Mammography facility characteristics associated with interpretive accuracy of screening mammography.
Although interpretive performance varies substantially among radiologists, such variation has not been examined among mammography facilities. Understanding sources of facility variation could become a foundation for improving interpretive performance. In this cross-sectional study conducted between 1996 and 2002, we surveyed 53 facilities to evaluate associations between facility structure, interpretive process characteristics, and interpretive performance of screening mammography (ie, sensitivity, specificity, positive predictive value [PPV1], and the likelihood of cancer among women who were referred for biopsy [PPV2]). Measures of interpretive performance were ascertained prospectively from mammography interpretations and cancer data collected by the Breast Cancer Surveillance Consortium. Logistic regression and receiver operating characteristic (ROC) curve analyses estimated the association between facility characteristics and mammography interpretive performance or accuracy (area under the ROC curve [AUC]). All P values were two-sided. Of the 53 eligible facilities, data on 44 could be analyzed. These 44 facilities accounted for 484 463 screening mammograms performed on 237 669 women, of whom 2686 were diagnosed with breast cancer during follow-up. Among the 44 facilities, mean sensitivity was 79.6% (95% confidence interval [CI] = 74.3% to 84.9%), mean specificity was 90.2% (95% CI = 88.3% to 92.0%), mean PPV1 was 4.1% (95% CI = 3.5% to 4.7%), and mean PPV2 was 38.8% (95% CI = 32.6% to 45.0%). The facilities varied statistically significantly in specificity (P < .001), PPV1 (P < .001), and PPV2 (P = .002) but not in sensitivity (P = .99). AUC was higher among facilities that offered screening mammograms alone vs those that offered screening and diagnostic mammograms (0.943 vs 0.911, P = .006), had a breast imaging specialist interpreting mammograms vs not (0.932 vs 0.905, P = .004), did not perform double reading vs independent double reading vs consensus double reading (0.925 vs 0.915 vs 0.887, P = .034), or conducted audit reviews two or more times per year vs annually vs at an unknown frequency (0.929 vs 0.904 vs 0.900, P = .018). Mammography interpretive performance varies statistically significantly by facility.


Development and validation of a questionnaire for measuring behavior and temperament traits in pet dogs.
To develop and validate a questionnaire to assess behavior and temperament traits of pet dogs. Cross-sectional survey of dog owners. Animals-1,851 dogs belonging to clients of a veterinary teaching hospital or members of national breed clubs and 203 dogs examined by canine behavior practitioners because of behavior problems. Owners were asked to complete a questionnaire consisting of 152 items eliciting information on how dogs responded to specific events and situations in their usual environment. Data from completed questionnaires were subjected to factor analysis, and the resulting factors were tested for reliability and validity. Factor analysis yielded 11 factors from 68 of the original questionnaire items that together accounted for 57% of the common variance in questionnaire item scores. Reliability was acceptable for all but 1 of these factors. Behavior problems in 200 of the 203 dogs with behavior problems could be assigned to 7 diagnostic categories that matched 7 of the factors identified during factor analysis of questionnaire responses. Dogs assigned to particular diagnostic categories had significantly higher scores for corresponding questionnaire factors than did those assigned to unrelated diagnostic categories, indicating that the factors were valid. Validity of the remaining 4 factors could not be examined because of a lack of information on dogs with behavior problems related to these factors. Findings suggest that the resulting 68-item questionnaire is a reliable and valid method of assessing behavior and temperament traits in dogs. The questionnaire may be useful in screening dogs for behavior problems and in evaluating the clinical effects of various treatments for behavior problems.


Annotation and characterization of the Plasmodium vivax rhoptry neck protein 4 (PvRON4).
The tight junction (TJ) is one of the most important structures established during merozoite invasion of host cells and a large amount of proteins stored in Toxoplasma and Plasmodium parasites' apical organelles are involved in forming the TJ. Plasmodium falciparum and Toxoplasma gondii apical membrane antigen 1 (AMA-1) and rhoptry neck proteins (RONs) are the two main TJ components. It has been shown that RON4 plays an essential role during merozoite and sporozoite invasion to target cells. This study has focused on characterizing a novel Plasmodium vivax rhoptry protein, RON4, which is homologous to PfRON4 and PkRON4. The ron4 gene was re-annotated in the P. vivax genome using various bioinformatics tools and taking PfRON4 and PkRON4 amino acid sequences as templates. Gene synteny, as well as identity and similarity values between open reading frames (ORFs) belonging to the three species were assessed. The gene transcription of pvron4, and the expression and localization of the encoded protein were also determined in the VCG-1 strain by molecular and immunological studies. Nucleotide and amino acid sequences obtained for pvron4 in VCG-1 were compared to those from strains coming from different geographical areas. PvRON4 is a 733 amino acid long protein, which is encoded by three exons, having similar transcription and translation patterns to those reported for its homologue, PfRON4. Sequencing PvRON4 from the VCG-1 strain and comparing it to P. vivax strains from different geographical locations has shown two conserved regions separated by a low complexity variable region, possibly acting as a "smokescreen". PvRON4 contains a predicted signal sequence, a coiled-coil α-helical motif, two tandem repeats and six conserved cysteines towards the carboxy-terminus and is a soluble protein lacking predicted transmembranal domains or a GPI anchor. Indirect immunofluorescence assays have shown that PvRON4 is expressed at the apical end of schizonts and co-localizes at the rhoptry neck with PvRON2. Genomic, transcriptional and expression data reported for PvRON4, as well as its primary structure characteristics suggest that this protein participates in reticulocyte invasion, as has been shown for its homologue PfRON4.


Stabilization of blood glucose by cooling with ice: an effective procedure for preservation of samples from adults and newborns.
Glycolysis causes a considerable decrease in blood glucose when whole blood is kept at room temperature without preservative. The most commonly used preservative, NaF, makes analysis of other serum constituents such as sodium and calcium and urea difficult or impossible, an especially serious limitation when sample size must be restricted. In samples at room temperature without preservative, plasma glucose decreased 36 mg/liter per hour in blood from adults and 60 mg/liter per hour in blood from newborns. Cooling on ice slowed these rates to 3.9 and 11, respectively. Plasma potassium increased 0.3 mmol/liter per hour in cooled specimens from both adults and newborns. Sodium, calcium, chloride and urea values were unaffected. We conclude that cooling effectively stabilizes plasma glucose for 4 h in samples from both adults and newborns and that potassium may be measured with negligible change for as long as 1 h and other constituents for the entire period.


Characteristic lipid profiles of canine non-Hodgkin's lymphoma from surgical biopsy tissue sections and fine needle aspirate smears by desorption electrospray ionization--mass spectrometry.
Canine non-Hodgkin's lymphoma (NHL) is a heterogeneous group of cancers representing approximately 15% of all canine cancers. Further, canine NHL mimics human disease in regards to histopathology and clinical behavior and could function as a comparative model. Diagnosis is currently performed by histopathological evaluation of surgical biopsy specimens and fine needle aspirate (FNA) cytology, an alternative and less invasive method for diagnosis. Desorption electrospray ionization - mass spectrometry (DESI-MS) imaging was performed on tissue sections of surgical biopsies and FNA smears. Mass spectra acquired from normal lymph nodes and NHL tumors were explored using multivariate statistics (e.g. principal component analysis). Tissue sections yielded a predicted sensitivity of 100% for normal and 93.1% for tumor. Further, preliminary results suggest B-cell and T-cell lymphoma can be discriminated (CV sensitivity of 95.5% and 85.7%, respectively). Normal and B-cell NHL FNA samples analyzed by DESI produced spectra that were similar to spectra obtained from surgical biopsies. FNA samples were evaluated using a PCA-LDA classification system built using tissue section data, exploring if the chemical information obtained from the different sample types is similar and whether DESI-MS performed on FNA samples is of diagnostic value. FNA prediction rate for normal (85.7%) and B-cell NHL (89.3%) indicated that DESI-MS analysis of FNA, not previously explored, could provide rapid preliminary diagnosis. Certainly, MS provides complementary molecular information to be used in conjunction with histopathology/cytology, potentially improving diagnostic confidence. The methodology outlined here is applicable to canine NHL, further supports canine models of human NHL, and translation to humans is envisioned.


Examining Effects of a Multisite Youth Outreach Program: A Meta-Analysis Approach.
This paper presents the application of a meta-analysis approach to the evaluation of youth-learning data from the nationally distributed This is How We "Role" program. The application of meta-analysis for examining the impact of other multisite youth programs encountering similar data analysis challenges is discussed. At each This is How We "Role" program site, university partners collected data to examine youth-participant learning. Data analysis from these unique sites was challenging as the approach had to accommodate the innate heterogeneity across sites due to differences in implementation, sample size, and learning context. The meta-analysis method revealed details of the underlying variation between sites that could be masked by typical regression approaches, estimated overall program effects, examined subgroups and identified heterogeneity across project sites. The results showed the This is How We "Role" program generally increased learning at each site and as a whole, even though the program effects varied across sites. This example demonstrates the utility of using the meta-analysis approach to similar multi-site youth development programs.


Autoantibody profiling reveals four protein candidate autoantigens associated with systemic lupus erythematosus.
Objectives In systemic lupus erythematosus (SLE) there are typically many autoantibodies. The disease heterogeneity could be better understood with discovery of phenotype-specific antigens targeted by autoantibodies. We here aimed to identify novel autoantigens potentially related to SLE disease and a major complication, atherosclerosis. Methods Antigen microarrays were used to profile IgG autoantibody reactivity against 77 protein fragments (20-140 amino acids (aa) long, median 89 aa) produced within the Human Protein Atlas project, in serum samples from SLE patients ( n = 107) and age- and sex-matched population-based controls ( n = 107). Common carotid intima-media thickness, plaque occurrence and echogenicity were determined by B-mode ultrasound. Results We determined significant differences between patients and controls in IgG reactivity against four proteins. In patients compared to controls, there was an increase of IgG reactivity against zinc finger protein 688 (ZNF688), early B cell factor 2 (EBF2), crystallin, alpha B (CRYAB) and tumor necrosis factor receptor superfamily member 13C (TNFRSF13C). Of these four antigens, only anti-ZNF688 was associated with carotid atherosclerosis (plaque occurrence) and vulnerable plaques in SLE. There was a weak association between anti-EBF2 and SLE disease activity but no significant associations were determined for other measured IgG reactivity. Conclusions In this discovery screening we here demonstrate new candidate autoantigens with differential reactivity (reflecting autoantibody levels) in SLE patients and in controls and in relation to atherosclerosis in SLE.


