Dynamic self-assembly of DNA minor groove-binding ligand DB921 into nanotubes triggered by an alkali halide.
We describe a novel self-assembling supramolecular nanotube system formed by a heterocyclic cationic molecule which was originally designed for its potential as an antiparasitic and DNA sequence recognition agent. Our structural characterisation work indicates that the nanotubes form via a hierarchical assembly mechanism that can be triggered and tuned by well-defined concentrations of simple alkali halide salts in water. The nanotubes assembled in NaCl have inner and outer diameters of ca. 22 nm and 26 nm respectively, with lengths that reach into several microns. Our results suggest the tubes consist of DB921 molecules stacked along the direction of the nanotube long axis. The tubes are stabilised by face-to-face π-π stacking and ionic interactions between the charged amidinium groups of the ligand and the negative halide ions. The assembly process of the nanotubes was followed using small-angle X-ray and neutron scattering, transmission electron microscopy and ultraviolet/visible spectroscopy. Our data demonstrate that assembly occurs through the formation of intermediate ribbon-like structures that in turn form helices that tighten and compact to form the final stable filament. This assembly process was tested using different alkali-metal salts, showing a strong preference for chloride or bromide anions and with little dependency on the type of cation. Our data further demonstrates the existence of a critical anion concentration above which the rate of self-assembly is greatly enhanced.


The reliability paradox: Why robust cognitive tasks do not produce reliable individual differences.
Individual differences in cognitive paradigms are increasingly employed to relate cognition to brain structure, chemistry, and function. However, such efforts are often unfruitful, even with the most well established tasks. Here we offer an explanation for failures in the application of robust cognitive paradigms to the study of individual differences. Experimental effects become well established - and thus those tasks become popular - when between-subject variability is low. However, low between-subject variability causes low reliability for individual differences, destroying replicable correlations with other factors and potentially undermining published conclusions drawn from correlational relationships. Though these statistical issues have a long history in psychology, they are widely overlooked in cognitive psychology and neuroscience today. In three studies, we assessed test-retest reliability of seven classic tasks: Eriksen Flanker, Stroop, stop-signal, go/no-go, Posner cueing, Navon, and Spatial-Numerical Association of Response Code (SNARC). Reliabilities ranged from 0 to .82, being surprisingly low for most tasks given their common use. As we predicted, this emerged from low variance between individuals rather than high measurement variance. In other words, the very reason such tasks produce robust and easily replicable experimental effects - low between-participant variability - makes their use as correlational tools problematic. We demonstrate that taking such reliability estimates into account has the potential to qualitatively change theoretical conclusions. The implications of our findings are that well-established approaches in experimental psychology and neuropsychology may not directly translate to the study of individual differences in brain structure, chemistry, and function, and alternative metrics may be required.


Resonance Raman studies of cytochrome P450BM3 and its complexes with exogenous ligands.
Resonance Raman spectra are reported for both the heme domain and holoenzyme of cytochrome P450BM3 in the resting state and for the ferric NO, ferrous CO, and ferrous NO adducts in the absence and presence of the substrate, palmitate. Comparison of the spectrum of the palmitate-bound form of the heme domain with that of the holoenzyme indicates that the presence of the flavin reductase domain alters the structure of the heme domain in such a way that water accessibility to the distal pocket is greater for the holoenzyme, a result that is consistent with analogous studies of cytochrome P450cam. The data for the exogenous ligand adducts are compared to those previously reported for corresponding derivatives of cytochrome P450cam and document significant and important differences for the two proteins. Specifically, while the binding of substrate induces relatively dramatic changes in the nu(Fe-XY) modes of the ferrous CO, ferric NO, and ferrous NO derivatives of cytochrome P450cam, no significant changes are observed for the corresponding derivatives of cytochrome P450BM3 upon binding of palmitate. In fact, the spectral data for substrate-free cytochrome P450BM3 provide evidence for distortion of the Fe-XY fragment, even in the absence of substrate. This apparent distortion, which is nonexistent in the case of substrate-free cytochrome P450cam, is most reasonably attributed to interaction of the Fe-XY fragment with the F87 phenylalanine side chain. This residue is known to lie very close to the heme iron in the substrate-free derivative of cytochrome P450BM3 and has been suggested to prevent hydroxylation of the terminal, omega, position of long-chain fatty acids.


APOE epsilon4 allele carriers: Biological, psychological, and social variables associated with cognitive impairment.
The apolipoprotein (APOE) epsilon4 allele genotype is a risk factor for dementia, but not all people with the APOE epsilon4 allele develop cognitive impairment (CI). Among participants with the APOE epsilon4 allele (N = 664), we identified biological, psychological, and social variables that discriminate between participants who develop CI from those who do not. We then determined if these variables predicted CI in noncarriers (N = 1421). In the sample as a whole we then determined if each of these identified variables moderate the relationship between the APOE epsilon4 allele and CI. We used data from a biracial community-dwelling sample of older adults. Data were collected at four time points over a 10-year period. Cognitive functioning was assessed at each wave, using the Short Portable Mental Status Questionnaire (SPMSQ). APOE genotyping was performed at Wave 3. Among APOE epsilon4 allele carriers, but not noncarriers, variables associated with CI included white race, female gender, low BMI, number of negative life events, and health problems (high blood pressure, heart disease, and stroke). In analyses testing for moderate effects and including the entire sample, significant interactions with APOE epsilon4 allele and predictor variables revealed that white race, low BMI, stroke, heart disease, and negative life events had a greater effect on CI among those with the APOE epsilon4 allele compared to those without the allele. There are biological, psychological, and social variables associated with increased risk for CI among individuals with the APOE epsilon4 allele.


Introduction to a theoretical model based on embodied cognition: a pilot study of the diagnosis and treatment of hemiphobia.
Neurorehabilitation programs have traditionally followed the mind-body dichotomy proposed by Descartes, which resulted in the creation of divergent theoretical frameworks. The purpose of this pilot study is to present a transdisciplinary proposal that integrates human experience via the embodied cognition concept, that is, to explore how the individual relates from their experiential totality. We illustrate this model with a case report: a woman with a physical imbalance caused by stroke, which we diagnose as an experiential disorder and we treat using a transdisciplinary approach. The diagnosis is made in relation to the individual's intentionality when balancing; it is then subjected to an analysis based on embodied cognition. A transdisciplinary therapeutic approach consists of devising an intentionality that takes into consideration all intentional components of her balance. Through clinical practice based on embodied cognition, we identify an experiential disorder, which we name hemiphobia. This condition is characterized by avoidant motor behavior, hyperactivation of physiological tone, feelings of anxiety, and the suppression of reasoning during the motor task of balancing. We apply a transdisciplinary treatment incorporating intentionality as embodied cognition, body schema, body image, motor therapy, and metacognitive skills. This application improved her motricity skills in balancing and walking. The development of a theoretical model based on embodied cognition, in conjunction with the transdisciplinary treatment of hemiphobia, make a more profound and complex learning model possible to achieve the conscious integration of the motor function, the emotional variable, and the cognitive dimension as essential components of neurorehabilitation.


Validity of single-site and multi-site models for estimating body composition of women using near-infrared interactance.
The purpose of this study was to develop a multi-site near-infrared (NIR) model (Model I) and compare its predictive accuracy to single-site models (IIA and IIB). In Model I, the sum of two optical density (OD) measures (Σ2OD), age, body weight, height, and physical activity level were used as potential predictors of body density (Db ). In Model IIA, the variables used in the manufacturer's NIR equation (biceps OD1 and OD2 , body weight, height, gender, and physical activity level) were the potential predictors. This model was modified by including age as an additional potential predictor in Model IIB. We also examined the test-retest reliability and interrelationships of OD measures taken at 10 anatomical sites, as well as the validity of the manufacturer's NIR equation, for estimating body composition of women. The subjects, 148 women between 20 and 72 years, were hydrostatically weighed to determine criterion Db . The Futrex-5000 was used to measure OD1 and OD2 at 10 anatomical sites. Only two sites (pectoral OD2 and biceps OD2 ) contributed significantly to the variance in Db . Thus, the sum of these two ODs (Σ2OD), was used as a potential predictor in the multi-site model. Test-retest reliability was high, with intraclass correlation coefficients ≥0.85 for many of the OD measurements. Intercorrelations of ODs ranged from 0.22 to 0.91. In the multi-site model (I), ΣOD, body weight, age, and height were significant predictors, accounting for 85.7% of the variance in Db . The SEE was 0.0076 g/ml or 3.3% BF. In the manufacturer's model (IIA), biceps OD2 , body weight, and height accounted for 76.3% of the variance in Db , and the SEE was 0.0094 g/ml (4.1% BF). When age was included as a predictor (Model IIB), the R2 increased (86.0%) and the SEE (0.0073 g/ml or 3.1% BF) decreased substantially. Cross-validation of the three equations yielded r2 s ranging between 0.688 (Model IIA) and 0.748 (Model I) and slightly larger SEEs (0.0094-0.001048 g/ml). There were no significant differences between average criterion Db and predicted Db for each equation. The manufacturer's equation programmed in the Futrex-5000 yielded a lower r2 (0.55), higher SEE (5.61% BF), and significantly underestimated criterion % BF by an average of 3% BF. Either the multi-site (model I) or single-site (Model IIB) equations is recommended to estimate body composition of this population. © 1992 Wiley-Liss, Inc.


Non-starch polysaccharides from kidney beans: comprehensive insight into their extraction, structure and physicochemical and nutritional properties.
Kidney beans (Phaseolus vulgaris L.) are an important legume source of carbohydrates, proteins, and bioactive molecules and thus have attracted increasing attention for their high nutritional value and sustainability. Non-starch polysaccharides (NSPs) in kidney beans account for a high proportion and have a significant impact on their biological functions. Herein, we critically update the information on kidney bean varieties and factors that influence the physicochemical properties of carbohydrates, proteins, and phenolic compounds. Furthermore, their extraction methods, structural characteristics, and health regulatory effects, such as the regulation of intestinal health and anti-obesity and anti-diabetic effects, are also summarized. This review will provide suggestions for further investigation of the structure of kidney bean NSPs, their relationships with biological functions, and the development of NSPs as novel plant carbohydrate resources.


