It's not just what you say, it's also how you say it: opening the 'black box' of informed consent appointments in randomised controlled trials.
Randomised controlled trials (RCTs) represent the gold standard methodology for determining effectiveness of healthcare interventions. Poor recruitment to RCTs can threaten external validity and waste resources. An inherent tension exists between safeguarding informed decision-making by participants and maximising numbers enrolled. This study investigated what occurs during informed consent appointments in an ongoing multi-centre RCT in the UK. Objectives were to investigate: 1] how study staff presented study information to participants; 2] what evidence emerged as to how well-informed participants were when proceeding to randomisation or treatment selection; and 3] what aspects of the communication process may facilitate improvements in providing evidence of informed consent. Qualitative analysis of a purposive sample of 23 recruitment appointments from three study centres and involving several recruitment staff applied techniques of thematic, content and conversation analysis (CA). Thematic analysis and CA revealed variation in appointment content and structure. Appointments were mostly recruiter-led or participant-led, and this structure was associated with what evidence emerged as to how participants understood information provided and whether they were in equipoise. Participant-led appointments provided this evidence more consistently. Detailed CA identified communication techniques which, when employed by recruiters, provided evidence as to how participants understood the choices before them. Strategic use of open questions, pauses and ceding the floor in the interaction facilitated detailed and systematic exploration of each participant's concerns and position regarding equipoise. We conclude that the current focus on content to be provided to achieve informed consent should be broadened to encompass consideration of how information is best conveyed to potential participants. A model of tailored information provision using the communication techniques identified and centred on eliciting and addressing participants' concerns is proposed. Use of these techniques is necessary to make potential participants' understanding of key issues and their position regarding equipoise explicit in order to facilitate truly informed consent.


Trajectories of resilience over 25 years of individuals who as adolescents consulted for substance misuse and a matched comparison group.
To examine trajectories of resilience over 25 years among individuals who as adolescents received treatment for substance misuse, the clinical sample (CS) and a matched general population sample (GP). Comparison of the CS and GP over 25 years using Swedish national registers of health care and criminality. A substance misuse clinic for adolescents in an urban area in Sweden. Resilience was defined as the absence of substance misuse, hospitalizations for physical illnesses related to substance misuse, hospitalization for mental illness and law-abiding behaviour from ages 21 to 45 years. The CS included 701 individuals who as adolescents had consulted a clinic for substance misuse. The GP included 731 individuals selected randomly from the Swedish population and matched for age, sex and birthplace. A total of 52.4% of the GP and 24.4% of the CS achieved resilience in all domains through 25 years. Among the CS, another one-third initially displayed moderate levels of resilience that rose to high levels over time, one-quarter displayed decreasing levels of resilience over time, while 9.3% showed little but improving resilience and 8.8% showed no resilience. Levels of resilience were associated with the severity of substance misuse and delinquency in adolescence. Individuals who had presented substance misuse problems in adolescence were less likely to achieve resilience over the subsequent 25 years than was a matched general population sample, and among them, four distinct trajectories of resilience were identified. The severity and type of problems presented in adolescence distinguished the four trajectories.


Informatics in radiology: postprocessing pitfalls in using CT for automatic and semiautomatic determination of global left ventricular function.
Recent advances in technical capabilities of computed tomographic (CT) scanners, including an increasing number of detector rows, improved spatial and temporal resolution, and the development of retrospective gating, have allowed the acquisition of four-dimensional (4D) datasets of the beating heart. As a result, the heart can be visualized in different phases and CT datasets can be used to assess cardiac function. Many software packages currently exist that allow automatic or semiautomatic evaluation of left ventricular function on the basis of 4D CT datasets. The level of automation varies from extensive, completely manual segmentation by the user to fully automatic evaluation of left ventricular function without any user interaction. Although the reproducibility of functional parameter assessment is reported to be high and intersoftware variability low for larger groups of patients, significant differences can exist among measurements obtained with different software tools from the same dataset. Thus, careful review of automatically or semiautomatically obtained results is required.


Three-dimensional high resolution OCT imaging of macular pathology.
Raster scanning spectral domain optical coherence tomography (SD-OCT) enables realistic three-dimensional (3D) imaging of macular disease. This approach allows the clinician to investigate the diagnostic situation in detail before and during pharmacological or surgical intervention. This study demonstrates the clinical potential of SD-OCT in chorioretinal disease. Selected datasets are presented to visualize typical morphologic findings, which are identified in more than 2700 patients. Scans are presented as online assessable 3D-models. Clinically relevant structures are visualized in macular disease and highlight the importance of precise imaging, which clearly is a clinical necessity to plan and indicate modern therapeutic strategies for our patients.


Family context and gender role socialization in middle childhood: comparing girls to boys and sisters to brothers.
We studied the extent of sex-typing across different areas of child functioning (personality, interests, activities) in middle childhood as a function of the traditionality of parents' gender role attitudes and the sex composition of the sibling dyad. Participants included 200 firstborn children (mean = 10.4 years old), their secondborn siblings (mean = 7.7 years old) and their mothers and fathers. Family members were interviewed in their homes about their attitudes and personal characteristics and completed a series of seven evening telephone interviews about their daily activities. We measured children's attitudes, personality characteristics, and interests in sex-typed leisure activities (e.g., sports, handicrafts) as well as time spent in sex-typed leisure activities and household tasks (e.g., washing dishes, home repairs) and with same and opposite sex companions (i.e., parents, peers). Analyses revealed that sex-typing was most evident in children's interests and activities. Further, comparisons of girls versus boys and sisters versus brothers revealed that differences in children's sex-typing as a function of fathers' attitudes and sibling sex constellation were most apparent for children's activities. A notable exception was sex-typed peer involvement; time spent with same versus opposite sex peers was impervious to context effects. Analyses focused on children's sex-typing as a function of mothers' attitudes generally were nonsignificant.


Gene-based meta-analysis of genome-wide association studies implicates new loci involved in obesity.
To date, genome-wide association studies (GWASs) have identified >100 loci with single variants associated with body mass index (BMI). This approach may miss loci with high allelic heterogeneity; therefore, the aim of the present study was to use gene-based meta-analysis to identify regions with high allelic heterogeneity to discover additional obesity susceptibility loci. We included GWAS data from 123 865 individuals of European descent from 46 cohorts in Stage 1 and Metabochip data from additional 103 046 individuals from 43 cohorts in Stage 2, all within the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Each cohort was tested for association between ∼2.4 million (Stage 1) or ∼200 000 (Stage 2) imputed or genotyped single variants and BMI, and summary statistics were subsequently meta-analyzed in 17 941 genes. We used the 'VErsatile Gene-based Association Study' (VEGAS) approach to assign variants to genes and to calculate gene-based P-values based on simulations. The VEGAS method was applied to each cohort separately before a gene-based meta-analysis was performed. In Stage 1, two known (FTO and TMEM18) and six novel (PEX2, MTFR2, SSFA2, IARS2, CEP295 and TXNDC12) loci were associated with BMI (P < 2.8 × 10(-6) for 17 941 gene tests). We confirmed all loci, and six of them were gene-wide significant in Stage 2 alone. We provide biological support for the loci by pathway, expression and methylation analyses. Our results indicate that gene-based meta-analysis of GWAS provides a useful strategy to find loci of interest that were not identified in standard single-marker analyses due to high allelic heterogeneity.