Gas chromatography time-of-flight mass spectrometry (GC-TOF-MS)-based metabolomics for comparison of caffeinated and decaffeinated coffee and its implications for Alzheimer's disease.
Findings from epidemiology, preclinical and clinical studies indicate that consumption of coffee could have beneficial effects against dementia and Alzheimer's disease (AD). The benefits appear to come from caffeinated coffee, but not decaffeinated coffee or pure caffeine itself. Therefore, the objective of this study was to use metabolomics approach to delineate the discriminant metabolites between caffeinated and decaffeinated coffee, which could have contributed to the observed therapeutic benefits. Gas chromatography time-of-flight mass spectrometry (GC-TOF-MS)-based metabolomics approach was employed to characterize the metabolic differences between caffeinated and decaffeinated coffee. Orthogonal partial least squares discriminant analysis (OPLS-DA) showed distinct separation between the two types of coffee (cumulative Q(2) = 0.998). A total of 69 discriminant metabolites were identified based on the OPLS-DA model, with 37 and 32 metabolites detected to be higher in caffeinated and decaffeinated coffee, respectively. These metabolites include several benzoate and cinnamate-derived phenolic compounds, organic acids, sugar, fatty acids, and amino acids. Our study successfully established GC-TOF-MS based metabolomics approach as a highly robust tool in discriminant analysis between caffeinated and decaffeinated coffee samples. Discriminant metabolites identified in this study are biologically relevant and provide valuable insights into therapeutic research of coffee against AD. Our data also hint at possible involvement of gut microbial metabolism to enhance therapeutic potential of coffee components, which represents an interesting area for future research.


Logistic Principal Component Analysis for Rare Variants in Gene-Environment Interaction Analysis.
The characteristics of low minor allele frequency (MAF) and weak individual effects make genome-wide association studies (GWAS) for rare variant single nucleotide polymorphisms (SNPs) more difficult when using conventional statistical methods. By aggregating the rare variant effects belonging to the same gene, collapsing is the most common way to enhance the detection of rare variant effects for association analyses with a given trait. In this paper, we propose a novel framework of MAF-based logistic principal component analysis (MLPCA) to derive aggregated statistics by explicitly modeling the correlation between rare variant SNP data, which is categorical. The derived aggregated statistics by MLPCA can then be tested as a surrogate variable in regression models to detect the gene-environment interaction from rare variants. In addition, MLPCA searches for the optimal linear combination from the best subset of rare variants according to MAF that has the maximum association with the given trait. We compared the power of our MLPCA-based methods with four existing collapsing methods in gene-environment interaction association analysis using both our simulation data set and Genetic Analysis Workshop 17 (GAW17) data. Our experimental results have demonstrated that MLPCA on two forms of genotype data representations achieves higher statistical power than those existing methods and can be further improved by introducing the appropriate sparsity penalty. The performance improvement by our MLPCA-based methods result from the derived aggregated statistics by explicitly modeling categorical SNP data and searching for the maximum associated subset of SNPs for collapsing, which helps better capture the combined effect from individual rare variants and the interaction with environmental factors.


Family Caregiving During the COVID-19 Pandemic.
The coronavirus disease 2019 (COVID-19) pandemic has negatively affected persons with existing chronic health conditions. The pandemic also has the potential to exacerbate the stresses of family caregiving. We compare family caregivers with noncaregivers on physical, psychosocial, and financial well-being outcomes during the pandemic and determine family caregivers most at risk for adverse outcomes. We conducted a cross-sectional online survey of 576 family caregivers and 2,933 noncaregivers from April to May 2020 in Pittsburgh, PA region with a national supplement. Outcome measures included concurrent anxiety, depression, fatigue, sleep disturbance, social participation, and financial well-being and perceived changes due to COVID-19 (loneliness, financial well-being, food security). We also measured sociodemographic, caregiving contextual variables, and COVID-19-related caregiver stressors (COVID Caregiver Risk Index). Controlling for sociodemographics, family caregivers reported higher anxiety, depression, fatigue, sleep disturbance, lower social participation, lower financial well-being, increased food insecurity (all p < .01), and increased financial worries (p = .01). Caregivers who reported more COVID-19-related caregiver stressors and disruptions reported more adverse outcomes (all p < .01). In addition, caregivers who were female, younger, lower income, providing both personal/medical care, and providing care for cognitive/behavioral/emotional problems reported more adverse outcomes. Challenges of caregiving are exacerbated by the COVID-19 pandemic. Family caregivers reported increased duties, burdens, and resulting adverse health, psychosocial, and financial outcomes. Results were generally consistent with caregiver stress-health process models. Family caregivers should receive increased support during this serious public health crisis.


Identification of the murine H-2D(b) and human HLA-A*0201 MHC class I-restricted HPV6 E7-specific cytotoxic T lymphocyte epitopes.
Recurrent respiratory papillomatosis is caused by human papillomavirus (HPV) infection, most commonly types 6 (HPV-6) and 11 (HPV-11). Due to failed host immune responses, HPV is unable to be cleared from the host, resulting in recurrent growth of HPV-related lesions that can obstruct the lumen of the airway within the upper aerodigestive tract. In our murine model, the HPV-6b and HPV-11 E7 antigens are not innately immunogenic. In order to enhance the host immune responses against the HPV E7 antigen, we linked calreticulin (CRT) to HPV-6b E7 and found that vaccinating C57BL/6 mice with the HPV-6b CRT/E7 DNA vaccine is able to induce a CD8+ T cell response that recognizes an H-2D(b)-restricted E7aa21-29 epitope. Additionally, vaccination of HLA-A*0201 transgenic mice with HPV-6b CRT/E7 DNA generated a CD8+ T cell response against the E7aa82-90 epitope that was not observed in the wild-type C57BL/6 mice, indicating this T cell response is restricted to HLA-A*0201. In vivo cytotoxic T cell killing assays demonstrated that the vaccine-induced CD8+ T cells are able to efficiently kill target cells. Interestingly, the H-2D(b)-restricted E7aa21-29 sequence and the HLA-A*0201-restricted E7aa82-90 sequence are conserved between HPV-6b and HPV-11 and may represent shared immunogenic epitopes. The identification of the HPV-6b/HPV-11 CD8+ T cell epitopes facilitates the evaluation of various immunomodulatory strategies in preclinical models. More importantly, the identified HLA-A*0201-restricted T cell epitope may serve as a peptide vaccination strategy, as well as facilitate the monitoring of vaccine-induced HPV-specific immunologic responses in future human clinical trials.


Cost-Effectiveness of Disease Management Programs for Cardiovascular Risk and COPD in The Netherlands.
Disease management programs (DMPs) for cardiovascular risk (CVR) and chronic obstructive pulmonary disease (COPD) are increasingly implemented in The Netherlands to improve care and patient's health behavior. The aim of this study was to provide evidence about the (cost-) effectiveness of Dutch DMPs as implemented in daily practice. We compared the physical activity, smoking status, quality-adjusted life-years, and yearly costs per patient between the most and the least comprehensive DMPs in four disease categories: primary CVR prevention, secondary CVR prevention, both types of CVR prevention, and COPD (N = 1034). Propensity score matching increased comparability between DMPs. A 2-year cost-utility analysis was performed from the health care and societal perspectives. Sensitivity analysis was performed to estimate the impact of DMP development and implementation costs on cost-effectiveness. Patients in the most comprehensive DMPs increased their physical activity more (except for primary CVR prevention) and had higher smoking cessation rates. The incremental QALYs ranged from -0.032 to 0.038 across all diseases. From a societal perspective, the most comprehensive DMPs decreased costs in primary CVR prevention (certainty 57%), secondary CVR prevention (certainty 88%), and both types of CVR prevention (certainty 98%). Moreover, the implementation of comprehensive DMPs led to QALY gains in secondary CVR prevention (certainty 92%) and COPD (certainty 69%). The most comprehensive DMPs for CVR and COPD have the potential to be cost saving, effective, or cost-effective compared with the least comprehensive DMPs. The challenge for Dutch stakeholders is to find the optimal mixture of interventions that is most suited for each target group.


Electrogenic sodium pumping in rabbit small intestinal smooth muscle.
Oscillations in the activity of an electrogenic Na pump has been suggested as the ionic mechanism underlying the intestinal control potential (slow wave). We investigated the electrogenicity of this pump in rabbit jejunal smooth muscle. Potassium admission to Na-rich tissues caused a large increase in membrane potential which after 10--20 min decreased toward values comparable with those of normal tissues. This hyperpolarization far exceeded EK and could be prevented by cooling or by ouabain. No hyperpolarization occurred upon K admission to Li-rich tissues in the absence of Na. Thus, the pump in this tissue can operate electrogenically. Goldman's equation was modified so as to account for the pump's contribution to the membrane potential. Using this equation, the calculated contribution of the pump, under normal "steady-state" conditions, is unlikely to exceed a few millivolts. It is concluded that although the pump in this tissue can be electrogenic, its contribution may be smaller than that required if the intestinal control potential resulted from rhythmic turning off and on of the electrogenic Na pump.


A survey of clinicians regarding respiratory physiotherapy intervention for intubated and mechanically ventilated patients with community-acquired pneumonia. What is current practice in Australian ICUs?
Community-acquired pneumonia (CAP) is a common cause for intensive care unit (ICU) admission resulting in high morbidity and mortality. There is a paucity of evidence regarding respiratory physiotherapy for intubated and mechanically ventilated patients with CAP, and anecdotally clinical practice is variable in this cohort. The aims of this study were to identify the degree of variability in physiotherapy practice for intubated adult patients with CAP and to explore ICU physiotherapist perceptions of current practice for this cohort and factors that influence physiotherapy treatment mode, duration, and frequency. A survey was developed based on common aspects of assessment, clinical rationale, and intervention for intubated and mechanically ventilated patients. Senior ICU physiotherapists across 88 Australian public and private hospitals were recruited. The response rate was 72%. Respondents (n = 75) stated their main rationale for providing a respiratory intervention were improved airway clearance (98%, n = 60/61), alveolar recruitment (74%, n = 45/61), and gas exchange (33%, n = 20/61). Respondents estimated that average intervention lasted between 16 and 30 minutes (70% of respondents, n = 41/59) and would be delivered once (44%) or twice (44%) daily. Results indicated large variability in reported practice; however, trends existed regarding positioning in alternate side-lying (81%, n = 52/64) or affected lung uppermost (83%, n = 53/64) and use of hyperinflation techniques (81%, 52/64). Decisions regarding duration were reported to be based on sputum volume (95%), viscosity (93%) and purulence (88%), cough effectiveness (95%), chest X-ray (87%), and auscultation (84%). Sixty percent reported that workload and staffing affected intervention duration and frequency. Intervention time was more likely increased when there was greater staffing (P = .03). Respiratory physiotherapy treatment varies for intubated patients with CAP. Further research is required to determine what is considered best practice for this patient population.