Fearful responding to repeated CO2 inhalation: a preliminary investigation.
In an effort to explore factors which maintain fear of physical sensations, repeated administration of 35% CO2 was used with college students scoring high and low on the Anxiety Sensitivity Index. Half of each group was administered 12 CO2 trials, while the other half received 9 CO2 trials, followed by a dishabituation trial (Trial 10) and 2 more CO2 administrations (Trials 11 and 12). Measures included subjective anxiety, heart rate, skin conductance, and number of panic symptoms reported. Results indicated a nonsignificant trend for the High ASI group to show increased pre-inhalation anxiety across trials, while the Low ASI group showed a rapid reduction in pre-inhalation anxiety. Post-inhalation skin conductance mirrored this pattern, although rapid reduction in post-inhalation heart rate was observed. Overall, the High ASI participants showed a notable lack of fear reduction across trials. Results are discussed in light of sensitization as a factor contributing to anticipatory anxiety, with implications for understanding the etiology and maintenance of Panic Disorder.


Infection after total knee arthroplasty. A retrospective study of the treatment of eighty-one infections.
The clinical presentation of an infection at the site of a total knee arthroplasty can be used as a guide to treatment, including the decision as to whether the prosthesis should be retained or removed. We reviewed the results of treatment of infection after total knee arthroplasty to evaluate the effectiveness of four treatment protocols based on the clinical setting of the infection. We retrospectively evaluated the results of treatment of eighty-one infections in seventy-six consecutive patients who either had an infection after a total knee arthroplasty or had multiple positive intraoperative cultures of specimens of periprosthetic tissue obtained during a revision total knee arthroplasty performed because of presumed aseptic loosening. The patients were managed according to one of four protocols. Five infections in five patients who had positive intraoperative cultures were treated with antibiotic therapy alone. Twenty-three early postoperative infections in twenty-one patients were treated with débridement, antibiotic therapy, and retention of the prosthesis. Twenty-nine late chronic infections in twenty-eight patients were treated with a delayed-exchange arthroplasty after a course of antibiotics. Seven acute hematogenous infections in six patients were treated with débridement, antibiotic therapy, and retention of the prosthesis. Seventeen infections in seventeen patients were not treated according to one of the four protocols. Sixteen late chronic infections were treated either with an arthrodesis (five infections) or with débridement, antibiotic therapy, and retention of the prosthesis (eleven infections). One acute hematogenous infection was treated with resection arthroplasty because of life-threatening sepsis. The mean duration of follow-up was 4.0 years (range, 0.3 to 14.0 years). Eleven patients who had an arthrodesis, a resection arthroplasty, or an above-the-knee amputation after less than two years of follow-up were included in the study as individuals who had a failure of treatment. In the group of patients who were managed according to protocol, the initial course of treatment was successful for all five infections that were diagnosed on the basis of positive intraoperative cultures, five of the ten deep early infections, all thirteen superficial early infections, twenty-four of the twenty-nine late chronic infections, and five of the seven acute hematogenous infections. Only one of eleven prostheses in patients who had a late chronic infection that was not treated according to protocol was successfully retained after débridement. Our treatment protocols, which were based on the clinical setting of the infection, were successful for most patients. A major factor associated with treatment failure was a compromised immune status. Bone loss and necrosis of the soft tissues around the joint also complicated the treatment of these infections.


The Arabidopsis LAZY1 Family Plays a Key Role in Gravity Signaling within Statocytes and in Branch Angle Control of Roots and Shoots.
During gravitropism, the directional signal of gravity is perceived by gravity-sensing cells called statocytes, leading to asymmetric distribution of auxin in the responding organs. To identify the genes involved in gravity signaling in statocytes, we performed transcriptome analyses of statocyte-deficient Arabidopsis thaliana mutants and found two candidates from the LAZY1 family, AtLAZY1/LAZY1-LIKE1 (LZY1) and AtDRO3/AtNGR1/LZY2 We showed that LZY1, LZY2, and a paralog AtDRO1/AtNGR2/LZY3 are redundantly involved in gravitropism of the inflorescence stem, hypocotyl, and root. Mutations of LZY genes affected early processes in gravity signal transduction without affecting amyloplast sedimentation. Statocyte-specific expression of LZY genes rescued the mutant phenotype, suggesting that LZY genes mediate gravity signaling in statocytes downstream of amyloplast displacement, leading to the generation of asymmetric auxin distribution in gravity-responding organs. We also found that lzy mutations reversed the growth angle of lateral branches and roots. Moreover, expression of the conserved C-terminal region of LZY proteins also reversed the growth direction of primary roots in the lzy mutant background. In lateral root tips of lzy multiple mutants, asymmetric distribution of PIN3 and auxin response were reversed, suggesting that LZY genes regulate the direction of polar auxin transport in response to gravity through the control of asymmetric PIN3 expression in the root cap columella.


Influenza vaccination coverage level at a cystic fibrosis center.
Influenza causes substantial morbidity and mortality, particularly in vulnerable populations. Annual vaccination is the most effective means to prevent or attenuate this illness. The vaccine is recommended for patients with cystic fibrosis (CF) older than 6 months, but the degree of adherence with this recommendation is unknown. To determine 1) the vaccination coverage level for the 1997-1998 influenza season in a population of CF patients, and 2) the factors associated with nonadherence with vaccination. Retrospective chart review, a mailed survey, and telephone interviews. Intermountain CF Center. This center, accredited by the CF Foundation, delivers health care to affected individuals throughout the Intermountain West. Care of children and adults is based at Primary Children's Medical Center and the University of Utah Hospital, respectively. The adjacent hospitals are comprehensive, tertiary care medical centers on the University of Utah campus in Salt Lake City. Approximately one third of the center's patient population lives in southern Idaho. There are 2 affiliate centers in Idaho, one based in Pocatello/Idaho Falls and the other in Boise. All patients over 6 months of age on the center's roster. We found documentation of influenza vaccination status in the medical records of 99 patients; 98 who received the vaccine and 1 who did not because of an allergy to egg products. Through the mailed surveys and telephone interviews, we collected data on 236 additional patients. Thus, we report data on 335 (92.5%) of 362 patients on the center's roster. A total of 256 (76.4%) of 335 patients received the influenza vaccine before the 1997-1998 flu season, including 181 (79.4%) of 228 children (<18 years of age) and 75 (70.1%) of 107 adult patients (</=18 years of age). We also analyzed the data assigning all patients to their major site of care, either the Salt Lake parent center or one of the Idaho affiliates. We found no difference in the vaccination rate when comparing parent center to affiliates: 179 (78.2%) of 229 patients at the parent center were vaccinated versus 77 (72.6%) of 106 patients at the affiliates. For the 79 patients who did not obtain the influenza vaccine, the major reasons were: "forgot," "too healthy," "too busy," "worried about the side effects," or "too sick at the time." The unvaccinated group had fewer clinic visits, fewer CF-related hospitalizations, and lived further from the care center than the vaccinated group. To further explore the association between contact with the center and vaccination status, we categorized patients into those who were evaluated in the outpatient clinic and/or hospitalized in 1997 and those who were not. We found that 80.8% of the 281 patients who actually received care at the center during 1997 were vaccinated as compared with only 59.5% of the 42 patients who did not receive care during that year. The timing of clinic visits also appears to be a critical factor. We found that 87.1% of patients who had a visit during the fourth quarter of the year had the vaccination as compared with 64.9% of patients who did not have a fourth quarter visit. A fourth quarter visit remained highly associated with vaccination in a logistic regression analysis, whereas number of clinic visits did not. The vaccination coverage level in this vulnerable population is higher than other high-risk groups of comparable age. Nonetheless, there is room for improvement. Strategies aimed at increasing patient contact with the CF center, particularly during the fourth quarter of the calendar year, may result in improved vaccination rates. Additional data encompassing a cross-section of CF centers would be helpful in ensuring that influenza vaccination is receiving adequate attention in this patient population. Systematic monitoring of influenza vaccination rates at a national level should be considered as a means of encouraging compliance with this important preventive measure. cystic fibrosis, influenza, vaccination, health care delivery.


Dickkopf-2 (DKK2) as Context Dependent Factor in Patients with Esophageal Adenocarcinoma.
Dickkopf-2 (DKK2) has been described as Wnt/beta-catenin pathway antagonist and its expression is mediated by micro RNA-221 (miRNA-221). So far, there is only limited data characterizing the role of DKK2 expression in esophageal cancer. A tissue micro array of 192 patients with esophageal adenocarcinoma was analyzed immunohistochemically for DKK2, miRNA-221 expression by RNA scope, and GATA6 amplification by fluorescence in-situ hybridization. The data was correlated with clinical, pathological and molecular data (TP53, HER2, c-myc, GATA6, PIK3CA, and KRAS amplifications). DKK2 expression was detectable in 21.7% and miRNA-221 expression in 33.5% of the patients. We observed no correlation between DKK2 or miRNA-221 expression and clinico-pathological data DKK2 expression was correlated with TP53 mutations and amplification of GATA6. We did not detect a survival difference in dependence of DKK2 for the total cohort, however, in patients without neoadjuvant treatment DKK2 expression correlated with a prolonged survival (median overall-survival 202 vs. 55 months, p = 0.012) which turned opposite in patients that underwent neoadjuvant treatment. High amounts of miRNA-221 were in trend associated with a prolonged overall-survival (p = 0.070). DKK2 as a Wnt antagonist is associated with prolonged survival in patients without neoadjuvant treatment and changes its prognostic value to the contrary in patients after neoadjuvant therapy. The modulatory effects of neoadjuvant treatment in connection with DKK2 expression are not fully understood, but when considering DKK2 as a tumor marker, it is necessary to see it in the context of neoadjuvant therapy.


Conformal boundary conditions and three-dimensional topological field theory
We present a general construction of all correlation functions of a two-dimensional rational conformal field theory, for an arbitrary number of bulk and boundary fields and arbitrary topologies. The correlators are expressed in terms of Wilson graphs in a certain three-manifold, the connecting manifold. The amplitudes constructed this way can be shown to be modular invariant and to obey the correct factorization rules.


