An intercomparison study of ELISAs for the detection of porcine reproductive and respiratory syndrome virus - evaluating six conditionally dependent tests.
Latent class analysis is a widely used statistical method for evaluating diagnostic tests without any gold standard. It requires the results of at least two tests applied to the same individuals. Based on the resulting response patterns, the method estimates the test accuracy and the unknown disease status for all individuals in the sample. An important assumption is the conditional independence of the tests. If tests with the same biological principle are used, the assumption is not fulfilled, which may lead to biased results. In a recent publication, we developed a method that considers the dependencies in the latent class model and estimates all parameters using frequentist methods. Here, we evaluate the practicability of the method by applying it to the results of six ELISA tests for antibodies against the porcine reproductive and respiratory syndrome (PRRS) virus in pigs that generally follow the same biological principle. First, we present different methods of identifying suitable starting values for the algorithm and apply these to the dataset and a vaccinated subgroup. We present the calculated values of the test accuracies, the estimated proportion of antibody-positive animals and the dependency structure for both datasets. Different starting values led to matching results for the entire dataset. For the vaccinated subgroup, the results were more dependent on the selected starting values. All six ELISA tests are well suited to detect antibodies against PRRS virus, whereas none of the tests had the best values for sensitivity and specificity simultaneously. The results thus show that the method used is able to determine the parameter values of conditionally dependent tests with suitable starting values. The choice of test should be based on the general fit-for-purpose concept and the population under study.


Photodynamic therapy with chloroaluminum sulfonated phthalocyanine in the rat window chamber.
The efficacy of photodynamic therapy tumor destruction is dependent upon both the interruption of the tumor vasculature and the resultant production of unstable oxygen species causing cellular oxidation and death. Chloroaluminum sulfonated phthalocyanine (CASP) is a recently developed photosensitizer. In order to study the direct vascular effects of CASP on a non-tumor system, a rat window chamber was utilized. Twelve rats were implanted with the window chamber, and were divided into two groups of six. Three rats served as controls for each group (receiving light alone, CASP alone, or no treatment). The remaining 6 rats received 10 mg/kg CASP intravenously 4 days after chamber placement. Photoactivation with light was performed 24 hours after injection (power density 200 mW/cm2, irradiance 100 J/cm2, lambda = 675 nm). Utilizing integrating sphere measurements and image analysis, marked vascular changes in the form of initial vasospasm followed by vaso-constriction and loss of chamber neovascularization were noted in the CASP-PDT group. The control groups exhibited no significant changes. Manipulation of the chamber vasculature at strategic time-points may translate into improved response rates for photodynamic therapy in a tumor model.


Pathotyping of Australian isolates of Marek's disease virus in commercial broiler chickens vaccinated with herpesvirus of turkeys (HVT) or bivalent (HVT/SB1) vaccine and association with viral load in the spleen and feather dander.
To pathotype Australian isolates of Marek's disease virus (MDV) in commercial broiler chickens using standard methods and to evaluate early markers of pathotype. A complete 3 × 4 factorial experiment with two replicates was conducted using 648 Cobb broiler chickens in 24 isolators. The experimental factors were vaccination (unvaccinated, herpesvirus of turkeys (HVT), bivalent (HVT + SB1 strain of serotype 2 MDV)) and MDV challenge (unchallenged or 500 plaque-forming units of isolates MFP57, 02LAR or FT158). Mortality, body weight, immune-organ weights and viral load were measured to 56 days post challenge (dpc). Vaccinal protective index (PI) and virulence rank (VR) were calculated based on gross Marek's disease (MD) pathology. The PIs provided by the HVT and bivalent vaccines against challenge with MPF57, 02LAR, and FT158 were 84.6% 56%, 61.4% and 82.2%, 60.8%, 57.7%, respectively, leading to putative pathotypes of virulent MDV for MPF57 and very virulent MDV for 02LAR and FT158. Significantly more of the unvaccinated chickens (85.7%) had MD lesions than chickens vaccinated with either the HVT (26.8%) or bivalent vaccine (27.6%). Strong linear relationships were observed between the incidence of MD at 56 dpc and MDV load in the spleen at 7 dpc (R(2) = 0.71) and MDV load in the isolator exhaust dust at 14 dpc (R(2) = 0.57) and 21 dpc (R(2) = 0.51). Immune organ weights had a weaker association with subsequent MD incidence. Pathotyping results in broiler chickens with maternal antibody broadly agreed with those in specific-pathogen-free chickens in other studies, with some important differences. MDV load in the spleen at 7 dpc and in isolator dust at both 14 and 21 dpc was a powerful early predictor of subsequent MD incidence.


Cortical synthesis of azimuth-sensitive single-unit responses with nonmonotonic level tuning: a thalamocortical comparison in the cat.
1. Azimuth and sound pressure level (SPL) tuning to noise stimulation was characterized in single-unit samples obtained from primary auditory cortex (AI) and in areas of the medial geniculate body (MGB) that project to AI. The primary aim of the study was to test the hypothesis that AI is an important site of synthesis of single-unit responses that exhibit both azimuth sensitivity (tendency for directionally restricted responsiveness) and nonmonotonic (NM) level tuning (tendency for decreased responsiveness with increasing SPL). This was accomplished by comparing the proportions of such responses in AI and MGB. 2. Samples consisted of high-best-frequency (BF) single units located in MGB (n = 217) and AI (n = 216) of barbiturate-anesthetized cats. The MGB sample was obtained mainly from recording sites located in two nuclei that project to AI, the ventral nucleus (VN, n = 118) and the lateral part of the posterior group of thalamic nuclei (Po, n = 84). In addition, a few MGB units were obtained from the medial division (n = 8) or uncertain locations (n = 7). Each unit's responses were studied using noise bursts presented from azimuthal sound directions distributed throughout 180 degrees of the frontal hemifield at 0 degrees elevation. SPL was varied over an 80-dB range in steps of < or = 20 dB at each location. Similarities and differences in azimuth and level tuning were evaluated statistically by comparing the AI sample with the entire MGB sample. If they were found to differ, the AI, VN, and Po samples were compared. 3. Azimuth function modulation was used as a measure of azimuth sensitivity, and its mean was greater in AI than in MGB. NM strength was defined as the percentage reduction in level function value at 75 dB SPL and its mean was greater in AI (showing a greater tendency for decreased responsiveness) than in MGB. Azimuth-sensitive (AS) NM units were identified by jointly categorizing each sample according to both azimuth sensitivity (sensitive and insensitive categories) and NM strength (NM and monotonic categories). AS NM units were much more common in the AI sample than in any of the MGB samples, suggesting that some such responses are synthesized in AI. 4. A vast majority of AI NM units have been reported to be AS, showing a preferential association (linkage) between these two response properties. This finding was confirmed in AI, but was not found to be the case in MGB. This suggests that a linkage between these response properties emerges in the cortex, presumably as a result of synthesis of NM AS responses. Although the functional significance of the linkage is unknown, NM responses may reflect excitatory/inhibitory antagonism that provides AS AI neurons with sensitivity to stimulus features beyond that which is present in MGB. 5. Breadth of azimuth tuning of AS cells was measured as the portion of the frontal hemifield over which azimuth function values were > 75% of maximum (preferred azimuth range, PAR). PARs were broadly distributed in each structure, and mean PAR was narrower in AI than in MGB. A preferred level range (PLR) was defined for NM level functions as the range over which values were > 75% of maximum, and mean PLRs were similar in each sample. There was a weak, but significant, positive correlation between PARs and PLRs in AI but not in MGB. This further suggests a linkage between azimuth and level tuning in AI that does not exist in MGB. 6. Best azimuth (midpoint of the PAR) was used to classify cells as contralateral preferring, ipsilateral preferring, midline preferring, or multipeaked. Samples from AI and MGB exhibited similar distributions of these categories. Contralateral-preferring cells represented a majority of each sample, whereass midline-preferring, ipsilateral-preferring, and multipeaked cells each represented smaller proportions. This suggests that the azimuth preference distribution in AI largely reflects that in MGB. 7. A best SPL was defined as the midpoint of the PLR. This wa


Role of spiramycin/cotrimoxazole association in the mother-to-child transmission of toxoplasmosis infection in pregnancy.
The purpose of this report is to evaluate the efficacy and safety of spiramycin/cotrimoxazole in the mother-to-child transmission of Toxoplasma gondii infection. We retrospectively analysed 76 infants born to mothers with toxoplasmosis during pregnancy and estimated the risk of mother-to-child transmission considering the gestational age at the time of infection. Seventy-six mothers were given spiramycin, cotrimoxazole and folinic acid; only two babies (2.6%) were infected by Toxoplasma and none of them showed signs or symptoms of congenital infection or interference of sulphamid on tetrahydrofolate reductase (THFR) either at birth or during follow-up. Treatment did not need to be stopped in any mother because of adverse drug effects. Our results seem to encourage the use of spiramycin/cotrimoxazole in women with toxoplasmosis during pregnancy.


Pimozide for schizophrenia or related psychoses.
Pimozide was first formulated in the late 1960s and continues to be marketed for the care of those with schizophrenia or related psychoses such as delusional disorder. Pimozide is generally well tolerated apart from extrapyramidal side effects. It has, however, been associated with cardiotoxicity and sudden unexplained deaths and electrocardiogram monitoring is now required before and during its use. To assess the effects of pimozide for people with schizophrenia, non-affective psychotic mental illness and delusional disorder in terms of clinical, social and economic outcomes. Electronic searches of Biological Abstracts (1982-1995), The Cochrane Schizophrenia Group's Register, EMBASE (1980-1995), Janssen-Cilag UK's register of studies (1999), MEDLINE (1966-1995), PsycLIT (1974-1995), hand-searching the references of all included studies and contacting the manufacturers of the compound. All randomised trials relating to people with schizophrenia, or similar disorders comparing pimozide to other drug treatments were sought. Studies where randomisation was implied rather than stated were included if they did not change the results. Primary outcomes were clinically significant change in global function, mental state, relapse, hospital admission, death, adverse events and acceptability of treatment. Studies were selected, rated and data extracted. For dichotomous data Relative Risks (RR) based on a random effects model with 95% confidence intervals (CI) were estimated. The number needed to treat statistic (NNT) was calculated where indicated. Analysis was by intention-to-treat. This review currently includes 34 studies focusing on those with schizophrenia, none on people with delusional disorder. Few people have been randomised to pimozide versus placebo. Data from two longer term studies does suggest that the active drug prevents relapse (n=66, RR 0.45 CI 0.24-0.86, NNT 4, CI 3-22) but the confidence interval is wide. Pimozide has similar efficacy to that of typical antipsychotic drugs for the outcomes of change in global functioning, mental state, relapse and leaving the study early. People allocated to pimozide did not have a higher mortality than those taking other antipsychotics. Pimozide was more likely to cause parkinsonian tremor (RR 1.6 CI 1.1-2.3, NNH 6 CI 3-44) and lead to a requirement for antiparkinsonian medication more frequently (RR 1.8, CI 1.2-2.6, NNH 3 CI 2-5) than other drugs. It was, however, less likely to cause sedation (RR 0.38 CI 0.2-0.7, NNH 6 CI 4-16). Although there are shortcomings in the data there is enough overall consistency, over different outcomes and time scales, to confirm that pimozide is a drug with similar efficacy to other more commonly used antipsychotics such as chlorpromazine for those with schizophrenia. There are no data to support or refute its use for those with delusional disorder.