Sex Differences in Renal Outcomes After Medical Treatment for Bilateral Primary Aldosteronism.
A higher incidence of bilateral primary aldosteronism in women is reported. Treatment of bilateral primary aldosteronism usually involves mineralocorticoid receptor antagonists. However, the impact of sex on renal outcomes is unknown. We compared renal outcomes between the sexes after mineralocorticoid receptor antagonist initiation by analyzing data obtained from 415 female and 313 male patients with bilateral primary aldosteronism who were treated with spironolactone or eplerenone in the JPAS (Japan Primary Aldosteronism Study). Over the course of 5 years, the temporal reduction in the estimated glomerular filtration rate was greater in women than in men (P<0.001). Systolic blood pressure levels were equal between the sexes, despite higher doses of antihypertensive drugs in men. The mean of the annual decline in estimated glomerular filtration rate during what we termed the late phase, or 6 to 60 months after mineralocorticoid receptor antagonist initiation, was larger in women than in men after adjusting for patient characteristics (-1.33 mL/min per 1.73 m2 per year versus -1.04 mL/min per 1.73 m2 per year, P<0.01). Female sex was a significant predictor of greater annual decline during the late phase in patients taking spironolactone but not in those taking eplerenone. Spironolactone use and diabetes were independent predictors of a greater annual decline in estimated glomerular filtration rate during the late phase in women. These findings suggest that female sex is associated with poorer renal outcomes in patients receiving mineralocorticoid receptor antagonist for bilateral primary aldosteronism.


Diarrhea incidence in low- and middle-income countries in 1990 and 2010: a systematic review.
Diarrhea is recognized as a leading cause of morbidity and mortality among children under 5 years of age in low- and middle-income countries yet updated estimates of diarrhea incidence by age for these countries are greatly needed. We conducted a systematic literature review to identify cohort studies that sought to quantify diarrhea incidence among any age group of children 0-59 mo of age. We used the Expectation-Maximization algorithm as a part of a two-stage regression model to handle diverse age data and overall incidence rate variation by study to generate country specific incidence rates for low- and middle-income countries for 1990 and 2010. We then calculated regional incidence rates and uncertainty ranges using the bootstrap method, and estimated the total number of episodes for children 0-59 mo of age in 1990 and 2010. We estimate that incidence has declined from 3.4 episodes/child year in 1990 to 2.9 episodes/child year in 2010. As was the case previously, incidence rates are highest among infants 6-11 mo of age; 4.5 episodes/child year in 2010. Among these 139 countries there were nearly 1.9 billion episodes of childhood diarrhea in 1990 and nearly 1.7 billion episodes in 2010. Although our results indicate that diarrhea incidence rates may be declining slightly, the total burden on the health of each child due to multiple episodes per year is tremendous and additional funds are needed to improve both prevention and treatment practices in low- and middle-income countries.


SARS-CoV-2 Infection Among People Living With HIV Compared With People Without HIV: Survey Results From the MACS-WIHS Combined Cohort Study.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) symptoms among people living with HIV (PLWH) are not well described. Longitudinal survey within the MACS/WIHS Combined Cohort Study (MWCCS) of PLWH compared with similar HIV-seronegative (SN) individuals. Telephone-administered survey of MWCCS participants at 13 clinical research sites across the United States addressing COVID-19 symptoms, SARS-CoV-2 testing, and pandemic impact on social distancing and antiretroviral therapy (ART) use. Primary data collection occurred during May (wave 1), June-July (wave 2), and August-September, 2020 (wave 3). One-third of MWCCS participants were tested for SARS-CoV-2 infection; 10% was tested ≥2 times. Similar proportions of PLWH and SN participants were tested, but SARS-CoV-2 positivity was higher among PLWH than among SN individuals (9.4% vs 4.8%, P = 0.003). Odds of SARS-CoV-2 positivity remained higher among PLWH after adjusting for age, sex, race/ethnicity, and study site (adjusted odds ratio = 2.0, 95% confidence interval = 1.2 to 3.2). SARS-CoV-2 positivity was not associated with CD4 cell counts among PLWH. Among SARS-CoV-2 positive participants, 9% had no symptoms, 7% had 1-2 mild symptoms, and 84% had ≥3 symptoms. Most of the (98%) participants reported physical distancing during all survey waves; self-reported ART adherence among PLWH was not adversely affected during the pandemic compared with the previous year (similar adherence in 89% of participants, improved in 9% of participants, and decreased in 2% of participants). Despite similar SARS-CoV-2 testing and physical distancing profiles by HIV serostatus among MWCCS participants, PLWH who reported SARS-CoV-2 testing were more likely to have a positive test result. Additional studies are needed to determine whether and why PLWH are at increased risk of SARS-CoV-2 infection.


Area Increase and Budding in Giant Vesicles Triggered by Light: Behind the Scene.
Biomembranes are constantly remodeled and in cells, these processes are controlled and modulated by an assortment of membrane proteins. Here, it is shown that such remodeling can also be induced by photoresponsive molecules. The morphological control of giant vesicles in the presence of a water-soluble ortho-tetrafluoroazobenzene photoswitch (F-azo) is demonstrated and it is shown that the shape transformations are based on an increase in membrane area and generation of spontaneous curvature. The vesicles exhibit budding and the buds can be retracted by using light of a different wavelength. In the presence of F-azo, the membrane area can increase by more than 5% as assessed from vesicle electrodeformation. To elucidate the underlying molecular mechanism and the partitioning of F-azo in the membrane, molecular dynamics simulations are employed. Comparison with theoretically calculated shapes reveals that the budded shapes are governed by curvature elasticity, that the spontaneous curvature can be decomposed into a local and a nonlocal contribution, and that the local spontaneous curvature is about 1/(2.5 µm). The results show that exo- and endocytotic events can be controlled by light and that these photoinduced processes provide an attractive method to change membrane area and morphology.


Genetic modifiers of the phenotype of mice deficient in mitochondrial superoxide dismutase.
Sod2-/- mice, which are deficient in the mitochondrial form of superoxide dismutase (MnSOD), have a short survival time that is strongly affected by genetic background. This suggests the existence of genetic modifiers that are capable of modulating the degree of mitochondrial oxidative damage caused by the MnSOD deficiency, thereby altering longevity. To identify these modifier(s), we generated recombinant congenic mice with quantitative trait loci (QTL) containing the putative genetic modifiers on the short-lived C57BL/6J genetic background. MnSOD deficient C57BL/6J mice with a QTL from the distal region of chromosome 13 from DBA/2J were able to survive for as long as those generated on the long-lived DBA/2J background. Within this region, the gene encoding nicotinamide nucleotide transhydrogenase (Nnt) was found to be defective in C57BL/6J mice, and no mature NNT protein could be detected. The forward reaction of NNT, a nuclear-encoded mitochondrial inner membrane protein, couples the generation of NADPH to proton transport and provides NADPH for the regeneration of two important antioxidant compounds, glutathione and thioredoxin, in the mitochondria. This action of NNT could explain its putative protective role in MnSOD-deficient mice.