Skin sensitization risk assessment model using artificial neural network analysis of data from multiple in vitro assays.
The sensitizing potential of chemicals is usually identified and characterized using in vivo methods such as the murine local lymph node assay (LLNA). Due to regulatory constraints and ethical concerns, alternatives to animal testing are needed to predict skin sensitization potential of chemicals. For this purpose, combined evaluation using multiple in vitro and in silico parameters that reflect different aspects of the sensitization process seems promising. We previously reported that LLNA thresholds could be well predicted by using an artificial neural network (ANN) model, designated iSENS ver.1 (integrating in vitro sensitization tests version 1), to analyze data obtained from two in vitro tests: the human Cell Line Activation Test (h-CLAT) and the SH test. Here, we present a more advanced ANN model, iSENS ver.2, which additionally utilizes the results of antioxidant response element (ARE) assay and the octanol-water partition coefficient (LogP, reflecting lipid solubility and skin absorption). We found a good correlation between predicted LLNA thresholds calculated by iSENS ver.2 and reported values. The predictive performance of iSENS ver.2 was superior to that of iSENS ver.1. We conclude that ANN analysis of data from multiple in vitro assays is a useful approach for risk assessment of chemicals for skin sensitization.


NSE, positively regulated by LINC00657-miR-93-5p axis, promotes small cell lung cancer (SCLC) invasion and epithelial-mesenchymal transition (EMT) process.
Background: Neuron specific enolase (NSE) is a specific biomarker for SCLC. However, the biological roles and aberrant expression of NSE in SCLC have not been well illustrated. Methods: The expression of NSE, miR-93-5p and LINC00657 in SCLC tissues and cell lines were detected using real time quantitative PCR (qRT-PCR) or immunohistochemistry. CCK8 assay was performed to detect cell proliferation. Cell migration and invasion capabilities were investigated by transwell assay. Epithelial-mesenchymal transition (EMT) process was verified by detecting epithelial marker E-cadherin and mesenchymal marker N-cadherin. The direct interactions between miR-93-5p and NSE or LINC00657 were predicted by bioinformatics tools and verified using dual luciferase reporter assay. Results: Upregulated expression of NSE in SCLC tumor tissues were positively associated with advanced tumor stage, distant metastasis and poor overall survival. Overexpression of NSE promoted cell proliferation, migration, invasion and EMT in SCLC cells, while silence of NSE inhibited these effects. Mechanically, NSE expression was positively correlated with LINC00657, and negatively correlated with miR-93-5p. Moreover, NSE was positively regulated by LINC00657 through sponging of miR-93-5p. LINC00657 and miR-93-5p promoted SCLC cell migration, invasion and EMT by NSE-mediated manner. Conclusion: Overall, our study revealed a novel role of NSE in SCLC. NSE was positively regulated by LINC00657 through competitively interacting with miR-93-5p, which may be potential targets for SCLC patients.


Screening Adolescents for Alcohol Use: Tracking Practice Trends of Massachusetts Pediatricians.
Substance use screening is a recommended component of routine healthcare for adolescents. A 2008 survey of Massachusetts primary care physicians found high rates of screening, but low rates of validated tool use, leading to the concern that physicians may be missing substance use-related problems and disorders. In an effort to improve practice, a cross-disciplinary group developed and distributed an adolescent screening, brief intervention, and referral to treatment toolkit in 2009. A new survey of Massachusetts primary care physicians was conducted in 2014; this report describes its findings, and compares them to those from 2008. A survey was mailed to a randomly selected sample of Massachusetts primary care physicians listed in the state Board of Registration in Medicine database. Item response frequencies were computed. Multiple logistic regression modeling was used to compare 2008 and 2014 responses, while controlling for any demographic differences between samples. Pediatrician respondents in 2014 (analysis N = 130) reported a high rate of annually screening patients for alcohol use (96.2%), but only 56.2% reported using a validated screening tool. Rates of screening and validated tool use were higher in 2014 than 2008. Insufficient knowledge as a reported barrier to screening decreased from 2008 to 2014. However, lack of time or staff resources remained key perceived barriers to screening. Our findings suggest that adolescent alcohol use screening practices among Massachusetts pediatricians have improved in recent years, during a time of national and statewide efforts to educate physicians. However, opportunities for practice improvement remain.


Potentially functional variants of p14ARF are associated with HPV-positive oropharyngeal cancer patients and survival after definitive chemoradiotherapy.
Since p14 (ARF) and human papillomavirus (HPV) 16 E6/E7 oncoproteins are important regulators participating in the p53/Rb pathways, genetic variations of p14 (ARF) may modify tumor HPV16 status and survival of HPV16-positive squamous cell carcinoma of the oropharynx (SCCOP) patients. We determined tumor HPV16 status and expression of p14/p53 and genotyped p14 (ARF) -rs3731217 and -rs3088440 polymorphisms in 552 incident SCCOP patients. We found that patients having variant genotypes for each p14 (ARF) polymorphism were approximately two or three times as likely to have HPV16-positive tumors compared with patients with corresponding common homozygous genotype, and such an association was particularly pronounced in patients with variant genotypes of both polymorphisms. After definitive chemoradiotherapy, patients having p14 (ARF) rs3731217 TG/GG variant genotypes had significantly better overall, disease-specific and disease-free survival than those having TT genotype, respectively. Multivariable analysis found that patients with p14 (ARF) -rs3731217 TT genotype had an ~7-, 11- and 3-fold increased risk for death overall, death due to SCCOP and recurrence than those with TG/GG variant genotypes, respectively. Furthermore, such significantly prognostic effect was also found when survival analysis was limited to HPV16-positive patients. Additionally, potentially functional relevance of the two variants was characterized to explore the genotype-phenotype correlation. Our findings indicate p14 (ARF) variants may predict tumor HPV16-positive SCCOP patients and survival.


Bioactive amide of prostaglandin E1 and ethanolamine plasmalogen analog of platelet-activating factor inhibits several pathways of human platelet aggregation.
The influence of an amide of prostaglandin E1 and ethanolamine plasmalogen platelet-activating factor analog 1-O-alk-1;-enyl-2-acetyl-sn-glycero-3-phospho-(N-11alpha, 15alpha-dioxy-9-keto-13-prostenoyl)ethanolamine (PGE1-PPAF) on platelet-activating factor (PAF)-, ADP-, and thrombin-induced human platelet aggregation has been studied. It was found that PGE1-PPAF inhibits the PAF-, ADP-, and thrombin-induced platelet aggregation in platelet-rich plasma. 1-O-alk-1;-enyl-2-acetyl-sn-glycero-3-phosphoethanolamine inhibited PAF-induced aggregation up to 50% but had no influence on platelet aggregation induced by ADP or thrombin. The ethanolamine plasmalogen analog of PAF 1-O-alk-1;-enyl-2-acetyl-sn-glycero-3-phospho-(N-palmitoyl)ethanolami ne, having a palmitoyl residue instead of PGE1, did not inhibit platelet aggregation induced by PAF, ADP, or thrombin. We propose that inhibition of human platelet aggregation by PGE1-PPAF is mediated by its action on platelet PAF-receptors and the adenylate cyclase system.


Inhibition of heat shock protein 90 rescues glucocorticoid-induced bone loss through enhancing bone formation.
Endogenous glucocorticoids (GCs) support normal bone development and bone mass maintenance, whereas long-term exposure to pharmacological dosages of GCs uncouples bone formation and resorption, resulting in GC-induced osteoporosis (GIOP). Heat shock protein 90 (HSP90) chaperoning glucocorticoid receptor (GR) signaling prompts us to speculate that HSP90 plays critical roles in GC-mediated bone formation and GIOP. In the present study, inhibition of HSP90 activity by 17-Demethoxy-17-allyaminogeldanmycin (17-AAG) or knockdown of HSP90 expression by siRNAs attenuated dexamethasone(Dex)-induced GR nuclear accumulation and transcriptional output of GR signaling, whereas overexpression of HSP90α or HSP90β enhanced GR transactivity in C3H10T1/2 cells. Though 17-AAG itself enhanced osteoblastic differentiation, it restored the Dex(10-8M)-induced and Dex(10-6M)-negated osteoblastic differentiation in C3H10T1/2 cells and primary calvarial osteoblasts. Moreover, systemic administration of 17-AAG to mice induced not only osteoclastogenesis but also osteoblastogenesis, whereas bone formation possibly exceeded bone resorption, eventually leading to the increased bone masses. Likewise, systemic administration of 17-AAG to mice restored GC-negated osteoblastogenesis and enhanced GC-induced osteoclastogenesis, similarly, 17-AAG-induced bone formation possibly exceeded both 17-AAG- and GC-induced bone resorption, eventually resulting in rescue of GIOP. Together, the present study has revealed that inhibition of HSP90 restores GIOP through enhancing bone formation, and our findings may help to shed light on the pathogenesis of GIOP and provide targets for the therapeutic intervention of the disease.


Recent-onset ecstasy use: association with deviant behaviors and psychiatric comorbidity.
Despite increases in ecstasy (MDMA) use in the United States, little is known about characteristics linked with recent-onset ecstasy use, especially psychiatric symptoms and deviant behaviors. To test whether individuals with high levels of other drug use are more likely to be recent-onset ecstasy users; to test whether psychiatric symptoms in adults are associated with recent-onset ecstasy use; to explore the association between recent-onset ecstasy use and concomitant deviant behaviors in adolescents and adults. Data from the 2001 National Survey on Drug Use and Health. Recent-onset ecstasy use was significantly more likely to occur among adolescents and adults (18-34 years old) who engaged in deviant behaviors during the past year as compared with those who did not engage in deviant behaviors during the past year. Higher levels of deviancy indicated a higher likelihood of being a recent-onset ecstasy user, and associations were strongest with nonviolent deviant behaviors such as selling illegal drugs and stealing. Associations between deviant behaviors and recent-onset ecstasy use were similar in strength to associations between deviant behaviors and recent-onset cocaine and marijuana use, respectively. Adults who had past-year psychiatric symptoms (both depressive and panic symptoms) were twice as likely to be recent-onset ecstasy users as compared with those without past-year psychiatric symptoms. Greater levels of drug involvement increased the odds of being a recent-onset ecstasy user. Recent-onset ecstasy use seems to be associated with a range of other behavioral problems and may reflect one aspect of a larger problem behavior syndrome.