Development of the external genitalia: conserved and divergent mechanisms of appendage patterning.
Over the past decade, the genetics of external genital development have begun to be understood. Male and female external genitalia develop from the genital tubercle. The early tubercle has a superficial resemblance to the limb bud, but an important distinction is that the limb consists of only mesoderm and ectoderm, whereas the genital tubercle also has an endodermal component, the urethral epithelium. Urethral epithelium, which expresses Sonic hedgehog, acts as a signaling region that controls outgrowth and pattern formation, and ultimately differentiates into the urethral tube. While there are intriguing parallels between limb and genital development, recent studies have identified some key differences, including the role of Fgf signaling. Our understanding of the mechanisms of genital development still lags far behind the limb, and major questions remain to be answered, including the molecular nature of the signals that initiate genital budding, sustain outgrowth, induce tissue polarity and orchestrate urethral tubulogenesis.


EZH2-dependent suppression of a cellular senescence phenotype in melanoma cells by inhibition of p21/CDKN1A expression.
Polycomb group (PcG) proteins such as Enhancer of zeste homolog 2 (EZH2) are epigenetic transcriptional repressors that function through recognition and modification of histone methylation and chromatin structure. Targets of PcG include cell cycle regulatory proteins which govern cell cycle progression and cellular senescence. Senescence is a characteristic of melanocytic nevi, benign melanocytic proliferations that can be precursors of malignant melanoma. In this study, we report that EZH2, which we find absent in melanocytic nevi but expressed in many or most metastatic melanoma cells, functionally suppresses the senescent state in human melanoma cells. EZH2 depletion in melanoma cells inhibits cell proliferation, restores features of a cellular senescence phenotype, and inhibits growth of melanoma xenografts in vivo. p21/CDKN1A is activated upon EZH2 knockdown in a p53-independent manner and contributes substantially to cell cycle arrest and induction of a senescence phenotype. EZH2 depletion removes histone deacetylase 1 (HDAC1) from the CDKN1A transcriptional start site and downstream region, enhancing histone 3 acetylation globally and at CDKN1A. This results in recruitment of RNA polymerase II, leading to p21/CDKN1A activation. Depletion of EZH2 synergistically activates p21/CDKN1A expression in combination with the HDAC inhibitor trichostatin A. Since melanomas often retain wild-type p53 function activating p21, our findings describe a novel mechanism whereby EZH2 activation during tumor progression represses p21, leading to suppression of cellular senescence and enhanced tumorigenicity.


Disease incidence and mortality among older Americans and Europeans.
Recent research has shown a widening gap in life expectancy at age 50 between the United States and Europe as well as large differences in the prevalence of diseases at older ages. Little is known about the processes determining international differences in the prevalence of chronic diseases. Higher prevalence of disease could result from either higher incidence or longer disease-specific survival. This article uses comparable longitudinal data from 2004 and 2006 for populations aged 50 to 79 from the United States and from a selected group of European countries to examine age-specific differences in prevalence and incidence of heart disease, stroke, lung disease, diabetes, hypertension, and cancer as well as mortality associated with each disease. Not surprisingly, we find that Americans have higher disease prevalence. For heart disease, diabetes, and cancer, incidence is lower in Europe when we control for sociodemographic and health behavior differences in risk, and these differences explain much of the prevalence gap at older ages. On the other hand, incidence is higher in Europe for lung disease and not different between Europe and the United States for hypertension and stroke. Our findings do not suggest a survival advantage conditional on disease in Europe compared with the United States. Therefore, the origin of the higher disease prevalence at older ages in the United States is to be found in higher prevalence earlier in the life course and, for some conditions, higher incidence between ages 50 and 79.


Is an Elastic Ankle Support Effective in Improving Jump Landing Performance, and Static and Dynamic Balance in Young Adults With and Without Chronic Ankle Instability?
In some patients, ankle sprains lead to chronic symptoms like pain or muscular weakness called chronic ankle instability (CAI). External ankle supports have shown to be effective in preventing sprains and reducing recurrence, but the underlying mechanisms are unclear. As sensorimotor variables are associated with injury incidence, an influence of external ankle support on landing performance and balance seems plausible. To analyze the effects of an elastic ankle support on jump landing performance and static and dynamic balance in patients with CAI and healthy controls. Crossover study. Functional tests in a laboratory setting. Twenty healthy students and 20 patients with CAI were included for study participation based on their scores in ankle stability and function questionnaires. Healthy and CAI participants performed each test with and without an elastic ankle support. (1) Jump landing performance was measured with the Landing Error Scoring System, (2) static balance was assessed with the Balance Error Scoring System, and (3) dynamic balance was assessed using the Y Balance Test. Linear mixed models were used to analyze the effects of the elastic ankle support on sensorimotor parameters. Healthy controls performed significantly better in the Landing Error Scoring System (P = .01) and Y Balance Test anterior direction (P = .01). No significant effects of elastic ankle support on Landing Error Scoring System, Balance Error Scoring System, or Y Balance Test performance were observed in the CAI or control group. There were no significant group-by-ankle support interactions. In the current study, the acute use of elastic ankle support was ineffective for enhancing jump landing performance, and static and dynamic balance. Further research is needed to identify the underlying mechanisms of the preventive effects of elastic ankle support.


Active sites and mechanisms in the direct conversion of methane to methanol using Cu in zeolitic hosts: a critical examination.
In this critical review we examine the current state of our knowledge in respect of the nature of the active sites in copper containing zeolites for the selective conversion of methane to methanol. We consider the varied experimental evidence arising from the application of X-ray diffraction, and vibrational, electronic, and X-ray spectroscopies that exist, along with the results of theory. We aim to establish both what is known regarding these elusive materials and how they function, and also where gaps in our knowledge still exist, and offer suggestions and strategies as to how these might be closed such that the rational design of more effective and efficient materials of this type for the selective conversion of methane might proceed further.


Persisting immune responses indicating long-term protection after booster dose with meningococcal group B outer membrane vesicle vaccine.
MenBvac is an outer membrane vesicle vaccine against systemic meningococcal disease caused by serogroup B Neisseria meningitidis. In this placebo-controlled double-blind study including 374 healthy adolescents, the safety and immunogenicity of a schedule of three primary doses 6 weeks apart followed by a fourth dose a year later were evaluated. Antibody responses to the vaccine strain and heterologous strains (non-vaccine-type strains) and the persistence of these antibodies were measured by the serum bactericidal assay (SBA) and enzyme-linked immunosorbent assay up to 1 year after the last dose. The proportion of subjects with SBA titers of > or = 4 against the vaccine strain increased from 3% prevaccination to 65% after the third dose. Ten months later, this proportion had declined to 28%. The fourth dose induced a booster response demonstrated by 93% of subjects achieving a titer of > or = 4. One year after the booster dose, 64% still showed SBA titers of > or = 4. Cross-reacting antibodies were induced against all heterologous strains tested, although the magnitude of SBA titers differed widely between the different strains. All four doses of MenBvac were safe. Both MenBvac and the placebo had reactogenicity profiles of mild to moderate local and systemic reactions. Pain, the most common reaction, was reported with similar frequencies in both groups. No serious adverse events occurred in the MenBvac group. This study confirmed the good immunogenicity of the primary course of MenBvac and demonstrated prolonged persistence and increased cross-reactivity of functional antibodies elicited by a booster dose.


Permeability predictions for sand-clogged Portland cement pervious concrete pavement systems.
Pervious concrete is an alternative paving surface that can be used to reduce the nonpoint source pollution effects of stormwater runoff from paved surfaces such as roadways and parking lots by allowing some of the rainfall to permeate into the ground below. This infiltration rate may be adversely affected by clogging of the system, particularly clogging or covering by sand in coastal areas. A theoretical relation was developed between the effective permeability of a sand-clogged pervious concrete block, the permeability of sand, and the porosity of the unclogged block. Permeabilities were then measured for Portland cement pervious concrete systems fully covered with extra fine sand in a flume using simulated rainfalls. The experimental results correlated well with the theoretical calculated permeability of the pervious concrete system for pervious concrete systems fully covered on the surface with sand. Two different slopes (2% and 10%) were used. Rainfall rates were simulated for the combination of direct rainfall (passive runoff) and for additional stormwater runoff from adjacent areas (active runoff). A typical pervious concrete block will allow water to pass through at flow rates greater than 0.2 cm/s and a typical extra fine sand will have a permeability of approximately 0.02 cm/s. The limit of the system with complete sand coverage resulted in an effective system permeability of approximately 0.004 cm/s which is similar to the rainfall intensity of a 30 min duration, 100-year frequency event in the southeastern United States. The results obtained are important in designing and evaluating pervious concrete as a paving surface within watershed management systems for controlling the quantity of runoff.


Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial.
Aside from the multikinase inhibitor sorafenib, there are no effective systemic therapies for the treatment of advanced hepatocellular carcinoma. To assess the efficacy of everolimus in patients with advanced hepatocellular carcinoma for whom sorafenib treatment failed. EVOLVE-1 was a randomized, double-blind, phase 3 study conducted among 546 adults with Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were intolerant of sorafenib. Patients were enrolled from 17 countries between May 2010 and March 2012. Randomization was stratified by region (Asia vs rest of world) and macrovascular invasion (present vs absent). Everolimus, 7.5 mg/d, or matching placebo, both given in combination with best supportive care and continued until disease progression or intolerable toxicity. Per the 2:1 randomization scheme, 362 patients were randomized to the everolimus group and 184 patients to the placebo group. The primary end point was overall survival. Secondary end points included time to progression and the disease control rate (the percentage of patients with a best overall response of complete or partial response or stable disease). No significant difference in overall survival was seen between treatment groups, with 303 deaths (83.7%) in the everolimus group and 151 deaths (82.1%) in the placebo group (hazard ratio [HR], 1.05; 95% CI, 0.86-1.27; P = .68; median overall survival, 7.6 months with everolimus, 7.3 months with placebo). Median time to progression with everolimus and placebo was 3.0 months and 2.6 months, respectively (HR, 0.93; 95% CI, 0.75-1.15), and disease control rate was 56.1% and 45.1%, respectively (P = .01). The most common grade 3/4 adverse events for everolimus vs placebo were anemia (7.8% vs 3.3%, respectively), asthenia (7.8% vs 5.5%, respectively), and decreased appetite (6.1% vs 0.5%, respectively). No patients experienced hepatitis C viral flare. Based on central laboratory results, hepatitis B viral reactivation was experienced by 39 patients (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy. Everolimus did not improve overall survival in patients with advanced hepatocellular carcinoma whose disease progressed during or after receiving sorafenib or who were intolerant of sorafenib. clinicaltrials.gov Identifier: NCT01035229.


Protein synthesis in heterotopically transplanted rat hearts.
This study examines protein synthesis in heterotopically transplanted rat hearts and several tissues of recipient rats. Donor hearts and recipient tissues synthesized many of the normally occurring proteins observed in tissues of unstressed rats. In addition, a stress-induced protein with a molecular mass of 71 kilodaltons was synthesized in donor heart, recipient heart and lung. Donor hearts incorporated more L-[35S]-methionine than did recipient hearts. Tissues of recipient rats also incorporated more label than the respective tissues of sham-recipient rats. These results suggest that ischemia, endured by the donor hearts during transplantation, induced these changes in protein synthesis.


The C-terminal heme regulatory motifs of heme oxygenase-2 are redox-regulated heme binding sites.
Heme oxygenase-2 (HO2), an enzyme that catalyzes the conversion of heme to biliverdin, contains three heme regulatory motifs (HRMs) centered at Cys127, Cys265, and Cys282. Previous studies using the soluble form of human HO2 spanning residues 1-288 (HO2sol) have shown that a disulfide bond forms between Cys265 and Cys282 and that, in this oxidized state, heme binds to the catalytic site of HO2sol via His45. However, various mutational and spectroscopic studies have confirmed the involvement of cysteine in Fe(3+)-heme binding upon reduction of the disulfide bond. In an effort to understand how the HRMs are involved in binding of heme to disulfide-reduced HO2sol, in the work described here, we further investigated the properties of Fe(3+)-heme bound to HO2. Specifically, we investigated binding of Fe(3+)-heme to a truncated form of soluble HO2 (residues 213-288; HO2tail) that spans the C-terminal HRMs of HO2 but lacks the catalytic core. We found that HO2tail in the disulfide-reduced state binds Fe(3+)-heme and accounts for the spectral features observed upon binding of heme to the disulfide-reduced form of HO2sol that cannot be attributed to heme binding at the catalytic site. Further analysis revealed that while HO2sol binds one Fe(3+)-heme per monomer of protein under oxidizing conditions, disulfide-reduced HO2sol binds slightly more than two. Both Cys265 and Cys282 were identified as Fe(3+)-heme ligands, and His256 also acts as a ligand to the Cys265-ligated heme. Additionally, Fe(3+)-heme binds with a much weaker affinity to Cys282 than to Cys265, which has an affinity much weaker than that of the His45 binding site in the catalytic core. In summary, disulfide-reduced HO2 has multiple binding sites with varying affinities for Fe(3+)-heme.


Endothelial-to-mesenchymal transition contributes to fibro-proliferative vascular disease and is modulated by fluid shear stress.
Neointimal hyperplasia is a common feature of fibro-proliferative vascular disease and characterizes initial stages of atherosclerosis. Neointimal lesions mainly comprise smooth muscle-like cells. The presence of these lesions is related to local differences in shear stress. Neointimal cells may arise through migration and proliferation of smooth muscle cells from the media. However, a role for the endothelium as a source of smooth muscle-like cells has largely been disregarded. Here, we investigated the role of endothelial-to-mesenchymal transition (EndMT) in neointimal hyperplasia and atherogenesis, and studied its modulation by shear stress. In human atherosclerotic plaques and porcine aortic tissues, myo-endothelial cells were identified, suggestive for EndMT. Flow disturbance by thoracic-aortic constriction in mice similarly showed the presence of myo-endothelial cells specifically in regions exposed to disturbed flow. While uniform laminar shear stress (LSS) was found to inhibit EndMT, endothelial cells exposed to disturbed flow underwent EndMT, in vitro and in vivo, and showed atherogenic differentiation. Gain- and loss-of-function studies using a constitutive active mutant of MEK5 and short hairpins targeting ERK5 established a pivotal role for ERK5 signalling in the inhibition of EndMT. Together, these data suggest that EndMT contributes to neointimal hyperplasia and induces atherogenic differentiation of endothelial cells. Importantly, we uncovered that EndMT is modulated by shear stress in an ERK5-dependent manner. These findings provide new insights in the role of adverse endothelial plasticity in vascular disease and identify a novel atheroprotective mechanism of uniform LSS, namely inhibition of EndMT.


Protocol for MRI-guided virus injection in macaque deep brain regions.
Effective delivery of viruses into required brain regions is critical to the success of optogenetic or chemogenetic experiments. However, in monkeys, due to the large size and heterogeneity of their brain, precise injections in deep brain regions have been challenging. Here, we present a protocol for virus injection in monkey deep brain regions under the guidance of MRI. We describe the steps for installing the guiding grid, MRI scanning, MRI-based localization, and virus injection. For complete details on the use and execution of this protocol, please refer to Chen et al. (2023).1.


Modulation of Aryl Hydrocarbon Receptor Expression Alleviated Neuropathic Pain in a Chronic Constriction Nerve Injury Animal Model.
Neuropathic pain is well known to occur after damage to the somatosensory system. Aryl hydrocarbon receptor (AhR) has neuroprotective effects when the central nervous system is subjected to internal and external stimulations. However, the exact mechanism by which AhR regulates neuropathic pain is poorly understood. Nerve explant culture and the chronic constrictive nerve injury (CCI) model in wild or AhR-knockout mice were used in this study. In the nerve explant culture, the ovoid number increased in the AhR-/- condition and was decreased by omeprazole (AhR agonist) in a dose-dependent manner. Increased nerve degeneration and the associated inflammation response appeared in the AhR-/- condition, and these changes were attenuated by omeprazole. High expression of AhR in the injured nerve was noted after CCI. Deletion of AhR aggravated nerve damages and this was restored by omeprazole. Deletion of AhR increased NGF expression and reduced axon number in the paw skin, but this was attenuated by omeprazole. A highly expressed inflammation reaction over the dorsal spinal cord, somatosensory cortex, and hippocampus was noted in the AhR-deleted animals. Administration of omeprazole attenuated not only the inflammatory response, but also the amplitude of somatosensory evoked potential. Deletion of AhR further aggravated the neurobehavior compared with the wild type, but such behavior was attenuated by omeprazole. Chronic constrictive nerve injury augmented AhR expression of the injured nerve, and AhR deletion worsened the damage, while AhR agonist omeprazole counteracted such changes. AhR agonists could be potential candidates for neuropathic pain treatment.


Fine-mapping of IgE-associated loci 1q23, 5q31, and 12q13 using 1000 Genomes Project data.
Genome-wide association studies (GWAS) repeatedly identified 1q23 (FCER1A), 5q31 (RAD50-IL13 and IL4), and 12q13 (STAT6) as major susceptibility loci influencing the regulation of total serum IgE levels. As GWAS may be insufficient to capture causal variants, we performed fine-mapping and re-genotyping of the three loci using 1000 Genomes Project datasets. Linkage disequilibrium tagging polymorphisms and polymorphisms of putative functional relevance were genotyped by chip technology (24 polymorphisms) or MALDI-TOF-MS (40 polymorphisms) in at least 1303 German children (651 asthmatics). The effect of polymorphisms on total serum IgE, IgE percentiles, and atopic diseases was assessed, and a risk score model was applied for gene-by-gene interaction analyses. Functional effects of putative causal variants from these three loci were studied in silico. Associations from GWAS were confirmed and extended. For 1q23 and 5q31, the majority of associations were found with mild to moderately elevated IgE levels, while in the 12q13 locus, single-nucleotide polymorphisms (SNPs) were associated with strongly elevated IgE levels. Gene-by-gene interaction analyses suggested that the presence of mutations in all three loci increases the risk for elevated IgE up to fourfold. This fine-mapping study confirmed previous associations and identified novel associations of SNPs in 1q23, 5q31, and 12q13 with different levels of serum IgE and their concomitant contribution to IgE regulation.


[Ethical principles of management and planning during influenza pandemic].
The article is dedicated to an actual problem of ethical component inclusion into the system of management and planning of epidemic control measures during threat emergence and in the course of influenza pandemic (epidemic) progress. Data regarding development of international ethical guidelines during influenza including WHO recommendations are presented and analysis of normative documents in Russian Federation is given. A necessity of comprehension and accounting of ethical values in pandemic preparedness is shown, main directions of action and responsibility are revealed. Key ethical positions of planning and implementation of measures during influenza pandemic are outlined, compliance with those determines the level of public support and thus provides the effectiveness of the implemented measures.


[Study of ocular hemodynamics and general somatic status of patients with primary open-angle glaucoma].
Ocular hemodynamics and general somatic status were studied in 50 patients with primary open-angle glaucoma. Complex ophthalmological and therapeutic examinations were carried out, macro- and microcirculatory hemodynamics of the eye was examined, case histories and therapeutic status of patients were analyzed with due regard for previous local hypotensive and general vascular therapy. Revised recommendations for glaucoma patients aimed at correcting their life style include diet, regular vascular and metabolic therapy, normalization of orbital circulation in order to improve ocular hemodynamics and increase the tolerance of the optic nerve to intraocular pressure fluctuations.


