and Personal Belief (WHOQOL-SRPB) scale for stroke survivors and their caregivers. In this cross-sectional study, 414 stroke survivors at 10 rehabilitation hospitals and 244 caregivers completed the WHOQOL-SRPB. The WHOQOL-SRPB's factorial structure was assessed with confirmatory factor analysis (CFA), criterion-related validity was evaluated with the WHOQOL-BREF, and internal consistency reliability was assessed with Cronbach's α and ordinal α. The CFA results supported the hypothesized eight-factor structure. The stroke survivor and the caregiver versions of the model both had excellent fit indices. The factor loadings for the final models were strong: 0.78-0.98 for stroke survivors and caregivers (p < 0.001). The criterion-related validity for the WHOQOL-SRPB showed weak to moderate correlations with all the WHOQOL-BREF dimensions. Both ordinal α and Cronbach's α had values more than 0.70. The WHOQOL-SRPB scale is a valid, reliable instrument for measuring spirituality in stroke survivors and caregivers. Given the importance of spirituality for stroke survivors and caregivers, the WHOQOL-SRPB scale is recommended as an important tool for clinical practice and research.


Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial.
Treatment options are limited for patients infected by hepatitis C virus (HCV) with advanced liver disease. We assessed the safety and efficacy of ledipasvir, sofosbuvir, and ribavirin in patients with HCV genotype 1 or 4 and advanced liver disease. We did an open-label study at 34 sites in Europe, Canada, Australia, and New Zealand. Cohort A included patients with Child-Turcotte-Pugh class B (CTP-B) or CTP-C cirrhosis who had not undergone liver transplantation. Cohort B included post-transplantation patients who had either no cirrhosis; CTP-A, CTP-B, or CTP-C cirrhosis; or fibrosing cholestatic hepatitis. Patients in each group were randomly assigned (1:1) using a computer-generated randomisation sequence to receive 12 or 24 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily (combination tablet), plus ribavirin (600-1200 mg daily). The primary endpoint was the proportion of patients achieving a sustained virological response 12 weeks after treatment (SVR12). All patients who received at least one dose of study drug were included in the safety analysis and all patients who received at least one dose of study drug and did not undergo liver transplantation during treatment were included in the efficacy analyses. Estimates of SVR12 and relapse rates and their two-sided 90% CI (Clopper-Pearson method) were provided. This exploratory phase 2 study was not powered for formal comparisons among treatment groups; no statistical hypothesis testing was planned or conducted. The trial is registered with EudraCT (number 2013-002802-30) and ClinicalTrials.gov (number NCT02010255). Between Jan 14, 2014, and Aug 19, 2014, 398 patients were screened. Of 333 patients who received treatment, 296 had genotype 1 HCV and 37 had genotype 4 HCV. In cohort A, among patients with genotype 1 HCV, SVR12 was achieved by 20 (87%, 90% CI 70-96) of 23 CTP-B patients with 12 weeks of treatment; 22 (96%, 81-100) of 23 CTP-B patients with 24 weeks of treatment; 17 (85%, 66-96) of 20 CTP-C patients (12 weeks treatment); and 18 (78%, 60-91) of 23 CTP-C patients (24 weeks treatment). In cohort B, among patients with genotype 1 HCV, SVR12 was achieved by 42 (93%, 84-98) of 45 patients without cirrhosis (12 weeks treatment); 44 (100%, 93-100) of 44 patients without cirrhosis (24 weeks treatment); 30 (100%, 91-100) of 30 CTP-A patients (12 weeks treatment); 27 (96%, 84-100) of 28 CTP-A patients (24 weeks treatment); 19 (95%, 78-100) of 20 CTP-B patients (12 weeks treatment); 20 (100%, 86-100) of 20 CTP-B patients (24 weeks treatment); one (50%, 3-98) of two CTP-C patients (12 weeks treatment); and four (80%, 34-99) of five CTP-C patients (24 weeks treatment). All five patients with fibrosing cholestatic hepatitis achieved SVR12 (100%, 90% CI 55-100). Among all patients with genotype 4 HCV, SVR12 was achieved by 14 (78%, 56-92) of 18 patients (12 weeks treatment) and 16 (94%, 75-100) of 17 patients (24 weeks treatment). Seven patients (2%) discontinued ledipasvir-sofosbuvir prematurely due to adverse events. 17 patients died, mainly from complications of hepatic decompensation. Ledipasvir-sofosbuvir and ribavirin provided high rates of SVR12 for patients with advanced liver disease, including those with decompensated cirrhosis before or after liver transplantation. Gilead Sciences.


Is vitamin D related to pathogenesis and treatment of Hashimoto's thyroiditis?
The aim of this study was to investigate vitamin D status by measuring serum 25(OH)D levels in euthyroid patients with Hashimoto's thyroiditis (HT) who lived and worked on the sunny island of Crete, Greece, and to evaluate whether vitamin D3 supplementation is beneficial for the management of HT patients with vitamin D deficiency. We studied 218 HT patients, euthyroid Caucasian Cretan Greek citizens: 180 females and 38 males. Among these patients, 186 (85.3%) had vitamin D deficiency defined as serum 25(OH)D levels < 30 ng/mL. The mean age of all these 218 HT patients was 35.3 ± 8.5 years. The mean age of the 186 vitamin D deficient HT patients (173 females and 13 males) was 37.3 ± 5.6 years. The 186 vitamin D deficient HT patients received vitamin D3 (cholecalciferol, CF) orally, 1200-4000 IU, every day for 4 months aiming to maintain serum 25(OH)D levels ≥ 40 ng/mL. Anthropometric characteristics (height, weight, waist circumference), systolic and diastolic blood pressure, serum concentration of 25(OH)D, thyrotropin (TSH), free thyroxine (FT4), anti-thyroid peroxidase (anti-TPO), antithyroglobulin (anti-TG), calcium and phosphorus levels and thyroid and kidney sonographic findings were recorded and measured before and after CF administration. There was a significant negative correlation only between serum 25(OH)D levels and anti-TPO levels among all 218 HT patients. Also, anti-TPO levels were significantly higher in 186/218 vitamin D deficient HT patients compared to 32/218 HT patients with no vitamin D deficiency (364 ± 181IU/mL versus 115.8 ± 37.1IU/mL, P<0.0001). Supplementation of CF in 186 vitamin D deficient HT patients caused a significant decrease (20.3%) in serum anti-TPO levels. Although at the end of the 4 months period of the study body mass index (BMI), serum anti-TG and TSH levels decreased by 2.2%, 5.3% and 4% respectively, these differences were not significant. No changes in the sonographic findings were observed. The majority (85.3%) of the Greek Caucasian patients with HT studied who lived and worked in Crete had low serum 25(OH)D levels inversely correlated with serum anti-TPO thyroid antibodies. After 4 months of CF supplementation in the 186 HT patients with vitamin D deficiency, a significant decrease (20.3%) of serum anti-TPO levels was found. These findings suggest that vitamin D deficiency may be related to pathogenesis of HT and that its supplementation could contribute to the treatment of patients with HT.