Effects of human sera on reactivity of lymphocytes in microcytotoxicity assays.
The effects of cancer patient and normal donor serum samples on the reactivity of patient and normal lymphocytes against both normal and malignant target cells were studied in microcytotoxicity assays. There were 17 of 140 cancer patient serum samples and 7 of 116 normal donor lymphocyte samples that selectively increased the growth of target cells in the presence of lymphocytes. This effect was most often noted with cancer patient serum against cultured tumor cells, but the effect was also noted against fibroblasts and with normal serum against both fibroblasts and tumor cells. Of 140 cancer-patient serum samples, 11 selectively decreased target cell survival in the presence of lymphocytes compared to medium and compared to other serum samples. In the absence of lymphocytes these serum samples were nontoxic. The effect was not observed with any of the normal serum samples studied. The lymphocyte-dependent serum toxicity appeared to be selectively directed against tumor target cells.


HPA axis dysregulation in adult adoptees twenty years after severe institutional deprivation in childhood.
Hypothalamic-pituitary-adrenal (HPA) axis function is disrupted in institutionally-deprived children - reduced morning cortisol, flattened diurnal slope and blunted reactivity persist even after successful adoption into positive family environments. Here we test whether such effects persist into adulthood. Cortisol release across the day (sampled at awakening, 30 and 45min later, and at four points across the day) was investigated in young adult adoptees who had lived in severe deprivation for up to 43 months in early childhood in Ceaușescu's Romanian orphanages and a comparison group of non-deprived UK adoptees (Total N=57; mean age=24±0.9years). The mediating role of cortisol levels on adult mental health was examined using data from standardized clinical assessments. Cortisol profiles were disrupted in the Romanian adoptees who experienced more than 6 months deprivation marked by a striking absence of the cortisol awakening response (CAR) and a significantly flatter cortisol curve until 1h 15min after awakening. Whereas institutional deprivation was associated with both cortisol secretion and emergence of emotional problems in young adulthood, path analysis revealed no evidence for a mediating role of CAR disruption in the sub-sample studied here. The results are in line with findings of HPA axis hypo-functionality following early adverse experience and provide strong evidence for long-term programming effects of HPA axis function through experience of institutional deprivation.


Largely enhanced efficiency in ZnO nanowire/p-polymer hybridized inorganic/organic ultraviolet light-emitting diode by piezo-phototronic effect.
ZnO nanowire inorganic/organic hybrid ultraviolet (UV) light-emitting diodes (LEDs) have attracted considerable attention as they not only combine the high flexibility of polymers with the structural and chemical stability of inorganic nanostructures but also have a higher light extraction efficiency than thin film structures. However, up to date, the external quantum efficiency of UV LED based on ZnO nanostructures has been limited by a lack of efficient methods to achieve a balance between electron contributed current and hole contributed current that reduces the nonradiative recombination at interface. Here we demonstrate that the piezo-phototronic effect can largely enhance the efficiency of a hybridized inorganic/organic LED made of a ZnO nanowire/p-polymer structure, by trimming the electron current to match the hole current and increasing the localized hole density near the interface through a carrier channel created by piezoelectric polarization charges on the ZnO side. The external efficiency of the hybrid LED was enhanced by at least a factor of 2 after applying a proper strain, reaching 5.92%. This study offers a new concept for increasing organic LED efficiency and has a great potential for a wide variety of high-performance flexible optoelectronic devices.


Isoniazid preventive therapy plus antiretroviral therapy for the prevention of tuberculosis: a systematic review and meta-analysis of individual participant data.
Isoniazid preventive therapy prevents active tuberculosis in people with HIV, but previous studies have found no evidence of benefit in people with HIV who had a negative tuberculin skin test, and a non-significant effect on mortality. We aimed to estimate the effect of isoniazid preventive therapy given with antiretroviral therapy (ART) for the prevention of tuberculosis and death among people with HIV across population subgroups. We searched PubMed, Embase, the Cochrane database, and conference abstracts from database inception to Jan 15, 2019, to identify potentially eligible randomised trials. Eligible studies were trials that enrolled HIV-positive adults (age ≥15 years) taking ART who were randomly assigned to either daily isoniazid preventive therapy plus ART or ART alone and followed up longitudinally for outcomes of incident tuberculosis and mortality. We approached all authors of included trials and requested individual participant data: coprimary outcomes were relative risk of incident tuberculosis and all-cause mortality. We did a single-stage meta-analysis of individual participant data using stratified Cox-proportional hazards models. We did prespecified subgroup analyses by sex, CD4 cell count, and evidence of immune sensitisation to tuberculosis (indicated by tuberculin skin test or interferon-γ release assays [IGRAs]). We also assessed the relative risk of liver injury in an additional prespecified analysis. This study is registered with PROSPERO, CRD42019121400. Of 838 records, we included three trials with data for 2611 participants and 8584·8 person-years of follow-up for the outcome of incident tuberculosis, and a subset of 2362 participants with 8631·6 person-years of follow-up for the coprimary outcome of all-cause mortality. Risk for tuberculosis was lower in participants given isoniazid preventive therapy and ART than participants given ART alone (hazard ratio [HR] 0·68, 95% CI 0·49-0·95, p=0·02). Risk of all-cause mortality was lower in participants given isoniazid preventive therapy and ART than participants given ART alone, but this difference was non-significant (HR 0·69, 95% CI 0·43-1·10, p=0·12). Participants with baseline CD4 counts of less than 500 cells per μL had increased risk of tuberculosis, but there was no significant difference in the benefit of isoniazid preventive therapy with ART by sex, baseline CD4 count, or results of tuberculin skin test or IGRAs. 65 (2·5%) of 2611 participants had raised alanine aminotransferase, but data were insufficient to calculate an HR. Isoniazid preventive therapy with ART prevents tuberculosis across demographic and HIV-specific and tuberculosis-specific subgroups, which supports efforts to further increase use of isoniazid preventive therapy with ART broadly among people living with HIV. National Institutes of Health and National Institute of Allergy and Infectious Diseases.


Phyllosphere Fungal Communities of Plum and Antifungal Activity of Indigenous Phenazine-Producing Pseudomonas synxantha Against Monilinia laxa.
European plum (Prunus domestica L.) is a significant commercial crop in Serbia in terms of total fruit production, and is traditionally processed into slivovitz brandy. The brown rot disease caused by Monilinia laxa drastically reduces plum yield almost every year. Fungal communities associated with leaves and fruits of four local Serbian plum cultivars (Požegača, Ranka, Čačanska Lepotica and Čačanska Rodna) were investigated in two phenological stages during early (May) and late (July) fruit maturation. Alpha diversity indices showed that fungal communities were heterogeneous and Beta diversity indicated that autochthonous fungal communities depended upon seasonal changes and the cultivars themselves. The phylum Ascomycota was the most abundant in all samples, with relative abundance (RA) between 46% in the Požegača cultivar (May) and 89% in the Lepotica cultivar (July). The most abundant genus for all plum cultivars in May was Aureobasidium, with RA from 19.27 to 33.69%, followed by Cryptococcus, with 4.8 to 48.80%. In July, besides Cryptococcus, different genera (Metschnikowia, Fusarium, and Hanseniaspora) were dominant on particular cultivars. Among all cultivable fungi, molecular identification of eleven M. laxa isolates from four plum cultivars was performed simultaneously. Bacterial isolates from the plum phyllosphere were tested for their potential antifungal activity against indigenous M. laxa isolates. The most potent antagonist P4/16_1, which significantly reduced mycelial growth of M. laxa, was identified as Pseudomonas synxantha. Further characterization of P4/16_1 revealed the production of volatile organic compounds and phenazine-1-carboxylic acid (PCA). Crude benzene extract of PCA exhibited 57-63% mycelial growth inhibition of M. laxa. LC/MS analysis of the crude extract confirmed the presence of phenazine derivatives amongst other compounds. Scanning electron microscopy revealed morpho-physiological changes in the hyphae of M. laxa isolates caused by the cell culture and the P. synxantha P4/16_1 crude benzene extract. This is the first report of antagonistic activity of P. synxantha against M. laxa induced by diffusible and volatile antifungal compounds, and it appears to be a promising candidate for further investigation for potential use as a biocontrol agent against brown rot-causing fungi.


Effect of citrus peel extracts on the cellular quiescence of prostate cancer cells.
The re-entry of quiescent cancer cells to the cell cycle plays a key role in cancer recurrence, which can pose a high risk after primary treatment. Citrus peel extracts (CPEs) contain compounds that can potentially impair tumour growth; however the mechanism of action and effects on cell cycle regulation remain unclear. In this study, the capacity of an ethyl acetate : hexane extract (CPE/hexane) and water extract (CPE/water) to modulate the cell cycle re-entry of quiescent (PC-3 and LNCaP) prostate cancer cells was tested in an in vitro culture system. Cell cycle analysis showed that the quiescent PC-3 and LNCaP cancer cells in the presence of CPE/water were impaired in their ability to enter the S phase where only 2-3% reduction of G0/G1 cells was noted compared to 12-18% reduction of control cells. In contrast, the CPE/hexane did not show any cell cycle inhibition activity in both cell lines. A low DNA synthesis rate and weak apoptosis were observed in quiescent cancer cells treated with CPEs. Hesperidin and narirutin, the predominant flavonoids found in citrus fruits, were not responsible for the observed biological activity, implicating alternative bioactive compounds. Notably, citric acid was identified as one of the compounds present in CPEs that acts as a cell cycle re-entry inhibitor. Citric acid exhibited a higher cell toxicity effect on PC-3 prostate cancer cells than non-cancerous RWPE-1 prostate cells, suggesting specific benefits for cancer treatment. In conclusion, CPE containing citric acid together with various bioactive compounds may be used as a chemopreventive agent for post-therapy cancer patients.