CRISPR multitargeter: a web tool to find common and unique CRISPR single guide RNA targets in a set of similar sequences.
Genome engineering has been revolutionized by the discovery of clustered regularly interspaced palindromic repeats (CRISPR) and CRISPR-associated system genes (Cas) in bacteria. The type IIB Streptococcus pyogenes CRISPR/Cas9 system functions in many species and additional types of CRISPR/Cas systems are under development. In the type II system, expression of CRISPR single guide RNA (sgRNA) targeting a defined sequence and Cas9 generates a sequence-specific nuclease inducing small deletions or insertions. Moreover, knock-in of large DNA inserts has been shown at the sites targeted by sgRNAs and Cas9. Several tools are available for designing sgRNAs that target unique locations in the genome. However, the ability to find sgRNA targets common to several similar sequences or, by contrast, unique to each of these sequences, would also be advantageous. To provide such a tool for several types of CRISPR/Cas system and many species, we developed the CRISPR MultiTargeter software. Similar DNA sequences in question are duplicated genes and sets of exons of different transcripts of a gene. Thus, we implemented a basic sgRNA target search of input sequences for single-sgRNA and two-sgRNA/Cas9 nickase targeting, as well as common and unique sgRNA target searches in 1) a set of input sequences; 2) a set of similar genes or transcripts; or 3) transcripts a single gene. We demonstrate potential uses of the program by identifying unique isoform-specific sgRNA sites in 71% of zebrafish alternative transcripts and common sgRNA target sites in approximately 40% of zebrafish duplicated gene pairs. The design of unique targets in alternative exons is helpful because it will facilitate functional genomic studies of transcript isoforms. Similarly, its application to duplicated genes may simplify multi-gene mutational targeting experiments. Overall, this program provides a unique interface that will enhance use of CRISPR/Cas technology.


Novel RAFT amphiphilic brush copolymer steric stabilisers for cubosomes: poly(octadecyl acrylate)-block-poly(polyethylene glycol methyl ether acrylate).
Copolymers, particularly Pluronics®, are typically used to sterically stabilise colloidal nanostructured particles composed of a lyotropic liquid crystalline bicontinuous cubic phase (cubosomes). There is a need to design and assess new functionalisable stabilisers for these colloidal drug delivery systems. Six amphiphilic brush copolymers, poly(octadecyl acrylate)-block-poly(polyethylene glycol methyl ether acrylate) (P(ODA)-b-P(PEGA-OMe)), synthesised by reversible addition-fragmentation chain transfer (RAFT), were assessed as novel steric stabilisers for cubosomes. It was found that increasing the density of PEG on the nanostructured particle surface by incorporating a PEG brush design (i.e., brush copolymer), provided comparable and/or increased stabilisation effectiveness compared to a linear PEG structure, Pluronic® F127, which is extensively used for steric stabilisation of cubosomes. Assessment was conducted both prior to and following the removal of the dodecyl trithiocarbonate end-group, by free radical-induced reduction. The reduced (P(ODA)-b-P(PEGA-OMe) copolymers were more effective steric stabilisers for phytantriol and monoolein colloidal particle dispersions than their non-reduced analogues. High throughput characterisation methodologies, including an accelerated stability assay (ASA) and synchrotron small angle X-ray scattering (SAXS), were implemented in this study for the rapid assessment of steric stabiliser effectiveness and lyotropic liquid crystalline phase identification. Phytantriol cubosomes stabilised with P(ODA)-b-P(PEGA-OMe) copolymers exhibited a double diamond cubic phase (Q(2)(D)), whilst monoolein cubosomes exhibited a primitive cubic phase (Q(2)(P)), analogous to those formed using Pluronic® F127.


Total rehabilitation of maxilla using a tooth-to-implant restoration: case report.
Dental implants in partially edentulous patients are a predictable therapeutic option. However, using tooth-to-implant restorations to rehabilitate partially edentulous patients involves highly complex biomechanical aspects. This type of prosthesis utilizes different kinds of support that react distinctly to the functional forces developed in the oral cavity. In some cases, a tooth-to-implant restoration is a treatment option for difficulties related to reduced bone volume, inadequate interdental space, or an implant's failure to osseointegrate. This case report describes the rehabilitation of a patient whose partially edentulous maxilla was treated with a tooth-to-implant restoration. In this case, telescopic crowns were used to better match the tooth-implant union. No biomechanical or functional problems were found 8 years post-treatment, indicating that the combination of implant and tooth support is a possible treatment option with an improved long-term prognosis.


Predictors risk factors for acute complex appendicitis pain in patients: Are there gender differences?
The purpose of this study is to determine the predictive risk factors for appendicitis and the cost-effectiveness of using abdominal helical computed tomography (CT) in comparison to abdominal ultrasonography (US) for the diagnosis of acute appendicitis in patients. The typical case was a patient with abdominal pain in the right lower quadrant and suspicion of appendicitis. A total of 643 patients who were consequently treated with appendectomy upon diagnosis of acute appendicitis between January 2015 and December 2018 were included in the study. The four diagnostic alternatives chosen were US, CT, biochemistry parameters, and physical examination in the hospital. There were statistically significant differences between male and female patients with regards to age, BMI, cigarette smoking, sheesha smoking, family history of diabetes, hypertension and family history of gastrointestinal discomfort (GI), anxiety (P < 0.001), red eye (P = 0.006), dizziness (P = 0.021), headache (P < 0.001), muscular symptoms, weakness and cramps (P < 0.001), bloating or swollen stomach (P < 0.001), UTI (P < 0.001), chest pain (P < 0.001), guarding (P < 0.001), loss of appetite (P = 0.004), nausea (P < 0.001) vomiting (P = 0.042), anorexia (P = 0.009), and constipation (P = 0.002). Moreover, there were statistically significant differences between male and female patients for pain (P < 0.001), pain right belly (P = 0.027), severe crumps (P = 0.007), high temperature and fever (P < 0.001), irritable bowel syndrome (P < 0.001), right iliac fossa (RIF) pain (P = 0.008), rebound tenderness (P = 0.024), positive bowel sounds (P = 0.029), and pointing tenderness (P < 0.001). Multivariate stepwise logistic regression showed nausea (P < 0.001), C-reactive protein (CRP) (P < 0.001), dizziness (P = 0.016), vomiting (P < 0.001), muscular symptoms (P = 0.007), irritable bowel syndrome (P = 0.034), guarding (P = 0.040), and loss appetite (P = 0.046) were considered at higher risk as predictors for appendicitis patients. CT is more cost-effective than the US and clinical examination for determining appendicitis. The current study suggested that nausea, C-reactive protein, dizziness, vomiting, muscular symptoms, irritable bowel syndrome, guarding, and loss appetite were considered as higher risk predictors for appendicitis patients.


Postepidemic analysis of Rift Valley fever virus transmission in northeastern kenya: a village cohort study.
In endemic areas, Rift Valley fever virus (RVFV) is a significant threat to both human and animal health. Goals of this study were to measure human anti-RVFV seroprevalence in a high-risk area following the 2006-2007 Kenyan Rift Valley Fever (RVF) epidemic, to identify risk factors for interval seroconversion, and to monitor individuals previously exposed to RVFV in order to document the persistence of their anti-RVFV antibodies. We conducted a village cohort study in Ijara District, Northeastern Province, Kenya. One hundred two individuals tested for RVFV exposure before the 2006-2007 RVF outbreak were restudied to determine interval anti-RVFV seroconversion and persistence of humoral immunity since 2006. Ninety-two additional subjects were enrolled from randomly selected households to help identify risk factors for current seropositivity. Overall, 44/194 or 23% (CI(95%):17%-29%) of local residents were RVFV seropositive. 1/85 at-risk individuals restudied in the follow-up cohort had seroconverted since early 2006. 27/92 (29%, CI(95%): 20%-39%) of newly tested individuals were seropositive. All 13 individuals with positive titers (by plaque reduction neutralization testing (PRNT₈₀) in 2006 remained positive in 2009. After adjustment in multivariable logistic models, age, village, and drinking raw milk were significantly associated with RVFV seropositivity. Visual impairment (defined as ≤ 20/80) was much more likely in the RVFV-seropositive group (P<0.0001). Our results highlight significant variability in RVFV exposure in two neighboring villages having very similar climate, terrain, and insect density. Among those with previous exposure, RVFV titers remained at > 1∶40 for more than 3 years. In concordance with previous studies, residents of the more rural village were more likely to be seropositive and RVFV seropositivity was associated with poor visual acuity. Raw milk consumption was strongly associated with RVFV exposure, which may represent an important new focus for public health education during future RVF outbreaks.


Exposure to PM2.5 during pregnancy causes lung inflammation in the offspring: Mechanism of action of mogrosides.
Epidemiological and toxicological studies have demonstrated that exposure to fine particulate matter (PM2.5) during pregnancy is harmful to the tissues of the offspring. However, the mechanism by which PM2.5 exposure causes lung damage in the offspring or potential dietary therapy for this condition remains unclear. Mogrosides (MGs) are derived from the traditional plant Siraitia grosvenorii and are used medicinally, where they can moisten the lungs and relieve coughing. In this study, pregnant rats were exposed to PM2.5 by intratracheal instillation and treated with MGs by gavage to model the effect of PM2.5 in the offspring and the interventional effect of MGs on lung tissue. We then used transcriptomics, metabolomics, and RT-qPCR as tools to look for metabolite and genetic changes in the offspring. We found that when compared to the control group, the mRNA levels of the inflammatory mediator Pla2g2d and the metabolites lysophosphatidylcholines (LysoPCs) and arachidonic acid (AA) were up-regulated in the lung tissues of PM2.5 group. In contrast, these inflammatory changes were restored after treatment with MGs during pregnancy. In addition, the levels of AA, LPC 15:0 and LPC 18:0 were elevated in the PM2.5 group compared with control group. This increase was inhibited by co-administration of MGs. The change of PGA1 was adverse. In conclusion, even a relatively low exposure to PM2.5 in rats during pregnancy produces inflammation in the lungs of the male offspring, and an intervention with MGs could significantly alleviate this effect. Furthermore, Pla2g2d may represent a potential target for MGs resulting in the improvement of PM2.5-induced lung injury.


The enterprise of synthesis: from concept to practice.
A retrospective account of natural products synthesis adopting the Chiral Synthon (Chiron) Approach and spanning nearly 50 years of personal research activity is presented highlighting the interplay between the eye and the mind's eye. Synthesis planning is discussed in terms of visual relational and visual reflexive thinking modalities relying on the recognition of naturally occurring nonracemic starting materials such as amino acids, carbohydrates, hydroxy acids, and terpenes in the carbon framework of target molecules. Lessons learned and synthetic methods developed are discussed in the context of selected natural products covered in this Perspective.