Serological Conservation of Parasite-Infected Erythrocytes Predicts Plasmodium falciparum Erythrocyte Membrane Protein 1 Gene Expression but Not Severity of Childhood Malaria.
Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), expressed on P. falciparum-infected erythrocytes, is a major family of clonally variant targets of naturally acquired immunity to malaria. Previous studies have demonstrated that in areas where malaria is endemic, antibodies to infected erythrocytes from children with severe malaria tend to be more seroprevalent than antibodies to infected erythrocytes from children with nonsevere malaria. These data have led to a working hypothesis that PfEMP1 variants associated with parasite virulence are relatively conserved in structure. However, the longevity of such serologically conserved variants in the parasite population is unknown. Here, using infected erythrocytes from recently sampled clinical P. falciparum samples, we measured serological conservation using pools of antibodies in sera that had been sampled 10 to 12 years earlier. The serological conservation of infected erythrocytes strongly correlated with the expression of specific PfEMP1 subsets previously found to be associated with severe malaria. However, we found no association between serological conservation per se and disease severity within these data. This contrasts with the simple hypothesis that P. falciparum isolates with a serologically conserved group of PfEMP1 variants cause severe malaria. The data are instead consistent with periodic turnover of the immunodominant epitopes of PfEMP1 associated with severe malaria.


Spine Day 2012: spinal pain in Swiss school children- epidemiology and risk factors.
The key to a better understanding of the immense problem of spinal pain seems to be to investigate its development in adolescents. Based on the data of Spine Day 2012 (an annual action day where Swiss school children were examined by chiropractors on a voluntary basis for back problems), the aim of the present study was to gain systematic epidemiologic data on adolescent spinal pain in Switzerland and to explore risk factors per gender and per spinal area. Data (questionnaires and physical examinations) of 836 school children were descriptively analyzed for prevalence, recurrence and severity of spinal pain. Of those, 434 data sets were included in risk factor analysis. Using logistic regression analysis, psycho-social parameters (presence of parental back pain, parental smoking, media consumption, type of school bag) and physical parameters (trunk symmetry, posture, mobility, coordination, BMI) were analyzed per gender and per spinal area. Prevalence of spinal pain was higher for female gender in all areas apart from the neck. With age, a steep increase in prevalence was observed for low back pain (LBP) and for multiple pain sites. The increasing impact of spinal pain on quality of life with age was reflected in an increase in recurrence, but not in severity of spinal pain. Besides age and gender, parental back pain (Odds ratio (OR)=3.26, p=0.011) and trunk asymmetry (OR=3.36, p=0.027) emerged as risk factors for spinal pain in girls. Parental smoking seemed to increase the risk for both genders (boys: OR=2.39, p=0.020; girls: OR=2.19, p=0.051). Risk factor analysis per spinal area resulted in trunk asymmetry as risk factor for LBP (OR=3.15, p=0.015), while parental smoking increased the risk for thoracic spinal pain (TSP) (OR=2.83, p=0.036) and neck pain (OR=2.23, p=0.038). The risk for TSP was further enhanced by a higher BMI (OR=1.15, p=0.027). This study supports the view of adolescent spinal pain as a bio-psycho-social problem that should be investigated per spinal area, age and gender. The role of trunk asymmetry and passive smoking as risk factors as well as the association between BMI and TSP should be further investigated, preferably in prospective studies.


Heritability of female extra-pair paternity rate in song sparrows (Melospiza melodia).
The forces driving the evolution of extra-pair reproduction in socially monogamous animals remain widely debated and unresolved. One key hypothesis is that female extra-pair reproduction evolves through indirect genetic benefits, reflecting increased additive genetic value of extra-pair offspring. Such evolution requires that a female's propensity to produce offspring that are sired by an extra-pair male is heritable. However, additive genetic variance and heritability in female extra-pair paternity (EPP) rate have not been quantified, precluding accurate estimation of the force of indirect selection. Sixteen years of comprehensive paternity and pedigree data from socially monogamous but genetically polygynandrous song sparrows (Melospiza melodia) showed significant additive genetic variance and heritability in the proportion of a female's offspring that was sired by an extra-pair male, constituting major components of the genetic architecture required for extra-pair reproduction to evolve through indirect additive genetic benefits. However, estimated heritabilities were moderately small (0.12 and 0.18 on the observed and underlying latent scales, respectively). The force of selection on extra-pair reproduction through indirect additive genetic benefits may consequently be relatively weak. However, the additive genetic variance and non-zero heritability observed in female EPP rate allow for multiple further genetic mechanisms to drive and constrain mating system evolution.


Escherichia coli SecB stimulates export without maintaining export competence of ribose-binding protein signal sequence mutants.
Ribose-binding protein (RBP) is exported to the periplasm of Escherichia coli via the general export pathway. An rbsB-lacZ gene fusion was constructed and used to select mutants defective in RBP export. The spontaneous Lac+ mutants isolated in this selection contained either single-amino-acid substitutions or a deletion of the RBP signal sequence. Intact rbsB genes containing eight different point mutations in the signal sequence were reconstructed, and the effects of the mutations on RBP export were examined. Most of the mutations caused severe defects in RBP export. In addition, different suppressor mutations in SecY/PrlA protein were analyzed for their effects on the export of RBP signal sequence mutants in the presence or absence of SecB. Several RBP signal sequence mutants were efficiently suppressed, but others were not suppressed. Export of an RBP signal sequence mutant in prlA mutant strains was partially dependent on SecB, which is in contrast to the SecB independence of wild-type RBP export. However, the kinetics of export of an RBP signal sequence mutant point to a rapid loss of pre-RBP export competence, which occurs in strains containing or lacking SecB. These results suggest that SecB does not stabilize the export-competent conformation of RBP and may affect translocation by stabilizing the binding of pre-RBP at the translocation site.


Differences in sociodemographic, drug use and health characteristics between never, former and current injecting, problematic hard-drug users in the Netherlands.
Injecting drug users are at increased risk for harmful effects compared to non-injecting drug users. Some studies have focused on differences in characteristics between these two groups (e.g., housing, overall health). However, no study has investigated the specific Dutch situation which in the last years has seen a decrease in homelessness among problematic hard-drug users and an increasing focus on physical health in low-threshold addiction care. The purpose of this study was to determine differences in sociodemographic, drug use and health characteristics between never-injecting (NIDUs), former-injecting (FIDUs) and current-injecting drug users (IDUs) and describe injecting practices. A total of 202 problematic hard-drug users (NIDU = 64; FIDU = 76; IDU = 62) were recruited from 22 low-threshold care facilities, including drug consumption rooms, methadone maintenance treatment, heroin-assisted therapy, day shelter and/or night shelter, supported housing and day activity centres. Data were collected on-site through structured face-to-face interviews. Results indicate that IDUs represented a separate group of problematic hard-drug users, with distinct sociodemographic and drug use characteristics. Overall, IDUs appeared to be the group with least favourable characteristics (unstable housing/homelessness, illegal activities, polydrug use) and NIDUs appeared to have the most favourable characteristics (stable housing, help with debts, less polydrug use). The FIDU group lies somewhere in between. The three groups did not differ significantly in terms of health. Regarding injecting practices, results showed that majority of IDUs had injected drugs for over 10 years and IDUs injected heroin, cocaine, amphetamine and/or methadone in the past 6 months. Sharing syringes was not common. A quarter reported public injecting. Unstable housing and homelessness are related to (former) injecting drug use, and stable housing is related to never-injecting drug use. Our study suggests that the number of 'new' IDUs is low. However, public injecting among IDUs is not uncommon and is associated with unstable housing. This emphasizes the potential of housing projects as a component of harm reduction measures. Therefore, prevention of (risks associated with) injecting drug use and supported housing programmes for problematic hard-drug users deserve the continuous attention of policymakers and professionals in low-threshold addiction care.