Dysregulation of the circ_0087502/miR-1179/TGFBR2 pathway supports gemcitabine resistance in pancreatic cancer.
Circular RNAs (circRNAs) are a cohort of non-coding RNAs generated by back-splicing events. Accumulating evidence supports the crucial role of circRNAs in human tumorigenesis, metastasis, and chemoresistance. However, the role and mechanism of circRNA circ_0087502 in pancreatic cancer are yet unknown. The expression and function of circ_0087502 in pancreatic cancer were investigated using qRT-PCR and cell experiments. The predicted binding between circ_0087502 and microRNA-1179 (miR-1179), and between miR-1179 and TGFBR2, were examined using reporter assays. Pancreatic cancer tissues and cell lines were discovered to express circ_0087502 at higher levels. Patients with pancreatic cancer who express circ_0087502 at high levels have a worse prognosis. In addition, circ_0087502 knockdown reduced the proliferation, migration, and invasion of pancreatic cancer cells and made them more sensitive to gemcitabine treatment. We found that circ_0087502 worked as a sponge for miR-1179, allowing miR-1179 to bind to the critical oncogene TGFBR2 in its 3'-untranslated region (3'-UTR). Pancreatic cancer cells were highly resistant to gemcitabine and had increased proliferation, migration, and invasion when miR-1179 was inhibited or overexpressed. These results confirm that circ_0087502 activates the miR-1179/TGFBR2 axis to promote gemcitabine resistance in pancreatic cancer. Thus, our data might lay the groundwork for developing novel therapeutic strategies targeting circ_0087502 in pancreatic cancer patients.


Depressive Symptoms and Their Interactions With Emotions and Personality Traits Over Time: Interaction Networks in a Psychiatric Clinic.
Associations between depression, personality traits, and emotions are complex and reciprocal. The aim of this study is to explore these interactions in dynamical networks and in a linear way over time depending on the severity of depression. Participants included 110 patients with depressive symptoms (DSM-5 criteria) who were recruited between October 2015 and February 2016 during their inpatient stay in a general psychiatric hospital in Hall in Tyrol, Austria. The patients filled out the Beck Depression Inventory-II, a German emotional competence questionnaire (Emotionale Kompetenz Fragebogen), Positive and Negative Affect Schedule, and the German versions of the Big Five Inventory-short form and State-Trait-Anxiety-Depression Inventory regarding symptoms, emotions, and personality during their inpatient stay and at a 3-month follow-up by mail. Network and regression analyses were performed to explore interactions both in a linear and a dynamical way at baseline and 3 months later. Regression analyses showed that emotions and personality traits gain importance for the prediction of depressive symptoms with decreasing symptomatology at follow-up (personality: baseline, adjusted R2 = 0.24, P < .001; follow-up, adjusted R2 = 0.65, P < .001). Network analyses additionally showed that the interaction network of depression, emotions, and personality traits is significantly denser and more interconnected (network comparison test: P = .03) at follow-up than at baseline, meaning that with decreased symptoms interconnections get stronger. During depression, personality traits and emotions are walled off and not strongly interconnected with depressive symptoms in networks. With decreasing depressive symptomatology, interfusing of these areas begins and interconnections become stronger. This finding has practical implications for interventions in an acute depressive state and with decreased symptoms. The network approach offers a new perspective on interactions and is a way to make the complexity of these interactions more tangible.


Routine intracoronary beta-irradiation. Acute and one year outcome in patients at high risk for recurrence of stenosis.
Intracoronary radiation is a promising therapy potentially reducing restenosis following catheter-based interventions. Currently, only limited data on this treatment are available. The feasibility and outcome in daily routine practice, however, is unknown. In 100 consecutive patients, intracoronary beta-radiation was performed with a (90)Strontium system (Novoste Beta-Cathtrade mark) following angioplasty. Predominantly complex (73% type B2 and C) and long lesions (length 24.3+/-15.3 mm) were included (37% de novo, 19% restenotic and 44% in-stent restenotic lesions). Radiation success was 100%. Mean prescribed dose was 19.8+/-2.5 Gy. A pullback procedure was performed in 19% lesions. Geographic miss occurred in 8% lesions. Periprocedural thrombus formation occurred in four lesions, dissection in nine lesions. During hospital stay, no death, acute myocardial infarction, or repeat revascularization was observed. Major adverse cardiac events occurred predominantly between 6 and 12 months after the index procedure with major adverse cardiac event-free survival of 66% at 12 months (one death, 10 Q-wave myocardial infarctions, 23 target vessel revascularizations; ranked for worst event). Routine catheter-based intracoronary beta-radiation therapy after angioplasty is safe and feasible with a high acute procedural success. The clinical 1-year follow-up showed delayed occurrence of major adverse cardiac events between 6 and 12 months after the index procedure.


The fluoride content of enamel as a diagnostic aid in fluorosis.
This study was undertaken to compare the fluoride content ([F]) of sound and hypoplastic enamel of dogs' teeth for use as a diagnostic aid for fluorosis. Enamel biopsies (0.5N HClO4; 15 seconds; 3.143 mm2) were conducted on macroscopically sound areas of the middle buccal surfaces of the right upper canine teeth. The [F], and the calcium concentrations of the etching solutions were determined using the potentiometric analytical method and the flame spectrophotometer respectively. Depth of etch (DOE) was calculated. The results of the study showed that the higher [F] in the hypoplastic enamel when compared to that of sound enamel (p > 0.05), was more a result than a cause of the hypoplasia. In this study, the [F] of the enamel was used successfully to exclude the possibility of fluorosis.


Enhancement of recovery of myocardial function by oxygen free-radical scavengers after reversible regional ischemia.
Reperfusion after reversible regional ischemia has been shown to result in delayed recovery of myocardial function, but the mechanism responsible for this phenomenon remains unknown. We explored the potential role of oxygen-free radicals as mediators of postischemic dysfunction in open-chest dogs undergoing a 15 min occlusion of the left anterior descending coronary artery (LAD) followed by 2 hr of reperfusion. Treated animals (n = 19) received an infusion of the oxygen free-radical scavengers superoxide dismutase (SOD; 15,000 U/kg) and catalase (CAT; 55,000 U/kg) for 1 hr starting 15 min before LAD occlusion, while control animals (n = 20) received an equal volume of saline. SOD and CAT produced no discernible effect on heart rate, aortic pressure, or left atrial pressure. Collateral flow to the ischemic zone (radioactive microspheres) was 0.07 +/- 0.01 ml/min/g in both groups. The size of the occluded bed as determined by postmortem perfusion was 26.1 +/- 1.2% of the left ventricle in the control group and 26.5 +/- 0.9% in the treated group. Systolic wall thickening (an index of regional function) was assessed with an epicardial pulsed-Doppler probe. The two groups exhibited comparable systolic thickening under baseline conditions and similar degrees of dyskinesia during ischemia. Nevertheless, recovery of function (expressed as percent of baseline) was considerably greater in the treated dogs, both at 1 hr (43.8 +/- 14.3 vs 12.8 +/- 11.6) and 2 hr of reperfusion (74.2 +/- 8.4 vs 31.6 +/- 9.8, p less than .005). This improved recovery of function obtained with SOD and CAT suggests that oxygen-free radicals play an important role in the genesis of myocardial dysfunction after a brief episode of regional ischemia.


Validation of a new study skills scale to provide an explanation for depressive symptoms among medical students.
Medical students are faced with enormous academic demands that may influence their emotional wellbeing. The high rate of depression among medical students and its negative impact is an impetus to find explanation for the factors associated with it. Study skills that students possess might be such a factor. The current tools for the assessment of the study skills may have certain limitations, particularly for different cultural settings. This study aimed to develop and validate a Study Skills Inventory (SSI), and to investigate the relationship between the students' study skills and the extent (severity) of depressive symptoms, measured using the validated tool. The first version of the SSI was developed through expert consensus. The inventory was then administered to a randomly selected group of medical students. Confirmatory factor analysis was conducted for the internal validity. External validation was conducted by comparing the results of the SSI with the "Approaches and Study Skills Inventory for Students" (ASSIST). After validation, the correlation between the SSI total score with the Beck Depression Inventory II (BDI-II) total score was investigated using the Pearson correlation coefficient. The means of the total study skills scores for each severity category of depression were compared using ANOVA. A total of 23 items, representing five sub-scales, were included in the inventory. Based on 372 student responses (response rate of 93%), the five-factor solution explained a cumulative variance of 52% and Cronach alpha was 0.84. The SSI total score had a significant negative association with the BDI-II depression score (Pearson correlation of -.348** and P<0.0001). This study showed evidence for acceptable reliability and validity of the newly developed SSI. Poor study skills were found to correlate with higher depressive symptoms. This association needs confirmation in future research and could open a new door for better understanding of student depression.


Identification, assessment and prioritization of ecotoxicological risks on the scale of a territory: Application to WWTP discharges in a geographical area located in northeast Lyon, France.
The ecotoxicological risk assessment methodologies developed up to now mainly focus on local pollution and do not incorporate an evaluation and prioritization of the different risk situations present in the same territory. This article presents the different phases of formulating an innovative methodology developed to fill this gap, and its application to all the 18 WasteWater Treatment Plants (WWTP) of a geographical area located northeast of Lyon, France. The aim was also take into account emerging pollutants that are very often "forgotten" in ecotoxicological risk assessments. The results of the study show the extreme diversity of the ecotoxicity of the pollutants present in discharges, with "minimum" PNEC values in the region of a millionth of a microgram (10-6 μg/l) and "maximum" PNEC values in the region of several tens of micrograms. They also show very considerable diversity of the flows of the receiving watercourses in the territory concerned (from several m3/s to 600 m3/s). The Risk Quotients (RQ) resulting from these 2 datasets, calculated for each WWTP and for each of the 10 pollutants most implicated in ecotoxicological risks (Diclofenac, Amoxicillin, Trimethoprim, Roxithromycin, 17β-estradiol, 17α-Ethynylestradiol, Estrone, Nonylphenol, Octylphenol, Nickel, et NH4+), vary from 0.000002 to 187.7 when using the median concentration values of these pollutants, and from 0.000007 to 3750 when using their maximum concentration values. Globally, they show that: (1) the risks are higher for small streams that receive WWTP discharges of average size, (2) the risks are low to very low for discharges into watercourses with high flow rates.