Primary or Delayed Repair for Complete Atrioventricular Septal Defect, Tetralogy of Fallot, and Ventricular Septal Defect: Relationship to Country Economic Status.
Primary repair in the first six months of life is routine for tetralogy of Fallot, complete atrioventricular septal defect, and ventricular septal defect in high-income countries. The objective of this analysis was to understand the utilization and outcomes of palliative and reparative procedures in high versus middle-income countries. The World Database of Pediatric and Congenital Heart Surgery identified patients who underwent surgery for: tetralogy of Fallot, complete atrioventricular septal defect, and ventricular septal defect. Patients were categorized as undergoing primary repair, repair after prior palliation, or palliation only. Country economic status was categorized as lower middle, upper middle, and high, defined by the World Bank. Multiple logistic regression models were utilized to identify independent predictors of hospital mortality. Economic categories included high (n = 571, 5.3%), upper middle (n = 5,342, 50%), and lower middle (n = 4,793, 49.7%). The proportion of patients and median age with primary repair were: tetralogy of Fallot, 88.6%, 17.7 months; complete atrioventricular septal defect, 83.4%, 7.7 months; and ventricular septal defect, 97.1%, ten months. Age at repair was younger in high income countries (P < .0001). Overall mortality after repair was lowest in high income countries. Risk factors for hospital mortality included prematurity, genetic syndromes, and urgent or emergent operations (all P < .05). Primary repair was selected in >90% of patients, but definitive repair was delayed in lower and upper middle income countries compared with high-income countries. Repair after prior palliation versus primary repair was not a risk factor for hospital mortality. Initial palliation continues to have a small but important role in the management of these three specific congenital heart defects.


Social work and the house of Islam: orienting practitioners to the beliefs and values of Muslims in the United States.
Despite the media attention focused on the Islamic community after the terrorist attacks on the World Trade Center on September 11, 2001, Muslims remain one of the most misunderstood populations in the United States. Few articles have appeared in the social work literature orienting practitioners to the Islamic community, and much of the mainstream media coverage misrepresents the population. This article reviews the basic beliefs, practices, and values that commonly characterize, or inform, the House of Islam in the United States. The organizations that embody and sustain the Muslim communities that constitute the House of Islam are profiled, and areas of possible value conflicts are examined. The article concludes by offering suggestions for integrating the article's themes into practice settings. Particular attention is given to enhancing cultural competence and to suggestions for spiritual assessment and interventions.


Two modes of cell death caused by exposure to nanosecond pulsed electric field.
High-amplitude electric pulses of nanosecond duration, also known as nanosecond pulsed electric field (nsPEF), are a novel modality with promising applications for cell stimulation and tissue ablation. However, key mechanisms responsible for the cytotoxicity of nsPEF have not been established. We show that the principal cause of cell death induced by 60- or 300-ns pulses in U937 cells is the loss of the plasma membrane integrity ("nanoelectroporation"), leading to water uptake, cell swelling, and eventual membrane rupture. Most of this early necrotic death occurs within 1-2 hr after nsPEF exposure. The uptake of water is driven by the presence of pore-impermeable solutes inside the cell, and can be counterbalanced by the presence of a pore-impermeable solute such as sucrose in the medium. Sucrose blocks swelling and prevents the early necrotic death; however the long-term cell survival (24 and 48 hr) does not significantly change. Cells protected with sucrose demonstrate higher incidence of the delayed death (6-24 hr post nsPEF). These cells are more often positive for the uptake of an early apoptotic marker dye YO-PRO-1 while remaining impermeable to propidium iodide. Instead of swelling, these cells often develop apoptotic fragmentation of the cytoplasm. Caspase 3/7 activity increases already in 1 hr after nsPEF and poly-ADP ribose polymerase (PARP) cleavage is detected in 2 hr. Staurosporin-treated positive control cells develop these apoptotic signs only in 3 and 4 hr, respectively. We conclude that nsPEF exposure triggers both necrotic and apoptotic pathways. The early necrotic death prevails under standard cell culture conditions, but cells rescued from the necrosis nonetheless die later on by apoptosis. The balance between the two modes of cell death can be controlled by enabling or blocking cell swelling.


Mental vulnerability as a predictor of early mortality.
Studies have demonstrated that mental vulnerability (ie, a tendency to experience psychosomatic symptoms or inadequate interpersonal interactions) is associated with various diseases. The objective of our study is to evaluate whether mental vulnerability is a risk factor for early mortality. We conducted a prospective cohort study of 3 random samples of the population in Copenhagen County, Denmark selected in 1976, 1982-1984, and 1991 (n = 6435). Baseline data collection included measures of mental vulnerability, social factors, comorbidity, biologic risk markers (eg, blood pressure, lipid levels), and lifestyle factors. We determined vital status of the study sample through linkage to the Civil Registration System until 2001 and to the Cause of Death Registry until 1998. The mean follow-up time was 15.9 years for analysis of total mortality and 13.6 years for analysis of mortality as the result of natural causes. The association between mental vulnerability and survival was examined using Kaplan-Meir plots and Cox proportional-hazard models adjusting for possible confounding factors. With respect to mental vulnerability, 79% of the sample was classified as not vulnerable, 13% as moderately vulnerable, and 8% as highly vulnerable. Compared with the nonvulnerable group, highly vulnerable persons showed increased total mortality (hazard ratio = 1.6; 95% confidence interval = 1.3-1.9) and increased mortality from natural causes (1.6; 1.2-2.0). The inclusion of the mental vulnerability score as a continuous variable gave similar results. Mental vulnerability may be an independent risk factor for premature mortality. The biologic mechanisms that may underlie this association need further exploration.


Cancer incidence in Gipuzkoa, Spain (1998-2002), and time trends from 1986.
To determine the cancer incidence in Gipuzkoa (Spain) from 1998 to 2002 and describe time trends since 1986. The annual incidence of cancer in Gipuzkoa from 1998 to 2002 was estimated as a rate per 100,000 inhabitants. Incidence trends for the period 1986-2002 were studied for all cancers and for the main cancer sites using Poisson regression and Joinpoint regression for prostate tumours. On average, one in 3 men and one in 5 women would probably be diagnosed with cancer at some time during their life (0-74 years). Among men, prostate surpassed lung as the most frequent cancer site. Among women, breast cancer represented approximately 30% of all cases of cancer (excluding non-melanoma skin cancers). There was an annual increase in the incidence of cancer of 1.5% (95% CI, 1.1-1.8) in men and 0.9% (95% CI, 0.5-1.3) in women. The incidence of prostate cancer in men increased over the study period, and especially between 1996 and 1999, with an annual increase of 34.7% (95% CI, 5.9-71.5). The incidence of lung cancer in women presented an annual increase of 5.2% (95% CI, 3.4-7.1). In contrast, the incidence of stomach cancer decreased during the study period. Cancer incidence in Gipuzkoa increased during the study period. This increase was particularly marked in lung cancer and skin melanoma, for which preventive strategies are fundamental.


Insights into microbial diversity in wastewater treatment systems: How far have we come?
Biological wastewater treatment processes are based on the exploitation of the concerted activity of microorganisms. Knowledge on the microbial community structure and the links to the changing environmental conditions is therefore crucial for the development and optimization of biological systems by engineers. The advent of molecular techniques occurred in the last decades quickly showed the inadequacy of culture-dependent methodologies to unveil the great level of diversity present in sludge samples. Initially, culture-independent technologies and more recently the application of -omics in wastewater microbiology, have drawn a new view of microbial diversity and function of wastewater treatment systems. This article reviews the current knowledge on the topic placing emphasis on crucial microbial processes carried out in biological wastewater treatment systems driven by specific groups of microbes, such as nitrogen and phosphorus removal bacteria, filamentous and electrogenic microorganisms, as well as Archaea. Despite the recent -omics has offered substantial insights into the diversity and ecophysiology of these bacteria never envisioned before by providing millions of sequence reads at an unprecedented scale, studies based on high-throughput sequencing are still scarce. In order to obtain significant gains in the analysis of structure-function relationships, a greater sequencing investment is needed, particularly to uncover gene expression patterns of functionally relevant genes.


Psychometric properties of the Brazilian version of the Difficulties in Emotion Regulation Scale (DERS).
Emotion regulation can be defined as the process by which individuals manage their emotional experience. It has been demonstrated that deficits in this ability are associated with various psychiatric disorders. In this direction, the Difficulties in Emotion Regulation Scale (DERS) was developed to measure difficulties in emotion regulation. To examine the psychometric properties of the Brazilian Portuguese version of the DERS. A total of 377 individuals from the general population, selected by convenience, completed a sociodemographic form, the adapted Brazilian Portuguese DERS and the Depression Anxiety Stress Scale (DASS-21). Factor structure, reliability, and concurrent validity of the adapted version of the instrument were investigated. The confirmatory factor analysis replicated the six-factor structure originally proposed for the instrument and confirmed the acceptability of a hierarchical model where all DERS subscales loaded on a general emotion dysregulation factor. Internal consistency indicators had adequate values for the general factor and subscales. The positive association between DERS and DASS-21 scores supports the instrument's concurrent validity. These results suggest that the Brazilian version of the DERS is reliable both as a general measure of difficulties in emotion regulation and as a measure of the constituents of this construct. Future research should investigate the psychometric properties of the scale in clinical and nonclinical populations, with equal gender proportions and diverse backgrounds, and preferably employing longitudinal designs.


C/EBP-delta induction by gp130 signaling. Role in transition to myelin gene expressing phenotype in a melanoma cell line model.
Expression of genes encoding structural myelin proteins marks the inception of the myelinating Schwann cell (SC) phenotype. Earlier embryonic SC as well as adult non-myelinating SC produce the intermediate filament glial fibrillary acid protein (GFAP), which disappears from the myelinating SC. We previously observed that triggering of the gp130 receptor system by the IL6RIL6 ligand, comprising interleukin-6 (IL-6) fused to the soluble IL-6 receptor, induces myelin gene expression in rat embryonic dorsal root ganglia (DRG) cultures as well as in the murine melanoma cell line B16/F10.9. Study of target genes regulated by IL6RIL6 indicates a strong and selective induction of the transcriptional regulator C/EBP-delta in DRG cultures and in the F10.9 cell line. As shown here, silencing of C/EBP-delta mRNA and protein expression by introduction of small interference RNA-producing plasmids in the F10.9 cells prevented the induction of myelin protein zero (P0) and myelin basic protein (MBP) mRNAs by IL6RIL6. Doxycycline-regulated overexpression of C/EBP-delta was sufficient to induce accumulation of P0 and MBP mRNAs, the effect being selective, because C/EBP-delta did not affect several other genes strongly regulated by IL6RIL6. Interestingly, GFAP was inhibited by C/EBP-delta overexpression, leading to a modulation of the ratio between myelin gene products versus GFAP and suggesting that C/EBP-delta plays a role in the switch to a myelinating phenotype. The down-regulation of Pax3, also typical of the transition to myelinating cells, was observed after C/EBP-delta expression in correlation to P0 induction and to decrease of melanogenesis and cell growth. In cultures of dissociated cells of embryonic rat DRG, where we knocked-down the C/EBP-delta mRNA, we found an inhibition of P0 mRNA induction by IL6RIL6, showing that the role of C/EBP-delta on this myelin gene is not unique to the melanoma system.