Collaborative decision skills training: Feasibility and preliminary outcomes of a novel intervention.
Increasing consumer empowerment and agency in treatment decision-making is a priority for improving recovery among people with serious mental illness (SMI), as it is associated with a number of positive outcomes, including improved treatment engagement and satisfaction. Although there are many tools to promote initiation of shared decision-making by providers, there are few tools empowering consumers to independently initiate collaborative decision-making (CDM). Therefore, this study tests the feasibility of a novel skills training intervention for outpatients with SMI, collaborative decision skills training (CDST). Twenty-one consumers with SMI currently receiving community-based day services participated in CDST. Four areas of feasibility were assessed-acceptability, demand, practicality, and preliminary evidence of efficacy. Feasibility results were favorable, including high acceptability and practicality. Demand results were mixed: rates of attendance were high and attrition was low, but participants did not complete homework as often as expected. Finally, there was evidence CDST has a positive impact on targeted outcomes; participants reported an increased sense of personal recovery, and displayed improvements in both knowledge and skills targeted by CDST. CDST is feasible to implement with fidelity and is received well by participants. Next steps include larger controlled trials of CDST, which will better inform efficacy and implementation related questions. (PsycINFO Database Record (c) 2020 APA, all rights reserved).


Increased sensitivity to climate change in disturbed ecosystems.
Human domination of the biosphere includes changes to disturbance regimes, which push many ecosystems towards early-successional states. Ecological theory predicts that early-successional ecosystems are more sensitive to perturbations than mature systems, but little evidence supports this relationship for the perturbation of climate change. Here we show that vegetation (abundance, species richness and species composition) across seven European shrublands is quite resistant to moderate experimental warming and drought, and responsiveness is associated with the dynamic state of the ecosystem, with recently disturbed sites responding to treatments. Furthermore, most of these responses are not rapid (2-5 years) but emerge over a longer term (7-14 years). These results suggest that successional state influences the sensitivity of ecosystems to climate change, and that ecosystems recovering from disturbances may be sensitive to even modest climatic changes. A research bias towards undisturbed ecosystems might thus lead to an underestimation of the impacts of climate change.


Expression of a cocaine-sensitive norepinephrine transporter in the human placental syncytiotrophoblast.
Maternal-facing brush border membrane vesicles isolated from normal term human placentas were found to accumulate norepinephrine in a concentrative manner in the presence of an inwardly directed NaCl gradient. Both Na+ and Cl- were obligatory for maximal uptake. The NaCl-dependent norepinephrine uptake was further stimulated by the presence of K+ or an acidic pH in the intravesicular medium. The uptake process was electrogenic, being stimulated by an inside-negative membrane potential, and this characteristic was observed in the absence as well as in the presence of K+ inside the vesicles. Kinetic analyses revealed that one Na+ and one Cl- were involved per transport of one norepinephrine molecule. The apparent Michaelis-Menten constant for norepinephrine was 104 +/- 5nM. The uptake process exhibited higher affinity for dopamine than for norepinephrine but had low affinity for serotonin and histamine. The uptake of norepinephrine was inhibited very effectively by nomifensine, desipramine, imipramine, and cocaine, but much less effectively by bupropion and GBR 12909. Northern blot analysis with the cDNA of the human (SK-N-SH cell) norepinephrine transporter as the probe revealed that the human placenta contained two mRNAs, 5.8 and 3.6 kb in size, which hybridized to the probe. The JAR human placental choriocarcinoma cells were found unable to accumulate norepinephrine in a NaCl-dependent manner. These cells were also found not to contain mRNAs which hybridized to the norepinephrine cDNA probe in northern blot. It is concluded that the human placental syncytiotrophoblast expresses a cocaine-sensitive norepinephrine transporter and that these findings may be directly relevant and important to the clinical complications of maternal cocaine abuse during pregnancy.


Co-morbidity and predictors of health status in older rural breast cancer survivors.
More than 66% of the 200,000 newly diagnosed annual breast cancers in the US occurs in women over 55 years. Treatment advances result in excellent survival, yet older breast cancer survivors with co-morbidity may live longer, but not better after cancer. Decline in physical function, increased social isolation, and diminished economic resources increase vulnerability among older women. Rural women represent an underserved population. The purpose is to examine associations between comorbidity and predictors of health status among older rural breast cancer survivors. Baseline data of 331 BCS age 55-90 years enrolled in the Rural Breast Cancer Survivors Study. Four surveys were used for data collection. Self-reported prescription medications were used as proxy for co-morbidity. Bivariate tests of association and multivariable recursive partitioning techniques were used for analysis. Mean number of prescription medication categories reported was 3.68 (SD = 2.3; range = 0-12). Common prescription categories were: anti-hormonal, anti-hypertensive, and cholesterol- reducing agents. 69% was overweight or obese. BMI >31 was significantly associated with both poorer physical and mental health. Multivariate analyses indicated physical health status was predicted by BMI, comorbid conditions, social support, and adverse changes in economic lifestyle. The same variables, with the exception of BMI, were predictors of mental health status. Assessing co-morbid conditions, mental health status, social support, and economic burden after breast cancer treatment may better inform cancer survivorship care and comprehensive geriatric assessment.


Premature Myocardial Infarction in the Middle East and North Africa: Rationale for the Gulf PREVENT Study.
The Middle East and North Africa (MENA) region has a high burden of morbidity and mortality due to premature (≤55 years in men; ≤65 years in women) myocardial infarction (MI) and acute coronary syndrome (ACS). Despite this, the prevalence of risk factors in patients presenting with premature MI or ACS is incompletely described. We compared lifestyle, clinical risk factors, and biomarkers associated with premature MI/ACS in the MENA region with selected non-MENA high-income countries. We identified English-language, peer-reviewed publications through PubMed (up to March 2018). We used the World Bank classification system to categorize countries. Patients with premature MI/ACS in the MENA region had a higher prevalence of smoking than older patients with MI/ACS but a lower prevalence of diabetes, hypertension, and dyslipidemia. Men with premature MI/ACS had a higher prevalence of smoking than women but a lower prevalence of diabetes and hypertension. The MENA region had sparse data on lifestyle, diet, psychological stress, and physical activity. To address these knowledge gaps, we initiated the ongoing Gulf Population Risks and Epidemiology of Vascular Events and Treatment (Gulf PREVENT) case-control study to improve primary and secondary prevention of premature MI in the United Arab Emirates, a high-income country in the MENA region.


Asymmetric total syntheses of tuberostemonine, didehydrotuberostemonine, and 13-epituberostemonine.
Detailed experimental approaches toward the pentacyclic Stemona alkaloids tuberostemonine and didehydrotuberostemonine and the close analogue 13-epituberostemonine are described. The syntheses originate with a hydroindolinone derivative that can be obtained on a large scale in a single step from carbobenzoxy-protected l-tyrosine. Highlights of the conversion of this hydroindolinone to the target structures are the three-fold use of ruthenium catalysts, first in azepine ring-closing metathesis and then in alkene isomerization and cross-metathesis propenyl-vinyl exchange, as well as the stereoselective attachment of a gamma-butyrolactone ring to a tetracycle core structure by use of a lithiated asymmetric bicyclo[3.2.1]octane (ABO) ortho ester. Structural analysis by density functional theory (DFT) methods revealed that the ease of oxidation of the natural product is likely due to the conformational preferences of the pyrrolidine and the fused cyclohexane rings.


The combined impact of adherence to five lifestyle factors on all-cause, cancer and cardiovascular mortality: a prospective cohort study among Danish men and women.
Individual lifestyle factors have been associated with lifestyle diseases and premature mortality by an accumulating body of evidence. The impact of a combination of lifestyle factors on mortality has been investigated in several studies, but few have applied a simple index taking national guidelines into account. The objective of the present prospective cohort study was to investigate the combined impact of adherence to five lifestyle factors (smoking, alcohol intake, physical activity, waist circumference and diet) on all-cause, cancer and cardiovascular mortality based on international and national health recommendations. A Cox proportional hazards model was used to estimate hazard ratios (HR) with 95 % CI. During a median follow-up of 14 years, 3941 men and 2827 women died. Among men, adherence to one additional health recommendation was associated with an adjusted HR of 0·73 (95 % CI 0·71, 0·75) for all-cause mortality, 0·74 (95 % CI 0·71, 0·78) for cancer mortality and 0·70 (95 % CI 0·65, 0·75) for cardiovascular mortality. Among women, the corresponding HR was 0·72 (95 % CI 0·70, 0·75) for all-cause mortality, 0·76 (95 % CI 0·73, 0·80) for cancer mortality and 0·63 (95 % CI 0·57, 0·70) for cardiovascular mortality. In the present study, adherence to merely one additional health recommendation had a protective effect on mortality risk, indicating a huge potential in enhancing healthy lifestyle behaviours of the population.


Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas.
Insulin-like growth factor-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal (GI) cancers. In this study, we sought to evaluate the effect of a new tyrosine kinase inhibitor of IGF-IR, NVP-AEW541, on the signal transduction and the progression of GI carcinomas. We assessed the effect of NVP-AEW541 on signal transduction, proliferation, survival, and migration in four GI cancer cells: colorectal adenocarcinoma HT29, pancreatic adenocarcinoma BxPC3, esophageal squamous cell carcinoma TE1, and hepatoma PLC/PRF/5. The effects of NVP-AEW541 alone and with chemotherapy were studied in vitro and in nude mouse xenografts. We also analyzed the effects of NVP-AEW541 on insulin signals and hybrid receptor formation between IGF-IR and insulin receptor. NVP-AEW541 blocked autophosphorylation of IGF-IR and both Akt and extracellular signal-regulated kinase activation by IGF but not by insulin. NVP-AEW541 suppressed proliferation and tumorigenicity in vitro in a dose-dependent manner in all cell lines. The drug inhibited tumor as a single agent and, when combined with stressors, up-regulated apoptosis in a dose-dependent fashion and inhibited mobility. NVP-AEW541 augmented the effects of chemotherapy on in vitro growth and induction of apoptosis. Moreover, the combination of NVP-AEW541 and chemotherapy was highly effective against tumors in mice. This compound did not influence hybrid receptor formation. Thus, NVP-AEW541 may have significant therapeutic utility in human GI carcinomas both alone and in combination with chemotherapy.


Toll-like receptor 2bright cells identify circulating monocytes in human and non-human primates.
Polychromatic flow cytometry is a useful tool for monitoring circulating whole blood monocytes, although gating strategies often vary depending on the study. Increased analyses of the myeloid system have revealed monocytes to be more plastic than previously understood and uncovered changes among surface markers previously considered to be stable. The myeloid system has also been found to have disparate surface markers between mouse, human, and non-human primate studies, which further complicates examination between species. This study has found bright Toll-like receptor 2 (TLR2) expression to be a consistent surface marker of circulating whole blood monocytes in humans and two species of macaques. Furthermore, within our pigtailed macaque model of HIV-associated CNS disease, where monocyte surface markers have previously been shown to reorganize during acute infection, TLR2 remains stably expressed on the surface of classical, intermediate, and non-classical monocytes. Our findings demonstrate that TLR2 is a useful surface marker for including all monocytes during other phenotypic changes that may alter the expression of common surface receptors. These results provide a practical tool for studying all types of monocytes during inflammation and infection within humans and macaques. © 2017 International Society for Advancement of Cytometry.


Antibacterial phototoxic effects of synthetic asymmetric and glycosylated curcuminoids in aqueous formulations: studies on curcumin and curcuminoids. LIV.
The aim of this study was to evaluate the in vitro phototoxic potential of synthetic asymmetric and glycosylated curcuminoids on planktonic model bacteria by counting the colony forming units. The Gram-positive Enterococcus faecalis and the Gram-negative Escherichia coli were exposed to aqueous solutions of the curcuminoids (⩽2.5 μM) in the presence or absence of selected pharmaceutical excipients (Pluronic F127, PEG 400 and HPγCD) in combination with a low irradiation dose (5 J/cm(2); λmax: 450 nm) of constant irradiance and time. All the asymmetric curcuminoids, but only one of the glycosylated curcuminoids demonstrated substantial phototoxic effect on E.faecalis (⩾4.7 log reduction). Only two of the asymmetric curcuminoids showed a moderate to low phototoxic effect on the more persistent E.coli. This study emphasized that aromatic hydroxyl substituents in the para-position are important to maintain the phototoxic potential of curcuminoids independent of molecular symmetry. Glycosylation of the aromatic substituents resulted in a substantial loss in phototoxicity towards planktonic bacteria, an apparent change in the non-radiative S₁-decay process and a weaker interaction with Pluronic F127 compared to the non-glycosylated curcuminoids. The selected excipients Pluronic F127, PEG 400 and HPγCD strongly influenced the phototoxic potential of the unsymmetrical, non-glycosylated compounds.


Microscopic kinetics and energetics distinguish GABA(A) receptor agonists from antagonists.
Although agonists and competitive antagonists presumably occupy overlapping binding sites on ligand-gated channels, these interactions cannot be identical because agonists cause channel opening whereas antagonists do not. One explanation is that only agonist binding performs enough work on the receptor to cause the conformational changes that lead to gating. This idea is supported by agonist binding rates at GABA(A) and nicotinic acetylcholine receptors that are slower than expected for a diffusion-limited process, suggesting that agonist binding involves an energy-requiring event. This hypothesis predicts that competitive antagonist binding should require less activation energy than agonist binding. To test this idea, we developed a novel deconvolution-based method to compare binding and unbinding kinetics of GABA(A) receptor agonists and antagonists in outside-out patches from rat hippocampal neurons. Agonist and antagonist unbinding rates were steeply correlated with affinity. Unlike the agonists, three of the four antagonists tested had binding rates that were fast, independent of affinity, and could be accounted for by diffusion- and dehydration-limited processes. In contrast, agonist binding involved additional energy-requiring steps, consistent with the idea that channel gating is initiated by agonist-triggered movements within the ligand binding site. Antagonist binding does not appear to produce such movements, and may in fact prevent them.


For whom is a health-promoting intervention effective? Predictive factors for performing activities of daily living independently.
Health-promoting interventions tailored to support older persons to remain in their homes, so-called "ageing in place" is important for supporting or improving their health. The health-promoting programme "Elderly Persons in the Risk Zone," (EPRZ) was set up for this purpose and has shown positive results for maintaining independence in activities of daily living for older persons 80 years and above at 1- and 2 year follow-ups. The aim of this study was to explore factors for maintaining independence in the EPRZ health-promoting programme. Total of 459 participants in the original trial was included in the analysis; 345 in the programme arm and 114 in the control arm. Thirteen variables, including demographic, health, and programme-specific indicators, were chosen as predictors for independence of activities of daily living. Logistic regression was performed separately for participants in the health promotion programme and in the control arm. In the programme arm, being younger, living alone and self-rated lack of tiredness in performing mobility activities predicted a positive effect of independence in activities of daily living at 1-year follow-up (odds ratio [OR] 1.18, 1.73, 3.02) and 2-year, (OR 1.13, 2.01, 2.02). In the control arm, being less frail was the only predictor at 1-year follow up (OR 1.6 1.09, 2.4); no variables predicted the outcome at the 2-year follow-up. Older persons living alone - as a risk of ill health - should be especially recognized and offered an opportunity to participate in health-promoting programmes such as "Elderly Persons in the Risk Zone". Further, screening for subjective frailty could form an advantageous guiding principle to target the right population when deciding to whom health-promoting intervention should be offered. The original clinical trial was registered at ClinicalTrials.gov. Identifier: NCT00877058 , April 6, 2009.


Spiritual Benefit from Cannabis.
Like many mind-altering plants, cannabis has been part of spiritual practices for thousands of years. It has deep roots in Hinduism, Islam, Rastafarianism, and indigenous traditions in Asia, Africa, and elsewhere. Yet almost no attention has been given to how contemporary adults employ it spiritually. A sample of 1087 participants (mean age = 38.9) completed an online survey assessing their use of cannabis and other substances, as well as spiritual and psychological characteristics. Spiritual benefit from cannabis was reported by 66.1% of the sample, and 5.5% reported it had sometimes been a spiritual hindrance. A MANOVA showed that those who reported spiritual benefit differed significantly from those who did not on several outcome variables, and a post hoc descriptive discriminant analysis revealed that expansiveness motivation, non-theistic daily spiritual experience, meditation frequency, and two mindfulness facets contributed most to differentiating the two groups. The majority of the sample (63%) was free of cannabis use disorder. Compared to disordered groups, the non-disordered group was significantly older and scored lower on experiential avoidance, psychological distress, and several motives for use. Results suggest that spiritual motives for cannabis use may be widespread. Implications for future research on spiritual use of cannabis are discussed.


Intrinsic phototransduction persists in melanopsin-expressing ganglion cells lacking diacylglycerol-sensitive TRPC subunits.
In mammals, intrinsically photosensitive retinal ganglion cells (ipRGCs) mediate various non-image-forming photic responses, such as circadian photoentrainment, pupillary light reflex and pineal melatonin suppression. ipRGCs directly respond to environmental light by activation of the photopigment melanopsin followed by the opening of an unidentified cation-selective channel. Studies in heterologous expression systems and in the native retina have strongly implicated diacylglycerol-sensitive transient receptor potential channels containing TRPC3, TRPC6 and TRPC7 subunits in melanopsin-evoked depolarization. Here we show that melanopsin-evoked electrical responses largely persist in ipRGCs recorded from early postnatal (P6-P8) and adult (P22-P50) mice lacking expression of functional TRPC3, TRPC6 or TRPC7 subunits. Multielectrode array (MEA) recordings performed at P6-P8 stages under conditions that prevent influences from rod/cone photoreceptors show comparable light sensitivity for the melanopsin-evoked responses in these mutant mouse lines in comparison to wild-type (WT) mice. Patch-clamp recordings from adult mouse ipRGCs lacking TRPC3 or TRPC7 subunits show intrinsic light-evoked responses equivalent to those recorded in WT mice. Persistence of intrinsic light-evoked responses was also noted in ipRGCs lacking TRPC6 subunits, although with significantly smaller magnitudes. These results demonstrate that the melanopsin-evoked depolarization in ipRGCs is not mediated by either TRPC3, TRPC6 or TRPC7 channel subunits alone. They also suggest that the melanopsin signaling pathway includes TRPC6-containing heteromeric channels in mature retinas.


Integration of Genome-Wide SNP Data and Gene-Expression Profiles Reveals Six Novel Loci and Regulatory Mechanisms for Amino Acids and Acylcarnitines in Whole Blood.
Profiling amino acids and acylcarnitines in whole blood spots is a powerful tool in the laboratory diagnosis of several inborn errors of metabolism. Emerging data suggests that altered blood levels of amino acids and acylcarnitines are also associated with common metabolic diseases in adults. Thus, the identification of common genetic determinants for blood metabolites might shed light on pathways contributing to human physiology and common diseases. We applied a targeted mass-spectrometry-based method to analyze whole blood concentrations of 96 amino acids, acylcarnitines and pathway associated metabolite ratios in a Central European cohort of 2,107 adults and performed genome-wide association (GWA) to identify genetic modifiers of metabolite concentrations. We discovered and replicated six novel loci associated with blood levels of total acylcarnitine, arginine (both on chromosome 6; rs12210538, rs17657775), propionylcarnitine (chromosome 10; rs12779637), 2-hydroxyisovalerylcarnitine (chromosome 21; rs1571700), stearoylcarnitine (chromosome 1; rs3811444), and aspartic acid traits (chromosome 8; rs750472). Based on an integrative analysis of expression quantitative trait loci in blood mononuclear cells and correlations between gene expressions and metabolite levels, we provide evidence for putative causative genes: SLC22A16 for total acylcarnitines, ARG1 for arginine, HLCS for 2-hydroxyisovalerylcarnitine, JAM3 for stearoylcarnitine via a trans-effect at chromosome 1, and PPP1R16A for aspartic acid traits. Further, we report replication and provide additional functional evidence for ten loci that have previously been published for metabolites measured in plasma, serum or urine. In conclusion, our integrative analysis of SNP, gene-expression and metabolite data points to novel genetic factors that may be involved in the regulation of human metabolism. At several loci, we provide evidence for metabolite regulation via gene-expression and observed overlaps with GWAS loci for common diseases. These results form a strong rationale for subsequent functional and disease-related studies.