Reproductive outcomes associated with flame retardants among couples seeking fertility treatment: A paternal perspective.
Polybrominated diphenyl ethers (PBDEs) have been phased out of production for nearly a decade yet are still frequently detected in serum of U.S. adults. PBDE concentrations have been associated with adverse reproductive outcomes and laboratory studies suggest hydroxylated-BDEs (OH-BDEs) may act as endocrine disruptors. We set out to assess the joint effects of paternal and maternal serum PBDE concentrations on in vitro fertilization (IVF) outcomes and the association between paternal serum OH-BDE concentrations and IVF outcomes. This analysis included 189 couples (contributing 285 IVF cycles) recruited between 2006 and 2016 from a longitudinal cohort based at Massachusetts General Hospital Fertility Center who completed at least one IVF cycle and had an available blood sample at study entry. Congeners (47, 99, 100, 153, and 154) and OH-BDEs (3-OH-BDE47, 5-OH-BDE47, 6-OH-BDE47 and 4-OH-BDE49) were quantified in serum. Log-transformed PBDEs and OH-BDEs were modeled in quartiles for associations with IVF outcomes using multivariable generalized mixed models and cluster weighted generalized estimating equations. Lipid-adjusted concentrations of PBDEs and OH-BDEs were higher in females than in male partners. There were no clear patterns of increases in risk of adverse IVF outcomes associated with PBDEs and OH-BDEs. However, some decreases in associations with IVF outcomes were observed in isolated quartiles. Our assessment of couple level exposure is unique and highlights the importance of including male and female exposures in the assessment of the influence of environmental toxicants on pregnancy outcomes.


Cost utility analysis of urethral bulking agents versus midurethral sling in stress urinary incontinence.
The aim of this study was to determine the cost utility of urethral bulking agents (BA) compared with midurethral slings (MUS) in the treatment of stress urinary incontinence (SUI) in patients without urethral hypermobility. A decision tree was constructed to compare the cost utility of urethral BA versus MUS in the setting of SUI without urethral hypermobility. Probability estimates for success, failure, and complications were obtained from the published literature. Immediate-term, short-term, and longer-term complications were accounted for over a 1-year time horizon in the model. One-way and 2-way sensitivity analyses and Monte Carlo simulations were performed to assess the robustness of our results. Our model demonstrated that MUS cost $436,465 more than BA for every 100 women treated in 1 year. Using MUS compared with BA leads to an incremental cost-effectiveness ratio of $70,400 per utility gained. Assuming a willingness to pay of $50,000, this makes MUS not cost-effective as a first-line treatment in many situations. When MUS costs less than $5132, it becomes a cost-effective first-line treatment, and when it costs less than $2035, it is cost saving. Bulking agents are more cost-effective than MUS over a 1-year time horizon in the treatment of SUI in patients without urethral hypermobility. In women who lack urethral hypermobility, BA remain a cost-effective option in this patient population.


Effects of dopaminergic modulation on automatic semantic priming: a double-blind study.
Enhanced automatic spreading of activation in the semantic network has been suggested to underlie formal thought disorder in patients with schizophrenia, but it is not clear how this relates to the dopaminergic dysfunction implicated in the disorder. Previous studies on dopaminergic modulation of priming in healthy volunteers have focused on controlled rather than automatic processes. The present study aimed to examine the effects of both a dopaminergic agonist and a dopaminergic antagonist on semantic priming while minimizing the contribution of controlled processes. We investigated the effects of levodopa (L-Dopa; 100 mg), haloperidol (2 mg) and placebo on priming in healthy participants within a randomized, double-blind, crossover design. We used a pronunciation priming task with word triplets; the middle word was an ambiguous word, whereas the first word of the triplet served to provide either a congruent, incongruent or unbiased context for the target word. Two stimulus onset asynchronies (SOA) were used: 150 ms and 750 ms. The study involved 34 participants. At an SOA of 150 ms, L-Dopa accelerated responses to incongruent targets and subordinate targets of ambiguous words, whereas haloperidol was associated with faster responses in congruent contexts and dominant targets. At an SOA of 750 ms, haloperidol accelerated responses to subordinate targets. Modulations in the relative magnitude of priming according to substance and condition rather than absolute priming were assessed. Effects of L-Dopa on automatic priming processes appear to be different than those on controlled processes. Our results are consistent with those of studies on semantic priming and the effects on antipsychotics in patients with schizophrenia.


Serological evaluation of precolostral serum samples to detect Bovine viral diarrhea virus infections in large commercial dairy herds.
The authors propose that screening newborn calves for Bovine viral diarrhea virus (BVDV) antibody prior to colostrum feeding is a useful strategy to detect herds with endemic BVDV infection. In the current study, precolostral serum samples of newborn calves in 2 Minnesota and 2 California dairy farms were examined. Precolostral BVDV antibodies were detected by serum neutralization and enzyme-linked immunosorbent assay in 7.4% (33/446) and 6.2% (32/515) of newborn calves in the California and Minnesota herds, respectively. The serum samples were also tested by reverse transcription polymerase chain reaction (RT-PCR), and BVDV was detected in 1.6% (7/446) and 3.5% (18/515) of newborn calves in the California and Minnesota herds, respectively. The primary advantages of precolostral testing are that calves congenitally infected with BVDV and seropositive at birth represent a larger percentage of calves born than BVDV-viremic calves and that fewer animals would need to be tested with an antibody test than a RT-PCR or antigen detection test to detect endemic BVDV infections at the herd level. Testing for BVDV antibody in calves prior to colostrum feeding detects fetal infections in both late-gestating cows and nonlactating heifers. Precolostral serum antibody detection is not confounded by vaccination and may be a more sensitive screening method than bulk milk RT-PCR and nonvaccinated sentinel calf strategies in large dairy herds.


Influence of Physiological Gastrointestinal Surfactant Ratio on the Equilibrium Solubility of BCS Class II Drugs Investigated Using a Four Component Mixture Design.
The absorption of poorly water-soluble drugs is influenced by the luminal gastrointestinal fluid content and composition, which control solubility. Simulated intestinal fluids have been introduced into dissolution testing including endogenous amphiphiles and digested lipids at physiological levels; however, in vivo individual variation exists in the concentrations of these components, which will alter drug absorption through an effect on solubility. The use of a factorial design of experiment and varying media by introducing different levels of bile, lecithin, and digested lipids has been previously reported, but here we investigate the solubility variation of poorly soluble drugs through more complex biorelevant amphiphile interactions. A four-component mixture design was conducted to understand the solubilization capacity and interactions of bile salt, lecithin, oleate, and monoglyceride with a constant total concentration (11.7 mM) but varying molar ratios. The equilibrium solubility of seven low solubility acidic (zafirlukast), basic (aprepitant, carvedilol), and neutral (fenofibrate, felodipine, griseofulvin, and spironolactone) drugs was investigated. Solubility results are comparable with literature values and also our own previously published design of experiment studies. Results indicate that solubilization is not a sum accumulation of individual amphiphile concentrations, but a drug specific effect through interactions of mixed amphiphile compositions with the drug. This is probably due to a combined interaction of drug characteristics; for example, lipophilicity, molecular shape, and ionization with amphiphile components, which can generate specific drug-micelle affinities. The proportion of each component can have a remarkable influence on solubility with, in some cases, the highest and lowest points close to each other. A single-point solubility measurement in a fixed composition simulated media or human intestinal fluid sample will therefore provide a value without knowledge of the surrounding solubility topography meaning that variability may be overlooked. This study has demonstrated how the amphiphile ratios influence drug solubility and highlights the importance of the envelope of physiological variation when simulating in vivo drug behavior.


Essential components of health assessment for older people in primary care: a cross-sectional survey of Australian general practitioners.
To examine general practitioners' views about how health assessments for older people should be conducted. General practitioners were randomly sampled from a national database of medical practitioners and invited to complete a survey. Survey items explored general practitioners' views about essential components of a 75+ Health Assessment and who should assess each component, consultation time, use of standardised templates and tools, and home visits. Overall, 185 (19.2%) general practitioners participated. Of 61 items presented, 24 were rated 'essential' by ≥70% of practitioners, with an average estimated consultation time of 65 minutes. Of the 24 essential items, it was perceived that 21 could be assessed by either a general practitioner or clinic nurse. Most practitioners indicated a standardised template (86%) and standardised tools for complex issues (79%) should be used, and home visits conducted (75%). General practitioners agreed on 24 items as essential for every health assessment, with assessments estimated to take more than one hour. Implications for public health: Increases to remuneration for prolonged assessments or mechanisms for improving efficiency and quality of assessments are needed. Acceptable mechanisms may include standardised patient-reported tools, standardised templates and the use of non-medical staff to assist with assessments.


Colorectal complications of renal allograft transplantation.
The occurrence of perforated sigmoid diverticulitis in a renal transplant recipient stimulated a review of colorectal complications in renal allograft recipients. One hundred twenty-five renal transplantations were performed in 113 patients between January 1968 and December 1975. Six patients (5%) were identified as having colorectal complications and five of these patients died as a direct result. Chart analysis of these 113 transplant recipients identified 55 patients as having undergone colonic evaluation (contrast enema, postmortem examination), with seven of these 55 (13%) found to have diverticulosis and major colonic complications eventually developing in four of these seven. Since the mortality from the complications of colorectal diseases in immunosuppressed patients is so prohibitive, in patients with diverticulosis and a previous history suggestive of diverticulitis, consideration should be given to exclusion from transplantation or elective segmental colectomy prior to transplantation.


Effect miR-214-3p on proliferation and apoptosis of breast cancer cells by targeting survivin protein.
Studies showed that microRNAs (miRs) play an important role in the development of breast cancer. It has been shown that there were significant differences between the expression levels of serum miR-214-3p in breast cancer patients and healthy controls. Since survivin is involved in cell cycle and apoptosis, this study aims to investigate the effect of miR-214-3p on the proliferation and apoptosis of breast cancer cells. Dual-Luciferase reporter system was used to validate the cell cycle-related target gene survivin. miRanda and TargetScan were used to predict miR-214-3p target genes. Lipofectamine 2000 was used to transfect the miR-214-3p mimics, miR-NC into the MCF-7 cells. The quantitative Real Time-PCR (qRT-PCR) was used to detect the expression levels of miR-214-3p and survivin. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was used to examine the cell proliferation of breast cancer cells. The flow cytometry assay was used to evaluate the apoptosis of breast cancer cells. Dual-Luciferase reporter assay showed that cells co-transfected with wild-type vector and miR-214-3p mimics had significant lower ratios of hRluc/Luc fluorescence compared to that of the control group (p<0.05). The expression level of miR-214-3p was increased along with the increase of time after transfection, whereas the expression level of survivin mRNA was decreased along with the increase of time post transfection. This result suggests that miR-214-3p regulates the mRNA expression of survivin. Transfection of miR-214-3p inhibitor increased the proliferation of MCF-7 cells and transfection of miR-214-3p mimics decreased the proliferation of MCF-7 cells compared to control group (p<0.05). Survivin gene is a downstream target of miR-214-3p in breast cancer cells. The expression of miR-214-3p and survivin is correlated with the proliferation and apoptosis of breast cancer cells.