Determining optimal COVID-19 testing center locations and capacities.
We study the problem of determining the locations and capacities of COVID-19 specimen collection centers to efficiently improve accessibility to polymerase chain reaction testing during surges in testing demand. We develop a two-echelon multi-period location and capacity allocation model that determines optimal number and locations of pop-up testing centers, capacities of the existing centers as well as assignments of demand regions to these centers, and centers to labs. The objective is to minimize the total number of delayed appointments and specimens subject to budget, capacity, and turnaround time constraints, which will in turn improve the accessibility to testing. We apply our model to a case study for locating COVID-19 testing centers in the Region of Waterloo, Canada using data from the Ontario Ministry of Health, public health databases, and medical literature. We also test the performance of the model under uncertain demand and analyze its outputs under various scenarios. Our analyses provide practical insights to the public health decision-makers on the timing of capacity expansions and the locations for the new pop-up centers. According to our results, the optimal strategy is to dynamically expand the existing specimen collection center capacities and prevent bottlenecks by locating pop-up facilities. The optimal locations of pop-ups are among the densely populated areas that are in proximity to the lab and a subset of those locations are selected with the changes in demand. A comparison with a static approach promises up to 39% cost savings under high demand using the developed multi-period model.


Signatures of balancing selection in toll-like receptor (TLRs) genes - novel insights from a free-living rodent.
Selective pressure from pathogens is considered a key selective force driving the evolution of components of the immune system. Since single components of the immune system may interact with many pathogens, and single pathogens may be recognized by multiple components of the immune system, gaining a better understanding of the mechanisms of parasite-driven selection requires the study of multiple genes and pathogens. Toll-like receptors (TLRs) are a large gene family that code for antigen-presenting components of the innate immune response. In the present paper we characterize polymorphism and signatures of selection in seven TLRs in free-living bank voles Myodes glareolus. We report the first evidence of balancing selection in several TLR genes, supported by positive values of Fu and Li's D* in TLR2 and TLR5, and positive values of Tajima's D in LRR regions within TLR1 and TLR2. We further found significant associations between amino-acid alleles of TLR1 and TLR5 and susceptibility to infection with the blood pathogen Bartonella. Interestingly, selection patterns in TLRs presenting virus-derived motifs (TLR7 and TLR9) differed considerably from those interacting with bacterial PAMPs. In contrast to the highly variable TLRs presenting bacterial motifs, TLR7 and TLR9 had low polymorphism and displayed signatures of directional selection. These findings suggest different functional responses across the TLR gene family and highlight the complexity of parasite-driven selection.


[Establishment of a scoring system for predicting the positive rate of prostatic biopsy for prostate cancer].
To identify the predictors of the positive results of transrectal ultrasound (TRUS)-guided biopsy for prostate cancer. We performed univariate and multivariate logistic regression analyses on the relevant data on 385 male patients that underwent TRUS-guided biopsy for prostate cancer, including such potential predictors as age, body mass index (BMI), symptoms, results of digital rectal examination (DRE), tPSA, fPSA, free/total PSA ratio (f/tPSA), prostate volume (PV), and PSA density (PSAD) for identification of the risk factors related to the positive rate of biopsy. Then we constructed a scoring system as a tool for predicting prostate cancer in repeat biopsies and determined the sensitivity of the system by calculating the false positive rate using the receiver operating characteristic curve. Among the 385 patients, 139 (36.1%) were diagnosed with prostate cancer. On multivariate analysis, age (P < 0.01), DRE (P < 0.01), tPSA (P < 0.01), fPSA (P < 0.01), f/tPSA (P < 0.01), PV (P < 0.01), and PSAD (P < 0.01) were all significant predictors of prostate cancer. Multivariate logistic regression analysis showed age, tPSA, f/tPSA, PV, and PSAD to be independent predictors, with ORs and 95% CIs of 1.07 (1.05-1.16), 1.05 (1.02-1.15), 0.97 (0.86-0.99), 0.98 (0.87-0.96), and 1.79 (1.48-2.06), respectively. Moreover, patients with the risk score of 3-5 had a significantly higher rate of prostate cancer than those with 0-2 (64% vs 11%, P < 0.001). The scoring system on the key predictors of prostate cancer can help urologists to identify the men in need of prostatic biopsy.


Pathological gamblers demonstrate frontal lobe impairment consistent with that of methamphetamine-dependent individuals.
Using tests that are frequently administered by neuropsychologists, the authors investigated whether pathological gambling is associated with frontal lobe abnormalities. The sample comprised 10 pathological gamblers, 25 methamphetamine-dependent subjects, and 19 matched comparison subjects. The pathological gamblers and methamphetamine-dependent subjects performed significantly less well than comparison subjects, and the gamblers' test scores were comparable to those of the methamphetamine-dependent participants. The overall magnitude of the effect size was large. These findings demonstrate that the severity of frontal lobe dysfunction in pathological gambling is similar to that observed in methamphetamine-dependent individuals on frequently used clinical measures.


Oral eltrombopag for up to three years is safe and well-tolerated in Japanese patients with previously treated chronic immune thrombocytopenia: an open-label, extension study.
Eltrombopag is an oral, nonpeptide, thrombopoietin receptor agonist approved for treatment of chronic immune thrombocytopenia (ITP). The safety, tolerability, and efficacy of eltrombopag for up to 3 years were evaluated in 19 Japanese patients with chronic ITP who had completed a prior 6-month study. Patients received eltrombopag once daily at the last dosage received in the prior study (12.5, 25, or 50 mg). Dose adjustments and treatment interruptions were permitted to maintain platelet counts of 50,000-200,000/μL. Primary evaluations were safety and tolerability of long-term eltrombopag treatment. The median duration of exposure was 27.5 months (range, 9.9-32.3). Adverse events were similar to those reported with short-term use of eltrombopag, and none led to treatment discontinuation. Nine serious adverse events were reported. Median platelet counts began to increase after 1 week of treatment and remained above 50,000/μL for most assessments. Bleeding episodes decreased from 63 % at baseline to 21 % after 2 weeks of treatment and remained below baseline for all assessments. Of 15 patients receiving concomitant baseline ITP medications, 10 permanently discontinued or achieved a sustained reduction of at least one treatment without requiring rescue treatment. Long-term treatment with eltrombopag was safe, well tolerated, and effective in Japanese patients with chronic ITP.


A morphological algorithm for measuring angle of airway branches in lung CT images.
Accurate measurement of human airway lumen bifurcation angle in the bronchial tree may be an important parameter for evidence of pulmonary diseases. Here, we describe a new method for recognizing and following airway bifurcation over numerous contiguous CT images. Based on morphological properties of airways and specific changes to airway properties while digitally navigating through the bifurcation, our method is able to track airways through several levels of bifurcation. Then, based on the center of the lumen area, determined by the level set segmentation algorithm, we estimate the centerline of each branch and calculate the angle between two bifurcating branches. By applying this method to an airway imaging phantom, we obtained accurate results in a short computational time. This new approach provides a rapid, automated, and accurate lung airway angle measurement and may prove useful to radiologists who use CT images for pulmonary disease assessment.


Targeting Piezo1 unleashes innate immunity against cancer and infectious disease.
Piezo1 is a mechanosensitive ion channel that has gained recognition for its role in regulating diverse physiological processes. However, the influence of Piezo1 in inflammatory disease, including infection and tumor immunity, is not well studied. We postulated that Piezo1 links physical forces to immune regulation in myeloid cells. We found signal transduction via Piezo1 in myeloid cells and established this channel as the primary sensor of mechanical stress in these cells. Global inhibition of Piezo1 with a peptide inhibitor was protective against both cancer and septic shock and resulted in a diminution in suppressive myeloid cells. Moreover, deletion of Piezo1 in myeloid cells protected against cancer and increased survival in polymicrobial sepsis. Mechanistically, we show that mechanical stimulation promotes Piezo1-dependent myeloid cell expansion by suppressing the retinoblastoma gene Rb1 We further show that Piezo1-mediated silencing of Rb1 is regulated via up-regulation of histone deacetylase 2. Collectively, our work uncovers Piezo1 as a targetable immune checkpoint that drives immunosuppressive myelopoiesis in cancer and infectious disease.


The Role of Endoplasmic Reticulum Stress-Glycogen Synthase Kinase-3 Signaling in Atherogenesis.
Cardiovascular disease (CVD) is the number one cause of global mortality and atherosclerosis is the underlying cause of most CVD. However, the molecular mechanisms by which cardiovascular risk factors promote the development of atherosclerosis are not well understood. The development of new efficient therapies to directly block or slow disease progression will require a better understanding of these mechanisms. Accumulating evidence supports a role for endoplasmic reticulum (ER) stress in all stages of the developing atherosclerotic lesion however, it was not clear how ER stress may contribute to disease progression. Recent findings have shown that ER stress signaling through glycogen synthase kinase (GSK)-3α may significantly contribute to macrophage lipid accumulation, inflammatory cytokine production and M1macrophage polarization. In this review we summarize our knowledge of the potential role of ER stress-GSK3 signaling in the development and progression of atherosclerosis as well as the possible therapeutic implications of this pathway.