BOLD cardiovascular magnetic resonance at 3.0 tesla in myocardial ischemia.
The purpose of this study was to determine the ability of blood oxygen level dependent (BOLD) cardiovascular magnetic resonance (CMR) to detect stress-inducible myocardial ischemic reactions in the presence of angiographically significant coronary artery disease (CAD). Forty-six patients (34 men; age 65 ± 9 years,) with suspected or known coronary artery disease underwent CMR at 3Tesla prior to clinically indicated invasive coronary angiography. BOLD CMR was performed in 3 short axis slices of the heart at rest and during adenosine stress (140 μg/kg/min) followed by late gadolinium enhancement (LGE) imaging. In all 16 standard myocardial segments, T2* values were derived at rest and under adenosine stress. Quantitative coronary angiography served as the standard of reference and defined normal myocardial segments (i.e. all 16 segments in patients without any CAD), ischemic segments (i.e. supplied by a coronary artery with ≥50% luminal narrowing) and non-ischemic segments (i.e. supplied by a non-significantly stenosed coronary artery in patients with significant CAD). Coronary angiography demonstrated significant CAD in 23 patients. BOLD CMR at rest revealed significantly lower T2* values for ischemic segments (26.7 ± 11.6 ms) compared to normal (31.9 ± 11.9 ms; p < 0.0001) and non-ischemic segments (31.2 ± 12.2 ms; p = 0.0003). Under adenosine stress T2* values increased significantly in normal segments only (37.2 ± 14.7 ms; p < 0.0001). Rest and stress BOLD CMR at 3Tesla proved feasible and differentiated between ischemic, non-ischemic, and normal myocardial segments in a clinical patient population. BOLD CMR during vasodilator stress identified patients with significant CAD.


A retrospective cohort study of comorbidity trajectories associated with traumatic brain injury in veterans of the Iraq and Afghanistan wars.
To identify and validate trajectories of comorbidity associated with traumatic brain injury in male and female Iraq and Afghanistan war Veterans (IAV). Derivation and validation cohorts were compiled of IAV who entered the Department of Veterans Affairs (VA) care and received 3 years of VA care between 2002-2011. Chronic disease and comorbidities associated with deployment including TBI were identified using diagnosis codes. A latent class analysis (LCA) of longitudinal comorbidity data was used to identify trajectories of comorbidity. LCA revealed five trajectories that were similar for women and men: (1) Healthy, (2) Chronic Disease, (3) Mental Health, (4) Pain and (5) Polytrauma Clinical Triad (PCT: pain, mental health and TBI). Two additional classes found in men were 6) Minor Chronic and 7) PCT with chronic disease. Among these gender-stratified trajectories, it was found that women were more likely to experience headache (Pain trajectory) and depression (Mental Health trajectory), while men were more likely to experience lower back pain (Pain trajectory) and substance use disorder (Mental Health trajectory). The probability of TBI was highest in the PCT-related trajectories, with significantly lower probabilities in other trajectories. It was found that TBI was most common in PCT-related trajectories, indicating that TBI is commonly comorbid with pain and mental health conditions for both men and women. The relatively young age of this cohort raises important questions regarding how disease burden, including the possibility of neurodegenerative sequelae, will accrue alongside normal age-related decline in individuals with TBI. Additional 'big data' methods and a longer observation period may allow the development of predictive models to identify individuals with TBI that are at-risk for adverse outcomes.


Do the abnormal results of an implantation renal biopsy affect the donor renal function?
Living kidney donation has become an important source for renal transplantation. Thus, renal function after donation is an important issue. In this study, we examined histological abnormalities in implantation biopsy specimens from living kidney donors and analyzed the renal function of the remaining kidney. Using the 2007 Banff classification system, we analyzed 121 kidneys from living donors who underwent implantation biopsies (IBs) between 2010 and 2011. Donor characteristics, intraoperative factors, and perioperative renal functions, such as serum creatinine and glomerular filtration rate (GFR), were evaluated. Univariate and multivariate regression analyses were performed to identify the factors related to each histological abnormality and postoperative 1-year donor renal function. Most histological abnormalities in healthy living donors were scored as 1 on the Banff scale. Univariate and multivariate analyses revealed that donor age was the only preoperative factor related to tubular atrophy (odds ratio [OR] = 1.104; P = .012) and glomerular sclerosis (OR = 1.050; P = .019). Intraoperative factors were not related to histological parameters. And histological abnormalities did not affect postoperative 1-year renal function. In contrast, donor age, preoperative GFR, and estimated blood loss were significantly related to 1-year postoperative GFR. Most histological abnormalities in healthy living donors were minor. The incidence of abnormalities correlated with donor age. However, postoperative renal functions in living donors were not affected by histological abnormalities. Larger-scale investigations with long-term follow-up analysis will be needed.


A qualitative exploration of school-based staff's experiences of delivering an alcohol screening and brief intervention in the high school setting: findings from the SIPS JR-HIGH trial.
Whilst underage drinking in the UK has been declining in recent years, prevalence is still higher than in most other Western European countries. Therefore, it is important to deliver effective interventions to reduce risk of harm. Semi-structured interviews with staff delivering an alcohol screening and brief intervention in the high-school setting. The analysis was informed by normalization process theory (NPT), interviews were open coded and then a framework applied based on the four components of NPT. Five major themes emerged from the analysis. The majority of participants felt that the intervention could be useful, and that learning mentors were ideally suited to deliver it. However, there was a feeling that the intervention should have been targeted at young people who drink the most. The intervention was generally well received in schools and seen as an effective tool for engaging young people in a discussion around alcohol. However, in the future schools need to consider the level of staffing in place to deliver the intervention. Furthermore, the intervention could focus more on the long-term risks of initiating alcohol consumption at a young age.


Concurrency and network disassortativity.
The relationship between a network's degree-degree correlation and a loose version of graph coloring is studied on networks with broad degree distributions. We find that, given similar conditions on the number of nodes, number of links, and clustering levels, fewer colors are needed to color disassortative than assortative networks. Since fewer colors create fewer independent sets, our finding implies that disassortative networks may have higher concurrency potential than assortative networks. This in turn suggests another reason for the disassortative mixing pattern observed in biological networks such as those of protein-protein interaction and gene regulation. In addition to the functional specificity and stability suggested by Maslov and Sneppen, a disassortative network topology may also enhance the ability of cells to perform crucial tasks concurrently. Hence, increased concurrency may also be a driving force in the evolution of biological networks.


Facial tightening with an advanced 4-MHz monopolar radiofrequency device.
Over the past 10 years, radiofrequency (RF) technology has been utilized for nonablative treatments for the treatment of rhytides and skin laxity. This manuscript reviews the scientific background of collagen synthesis in vivo and in response to RF energy as well as a clinical study of 17 patients receiving a series of facial treatments with a 4-MHz monopolar RF (Pellevé, Ellman International, Inc, Oceanside, NY). Clinical methods, results, and a review of the literature for RF aesthetic treatments of the face are presented. Seventeen patients were treated in one site with 6 total treatments scheduled as follows: 1 session was performed every 15 days for 2 consecutive sessions, 1 session every month for 2 consecutive sessions, and 1 session every 2 months for 2 consecutive sessions. Both the treating physician and the patients via live viewing and comparison with baseline photographs performed assessment of results. Results are reported as averages across the 17 patients. Two weeks after the first treatment, patients noted an overall average of 25% to 30% improvement. Just before the last or sixth treatment, there was an average of 50% improvement noted by the physician, with patients ranking an average self-improvement of 48%. The treating physician rated average improvement of 46% compared with baseline, whereas the patients ranked average improvement of 30% compared with baseline at 1 year after treatment was initiated (6 months after the final treatment). Patients find this treatment to be very well tolerated, with minimal to no discomfort and no downtime or significant side effects. The Pellevé 4-MHz monopolar RF device is effective, safe, and very well tolerated for treating laxity, texture, and wrinkles of the skin without complication or discomfort. Evidence in the literature supports the scientific mechanism of action of acute collagen modification and continued neocollagenesis observed with the system. In this cohort, patients maintain approximately 50% improvement on average at 6 months and a 30% to 50% improvement 1 year after beginning the treatments, 6 months after completion.


Hidradenitis Suppurativa: A Guide for the Practicing Physician.
Hidradenitis suppurativa is a chronic inflammatory disease of apocrine gland-bearing skin. Although immunologic derangements, genetic predisposition, obesity, and smoking are likely important factors, the pathogenesis of the disease and the effect of available treatments on disease course have not been fully elucidated. In the absence of proper treatment, chronic inflammation results in diffuse scarring and a wide array of complications, including the development of cutaneous squamous cell carcinoma. This severe and chronic disease can have detrimental effects on self-esteem and quality of life. No ideal treatment regimen has been defined, but several therapies have been found to reduce lesion severity and improve symptoms. We reviewed the literature through July 2014 for existing treatments. Published articles were obtained via systematic review of medical databases (PubMed, Embase, Google Scholar) and scrutiny of citation lists using the search terms "hidradenitis suppurativa" and "acne inversa". Given the scarce literature on treatment strategies, we also reviewed data from any case reports or prospective and retrospective studies that were located. On the basis of the existing literature, we provide an evidence-based algorithm for the management of this disease in the primary care setting. More research is needed to evaluate the comparative effectiveness of topical and systemic treatments and to better understand the pathogenesis, natural history, and subtypes of hidradenitis suppurativa.