Incidence of type 1 diabetes in 0 to 14 year olds in Australia from 2002 to 2017.
To determine the incidence of childhood onset type 1 diabetes in Australia from 2002 to 2017, and analyze incidence rate trends by calendar year, sex, and age at diagnosis. Children newly diagnosed with type 1 diabetes aged <15 years between 2002 and 2017 were identified from the National Diabetes Register, estimated to be ~99% complete. Data were obtained for diagnosis year, sex, age, and residential State/Territory at time of diagnosis. Population estimates by year, sex, single year of age, and State/Territory were obtained from the Australian Bureau of Statistics and Poisson regression used to examine incidence and trends by calendar year, sex, and age group at diagnosis. Between 2002 and 2017, there were 16 783 newly diagnosed cases of type 1 diabetes in children aged < 15 years (8684 boys: 8099 girls), giving a mean incidence of 25.0/1 00 000 person years (95%CI: 24.6, 25.4). A sinusoidal pattern in the incidence rate trend was observed with 5-yearly cycles providing the best model fit. No significant difference was observed in boys compared to girls (IRR 0.98 [95%CI: 0.95, 1.01]). Compared to 0 to 4 year olds, the mean incidence was 75% higher in 5 to 9 year olds, and 224% higher in 10 to 14 year olds. A decreasing incidence rate trend was observed in 0 to 4 year old boys and girls. This study reports updated incidence and incidence rate trends in children and adolescents diagnosed with type 1 diabetes in Australia. A cyclical pattern in incidence trend persists, with an overall decreasing trend observed only in the youngest age group.


The Relevance of the 'Easterlin hypothesis' and the 'new home economics' to fertility movements in Great Britain.
Summary The hypothesis that a family's economic status relative to its aspirations (relative economic status) is an important determinant of its fertility behaviour has been developed and applied to the explanation of swings in American fertility by R. A. Easterlin. However, a recent application by Butz and Ward of a model derived from the 'new home economics' (pioneered by Becker and Mincer) strongly suggests that relative economic status is not the dominant factor in explaining fertility movements in the U.S.A. Rather, both current men's and women's wages operate independently in explaining the movement in fertility, and in particular the decline in fertility is attributed to rising women's wages. In this paper we explore the relevance of both the Easterlin hypothesis and the hypotheses derived from the 'new home economics' to the 1955-75 fertility swing in Great Britain. We find that we must reject the Easterlin hypothesis on the basis of the measures of relative economic status suggested by Easterlin and Wachter. A variant of the Easterlin hypothesis suggested by Oppenheimer does receive some support from the available evidence, and the evidence provides strong support for the model of fertility behaviour derived from the 'new home economics', which emphasizes the distinction between the effects of changes in men's and women's real wages on fertility decisions. The cause of the fertility decline is attributed to rising women's wages and employment opportunities through their direct effect on the opportunity cost of time and children among working wives and through their effect on the labour force participation of married women of childbearing age. The test of this model and the estimates of its parameters are not definitive, however, because of deficiencies in the data and problems of statistical estimation. We nevertheless conclude that both this model and the Oppenheimer variant of the Easterlin hypothesis, as well as other elements of a more comprehensive economic theory of fertility, point to a continuation of low fertility and the possibility of a secular decline with fertility approaching some lower asymptote.


Oxygen Vacancy Induced Flat Phonon Mode at FeSe /SrTiO3 interface.
A high-frequency optical phonon mode of SrTiO3 (STO) was found to assist the high-temperature superconductivity observed recently at the interface between monolayer FeSe and STO substrate. However, the origin of this mode is not clear. Through first-principles calculations, we find that there is a novel polar phonon mode on the surface layers of the STO substrate, which does not exist in the STO crystals. The oxygen vacancies near the FeSe/STO interface drives the dispersion of this phonon mode to be flat and lowers its energy, whereas the charge transfer between STO substrate and FeSe monolayer further reduces its energy to 81 meV. This energy is in good agreement with the experimental value fitted by Lee et al. for the phonon mode responsible for the observed replica band separations and the increased superconducting gap. The oxygen-vacancy-induced flat and polar phonon mode provides clues for understanding the origin of high Tc superconductivity at the FeSe/STO interface.


The impact of I(Kr) blockade on medicinal chemistry programs.
Inhibition of the cardiac I(Kr) current leads to prolongation of the QT interval and to a risk of ventricular arrhythmia. This activity has been observed for a wide range of small molecules and results from their binding to the hERG ion channel. The off-target inhibition of I(Kr) presents a daunting challenge for many medicinal chemistry programs. This review article presents case studies that describe a rang of findings across several projects at Merck. The article begins with a review of findings from the original efforts to identify I(Kr) blockers as antiarrhythmic therapeutics. A discussion follows of in vitro and in vivo assays that have been utilized for the assessment of I(Kr) inhibition. General SAR rules that have been found to be useful guides for diminishing hERG activity in lead compounds are discussed and case studies are presented that illustrate specific observations. The case studies highlight how the issue of hERG antagonism was navigated on four distinct medicinal chemistry programs.


[Miliary tuberculosis and tuberculous peritonitis during infliximab treatment for rheumatoid arthritis].
A 55-year-old woman treated with infliximab for rheumatoid arthritis was admitted due to progressive ascites. A CT scan showed massive ascites, bilateral pleural effusion, disseminated granular shadows in the lung, and multiple swollen mediastinal lymph nodes. A FDG-PET/CT scan showed increases of FDG uptake in the mesentery and peritoneum, mimicking peritoneal carcinomatosis. Subsequent pleural and peritoneal fluid analysis showed elevated adenosine deaminase activity levels with no malignant cells. A right pleural biopsy specimen revealed Langhans giant cells and granulomas. Finally, a diagnosis of miliary tuberculosis was established because cultures of the sputum and gastric fluid were positive for Mycobacterium tuberculosis. Several weeks after a standard anti-tuberculosis regimen with 4 drugs was initiated, her clinical condition and radiological findings ameliorated. Since the initial manifestations of tuberculosis tend to be more severe during treatment of rheumatoid arthritis with tumor necrosis factor-alpha inhibitors such as infliximab due to immune suppression, we should pay closer attention to the possibility of tuberculosis infection in these patients.


Gays, guys, and mchicha mwiba: same-sex relations and subjectivities in Dar es Salaam.
Drawing on 15 months of fieldwork, this article explores ways in which same-sex relations are perceived and performed in Dar es Salaam, Tanzania. While several different constructions of same-sex sexuality coexist in Dar es Salaam, it is common to conceive of same-sex practicing men as falling into two main categories. Men belonging to each of these differ with respect to the corporeal, gendered, and social positions that are open to them, and typically form dyads across the conceptual boundary of difference that runs between them. The article speaks to the importance of examining sexuality and gender in particular sociocultural settings.


Pulmonary arterial hypertension in patients treated by dasatinib.
The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib. This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (n=2) or calcium channel blocker (n=1). After a median follow-up of 9 months (min-max 3-36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (≤20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%. Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib.


AA2P-mediated DNA demethylation synergizes with stem cell agonists to promote expansion of hematopoietic stem cells.
Small molecules have enabled expansion of hematopoietic stem and progenitor cells (HSPCs), but limited knowledge is available on whether these agonists can act synergistically. In this work, we identify a stem cell agonist in AA2P and optimize a series of stem cell agonist cocktails (SCACs) to help promote robust expansion of human HSPCs. We find that SCACs provide strong growth-promoting activities while promoting retention and function of immature HSPC. We show that AA2P-mediated HSPC expansion is driven through DNA demethylation leading to enhanced expression of AXL and GAS6. Further, we demonstrate that GAS6 enhances the serial engraftment activity of HSPCs and show that the GAS6/AXL pathway is critical for robust HSPC expansion.


A fluorophore attached to nicotinic acetylcholine receptor beta M2 detects productive binding of agonist to the alpha delta site.
To study conformational transitions at the muscle nicotinic acetylcholine (ACh) receptor (nAChR), a rhodamine fluorophore was tethered to a Cys side chain introduced at the beta 19' position in the M2 region of the nAChR expressed in Xenopus oocytes. This procedure led to only minor changes in receptor function. During agonist application, fluorescence increased by (Delta F/F) approximately 10%, and the emission peak shifted to lower wavelengths, indicating a more hydrophobic environment for the fluorophore. The dose-response relations for Delta F agreed well with those for epibatidine-induced currents, but were shifted approximately 100-fold to the left of those for ACh-induced currents. Because (i) epibatidine binds more tightly to the alpha gamma-binding site than to the alpha delta site and (ii) ACh binds with reverse-site selectivity, these data suggest that Delta F monitors an event linked to binding specifically at the alpha delta-subunit interface. In experiments with flash-applied agonists, the earliest detectable Delta F occurs within milliseconds, i.e., during activation. At low [ACh] (< or = 10 microM), a phase of Delta F occurs with the same time constant as desensitization, presumably monitoring an increased population of agonist-bound receptors. However, recovery from Delta F is complete before the slowest phase of recovery from desensitization (time constant approximately 250 s), showing that one or more desensitized states have fluorescence like that of the resting channel. That conformational transitions at the alpha delta-binding site are not tightly coupled to channel activation suggests that sequential rather than fully concerted transitions occur during receptor gating. Thus, time-resolved fluorescence changes provide a powerful probe of nAChR conformational changes.


Female Cape sugarbirds (Promerops cafer) modify egg investment both for extra-pair mates and for male tail length.
The differential allocation hypothesis predicts that females should invest more in reproduction when paired with attractive males. We measured egg volume in Cape sugarbirds (Promerops cafer), a sexually dimorphic passerine, in relation to paternity of the offspring and in response to an experimental tail length treatment. We manipulated tail length, after pair formation, but before egg laying: males had their tails either shortened or left unmanipulated. Our manipulation was designed to affect female allocation in a particular breeding attempt rather than long-term mate choice: males with shortened tails would appear to be signalling at a lower level than they should given their quality. We found that egg volume was smaller in the nests of males with experimentally shortened tails but larger when the offspring were the result of extra-pair matings. Both these findings are consistent with the differential allocation hypothesis. We suggest that tail length may be used by females as a cue for mate quality, eliciting reduced female investment when breeding with social mates; and with males with shortened tails.