Increased toll-like receptors and p53 levels regulate apoptosis and angiogenesis in non-muscle invasive bladder cancer: mechanism of action of P-MAPA biological response modifier.
The new modalities for treating patients with non-muscle invasive bladder cancer (NMIBC) for whom BCG (Bacillus Calmette-Guerin) has failed or is contraindicated are recently increasing due to the development of new drugs. Although agents like mitomycin C and BCG are routinely used, there is a need for more potent and/or less-toxic agents. In this scenario, a new perspective is represented by P-MAPA (Protein Aggregate Magnesium-Ammonium Phospholinoleate-Palmitoleate Anhydride), developed by Farmabrasilis (non-profit research network). This study detailed and characterized the mechanisms of action of P-MAPA based on activation of mediators of Toll-like Receptors (TLRs) 2 and 4 signaling pathways and p53 in regulating angiogenesis and apoptosis in an animal model of NMIBC, as well as, compared these mechanisms with BCG treatment. Our results demonstrated the activation of the immune system by BCG (MyD88-dependent pathway) resulted in increased inflammatory cytokines. However, P-MAPA intravesical immunotherapy led to distinct activation of TLRs 2 and 4-mediated innate immune system, resulting in increased interferons signaling pathway (TRIF-dependent pathway), which was more effective in the NMIBC treatment. Interferon signaling pathway activation induced by P-MAPA led to increase of iNOS protein levels, resulting in apoptosis and histopathological recovery. Additionally, P-MAPA immunotherapy increased wild-type p53 protein levels. The increased wild-type p53 protein levels were fundamental to NO-induced apoptosis and the up-regulation of BAX. Furthermore, interferon signaling pathway induction and increased p53 protein levels by P-MAPA led to important antitumor effects, not only suppressing abnormal cell proliferation, but also by preventing continuous expansion of tumor mass through suppression of angiogenesis, which was characterized by decreased VEGF and increased endostatin protein levels. Thus, P-MAPA immunotherapy could be considered an important therapeutic strategy for NMIBC, as well as, opens a new perspective for treatment of patients that are refractory or resistant to BCG intravesical therapy.


Suppression of Hydroxycinnamate Network Formation in Cell Walls of Rice Shoots Grown under Microgravity Conditions in Space.
Network structures created by hydroxycinnamate cross-links within the cell wall architecture of gramineous plants make the cell wall resistant to the gravitational force of the earth. In this study, the effects of microgravity on the formation of cell wall-bound hydroxycinnamates were examined using etiolated rice shoots simultaneously grown under artificial 1 g and microgravity conditions in the Cell Biology Experiment Facility on the International Space Station. Measurement of the mechanical properties of cell walls showed that shoot cell walls became stiff during the growth period and that microgravity suppressed this stiffening. Amounts of cell wall polysaccharides, cell wall-bound phenolic acids, and lignin in rice shoots increased as the shoot grew. Microgravity did not influence changes in the amounts of cell wall polysaccharides or phenolic acid monomers such as ferulic acid (FA) and p-coumaric acid, but it suppressed increases in diferulic acid (DFA) isomers and lignin. Activities of the enzymes phenylalanine ammonia-lyase (PAL) and cell wall-bound peroxidase (CW-PRX) in shoots also increased as the shoot grew. PAL activity in microgravity-grown shoots was almost comparable to that in artificial 1 g-grown shoots, while CW-PRX activity increased less in microgravity-grown shoots than in artificial 1 g-grown shoots. Furthermore, the increases in expression levels of some class III peroxidase genes were reduced under microgravity conditions. These results suggest that a microgravity environment modifies the expression levels of certain class III peroxidase genes in rice shoots, that the resultant reduction of CW-PRX activity may be involved in suppressing DFA formation and lignin polymerization, and that this suppression may cause a decrease in cross-linkages within the cell wall architecture. The reduction in intra-network structures may contribute to keeping the cell wall loose under microgravity conditions.


Myocardial CT perfusion imaging for ischemia detection.
Coronary computed tomography angiography (CCTA) plays an important role in many specific scenarios such as in symptomatic patients with intermediate pretest of coronary artery disease (CAD), as well as in the triage of patients with acute chest pain with TIMI risk ≤2. However, it cannot detect the presence of associated ischemia, which is critical for clinical decision making among patients with moderate to severe stenosis. Although functional information can be obtained with different non-invasive tools, cardiac CT is the unique modality that can perform a comprehensive evaluation of coronary anatomy plus the functional significance of lesions. Myocardial CT perfusion (CTP) can be performed with different approaches such as static and dynamic CTP. In addition, static CTP can be performed using single energy CT (SECT) or dual energy CT (DECT). In this review, we will discuss the technical parameters and the available clinical evidence of static CTP using both SECT and DECT.


[Leptin as a marker of sexual dimorphism in newborn infants].
To determine cord blood leptin levels in newborns appropriate for gestational age, according to gender, birth weight, birth height and ponderal index. A cross-sectional study was carried out with 132 term newborns appropriate for gestational age (68 females, 64 males), gestational age between 35-42 weeks. Data were collected through interviews with the mothers at the maternity, anthropometrycal study of the newborns, and cord blood estradiol, testosterone and leptin assays obtained immediately after birth. The levels of leptin were significantly higher in females than in males (8.34+/-0.65 ng/ml versus 6.06+/-0.71 ng/ml; p = 0.000). The concentrations of estradiol and testosterone did not differ between males and females. Leptin levels were positively correlated with gestational age (r = 0.394, p < 0.01), birth weight (r = 0.466, p < 0.01), birth length (r = 0.335, p < 0.01) and ponderal index (r = 0.326, p < 0.01). Leptin concentration in the umbilical cord is positively correlated with gestational age, birth weight, birth height, and ponderal index, suggesting its participation in the neonatal growth process. In addition, a gender difference with higher levels of leptin in females neonates was observed, suggesting that the sexual dimorphism in relation to body composition already exists in newborns.


Use of ultrasound-guided axillary node core biopsy in staging of early breast cancer.
The aim of this study was to see how effective ultrasound-guided needle biopsy was at detecting lymph node involvement in patients with early breast cancer. Patients with newly diagnosed invasive breast cancer underwent axillary ultrasound (US) where lymph node size and morphology were noted. A core biopsy (CB) was undertaken of any node greater than 5 mm in longitudinal section. Patients with benign CBs proceeded to sentinel lymph node (SLN) biopsy, whereas those with malignancy underwent axillary lymph node dissection (ALND). US and CB findings were correlated with final surgical histology in all cases. One hundred and thirty-nine patients were examined, of whom 52.5% had lymph node metastases on final histology. One hundred and twenty-one patients (87%) underwent axillary node CB. The overall sensitivity of CB for detecting lymph node metastases was 53.4% (60.3% for macrometastases; 26.7% for micrometastases). The US morphological characteristics most strongly associated with malignancy were absence of a hilum and a cortical thickness greater than 4 mm. However, one third of patients with normal lymph node morphology had nodal metastases, and only 12% of these were diagnosed on CB. CB of axillary lymph nodes can diagnose a substantial number of patients with lymph node metastases, allowing these patients to proceed directly to ALND, avoiding unnecessary SLN biopsy.