Cytokinins act synergistically with salicylic acid to activate defense gene expression in rice.
Hormone crosstalk is pivotal in plant-pathogen interactions. Here, we report on the accumulation of cytokinins (CK) in rice seedlings after infection of blast fungus Magnaporthe oryzae and its potential significance in rice-M. oryzae interaction. Blast infection to rice seedlings increased levels of N(6)-(Δ(2)-isopentenyl) adenine (iP), iP riboside (iPR), and iPR 5'-phosphates (iPRP) in leaf blades. Consistent with this, CK signaling was activated around the infection sites, as shown by histochemical staining for β-glucuronidase activity driven by a CK-responsive OsRR6 promoter. Diverse CK species were also detected in the hyphae (mycelium), conidia, and culture filtrates of blast fungus, indicating that M. oryzae is capable of production as well as hyphal secretion of CK. Co-treatment of leaf blades with CK and salicylic acid (SA), but not with either one alone, markedly induced pathogenesis-related genes OsPR1b and probenazole-induced protein 1 (PBZ1). These effects were diminished by RNAi-knockdown of OsNPR1 or WRKY45, the key regulators of the SA signaling pathway in rice, indicating that the effects of CK depend on these two regulators. Taken together, our data imply a coevolutionary rice-M. oryzae interaction, wherein M. oryzae probably elevates rice CK levels for its own benefits such as nutrient translocation. Rice plants, on the other hand, sense it as an infection signal and activate defense reactions through the synergistic action with SA.


Pheophorbide a from Capsosiphon fulvescens Inhibits Advanced Glycation End Products Mediated Endothelial Dysfunction.
During hyperglycemia, the first step toward the formation of advanced glycation end products is the nonenzymatic glycation between the carbonyl group of a sugar and the primary amino group of a protein. Advanced glycation end products are then produced through more complex reactions. Reactive oxygen species derived from advanced glycation end products may play a key role in inflammation of the endothelium, leading to the complications seen in diabetes. Glycolaldehyde-induced advanced glycation end products have been reported to express proinflammatory cytokines, such as tumor necrosis factor-α and interleukin-1β. This study focused on Capsosiphon fulvescens, a Capsosiphonaceae type of green algae that has shown potential as a functional food material. Pheophorbide a, an anti-glycation compound, was isolated from C. fulvescens by extraction using a mixture of ethanol and water, followed by column fractionation of the resulting extract. The compound separated from C. fulvescens was identified by means of high-performance liquid chromatography combined with mass spectrometry. Pheophorbide a showed scavenging activity of the intracellular reactive oxygen species as well as monocyte adhesiveness inhibitory activity on the human myelomonocytic cell line (THP-1) and human umbilical vein endothelial cells cocultivation system. The mRNA levels of inflammation-related genes such as monocyte chemoattractant protein-1 and interleukin-6 were significantly decreased by pheophorbide a, and advanced glycation end products-stimulated tumor necrosis factor-α and interleukin-1β were downregulated as well. These results indicate that pheophorbide a has significant reactive oxygen species-scavenging activity, monocyte adhesive inhibitory activity, and downregulatory activity of cytokines related to inflammation affecting the endothelium. Pheophorbide a could therefore be a promising candidate for modulating endothelial cell dysfunction.


Visual similarity is greater for line drawings of nonliving than living things: the importance of musical instruments and body parts.
It has been argued that greater intra-category structural similarity for living things, and the subsequent "visual crowding," makes them more difficult to recognize and name for neurologically damaged individuals and normal subjects (Humphreys et al., 1988). Nevertheless, the precise meaning and quantification of structural similarity remains unclear, as does the rationale for why it necessarily should be greater for living things. We derived a new measure of visual overlap from the Snodgrass and Vanderwart corpus of line drawings: the degree of pixel overlap within subcategories (Euclidean distance: ED). Contrary to existing notions of visual crowding and extant measures of contour overlap, within-category ED indicated less within-category visual overlap for living things. Furthermore, musical instruments clustered with living things (having low overlap), while body parts clustered with nonliving things (having high overlap). These counter-intuitive findings accord with patient data and thus, provide evidence for the psychological reality and utility of ED.


IL-17A induces Pendrin expression and chloride-bicarbonate exchange in human bronchial epithelial cells.
The epithelium plays an active role in the response to inhaled pathogens in part by responding to signals from the immune system. Epithelial responses may include changes in chemokine expression, increased mucin production and antimicrobial peptide secretion, and changes in ion transport. We previously demonstrated that interleukin-17A (IL-17A), which is critical for lung host defense against extracellular bacteria, significantly raised airway surface pH in vitro, a finding that is common to a number of inflammatory diseases. Using microarray analysis of normal human bronchial epithelial (HBE) cells treated with IL-17A, we identified the electroneutral chloride-bicarbonate exchanger Pendrin (SLC26A4) as a potential mediator of this effect. These data were verified by real-time, quantitative PCR that demonstrated a time-dependent increase in Pendrin mRNA expression in HBE cells treated with IL-17A up to 48 h. Using immunoblotting and immunofluorescence, we confirmed that Pendrin protein expression is increased in IL-17 treated HBE cells and that it is primarily localized to the mucosal surface of the cells. Functional studies using live-cell fluorescence to measure intracellular pH demonstrated that IL-17A induced chloride-bicarbonate exchange in HBE cells that was not present in the absence of IL-17A. Furthermore, HBE cells treated with short interfering RNA against Pendrin showed substantially reduced chloride-bicarbonate exchange. These data suggest that Pendrin is part of IL-17A-dependent epithelial changes and that Pendrin may therefore be a therapeutic target in IL-17A-dependent lung disease.


Steady-state vitamin K2 (menaquinone-7) plasma concentrations after intake of dairy products and soft gel capsules.
In a previous human intervention study, we observed an improved vitamin K status after 8 weeks of intake of a yogurt that was fortified with vitamin K2 (as menaquinone-7, MK-7) and enriched with vitamins C and D3, magnesium and polyunsaturated fatty acids. It was hypothesized that the added nutrients contributed to this improvement. Here we report on a study in which we compared the fasting plasma concentrations of MK-7 from (a) yogurt enriched with MK-7, vitamins D3 and C, magnesium, n-3 poly unsaturated fatty acids (n-3 PUFA) and fish oil (yogurt Kplus), (b) yogurt fortified with MK-7 only (yogurt K) and (c) soft gel capsules containing only MK-7. For 42 days, healthy men and postmenopausal women between 45 and 65 years of age daily consumed either yogurt K, yogurt Kplus or capsules. Circulating MK-7, 25-hydroxy vitamin D (25(OH)D) and markers for vitamin K status (uncarboxylated osteocalcin (ucOC) and desphospho-uncarboxylated matrix Gla-protein (dp-ucMGP)) were assessed. Plasma MK-7 was also measured during the washout period of 2 weeks. MK-7 and dp-ucMGP were measured in citrated plasma, and 25(OH)D3 and ucOC were measured in the serum. The increase in plasma MK-7 with the yogurt Kplus product was more pronounced than the increase in MK-7 with the capsules. Circulating dp-ucMGP and ucOC were significantly lowered after consumption of the yogurt products and the MK-7 capsules, reflecting vitamin K status improvement. No significant differences in fasting plasma concentrations of various biomarkers between the yogurts were found. Dairy matrix and nutrient composition may affect MK-7 delivery and improvement of vitamin K status. Yogurt fortified with MK-7 is a suitable matrix to improve the nutritional status of the fat-soluble vitamins.


Complex regional pain syndrome type I after diphtheria-tetanus (Di-Te) vaccination.
Complex regional pain syndrome type I (CRPS I) is a disorder of one or more extremities characterized by pain, abnormal sensitivity (allodynia), swelling, limited range of motion, vasomotor instability, fatigue and emotional distress. The symptoms may be aggravated by even minor activity or weather change. It is usually provoked by injury, surgery or injection but in a small proportion of patients CRPS I develops without a clear causative event. There are several literature reports on CRPS after rubella and hepatitis B vaccination. We present a case of CRPS I affecting the left arm after diphtheria and tetanus (Di-Te) vaccination in the left deltoid muscle in a young girl having experienced profound emotional stress before the vaccination procedure. History data on previous minor trauma at the site of vaccination or emotional stress may necessitate temporary vaccination delay due to their proneness to impaired local or systemic immune response and CRPS as a complication of vaccination. If a child or an adult has prominent swelling and severe pain after vaccination, the diagnosis of CRPS I should be considered and if confirmed, the multidisciplinary treatment should start as soon as possible.


Recent advances in understanding the roles of whole genome duplications in evolution.
Ancient whole-genome duplications (WGDs)- paleopolyploidy events-are key to solving Darwin's 'abominable mystery' of how flowering plants evolved and radiated into a rich variety of species. The vertebrates also emerged from their invertebrate ancestors via two WGDs, and genomes of diverse gymnosperm trees, unicellular eukaryotes, invertebrates, fishes, amphibians and even a rodent carry evidence of lineage-specific WGDs. Modern polyploidy is common in eukaryotes, and it can be induced, enabling mechanisms and short-term cost-benefit assessments of polyploidy to be studied experimentally. However, the ancient WGDs can be reconstructed only by comparative genomics: these studies are difficult because the DNA duplicates have been through tens or hundreds of millions of years of gene losses, mutations, and chromosomal rearrangements that culminate in resolution of the polyploid genomes back into diploid ones (rediploidisation). Intriguing asymmetries in patterns of post-WGD gene loss and retention between duplicated sets of chromosomes have been discovered recently, and elaborations of signal transduction systems are lasting legacies from several WGDs. The data imply that simpler signalling pathways in the pre-WGD ancestors were converted via WGDs into multi-stranded parallelised networks. Genetic and biochemical studies in plants, yeasts and vertebrates suggest a paradigm in which different combinations of sister paralogues in the post-WGD regulatory networks are co-regulated under different conditions. In principle, such networks can respond to a wide array of environmental, sensory and hormonal stimuli and integrate them to generate phenotypic variety in cell types and behaviours. Patterns are also being discerned in how the post-WGD signalling networks are reconfigured in human cancers and neurological conditions. It is fascinating to unpick how ancient genomic events impact on complexity, variety and disease in modern life.