Cognitive dysfunctions and pathological gambling in patients with Parkinson's disease.
The purpose of this study was to investigate the neuropsychological correlates of pathological gambling (PG) in Parkinson's disease (PD). Fifteen patients with PD affected by PG (identified based on DSM-IV criteria; PD+PG) without clinically evident dementia were compared with 15 nondemented patients with PD not affected by PG (PD-PG). Two groups of patients with PD were matched for age, length of education, and gender. Clinical and neuropsychiatric features were assessed; several cognitive domains, mainly related to executive functions, were explored by means of standardized neuropsychological tasks. PD+PG and PD-PG did not differ on clinical and neuropsychiatric aspects. PD+PG patients performed significantly worse than PD-PG patients on cognitive tasks that evaluated visuo-spatial long-term memory and several frontal lobe functions. After Bonferroni correction, differences remained significant on the Frontal Assessment Battery (FAB) (P = 0.001), on phonological fluency task (P = 0.003), and on the Trail Making Test, part B minus part A (P = 0.002). Logistic regression analysis demonstrated that low scores on the FAB were the only independent predictor of PG (odds ratio, 27.9; 95% CI: 2.82-277.95, P = 0.004). The results indicate an association between PG and frontal lobe dysfunctions in nondemented patients with PD. Low scores on the FAB indicate patients with PD at high risk for PG.


Effects of bodybuilding and protein supplements in saliva, gingival crevicular fluid, and serum.
The effects of bodybuilding and protein supplements on periodontal tissues have not yet been evaluated. The present study aimed to examine the periodontal status and interleukin (IL)-1β, apoptosis-associated speck-like protein containing C-terminal caspase-recruitment domain (ASC), and caspase 1 (CASP1) gene expression levels of body builders compared with those of controls. Twenty-five bodybuilders with gingivitis (BB-G) who used protein powder supplements were compared with 25 nonexercising males with (G) and 25 without (H) gingivitis. Saliva, gingival crevicular fluid (GCF), and serum were collected for gene expression analysis. Plaque index (PI), gingival index (GI), probing depth (PD), clinical attachment level (CAL), and bleeding on probing (BOP) were recorded. GI and BOP were higher in group BB-G and G than in group H (P < 0.01), but PI, PD, and CAL were similar between groups (P > 0.05). In GCF, CASP1, ASC, and IL-1β expression were upregulated in group G compared with groups BB-G and H (P < 0.01). In addition, ASC (P < 0.05) and IL-1β (P < 0.01) were downregulated in group BB-G compared with group H. CASP1, IL-1β (P < 0.01), and ASC in the saliva were downregulated in group BB-G compared with groups H and G (P < 0.05). CASP1, IL-1β, and ASC may play a role in the pathogenesis of gingivitis. Bodybuilding and supplement usage may decrease gingival inflammation by downregulating CASP1, IL-1β, and ASC.


Dissemination of Klebsiella pneumoniae ST11 isolates with carbapenem resistance in integrated and emergency intensive care units in a Chinese tertiary hospital.
The aim of the present study was to investigate the dissemination of carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates in integrated intensive care units (IICUs) and emergency ICUs (EICUs) for controlling the spread of CRKP in different ICUs of the hospital. From January 2016 to April 2017, a total of 46 non-duplicate CRKP isolates were consecutively isolated from a tertiary hospital. The production of carbapenemases was determined by the modified carbapenem inactivation method (mCIM) test. The resistance and virulence-associated genes were detected by PCR and DNA sequencing. A hypermucoviscosity phenotype was identified by the string test. Bacterial clonal relatedness of the CRKP isolates tested was determined by multi-locus sequence typing (MLST) and PFGE. All CRKP isolates showed multiple drug resistance. All CRKP isolates harboured blaKPC-2-encoding carbapenemase and at least one of the other β-lactamase genes tested, with positive rates of 89.1 % (41/46) for blaCTX-M-65. qnrS was found among 76.1 % (35/46) of the CRKP isolates. A hypermucoviscosity phenotype was found in only two (4.3 %, 2/46) CRKP isolates. The virulence-associated genes with positive rates of more than 90 % among the 46 isolates tested included wabG (100 %, 46/46), ycf (100 %, 46/46), ureA (95.6 %, 44/46) and fim H (95.6 %, 44/46). MLST results showed that 46 CRKP isolates belonged to ST11 (95.6 %, 44/46) and ST86 (4.4 %, 2/46). PFGE patterns showed four clusters. The CRKP ST11 clone with co-production of CTX-M-65 and KPC-2 disseminated in ICUs of this tertiary teaching hospital in central China. The emergence of CRKP with a hypermucoviscosity phenotype in ICUs should be of particular concern.


Prospecting for unannotated enzymes: discovery of a 3',5'-nucleotide bisphosphate phosphatase within the amidohydrolase superfamily.
In bacteria, 3',5'-adenosine bisphosphate (pAp) is generated from 3'-phosphoadenosine 5'-phosphosulfate in the sulfate assimilation pathway, and from coenzyme A by the transfer of the phosphopantetheine group to the acyl-carrier protein. pAp is subsequently hydrolyzed to 5'-AMP and orthophosphate, and this reaction has been shown to be important for superoxide stress tolerance. Herein, we report the discovery of the first instance of an enzyme from the amidohydrolase superfamily that is capable of hydrolyzing pAp. Crystal structures of Cv1693 from Chromobacterium violaceum have been determined to a resolution of 1.9 Å with AMP and orthophosphate bound in the active site. The enzyme has a trinuclear metal center in the active site with three Mn(2+) ions. This enzyme (Cv1693) belongs to the Cluster of Orthologous Groups cog0613 from the polymerase and histidinol phosphatase family of enzymes. The values of kcat and kcat/Km for the hydrolysis of pAp are 22 s(-1) and 1.4 × 10(6) M(-1) s(-1), respectively. The enzyme is promiscuous and is able to hydrolyze other 3',5'-bisphosphonucleotides (pGp, pCp, pUp, and pIp) and 2'-deoxynucleotides with comparable catalytic efficiency. The enzyme is capable of hydrolyzing short oligonucleotides (pdA)5, albeit at rates much lower than that of pAp. Enzymes from two other enzyme families have previously been found to hydrolyze pAp at physiologically significant rates. These enzymes include CysQ from Escherichia coli (cog1218) and YtqI/NrnA from Bacillus subtilis (cog0618). Identification of the functional homologues to the experimentally verified pAp phosphatases from cog0613, cog1218, and cog0618 suggests that there is relatively little overlap of enzymes with this function in sequenced bacterial genomes.


What can communication science tell us about promoting optimal dietary behavior?
Four of the 10 leading causes of death can be attributed to poor dietary behaviors. Nutrition professionals continue to struggle with the most effective ways to deliver nutrition messages that will result in changes in dietary behavior. On July 14-15, 2005, the National Cancer Institute and the Division of Nutrition Research Coordination, both of the National Institutes of Health, hosted a meeting to explore the state of the science concerning this issue. This paper provides an introduction to that meeting and the articles that resulted from it.


Management of undifferentiated thyroid cancer.
Management of thyroid carcinoma relies upon the tumour cells maintaining the differentiated functions that are typical of normal thyroid follicular cells, such as: dependence upon thyrotropin for growth, production of thyroglobulin and effective transport of iodine. Likewise, differentiated thyroid carcinomas often exhibit an auspicious clinical behaviour with a slow rate of growth and low potential for invasion and distant metastasis. These features permit therapy of disseminated tumour, effective follow-up surveillance and the assumption of a good prognosis. As each of these features are lost, the opportunities for both disease status assessment and therapeutic intervention diminish accordingly. A major obstacle is our failure to define effective systemic treatments to replace radioiodine therapy, whose loss is consonant with the loss of iodine transport and retention. The extreme of undifferentiated clinical behaviour is epitomized by anaplastic thyroid carcinoma, a rare, terminally dedifferentiated malignancy that is rapidly and invariably fatal. It is important to be attuned to clinical clues suggesting the presence of dedifferentiated tumour and related prognostic signs. This allows the application of currently limited therapeutic options and defines the need for research to develop new systemic treatments.


Replication of MERS and SARS coronaviruses in bat cells offers insights to their ancestral origins.
Previous findings of Middle East Respiratory Syndrome coronavirus (MERS-CoV)-related viruses in bats, and the ability of Tylonycteris-BatCoV HKU4 spike protein to utilize MERS-CoV receptor, human dipeptidyl peptidase 4 hDPP4, suggest a bat ancestral origin of MERS-CoV. We developed 12 primary bat cell lines from seven bat species, including Tylonycteris pachypus, Pipistrellus abramus and Rhinolophus sinicus (hosts of Tylonycteris-BatCoV HKU4, Pipistrellus-BatCoV HKU5, and SARS-related-CoV respectively), and tested their susceptibilities to MERS-CoVs, SARS-CoV, and human coronavirus 229E (HCoV-229E). Five cell lines, including P. abramus and R. sinicus but not T. pachypus cells, were susceptible to human MERS-CoV EMC/2012. However, three tested camel MERS-CoV strains showed different infectivities, with only two strains capable of infecting three and one cell lines respectively. SARS-CoV can only replicate in R. sinicus cells, while HCoV-229E cannot replicate in any bat cells. Bat dipeptidyl peptidase 4 (DPP4) sequences were closely related to those of human and non-human primates but distinct from dromedary DPP4 sequence. Critical residues for binding to MERS-CoV spike protein were mostly conserved in bat DPP4. DPP4 was expressed in the five bat cells susceptible to MERS-CoV, with significantly higher mRNA expression levels than those in non-susceptible cells (P = 0.0174), supporting that DPP4 expression is critical for MERS-CoV infection in bats. However, overexpression of T. pachypus DPP4 failed to confer MERS-CoV susceptibility in T. pachypus cells, suggesting other cellular factors in determining viral replication. The broad cellular tropism of MERS-CoV should prompt further exploration of host diversity of related viruses to identify its ancestral origin.