Association of trypanolytic ApoL1 variants with kidney disease in African Americans.
African Americans have higher rates of kidney disease than European Americans. Here, we show that, in African Americans, focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (H-ESKD) are associated with two independent sequence variants in the APOL1 gene on chromosome 22 {FSGS odds ratio = 10.5 [95% confidence interval (CI) 6.0 to 18.4]; H-ESKD odds ratio = 7.3 (95% CI 5.6 to 9.5)}. The two APOL1 variants are common in African chromosomes but absent from European chromosomes, and both reside within haplotypes that harbor signatures of positive selection. ApoL1 (apolipoprotein L-1) is a serum factor that lyses trypanosomes. In vitro assays revealed that only the kidney disease-associated ApoL1 variants lysed Trypanosoma brucei rhodesiense. We speculate that evolution of a critical survival factor in Africa may have contributed to the high rates of renal disease in African Americans.


Richness, origin and structure of an Eimeria community in a population of Eastern cottontail (Sylvilagus floridanus) introduced into Italy.
The composition and structure of a community of Eimeria was investigated in a population of Eastern cottontail (Sylvilagus floridanus) introduced into Italy. Eight Eimeria species were found, of which all but 1 had North American origins and were presumably introduced into Italy together with imported cottontails. The success of cottontails in spreading microparasites is probably related to their massive release for hunting purposes. Nearly all cottontails were infected with at least 1 Eimeria species, with bimonthly prevalence ranging from 0-6.3% (E. leporis) to 42.9-89.3% (E. environ). Bayesian model averaging and multivariate techniques were used to investigate the relationships between the occurrence of each parasite and the structure of the relative community. Among the host parameters, only sex was found to be associated with the prevalence of E. honessi, while the rest of the parameters were only weakly correlated with prevalence and species richness. This indicates that individual phenotypic host characteristics are probably less important than environmental factors in determining levels of parasite prevalence and diversity. The community of Eimeria species was probably structured by competition, with less species co-occurrence than expected under a null hypothesis. This was made evident by the low co-occurrence of E. environ and E. neoirresidua with E. poudrei, E. honessi, and E. maior.


Anatomical and morphometric analysis of accessory infraorbital foramen.
The aim of the present study was to analyze the anatomical and morphometric variation in shape, frequency of occurrence, direction, and position of accessory infraorbital foramen (AIOF) in relation to infraorbital foramen (IOF) in cadaveric dry skulls to minimize clinical complications and aid in surgical maneuvering in the maxillofacial region and implementing the regional block anesthesia. The IOF is an important anatomical landmark in these surgical manipulations. Because there is limited literature available on AIOF, which transmits accessory branch of the infraorbital nerve, the present study was designed. In the current study, 45 human dry skulls and 20 disarticulated maxillae have been used irrespective of sex. The other parameters included measuring the distance of AIOF from anterior nasal spine, frontomaxillary suture, infraorbital margin, IOF, and zygomaticomaxillary suture. The transverse and vertical diameter of foramen was also noted. All these measurements were taken using a digital caliper. The result of our study reveals that the presence of AIOF is more on the right side compared with the left side. Because the presence of accessory infraorbital nerve needs to be taken care of during maxillofacial surgical interventions, knowledge regarding the presence of AIOF should be taken into consideration for preoperative evaluation.


Safety of anacetrapib in patients with or at high risk for coronary heart disease.
Anacetrapib is a cholesteryl ester transfer protein inhibitor that raises high-density lipoprotein (HDL) cholesterol and reduces low-density lipoprotein (LDL) cholesterol. We conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety profile of anacetrapib in patients with coronary heart disease or at high risk for coronary heart disease. Eligible patients who were taking a statin and who had an LDL cholesterol level that was consistent with that recommended in guidelines were assigned to receive 100 mg of anacetrapib or placebo daily for 18 months. The primary end points were the percent change from baseline in LDL cholesterol at 24 weeks (HDL cholesterol level was a secondary end point) and the safety and side-effect profile of anacetrapib through 76 weeks. Cardiovascular events and deaths were prospectively adjudicated. A total of 1623 patients underwent randomization. By 24 weeks, the LDL cholesterol level had been reduced from 81 mg per deciliter (2.1 mmol per liter) to 45 mg per deciliter (1.2 mmol per liter) in the anacetrapib group, as compared with a reduction from 82 mg per deciliter (2.1 mmol per liter) to 77 mg per deciliter (2.0 mmol per liter) in the placebo group (P<0.001)--a 39.8% reduction with anacetrapib beyond that seen with placebo. In addition, the HDL cholesterol level increased from 41 mg per deciliter (1.0 mmol per liter) to 101 mg per deciliter (2.6 mmol per liter) in the anacetrapib group, as compared with an increase from 40 mg per deciliter (1.0 mmol per liter) to 46 mg per deciliter (1.2 mmol per liter) in the placebo group (P<0.001)--a 138.1% increase with anacetrapib beyond that seen with placebo. Through 76 weeks, no changes were noted in blood pressure or electrolyte or aldosterone levels with anacetrapib as compared with placebo. Prespecified adjudicated cardiovascular events occurred in 16 patients treated with anacetrapib (2.0%) and 21 patients receiving placebo (2.6%) (P = 0.40). The prespecified Bayesian analysis indicated that this event distribution provided a predictive probability (confidence) of 94% that anacetrapib would not be associated with a 25% increase in cardiovascular events, as seen with torcetrapib. Treatment with anacetrapib had robust effects on LDL and HDL cholesterol, had an acceptable side-effect profile, and, within the limits of the power of this study, did not result in the adverse cardiovascular effects observed with torcetrapib. (Funded by Merck Research Laboratories; ClinicalTrials.gov number, NCT00685776.).


Grandparent caregiving in Cambodian skip-generation households: Roles and impact on child nutrition.
This study aims to understand nutrition-related roles, responsibilities and ethical issues of grandparents caring for their grandchildren in skip-generation households in rural Cambodia. Over the past decade, Cambodia has experienced a rise in economic migration of working age populations. This has resulted in increasing numbers of 'skip-generation' households, in which grandparents and grandchildren co-reside without parents, reflecting potential household vulnerability. This qualitative study involved in-depth interviews and focus group discussions with Cambodian grandparents who were primary caregivers to grandchildren for six months or longer. A total of 39 grandparents were recruited at two sites in north-west Cambodia. Interviews and focus group discussions were conducted in Khmer and were recorded, transcribed and translated into English. Data were analysed using thematic analysis. Grandparents in this study looked after an average of three children, aged between two months and 18 years old. Overall, 40% were sole caregivers. Analysis showed that grandparents, particularly grandmothers, played a central role in their grandchildren's health and nutrition. Although grandchildren's health and nutrition were a major priority to grandparents, they reported facing significant challenges to safeguard their grandchildren's and their own nutritional needs. As a result, grandparents frequently faced difficult ethical trade-offs and prioritised their grandchildren's health and nutrition over their own. This study highlights that in order to improve child nutrition, policies and interventions need to be designed in ways that support and enable grandparent caregivers to meet their grandchildren's health and nutritional needs without neglecting their own.