Diagnostic accuracy of verbal autopsies in ascertaining the causes of stillbirths and neonatal deaths in rural Ghana.
This study evaluated the diagnostic accuracy of a verbal autopsy (VA) tool in ascertaining the causes of stillbirths and neonatal deaths in rural Ghana and was nested within a community-based maternal vitamin A supplementation trial (ObaapaVitA trial). All stillbirths and neonatal deaths between 1 January 2003 and 30 June 2004 were prospectively included. Community VAs were carried out within 6 months of death and were classified with a primary cause of death by three experienced paediatricans. The reference standard diagnosis was obtained by the study paediatrician in 4 district hospitals in the study area. There were 20,317 deliveries, 661 stillbirths and 590 neonatal deaths with a VA diagnosis in the study population. A total of 311 stillbirths and 191 neonatal deaths had both a VA and a hospital reference standard diagnosis. The VA performed poorly for stillbirth diagnoses such as congenital abnormalities and maternal haemorrhage. Accuracy was higher for intrapartum obstetric complications and antepartum maternal disease. For neonatal deaths, sensitivity was >60% for all major causes; specificity was 76% for birth asphyxia but >85% for prematurity and infection. Overall, VA diagnostic accuracy was higher than expected in this rural African setting. Our classification system was based on the expected public health importance of the individual causes of death, differing implications for intervention and the ability to distinguish between the individual causes in low-resource settings. We believe this system was easier to use than traditional approaches and resulted in high precision and accuracy. However, further simplifications are needed to allow use of the World Health Organisation VA in routine child health programmes. The diagnostic accuracy of the VA tool should also be assessed in other regions and in multicentre studies.


Immunoglobulin heavy chain locus of the rat: striking homology to mouse antibody genes.
DNA encoding the rat diversity segment (D), joining segment (JH), and constant (C) region mu, gamma 2a, gamma 1, gamma 2b, epsilon and alpha of the Ig heavy chain has been isolated from a cosmid library. Restriction mapping allowed us to identify two gene clusters: D-JH-C mu and C gamma 1-C gamma 2b-C epsilon-C alpha in addition to a single C gamma 2a gene. Analysis of genomic DNA by Southern blotting permitted identification of the C gamma 2c gene and led to the proposal of the following gene order for the rat Ig heavy chain locus: D-JH-C mu-C delta-(C gamma 2c, C gamma 2a)-C gamma 1-C gamma 2b-C epsilon-C alpha. There is striking homology between the rat and mouse Ig heavy chain loci as regards gene order and distance between CH genes. Partial DNA sequencing confirms this homology and shows that exon sequences are more conserved than are intron sequences. One of the most conserved intron regions between rat and mouse is that spanning the Ig heavy chain enhancer (91% homology). However, the relationship between the different C gamma subclasses in rat differs from that in mouse. Comparison of the C gamma CH3 domains shows that the rat C gamma 2b gene is most homologous to mouse C gamma 2a/b, whereas the rat C gamma 1 and C gamma 2a genes, both very similar to each other, are most homologous to the mouse C gamma 1 gene.


Protocol of the Australasian Malignant Pleural Effusion-2 (AMPLE-2) trial: a multicentre randomised study of aggressive versus symptom-guided drainage via indwelling pleural catheters.
Malignant pleural effusions (MPEs) can complicate most cancers, causing dyspnoea and impairing quality of life (QoL). Indwelling pleural catheters (IPCs) are a novel management approach allowing ambulatory fluid drainage and are increasingly used as an alternative to pleurodesis. IPC drainage approaches vary greatly between centres. Some advocate aggressive (usually daily) removal of fluid to provide best symptom control and chance of spontaneous pleurodesis. Daily drainages however demand considerably more resources and may increase risks of complications. Others believe that MPE care is palliative and drainage should be performed only when patients become symptomatic (often weekly to monthly). Identifying the best drainage approach will optimise patient care and healthcare resource utilisation. A multicentre, open-label randomised trial. Patients with MPE will be randomised 1:1 to daily or symptom-guided drainage regimes after IPC insertion. Patient allocation to groups will be stratified for the cancer type (mesothelioma vs others), performance status (Eastern Cooperative Oncology Group status 0-1 vs ≥2), presence of trapped lung (vs not) and prior pleurodesis (vs not). The primary outcome is the mean daily dyspnoea score, measured by a 100 mm visual analogue scale (VAS) over the first 60 days. Secondary outcomes include benefits on physical activity levels, rate of spontaneous pleurodesis, complications, hospital admission days, healthcare costs and QoL measures. Enrolment of 86 participants will detect a mean difference of VAS score of 14 mm between the treatment arms (5% significance, 90% power) assuming a common between-group SD of 18.9 mm and a 10% lost to follow-up rate. The Sir Charles Gairdner Group Human Research Ethics Committee has approved the study (number 2015-043). Results will be published in peer-reviewed journals and presented at scientific meetings. ACTRN12615000963527; Pre-results.


Ascorbate pool, sugars and organic acids in black currant (Ribes nigrum L.) berries are strongly influenced by genotype and post-flowering temperature.
Marked effects of the climatic environment on fruit chemical composition have often been demonstrated in field experiments. However, complex covariations of several climatic factors in the natural environment complicate the interpretation of such experiments and the identification of the causal factors. This can be better achieved in a phytotron where the various climatic factors can be varied systematically. Therefore, we grew four black currant cultivars of contrasting origin in a phytotron under controlled post-flowering temperature and photoperiod conditions and analysed the berries for their ascorbic acid, sugar and organic acid contents. The analyses revealed significant effects of genotype on all investigated compounds. Particularly large cultivar differences were observed in the concentrations of l-ascorbic acid (AA) and sucrose. The concentrations of both AA and dehydroascorbic acid (DHAA), as well as the concentrations of all major sugars, decreased consistently with an increasing temperature over the temperature range 12-24 °C. Fructose and glucose were the predominant sugars with concentrations several fold higher than that for sucrose. AA was the main contributor to the total ascorbate pool in black currant berries. The AA/DHAA ratio varied from 5.6 to 10.3 among the studied cultivars. The concentration of citric acid, which was the predominant organic acid in black currant berries, increased with an increasing temperature, whereas the opposite trend was observed for malic and shikimic acid. Quninic acid was always present at relatively low concentrations. By contrast, photoperiod had no significant effect on berry content of any of the investigated compounds. It is concluded that the post-flowering temperature has marked effects on the concentration of important chemical compounds responsible for taste and nutritional value of black currant berries, whereas photoperiod has no such effect in the studied cultivars. © 2016 Society of Chemical Industry.


Mitochondrial involvement in brain function and dysfunction: relevance to aging, neurodegenerative disorders and longevity.
It is becoming increasingly evident that the mitochondrial genome may play a key role in neurodegenerative diseases. Mitochondrial dysfunction is characteristic of several neurodegenerative disorders, and evidence for mitochondria being a site of damage in neurodegenerative disorders is partially based on decreases in respiratory chain complex activities in Parkinson's disease, Alzheimer's disease, and Huntington's disease. Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant balance perturbation, are thought to underlie defects in energy metabolism and induce cellular degeneration. Efficient functioning of maintenance and repair process seems to be crucial for both survival and physical quality of life. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of genes termed vitagenes. A promising approach for the identification of critical gerontogenic processes is represented by the hormesis-like positive effect of stress. In the present review, we discuss the role of energy thresholds in brain mitochondria and their implications in neurodegeneration. We then review the evidence for the role of oxidative stress in modulating the effects of mitochondrial DNA mutations on brain age-related disorders and also discuss new approaches for investigating the mechanisms of lifetime survival and longevity.


Group membership dictates the neural correlates of social optimism biases.
Optimism bias, i.e. expecting the future to hold more desirable than undesirable outcomes, also extends to people that we like or admire. However, it remains unknown how the brain generates this social optimism bias. In this study, respondents estimated the likelihood of future desirable and undesirable outcomes for an in-group and three out-groups: warm-incompetent, cold-competent, and cold-incompetent. We found a strong social optimism bias for the in-group and the warm out-group and an inverted pattern for the cold-incompetent out-group. For all groups, scores of social optimism bias correlated with the brain activity in structures that respondents differentially engaged depending on the target social group. In line with our hypotheses, evaluating the in-group recruited the ventromedial prefrontal cortex and the precuneus/posterior cingulate cortex, whereas evaluating the warm out-group engaged the posterior insula, mid cingulate cortex, and somatosensory cortices. These findings suggest different underlying cognitive mechanisms of social optimism bias for these groups, despite similar behavioural patterns. Thinking about the cold out-groups recruited the right anterior temporal lobe, and temporoparietal junction. Evaluating the cold-incompetent out-group additionally recruited the anterior insula, inferior frontal cortex and dorsomedial frontal cortex. We discuss these neuroimaging findings with respect to their putative cognitive functions.


Does rejection hurt? An FMRI study of social exclusion.
A neuroimaging study examined the neural correlates of social exclusion and tested the hypothesis that the brain bases of social pain are similar to those of physical pain. Participants were scanned while playing a virtual ball-tossing game in which they were ultimately excluded. Paralleling results from physical pain studies, the anterior cingulate cortex (ACC) was more active during exclusion than during inclusion and correlated positively with self-reported distress. Right ventral prefrontal cortex (RVPFC) was active during exclusion and correlated negatively with self-reported distress. ACC changes mediated the RVPFC-distress correlation, suggesting that RVPFC regulates the distress of social exclusion by disrupting ACC activity.


Test-retest reliability of a single-channel, wireless EEG system.
Recording systems to acquire electroencephalogram (EEG) data are traditionally lab-based. However, there are shortcomings to this method, and the ease of use and portability of emerging wireless EEG technologies offer a promising alternative. A previous validity study demonstrated data derived from a single-channel, wireless system (NeuroSky ThinkGear, San Jose, California) is comparable to EEG recorded from conventional lab-based equipment. The current study evaluated the reliability of this portable system using test-retest and reliable change analyses. Relative power (RP) of delta, theta, alpha, and beta frequency bands was derived from EEG data obtained from a single electrode over FP1 in 19 healthy youth (10-17years old), 21 healthy adults (18-28years old), and 19 healthy older adults (55-79years old), during eyes-open, eyes-closed, auditory oddball, and visual n-back conditions. Intra-class correlations (ICCs) and Coefficients of Repeatability (CRs) were calculated from RP data re-collected one-day, one-week, and one-month later. Participants' levels of mood and attention were consistent across sessions. Eyes-closed resting EEG measurements using the portable device were reproducible (ICCs 0.76-0.85) at short and longer retest intervals in all three participant age groups. While still of at least fair reliability (ICCs 0.57-0.85), EEG obtained during eyes-open paradigms was less stable, and any change observed over time during these testing conditions can be interpreted utilizing the CR values provided. Combined with existing validity data, these findings encourage application of the portable EEG system for the study of brain function.