Factors influencing the behaviour and perceptions of Australian veterinarians towards antibiotic use and antimicrobial resistance.
Antimicrobial resistance (AMR) is a global crisis with impacts on the future health and welfare of humans and animals. Determining key factors that influence veterinarians' antimicrobial prescribing behaviours can bridge the gap between prescribing guidelines and clinical usage. Veterinarians practicing in Australia were surveyed on their frequency in prescribing different antibiotics; factors influencing their antibiotic prescribing behaviours; and their perceptions of current drivers of AMR. Antibiotics were prescribed in a third of consultations with key differences in the frequency of use of specific antibiotics by small companion animal (SCA), equine and livestock veterinarians, which broadly aligned with antibiotic registration restrictions in Australia. SCA veterinarians reported prescribing broad-spectrum antibiotics of higher importance to human health more frequently than livestock veterinarians. Factors that were reported as 'strong' or 'moderate' barriers to appropriate antibiotic prescribing were the 1) cost of culture and susceptibility testing and 2) lack of access to rapid and affordable diagnostic tests. Fear of losing clients, colleague pressure, and lack of their own understanding about antibiotics were considered to be 'no' or 'somewhat' of a barrier to appropriate prescribing by respondents. SCA veterinarians placed greater importance on the contribution of antibiotic use in livestock to AMR, than antibiotic use in companion animals. Despite reporting use of fewer, mostly narrow spectrum antibiotics of lower importance to human and animal health, livestock veterinarians were generally more aware of their potential contribution to AMR. This study provides insights into the similarities and differences in SCA, equine and livestock veterinarians practicing in Australia and informs sector-specific strategies to improve antimicrobial stewardship.


Understanding the Biomineralization Role of Magnetite-Interacting Components (MICs) From Magnetotactic Bacteria.
Biomineralization is a process that takes place in all domains of life and which usually helps organisms to harden soft tissues by creating inorganic structures that facilitate their biological functions. It was shown that biominerals are under tight biological control via proteins that are involved in nucleation initiation and/or which act as structural skeletons. Magnetotactic bacteria (MTB) use iron biomineralization to create nano-magnetic particles in a specialized organelle, the magnetosome, to align to the geomagnetic field. A specific set of magnetite-associated proteins (MAPs) is involved in regulating magnetite nucleation, size, and shape. These MAPs are all predicted to contain specific 17-22 residue-long sequences involved in magnetite formation. To understand the mechanism of magnetite formation, we focused on three different MAPs, MamC, Mms6 and Mms7, and studied the predicted iron-binding sequences. Using nuclear magnetic resonance (NMR), we differentiated the recognition mode of each MAP based on ion specificity, affinity, and binding residues. The significance of critical residues in each peptide was evaluated by mutation followed by an iron co-precipitation assay. Among the peptides, MamC showed weak ion binding but created the most significant effect in enhancing magnetite particle size, indicating the potency in controlling magnetite particle shape and size. Alternatively, Mms6 and Mms7 had strong binding affinities but less effect in modulating magnetite particle size, representing their major role potentially in initiating nucleation by increasing local metal concentration. Overall, our results explain how different MAPs affect magnetite synthesis, interact with Fe2+ ions and which residues are important for the MAPs functions.


Effects of repeated administration of propentofylline on memory impairment produced by basal forebrain lesion in rats.
The effects of repeated propentofylline administration on impairments of learning and memory in rats with basal forebrain lesions were investigated in several behavioral tasks (water maze, habituation and passive avoidance tasks). Rats were subjected to all the tasks in sequence. Basal forebrain lesions produced by bilateral injections of ibotenic acid (approximately 6 micrograms on each side) severely impaired performance in water maze, habituation and passive avoidance tasks. Repeated administration of propentofylline (10 and 25 mg/kg per day for 14 days, p.o.) improved the deficits of performance in a water maze task, even when administration began one week after the basal forebrain lesions were produced. The impaired performance in habituation and passive avoidance tasks was also markedly ameliorated after repeated administration (24 and 26 days) of propentofylline. The rats with basal forebrain lesions exhibited a significant decrease in choline acetyltransferase activity in the cortex. Propentofylline significantly increased hippocampal choline acetyltransferase activity in basal forebrain-lesioned rats compared with that in vehicle-treated basal forebrain-lesioned rats. However, cortical choline acetyltransferase activity in basal forebrain-lesioned animals was not affected by repeated propentofylline administration. These results indicate that repeated administration of this agent ameliorated the impaired performance of basal forebrain-lesioned rats in part by increasing hippocampal choline acetyltransferase activity. Propentofylline might be useful for the treatment of amnesia and dementia.


Combining antibody markers for serosurveillance of SARS-CoV-2 to estimate seroprevalence and time-since-infection.
Serosurveillance is an important epidemiologic tool for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), used to estimate infection rates and the degree of population immunity. There is no general agreement on which antibody biomarker(s) should be used, especially with the rollout of vaccines globally. Here, we used random forest models to demonstrate that a single spike or receptor-binding domain (RBD) antibody was adequate for classifying prior infection, while a combination of two antibody biomarkers performed better than any single marker for estimating time-since-infection. Nucleocapsid antibodies performed worse than spike or RBD antibodies for classification, but can be useful for estimating time-since-infection, and in distinguishing infection-induced from vaccine-induced responses. Our analysis has the potential to inform the design of serosurveys for SARS-CoV-2, including decisions regarding a number of antibody biomarkers measured.


Incorporating conditional random fields and active learning to improve sentiment identification.
Many machine learning, statistical, and computational linguistic methods have been developed to identify sentiment of sentences in documents, yielding promising results. However, most of state-of-the-art methods focus on individual sentences and ignore the impact of context on the meaning of a sentence. In this paper, we propose a method based on conditional random fields to incorporate sentence structure and context information in addition to syntactic information for improving sentiment identification. We also investigate how human interaction affects the accuracy of sentiment labeling using limited training data. We propose and evaluate two different active learning strategies for labeling sentiment data. Our experiments with the proposed approach demonstrate a 5%-15% improvement in accuracy on Amazon customer reviews compared to existing supervised learning and rule-based methods.


Adrenal cortical carcinoma metastatic to the brain in a child.
A 9-year-old girl presented with profoundly decreased vision in both eyes and bilateral optic disc swelling. Magnetic resonance imaging showed a large intraventricular mass. Excisional biopsy diagnosed metastatic adrenal cortical carcinoma (ACC). This is, to the best of our knowledge, the first reported case of ACC metastatic to the brain in a child. It also illustrates the importance of differentiating optic neuritis from papilledema in children.


Spatial Dynamic Functional Connectivity Analysis Identifies Distinctive Biomarkers in Schizophrenia.
Dynamic functional network connectivity (dFNC) analysis is a widely-used to study associations between dynamic functional correlations and cognitive abilities. Traditional methods analyze time-varying association of different spatial networks while assuming that the spatial network itself is stationary. However, there has been very little work focused on voxelwise spatial variability. Exploiting the variability across both the temporal and spatial domains provide a more promising direction to obtain reliable dynamic functional patterns. However, methods for extracting time-varying spatio-temporal patterns from large-scale functional magnetic resonance imaging (fMRI) data present some challenges, such as degradation in performance with respect to increase in size of the data, estimation of the number of dynamic components, and the potential sensitivity of the resulting dFNCs to selection of the networks. In this work, we implement subsequent extraction of exemplars and dynamics using a constrained independent vector analysis, a data-driven method that efficiently estimates spatial and temporal dynamics from large-scale resting-state fMRI data. We explore the benefits of analyzing spatial dFNC (sdFNC) patterns over temporal dFNC (tdFNC) patterns in the context of differentiating healthy controls and patients with schizophrenia. Our results indicate that for resting-state fMRI data, sdFNC patterns were able to better classify patients and controls, and yield more distinguishing features compared with tdFNC patterns. We also estimate structured patterns of connectivity/states using sdFNC patterns, an area that has not been studied so far, and observe that sdFNC was able to successfully capture distinct information from healthy controls and patients with schizophrenia. In addition, sdFNC patterns were also able to identify functional patterns that associate with signs of paranoia and abnormalities in the patients group. We also observe that patients with schizophrenia tend to switch to or stay in a state corresponding to a hyperconnected brain network.


Standardising surface electromyogram recordings for assessment of activity and fatigue in the human upper trapezius muscle.
The objectives of this work were to determine optimal surface electromyogram (EMG) electrode locations, and inter-electrode distance (IED), when assessing activity and fatigue in the human upper trapezius muscle. Surface EMG signals were recorded from the upper trapezius muscle of 11 healthy male subjects using a linear array of 16 surface electrodes. Five arm positions were investigated (arms at the side of the body, 45 degrees and 90 degrees flexion, 45 degrees and 90 degrees abduction). Fatiguing (1 kg hand load held for 3 min) and non-fatiguing (no load, 0.5 kg and 1 kg hand load held for 3 s) contractions were made. The variabilities of the average rectified value, root mean square, mean and median power spectral frequency and slope over time of these parameters as functions of electrode location and IED (from 5 mm over a range of 35 mm in steps of 5 mm) were quantitatively evaluated. A criterion for selecting the optimal electrode position was applied. This criterion indicated an optimal location measured from the acromion (38% of the distance from the lateral edge of acromion to the spine of the seventh cervical vertebra) which was statistically the same for all the EMG descriptors, arm positions and IED investigated. Finally, it was found that both EMG variables and indexes of muscle fatigue depended on IED which should thus be properly standardised. On the basis of the sensitivity of the EMG descriptors to electrode location and cross-talk reduction, an IED of 20 mm is suggested when a global analysis of activity in the upper trapezius muscle is made using a single pair of electrodes. This study emphasises that a surface EMG analysis of the upper trapezius muscle, following a proper placement of the electrodes and selection of IED, can give reliable indications of muscle activity and fatigue. Data on the myoelectric manifestations of muscle fatigue of the upper trapezius muscle are provided for the optimal electrode location.


Periodontal Condition in Patients with Rheumatoid Arthritis: Effect of Anti-rheumatic Drugs.
Rheumatoid arthritis and periodontitis are chronic inflammatory diseases with a possible bidirectional relationship. This link may be affected by many factors like drug consumption. This study was designed to evaluate the periodontal condition in patients with rheumatoid arthritis, considering the effect of disease modifying anti-rheumatic drugs. This case-control study included 25 newly diagnosed rheumatoid arthritis patients with negative history of taking anti-rheumatic drugs, 25 patients who received anti-rheumatic drugs for more than three years and 50 healthy individuals as a control group. Periodontal indices, including plaque index, gingival index, probing depth, clinical attachment loss, and rheumatologic indices were recorded and compared between these groups. Rheumatoid arthritis patients were significantly more affected by periodontitis compared with healthy subjects (p= 0.006). There was no significant difference in rheumatologic indices between patients with and without periodontitis. Clinical attachment loss in old rheumatoid arthritis patients and gingival index in newly diagnosed ones were significantly more compared to the control group (p= 0.003 and p< 0.001 respectively). We could not find a linear relationship between the severity of rheumatoid arthritis and chronic periodontitis (p= 0.1, r= -0.224). Periodontitis and clinical attachment loss were more in patients with rheumatoid arthritis than the healthy group, especially in drug consumers. Gingival index in patients without the history of consuming anti-rheumatic drugs was significantly higher than those who were drug consumers, indicating the effect of the medications on the signs of inflammation.