Associations between the impact of terrorism and health perceptions of patients.
Previous studies have demonstrated the effects of the September 11th 2001 terrorist attacks on anxiety and anxiety-related conditions in Americans. However, data regarding associations between the attacks and patients' health perceptions are lacking. The objective of this study was to explore associations between the personal impact of the September 11th attacks and patients' perceptions of health and illness. We performed a cross-sectional survey of 303 adult African-American, Caucasian, and Hispanic patients at primary care clinics in Houston, Texas. Data were collected between October 15, 2001 and March 1, 2002. We developed items to measure the impact of the September 11th attacks and patients' quality of life. Previously validated scales were used to measure health status, health locus of control, preferences regarding the patient-physician relationship, and patients' explanatory models of illness. Twenty-two percent of patients reported no impact from the attacks, 41% reported mildly negative impact, 22% reported moderately negative impact, and 15% reported extremely negative impact in their lives. In multivariate analysis, demographic characteristics were not associated with impact from the attacks. However, patients who perceived a more external locus of control with respect to health and patients who reported greater meaning of illness in their lives also reported more negative impact from the September 11th attacks. The September 11th terrorist attacks had at least a somewhat negative impact for a majority of patients far from the site of the nearest attack, and regardless of their demographic backgrounds. The amount of negative impact that patients perceived as a result of the terrorist attacks correlates with certain illness perceptions, including an external health locus of control and a perception of greater meaning of illness in one's life. Such correlations may indicate an effect of terrorism on patients' illness behaviors. Further research is needed to better understand effects of the threat of terrorism on the general health and illness behaviors of patients.


Forces acting on codon bias in malaria parasites.
Malaria parasite genomes have a range of codon biases, with Plasmodium falciparum one of the most AT-biased genomes known. We examined the make up of synonymous coding sites and stop codons in the core genomes of representative malaria parasites, showing first that local DNA context influences codon bias similarly across P. falciparum, P. vivax and P. berghei, with suppression of CpG dinucleotides and enhancement of CpC dinucleotides, both within and aross codons. Intense asexual phase gene expression in P. falciparum and P. berghei is associated with increased A3:G3 bias but reduced T3:C3 bias at 2-fold sites, consistent with adaptation of codons to tRNA pools and avoidance of wobble tRNA interactions that potentially slow down translation. In highly expressed genes, the A3:G3 ratio can exceed 30-fold while the T3:C3 ratio can be less than 1, according to the encoded amino acid and subsequent base. Lysine codons (AAA/G) show distinctive behaviour with substantially reduced A3:G3 bias in highly expressed genes, perhaps because of selection against frameshifting when the AAA codon is followed by another adenine. Intense expression is also associated with a strong bias towards TAA stop codons (found in 94% and 89% of highly expressed P. falciparum and P. berghei genes respectively) and a proportional rise in the TAAA stop 'tetranucleotide'. The presence of these expression-linked effects in the relatively AT-rich malaria parasite species adds weight to the suggestion that AT-richness in the Plasmodium genus might be a fitness adaptation. Potential explanations for the relative lack of codon bias in P. vivax include the distinct features of its lifecycle and its effective population size over evolutionary time.


Promoter hypermethylation of multiple genes in sputum precedes lung cancer incidence in a high-risk cohort.
A sensitive screening approach for lung cancer could markedly reduce the high mortality rate for this disease. Previous studies have shown that methylation of gene promoters is present in exfoliated cells within sputum prior to lung cancer diagnosis. The purpose of the current study is to conduct a nested case-control study of incident lung cancer cases from an extremely high-risk cohort for evaluating promoter methylation of 14 genes in sputum. Controls (n = 92) were cohort members matched to cases (n = 98) by gender, age, and month of enrollment. The comparison of proximal sputum collected within 18 months to >18 months prior to diagnosis showed that the prevalence for methylation of gene promoters increased as the time to lung cancer diagnosis decreased. Six of 14 genes were associated with a >50% increased lung cancer risk. The concomitant methylation of three or more of these six genes was associated with a 6.5-fold increased risk and a sensitivity and specificity of 64%. This is the first study to prospectively examine a large panel of genes for their ability to predict lung cancer and shows the promise of gene promoter hypermethylation in sputum as a molecular marker for identifying people at high risk for cancer incidence.


Postural muscle responses and adaptations to backward platform perturbations in young people with and without intellectual disability.
This study examines postural muscle responses to backward perturbations in young people (16-20 years) with and without intellectual disability (ID). The study included 56 young people with ID and 43 age-matched without ID volunteers. The subjects stood on a platform that was moved backwards in a surface translation. Lower and upper leg muscles and lower back spine muscles were recorded with surface electromyography (EMG). Muscle onset latency, time to peak amplitude (EMG), adaptation of muscle responses to repeated perturbations (using integrated EMG (IEMG) for epochs), and synergies and strategies were assessed. The result showed no differences between the two groups in muscle onset latency, synergies, and strategies. Young people with ID reduced their time to peak amplitude in investigated muscles, a response that was different from the group without ID. Also, young people with ID tended to adapt their IEMG less compared to the controls. These findings suggest that young people with ID have limited ability to use somatosensory information and adapt their postural muscle responses to repeated external perturbations.


PtxtPME1 and homogalacturonans influence xylem hydraulic properties in poplar.
While the xylem hydraulic properties, such as vulnerability to cavitation (VC), are of paramount importance in drought resistance, their genetic determinants remain unexplored. There is evidence that pectins and their methylation pattern are involved, but the detail of their involvement and the corresponding genes need to be clarified. We analyzed the hydraulic properties of the 35S::PME1 transgenic aspen that ectopically under- or over-express a xylem-abundant pectin methyl esterase, PtxtPME1. We also produced and analyzed 4CL1::PGII transgenic poplars expressing a fungal polygalacturonase, AnPGII, under the control of the Ptxa4CL1 promoter that is active in the developing xylem after xylem cell expansion. Both the 35S::PME1 under- and over-expressing aspen lines developed xylem with lower-specific hydraulic conductivity and lower VC, while the 4CL1::PGII plants developed xylem with a higher VC. These xylem hydraulic changes were associated with modifications in xylem structure or in intervessel pit structure that can result in changes in mechanical behavior of the pit membrane. This study shows that homogalacturonans and their methylation pattern influence xylem hydraulic properties, through its effect on xylem cell expansion and on intervessel pit properties and it show a role for PtxtPME1 in the xylem hydraulic properties.


Robotics in uro-oncologic surgery.
In urology, the main use for the robotic technique has been in radical prostatectomy for prostate cancer. Robotic surgery for other organs, such as the kidneys and bladder, has been less explored. However, partial nephrectomy or radical nephroureterectomy can be difficult for inexperienced laparoscopic surgeons. The advent of the da Vinci robot, with multijointed endowristed instruments and stereoscopic vision, decreases the technical difficulty of intracorporeal suturing and improves the reconstructive steps. The objective of this article is to offer an overview of all robotic procedures recently developed in the field of urology. We evaluate the feasibility of these procedures and their potential advantages and disadvantages. We also describe perioperative, postoperative, and oncologic outcomes of robot-assisted surgery as well as perform a comparison with open and laparoscopic techniques. Comparative data and an adequate follow-up are needed to demonstrate equivalent oncologic outcomes in comparison with traditional open or laparoscopic procedures.