Survivin modulatory role in autoimmune and autoinflammatory diseases.
Baculoviral IAP repeat containing 5 (BIRC5) gene encodes the important protein as survivin, a multifunctional protein, which is involved in cellular and molecular networks, progression of cell cycle, homeostasis, developmental morphogenesis, and apoptosis. The proximal BIRC5 promoter possesses specific binding sites for key transcription factors such as nuclear factor κB and signal transducer and activator of transcription 3. Upregulation of survivin exacerbates the autoimmune diseases (AIDs) including multiple sclerosis and myasthenia gravis by reducing the activity threshold of survivin-specific cytotoxic T cells. DNA damage along with upregulation or downregulation of survivin have been demonstrated in initiation and pathogenesis of cancers and AIDs. However, detailed mechanism of survivin function in pathogenesis of AIDs is not well understood. This review focuses on the structure, specificity, regulation, and function of survivin in physiologic conditions and pathogenesis of AIDs.


Investigation of vitamin D status and its correlation with insulin resistance in a Chinese population.
Although many studies worldwide have focused on the relationship between vitamin D and insulin resistance, results remain controversial. Furthermore, concentrations of serum 25-hydroxyvitamin D (25(OH)D) in the Chinese population are unclear. We aimed to investigate vitamin D status and its correlation with insulin resistance among a Chinese adult population. Serum 25(OH)D, fasting blood glucose, fasting insulin, glycated Hb (HbA1c) and other metabolic parameters were assessed. Neck circumference, waist circumference, hip circumference, weight and height were also measured. Lifestyle factors including smoking and drinking status were obtained. Diabetes mellitus was diagnosed by HbA1c according to the 2010 American Diabetes Association criteria. Eastern China. Of 7200 residents included, 6597 individuals were ultimately analysed. We enrolled 2813 males (mean age 52·7 (sd 13·5) years) and 3784 females (52·3 (sd 13·5) years); mean serum 25(OH)D concentration was 43·1 (sd 11·6) and 39·6 (sd 9·8) nmol/l, respectively. Additionally, 83·3 % of participants were 25(OH)D deficient. A significant difference in 25(OH)D was observed between males and females in winter and spring (P<0·001). Furthermore, 25(OH)D concentrations were inversely associated with the homeostasis model assessment of insulin resistance (HOMA-IR) in the overweight and pre-diabetic populations. After adjusting for several variables, 25(OH)D was significantly associated with HOMA-IR in winter. When 25(OH)D values were categorized into quartiles, HOMA-IR was significantly associated with decreasing 25(OH)D. The majority of the Chinese population was vitamin D deficient and this deficiency was negatively associated with insulin resistance, particularly in the overweight and pre-diabetic populations. Moreover, these associations might be more evident in the winter.


Corporeal illusions in chronic spinal cord injuries.
While several studies have investigated corporeal illusions in patients who have suffered from a stroke or undergone an amputation, only anecdotal or single case reports have explored this phenomenon after spinal cord injury. Here we examine various different types of bodily misperceptions in a comparatively large group of 49 people with spinal cord injury in the post-acute and chronic phases after the traumatic lesion onset. An extensive battery of questionnaires concerning a variety of body related feelings was administered and the results were correlated to the main clinical variables. Six different typologies of Corporeal Illusion emerged: Sensations of Body Loss; Body-Part Misperceptions; Somatoparaphrenia-like sensations; Disownership-like sensations; Illusory motion and Misoplegia. All of these (with the exception of Misoplegia) are modulated by clinical variables such as pain (visceral, neuropathic and musculoskeletal), completeness of the lesion, level of the lesion and the length of time since lesion onset. In contrast, no significant correlations between bodily illusions and personality variables were found. These results support data indicating that at least some cognitive functions (in particular the body, action and space representations) are embodied and that somatosensory input and motor output may be necessary to build and maintain a typical self-body representation.


Skeletal Class III phenotype: Link between animal models and human genetics: A scoping review.
This study aimed to identify evidence from animal studies examining genetic variants underlying maxillomandibular discrepancies resulting in a skeletal Class III (SCIII) malocclusion phenotype. Following the Manual for Evidence Synthesis of the JBI and the PRISMA extension for scoping reviews, a participant, concept, context question was formulated and systematic searches were executed in the PubMed, Scopus, WOS, Scielo, Open Gray, and Mednar databases. Of the 779 identified studies, 13 met the selection criteria and were included in the data extraction. The SCIII malocclusion phenotype was described as mandibular prognathism in the Danio rerio, Dicentrarchus labrax, and Equus africanus asinus models; and as maxillary deficiency in the Felis silvestris catus, Canis familiaris, Salmo trutta, and Mus musculus models. The identified genetic variants highlight the significance of BMP and TGF-β signaling. Their regulatory pathways and genetic interactions link them to cellular bone regulation events, particularly ossification regulation of postnatal cranial synchondroses. In conclusion, twenty genetic variants associated with the skeletal SCIII malocclusion phenotype were identified in animal models. Their interactions and regulatory pathways corroborate the role of these variants in bone growth, differentiation events, and ossification regulation of postnatal cranial synchondroses.


Color stability of bleached teeth over time: an in vitro study.
The aim of this study was to evaluate the in vitro color stability of bleached teeth by means of a 6-day staining procedure. 20 caries-free randomly divided into two groups. Test group: a bleaching agent (Zoom 2, Discus Dental) was applied to the labial surfaces following the manufacturer's instructions. no bleaching treatment. using a thermo-cycling device, all teeth were alternately immersed in a 0.9% saline solution at 37 °C for 1 hour, and in a coffee solution at 55 °C for another hour, in order to simulate the natural tooth-staining process. This procedure was repeated 12 times a day for 6 days. Teeth were polished once a day with a rubber cup and polishing paste. CIELAB color variables (L, a, b) were assessed by means of a spectrophotometer (VITA Easyshade®) and a custom alignment device at baseline, after bleaching, and once a day throughout the 6-day staining treatment. The bleaching result and the color stability of bleached and control group teeth were assessed by matched pair t test and MANOVA. The bleaching agent had a significant whitening effect. The staining treatment did not produce any significant color change on bleached teeth, which maintained the same whiteness achieved after the bleaching treatment. The staining treatment did not produce any significant color change on control teeth. The two groups showed significant differences in both whiteness and lightness changes as a result of the polishing treatment. The Zoom 2 whitening agent produced immediate and long-lasting bleaching results, even if the reduction of b value mainly occurred 24 and 48 hours after the bleaching treatment.


Environmental risk assessment of replication competent viral vectors applied in clinical trials: potential effects of inserted sequences.
Risk assessments of clinical applications involving genetically modified viral vectors are carried out according to general principles that are implemented in many national and regional legislations, e.g., in Directive 2001/18/EC of the European Union. Recent developments in vector design have a large impact on the concepts that underpin the risk assessments of viral vectors that are used in clinical trials. The use of (conditionally) replication competent viral vectors (RCVVs) may increase the likelihood of the exposure of the environment around the patient, compared to replication defective viral vectors. Based on this assumption we have developed a methodology for the environmental risk assessment of replication competent viral vectors, which is presented in this review. Furthermore, the increased likelihood of exposure leads to a reevaluation of what would constitute a hazardous gene product in viral vector therapies, and a keen interest in new developments in the inserts used. One of the trends is the use of inserts produced by synthetic biology. In this review the implications of these developments for the environmental risk assessment of RCVVs are highlighted, with examples from current clinical trials. The conclusion is drawn that RCVVs, notwithstanding their replication competency, can be applied in an environmentally safe way, in particular if adequate built-in safeties are incorporated, like conditional replication competency, as mitigating factors to reduce adverse environmental effects that could occur.


The effect of muscle paralysis on the radial growth of collagen fibrils in developing tendon.
Voluntary muscle activity in chick embryos was paralysed by administration in ovo of tubocurarine hydrochloride, administered in single or multiple doses, from day 9 to day 13 after fertilization. Control eggs were given saline instead of tubocurarine or were simply incubated without operative interference. Embryos were killed at 9, 13, 14, 16 and 19 days after fertilization. Flexor digitorum tendons were removed, fixed in glutaraldehyde, embedded in plastic, sectioned, and stained with phosphotungstic acid for electron microscopy. The diameters of the tendon collagen fibrils were measured, on electron micrographs, using a Magiscan Mk II programme. Tendon collagen fibril expansion was not inhibited by tubocurarine treatment. It is concluded that the rapid increase of collagen fibril diameters, which coincides in the normal embryo with the first onset of use of the associated muscle, is not dependent on muscle activity. There remains a possibility that other ways of producing tension in the tendon could provide sufficient stimulus to fibril expansion.


Safe mechanical ventilation in patients without acute respiratory distress syndrome (ARDS).
Insights into the pathogenesis of lung deformation injury inspired a benchmark clinical trial, which demonstrated that reducing tidal volumes compared to previous norms was associated with improved patient survival in acute respiratory distress syndrome (ARDS). Since many critically ill patients without ARDS possess ventilator associated lung injury (VALI) risk factors, there is no need to expose them to tidal volumes that are larger than would be needed to achieve acceptable blood gas tensions. In the following perspective we will argue that lung protection from deformation injury should guide ventilator management in all patients, irrespective of the presence of ARDS. That is not to say that all lung diseases share the same VALI risk, but we contend that adopting a low tidal ventilation strategy is a simple and safe starting point in most instances. We will review studies in the medical and surgical literature that have addressed "lung protective ventilation" in patients without ARDS and summarize them with a focus on tidal volume, positive end expiratory pressure and oxygen supplementation settings. In addition, we will briefly discuss under what circumstance one might consider deviating from a conventional approach.