[Diagnostic possibilities of an immunoenzyme test-system for determining the spectrum of antibodies to structural and nonstructural hepatitis C virus antigens].
A new enzyme immunoassay EIA-HCV-Spectr test system constructed on the base of recombinant proteins and synthetic peptides allows separate detection of antibodies to E1/E2, core, HS3, NS4, and NS5 antigens of hepatitis C virus (HCV). The system is highly specific and more sensitive than the test systems used in screening studies, which allows its use as a final test for antiHCV antibodies. Antibodies to various HCV antigens were analyzed using this test system in patients with acute and chronic hepatitis C and asymptomatic donors with antiHCV. In acute hepatitis C during the first-second week after clinical manifestation, antibodies to nonstructural virus proteins are detected 3-4 times less often than in chronic hepatitis C. Acute hepatitis C is characterized by the presence of antibodies only to core antigen (66%). In chronic condition combinations of antibodies to structural and nonstructural HCV antigens predominate: core + NS4, core + NS3 + NS4, core + NS3 + NS5, core + NS4 + NS5, and core + NS3 + NS4 + NS5. In asymptomatic donors with antiHCV and in patients with chronic hepatitis C the spectra of antibodies were similar in 45.7% cases.


M-DDC: MRI based demyelinative diseases classification with U-Net segmentation and convolutional network.
Childhood demyelinative diseases classification (DDC) with brain magnetic resonance imaging (MRI) is crucial to clinical diagnosis. But few attentions have been paid to DDC in the past. How to accurately differentiate pediatric-onset neuromyelitis optica spectrum disorder (NMOSD) from acute disseminated encephalomyelitis (ADEM) based on MRI is challenging in DDC. In this paper, a novel architecture M-DDC based on joint U-Net segmentation network and deep convolutional network is developed. The U-Net segmentation can provide pixel-level structure information, that helps the lesion areas location and size estimation. The classification branch in DDC can detect the regions of interest inside MRIs, including the white matter regions where lesions appear. The performance of the proposed method is evaluated on MRIs of 201 subjects recorded from the Children's Hospital of Zhejiang University School of Medicine. The comparisons show that the proposed DDC achieves the highest accuracy of 99.19% and dice of 71.1% for ADEM and NMOSD classification and segmentation, respectively.


Orofacial Manifestations in a Middle-Aged Woman with Cowden Syndrome: A Case Image.
A 56-year-old Brazilian woman sought dental care, presenting with multiple asymptomatic papillomatous lesions with a coalescent pattern and intermingled cobblestone-like clefts along the alveolar ridge and marginal and attached gingivae. Multiple whitish papules were also observed on the face, neck, and limbs. Incisional biopsies of these lesions were performed. Microscopically, the skin lesion revealed epithelial clear cells and intraepithelial keratinization with areas of orthokeratosis, while the gingival lesions showed a parakeratinized stratified squamous epithelium with collagenous connective tissue. These features were consistent with those of a trichilemmoma and fibroepithelial hyperplasia, respectively. This article illustrates a case of Cowden syndrome (CS), a rare multisystem genetic condition in which both cutaneous and mucosal tissues were affected. Fewer than 40 cases of CS with oral involvement affecting middle-aged adults have been documented hitherto.


The Brief Pain Inventory: pain's interference with functions is different in cancer pain compared with noncancer chronic pain.
The Brief Pain Inventory (BPI) is a highly recommended and frequently used multidimensional pain assessment tool. The BPI includes 2 dimensions: pain intensity and pain's interference with functions. Our aims were to explore how patients respond to pain interference items by comparing responses from patients who had cancer with patients who had noncancer chronic pain (NCCP), and to explore how different levels of health-related quality of life affect upon pain's interference with functions. Three hundred patients with cancer and 286 patients with NCCP were asked to complete the BPI and the European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire (EORTC QLQ-C30). The pain interference items were indexed into total interference, interference with physical functions, and interference with psychologic functions. Regression analyses were used to explore differences in pain's interference by group, pain intensity, and a possible interaction effect between them. The analyses were adjusted for age, sex, and all EORTC QLQ-C30 scales. The cancer patients reported higher values of physical interference than NCCP patients with the same level of pain intensity (P<0.001). NCCP patients reported higher values of psychologic interference than cancer patients (P=0.023). For total interference, these effects eliminated each other. When adjusting for age, sex, and the EORTC QLQ-C30 subscales, the results still remained significant except that adjusting for the subscale for physical function made the group effect insignificant for physical interference (P=0.30). The results indicate that patients are unable to report isolated pain's interference using the BPI. When reporting pain's interference with physical functioning, the level of physical functioning is more important than the level of pain. Patients' diagnoses have to be taken into account when interpreting reported pain's interference with functions.


Olfactory Bulb Volume Changes in Patients With Nasal Septal Deviation.
The olfactory bulb (OB) plays a pivotal role in the processing of olfactory information. The aim of this study was to investigate the OB volume changes and its possible associations with nasal septal deviation. Cross-sectional study. Otolaryngology Department of Bozok University School of Medicine and Neurology Department of Yozgat State Hospital. Ninety patient's cranial magnetic resonance imaging (MRI) studies (46 males and 44 females, mean age 36 ± 13.4 years; range 18-56 years) with isolated nasal septal deviations were recruited for the study. Olfactory bulb volumes in all study subjects were evaluated in T2-weighted coronal MRI images by planimetric manual contouring. Nasal septal deviation angles were found to range between 5° and 23.21° (mean 13.6° ± 3.58°). The right-sided deviations included 17 mild (<9°, Group I), 20 moderate (9°-15°, Group II), and 16 severe (15° and up, Group III) patients. The left-sided deviations included 14 mild (<9°, Group I), 13 moderate (9°-15°, Group II), and 10 severe (15° and up, Group III) subjects. Olfactory bulb volumes were calculated in both right- and left-sided deviation groups. In the patients with left-sided septal deviations of Groups I, II, and III, the left OB volumes of Groups I, II, and III were 46.49 ± 3.87, 47.46 ± 3.36, and 60.68 ± 5.65 mm and the right OB volumes were 53.37 ± 3.76, 56.47 ± 4.43, and 76.69 ± 6.84 mm, respectively. The statistical evaluation of the right OB volumes did not produce significant difference between Groups I and II (P = 0.73). The authors demonstrated statistically significant differences in comparison of Groups I to III and Groups II to III (P = 0.002 and P = 0.016, respectively). In the right septal deviation group for Groups I, II, and III, mean volumes of right OB volumes were 45.59 ± 4.46, 48.63 ± 3.78, and 61.35 ± 5.84 mm, respectively, and the left OB volumes were 54.67 ± 4.73, 57.65 ± 4.53, and 75.84 ± 7.67 mm, respectively. There was no statistically significant difference between Groups I and II (P = 0.95) left OB volumes in the right-sided deviation group, but statistically significant difference was demonstrated in Groups I to III and Groups II to III compartments (P = 0.002 and P = 0.003). In our study, while mild and moderate septal deviations lacked any significant affect on OB volumes, severe deviations were found to have significant impact on these parameter. Additionally the contralateral OB volumes in the severe septum deviation group were significantly bigger when compared to the ipsilateral OB volumes. Further multidisciplinary studies are required to evaluate the clinical significance of OB volume changes in diagnosis and follow-up of several otolaryngologic or nonotolaryngologic diseases.


Decreased miR-200b-3p in cancer cells leads to angiogenesis in HCC by enhancing endothelial ERG expression.
Transcription factor ERG (erythroblast transformation-specific (ETS)-related gene) is essential in endothelial differentiation and angiogenesis, in which microRNA (miR)-200b-3p targeting site is expected by miRNA target prediction database. miR-200b is known decreased in hepatocellular carcinoma (HCC), however, the functional relation between ERG and miR-200b-3p, originating from pre-miR-200b, in HCC angiogenesis remains unclear. We investigated whether hepatocyte-derived miR-200b-3p governs angiogenesis in HCC by targeting endothelial ERG. Levels of miR-200b-3p in HCC tissues were significantly lower than those in adjacent non-HCC tissues. Poorly differentiated HCC cell line expressed lower level of miR-200b-3p compared to well-differentiated HCC cell lines. The numbers of ERG-positive endothelial cells were higher in HCC tissues than in adjacent non-HCC tissues. There was a negative correlation between the number of ERG-positive cells and miR-200b-3p expression in HCC tissues. Culture supernatants of HCC cell lines with miR-200b-3p-overexpression reduced cell migration, proliferation and tube forming capacity in endothelial cells relative to the control, while those with miR-200b-3p-inhibition augmented the responses. Exosomes isolated from HCC culture supernatants with miR-200b-3p overexpression suppressed endothelial ERG expression. These results suggest that exosomal miR-200b-3p from hepatocytes suppresses endothelial ERG expression, and decreased miR-200b-3p in cancer cells promotes angiogenesis in HCC tissues by enhancing endothelial ERG expression.


[Study of cryoprotective properties of antifreeze glycoproteins from the white sea cod Gadus morhua on low temperature freezing of mouse embryos].
The effect of antifreeze glycoproteins on morphological preservation and viability of mouse embryos cryopreserved in liquid nitrogen was studied. Cryomicroscopic observations indicated that as distinct from the cryoprotector dimethylsulfoxide antifreeze glycoproteins cause phenomena typical of vitrification (absence of visible crystallization, transparency of medium). The embryos frozen in the presence of freeze glycoproteins had after thawing a higher morphological preservation (87.5%) than those frozen with 1M and 3M dimethylsulfoxide (53.8 and 71.1%, respectively). However, they were nonviable and did not develop in culture. A high viability after cryoconservation was achieved only when antifreeze glycoproteins (20 mg/ml) were used together with dimethylsulfoxide (3M). In this case, the number of viable embryos, which developed in culture to the stage of compact morula and blastocyst, was 65.0%, i.e. two and four times higher than in the presence of 3 M and 1 M dimethylsulfoxide, respectively.