Case-control study of endogenous steroid hormones and endometrial cancer.
It has been suggested that identified risk factors for endometrial cancer operate through a single etiologic pathway, i.e., exposure to relatively high levels of unopposed estrogen (estrogen in the absence of progestins). Only a few studies, however, have addressed this issue directly. We assessed the risk of developing endometrial cancer among both premenopausal and postmenopausal women in relation to the circulating levels of steroid hormones and sex hormone-binding globulin (SHBG). The independent effect of hormones was assessed after adjustment for other known risk factors. The data used in the analysis are from a case-control study conducted in five geographic regions in the United States. Incident cases were newly diagnosed during the period from June 1, 1987, through May 15, 1990. The case patients, aged 20-74 years, were matched to control subjects by age, race, and geographic region. The community control subjects were obtained by random-digit-dialing procedures (for subjects 20-64 years old) and from files of the Health Care Financing Administration (for subjects > or = 65 years old). Additional control subjects who were having a hysterectomy performed for benign conditions were obtained from the participating centers. Women reporting use of exogenous estrogens or oral contraceptives within 6 months of interview were excluded, resulting in 68 case patients and 107 control subjects among premenopausal women and 208 case patients and 209 control subjects among postmenopausal women. The hormone analyses were performed on blood samples obtained from case patients or from hysterectomy control subjects before surgery. The odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by use of an unconditional logistic regression analysis after we controlled for matching variables and potential confounders. All P values were two-sided. High circulating levels of androstenedione were associated with 3.6-fold and 2.8-fold increased risks among premenopausal and postmenopausal women, respectively, after adjustment for other factors (P for trend = .01 and < .001, respectively). Risks related to other hormone fractions varied by menopausal status. Among postmenopausal women, a reduced risk was associated with high SHBG levels and persisted after adjustment was made for obesity and other factors (OR = 0.51; 95% CI = 0.27-0.95). High estrone levels were associated with increased risk (OR = 3.8; 95% CI = 2.2-6.6), although adjustment for other risk factors (particularly body mass index) diminished the effect (OR = 2.2; 95% CI = 1.2-4.4). Albumin-bound estradiol (E2), a marker of the bioavailable fraction, also remained an important risk factor after adjustment was made for other factors (OR = 2.0; 95% CI = 1.0-3.9). In contrast, high concentrations of total, free, and albumin-bound E2 were unrelated to increased risk in premenopausal women. In both premenopausal and postmenopausal groups, risks associated with obesity and fat distribution were not affected by adjustment for hormones. High endogenous levels of unopposed estrogen are related to increased risk of endometrial cancer, but their independence from other risk factors is inconsistent with being a common underlying biologic pathway through which all risk factors for endometrial cancer operate. Further research should focus on alternative endocrinologic mechanisms for risk associated with obesity and body fat distribution and for the biologic relevance of the increased risk associated with androstenedione in both premenopausal and postmenopausal disease.


Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.
This is the first randomised controlled trial for assessment of the immunogenicity and safety of a candidate non-replicating adenovirus type-5 (Ad5)-vectored COVID-19 vaccine, aiming to determine an appropriate dose of the candidate vaccine for an efficacy study. This randomised, double-blind, placebo-controlled, phase 2 trial of the Ad5-vectored COVID-19 vaccine was done in a single centre in Wuhan, China. Healthy adults aged 18 years or older, who were HIV-negative and previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-free, were eligible to participate and were randomly assigned to receive the vaccine at a dose of 1 × 1011 viral particles per mL or 5 × 1010 viral particles per mL, or placebo. Investigators allocated participants at a ratio of 2:1:1 to receive a single injection intramuscularly in the arm. The randomisation list (block size 4) was generated by an independent statistician. Participants, investigators, and staff undertaking laboratory analyses were masked to group allocation. The primary endpoints for immunogenicity were the geometric mean titres (GMTs) of specific ELISA antibody responses to the receptor binding domain (RBD) and neutralising antibody responses at day 28. The primary endpoint for safety evaluation was the incidence of adverse reactions within 14 days. All recruited participants who received at least one dose were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, NCT04341389. 603 volunteers were recruited and screened for eligibility between April 11 and 16, 2020. 508 eligible participants (50% male; mean age 39·7 years, SD 12·5) consented to participate in the trial and were randomly assigned to receive the vaccine (1 × 1011 viral particles n=253; 5 × 1010 viral particles n=129) or placebo (n=126). In the 1 × 1011 and 5 × 1010 viral particles dose groups, the RBD-specific ELISA antibodies peaked at 656·5 (95% CI 575·2-749·2) and 571·0 (467·6-697·3), with seroconversion rates at 96% (95% CI 93-98) and 97% (92-99), respectively, at day 28. Both doses of the vaccine induced significant neutralising antibody responses to live SARS-CoV-2, with GMTs of 19·5 (95% CI 16·8-22·7) and 18·3 (14·4-23·3) in participants receiving 1 × 1011 and 5 × 1010 viral particles, respectively. Specific interferon γ enzyme-linked immunospot assay responses post vaccination were observed in 227 (90%, 95% CI 85-93) of 253 and 113 (88%, 81-92) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Solicited adverse reactions were reported by 183 (72%) of 253 and 96 (74%) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Severe adverse reactions were reported by 24 (9%) participants in the 1 × 1011 viral particles dose group and one (1%) participant in the 5 × 1010 viral particles dose group. No serious adverse reactions were documented. The Ad5-vectored COVID-19 vaccine at 5 × 1010 viral particles is safe, and induced significant immune responses in the majority of recipients after a single immunisation. National Key R&D Programme of China, National Science and Technology Major Project, and CanSino Biologics.


The role of depression and catastrophizing in musculoskeletal pain.
Many patients with musculoskeletal pain also suffer from a depressed mood. Catastrophizing is one process that may link depression and pain since it is a key concept in models of both problems. Earlier research has suggested that catastrophizing measures something above and beyond depression. This study tests the idea that if depressed mood and catastrophizing are separate entities then when one is absent the other should still contribute to poor outcome, and, when both are present there should be an additional adverse effect. To this end, a prospective design, with a built-in replication from two clinical samples of patients with sub-acute pain (one from Sweden, N=373; one from Australasia, N=259), was employed. Participants were classified as to having high/low scores on measures of depression and catastrophizing. Subsequently, these classifications were studied in relation to outcome variables cross-sectionally and at follow-up. Results showed a small to moderate correlation between catastrophizing and depression and that there are individuals with one, but not the other problem. Further, having one or the other of the entities was associated with current pain problems and outcome, while having both increased the associations substantially. The replication showed very similar results Our data demonstrate that pain catastrophizing and heightened depressed mood have an additive and adverse effect on the impact of pain, relative to either alone. It suggests that each should be assessed in the clinic and that future research should focus on treatments specifically designed to tackle both depressed mood and catastrophizing.


Radiation-exposed populations: who, why, and how to study.
Everyone is exposed to natural and manmade ionizing radiation that can originate from sources in the environment and in medical and occupational settings. There is notable variation, however, among individuals and across populations in the types of sources of radiation and in the frequency, level, and duration of exposure. Adverse health effects associated with radiation exposure have been known for decades, and ionizing radiation exposure has been linked with a broad range of different types of cancer and benign neoplasms as well as birth defects, reproductive effects, and diseases of the circulatory, hematologic, and neurologic systems. Our present understanding of radiation-related health risks derives primarily from multidisciplinary health risk (epidemiologic) studies that provide the key information on radiation-associated health outcomes, quantify radiation-related disease risks, and enhance understanding of mechanisms of radiation-related disease pathogenesis. Such information is central to quantifying risks in relation to benefits; addressing public concerns, including societal and clinical needs in relation to radiation exposure; and providing the database needed for establishing recommendations for radiation protection. Because of the importance of determining risks compared to benefits for all situations where exposure to ionizing radiation might result, it is useful for planning new health risks studies to categorize exposed populations according to the sources and types of radiation. This paper describes a wide range of populations exposed to radiation and the motivation and key methodological criteria that drive the rationale and priority of studying such populations. Also, discussed are alternative methods for evaluating radiation-related health risks in these populations, with a major focus on epidemiologic approaches. This paper concludes with a short summary of major highlights from radiation epidemiologic research and important unanswered questions.Introduction of Exposed Populations (Video 1:29, http://links.lww.com/HP/A22).


In vitro phenotypic, genomic and proteomic characterization of a cytokine-resistant murine β-TC3 cell line.
Type 1 diabetes mellitus (T1DM) is caused by the selective destruction of insulin-producing β-cells. This process is mediated by cells of the immune system through release of nitric oxide, free radicals and pro-inflammatory cytokines, which induce a complex network of intracellular signalling cascades, eventually affecting the expression of genes involved in β-cell survival.The aim of our study was to investigate possible mechanisms of resistance to cytokine-induced β-cell death. To this purpose, we created a cytokine-resistant β-cell line (β-TC3R) by chronically treating the β-TC3 murine insulinoma cell line with IL-1β + IFN-γ. β-TC3R cells exhibited higher proliferation rate and resistance to cytokine-mediated cell death in comparison to the parental line. Interestingly, they maintained expression of β-cell specific markers, such as PDX1, NKX6.1, GLUT2 and insulin. The analysis of the secretory function showed that β-TC3R cells have impaired glucose-induced c-peptide release, which however was only moderately reduced after incubation with KCl and tolbutamide. Gene expression analysis showed that β-TC3R cells were characterized by downregulation of IL-1β and IFN-γ receptors and upregulation of SOCS3, the classical negative regulator of cytokines signaling. Comparative proteomic analysis showed specific upregulation of 35 proteins, mainly involved in cell death, stress response and folding. Among them, SUMO4, a negative feedback regulator in NF-kB and JAK/STAT signaling pathways, resulted hyper-expressed. Silencing of SUMO4 was able to restore sensitivity to cytokine-induced cell death in β-TC3R cells, suggesting it may play a key role in acquired cytokine resistance by blocking JAK/STAT and NF-kB lethal signaling.In conclusion, our study represents the first extensive proteomic characterization of a murine cytokine-resistant β-cell line, which might represent a useful tool for studying the mechanisms involved in resistance to cytokine-mediated β-cell death. This knowledge may be of potential benefit for patients with T1DM. In particular, SUMO4 could be used as a therapeutical target.


Assessing the diagnostic accuracy for pleomorphic adenoma and Warthin tumor by employing the Milan System for Reporting Salivary Gland Cytopathology: An international, multi-institutional study.
The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) has established distinct diagnostic categories for reporting cytopathological findings, and each is associated with a defined risk of malignancy (ROM). However, the ROM is applied at the overall category level and is not specific for particular morphological entities within a category. Here, the diagnostic performance of the MSRSGC for pleomorphic adenoma (PA) and Warthin tumor (WT) is reported. The pathology archives of 11 institutions from 4 countries were retrospectively searched to identify all salivary gland fine-needle aspiration (FNA) biopsies with a differential or definitive diagnosis of PA or WT and all resection specimens with a diagnosis of PA or WT; only paired cases were included. All FNA diagnoses were retrospectively classified according to the MSRSGC. A total of 1250 cases met the inclusion criteria, and they included 898 PA cases and 352 WT cases. The ROM in the benign neoplasm category was 3.0% and 1.3% for cases with a differential or definitive diagnosis of PA and WT, respectively. The ROM in the salivary gland neoplasm with uncertain malignant potential (SUMP) category was 2.7% and 18.8% for PA and WT, respectively (P = .0277). The diagnostic accuracy for PA and WT was 95.1% and 96.1%, respectively. The diagnostic accuracy for PA and WT on FNA is high. Furthermore, these findings highlight the difference in the ROMs associated with 2 specific differential diagnoses in the SUMP category: basaloid neoplasms and oncocytoid neoplasms.


Image evaluation and its application to lunar orbiter.
The techniques employed to evaluate the performance of conventional aerial imaging systems are extended to the evaluation of space imaging systems. The general concepts are illustrated by employing the Lunar Orbiter as an example. Quality parameters are selected, and methods for their measurements from the Lunar Orbiter imagery are described. Results from statistical communication theory are employed to relate system performance as determined by design objectives to the quality of the reconstructed image. The evaluation of the performance of the Lunar Orbiter I and II imaging systems based upon these results is described. One of the criteria describing the detectability of small objects on the lunar surface is shown to correlate with data obtained from visual inspection of the photographs by trained observers.


FES kinases are required for oncogenic FLT3 signaling.
The closely related non-receptor tyrosine kinases FEline Sarcoma (FES) and FEs Related (FER) are activated by cell surface receptors in hematopoietic cells. Despite the early description of oncogenic viral forms of fes, v-fes, and v-fps, the implication of FES and FER in human pathology is not known. We have recently shown that FES but not FER is necessary for oncogenic KIT receptor signaling. Here, we report that both FES and FER kinases are activated in primary acute myeloid leukemia (AML) blasts and in AML cell lines. FES and FER activation is dependent on FLT3 in cell lines harboring constitutively active FLT3 mutants. Moreover, both FES and FER proteins are critical for FLT3-internal tandem duplication (ITD) signaling and for cell proliferation in relevant AML cell lines. FER is required for cell cycle transitions, whereas FES seems necessary for cell survival. We concluded that FES and FER kinases mediate essential non-redundant functions downstream of FLT3-ITD.


CHRONIC ENTERITIS IN PATIENTS UNDERGOING PELVIC RADIOTHERAPY: PREVALENCE, RISK FACTORS AND ASSOCIATED COMPLICATIONS.
the radiation of tumours located in pelvic organs can cause mucositis in the bowel. The aim of this study was to determine the prevalence, risk factors, and complications of chronic radiation enteritis in patients who had received pelvic radiotherapy. cross-sectional study recruiting 150 patients that had been treated with radiation therapy during the year 2008 because of a prostate, cervical, endometrial or rectal cancer. The patients were asked about symptoms related to enteritis, and about changes in body weight and in dietary patterns. Sex, age, treatment modalities, acute enteritis, and type of cancer were considered possible risk factors, and were analysed with univariate and multivariate methods. the study included 100 patients, 84% males, median age 72.3 years. Chronic radiation enteritis was found in 20% of the patients, most of them grade 1 (45%). Furthermore, 10% had lost ≥ 5 kg of weight, 3% had been hospitalized due to diarrhoea or bowel obstruction, and 11% had changed their diet, mainly by removing vegetables, legumes and pastry. Male gender, age, previous acute radiation enteritis, and chemotherapy were associated with chronic enteritis, but only chemotherapy remained independently related to bowel toxicity after multivariate analysis (OR = 3.59 [95% CI 1.20-10.73]). chronic enteritis is common among patients treated with pelvic radiotherapy, especially if chemotherapy is associated. The complication rate is low, but a significant number of patients change their usual diet in order to prevent symptoms.


PCR testing of pooled longitudinally collected cervical specimens of women to increase the efficiency of studying human papillomavirus infection.
In large active cohort studies of women investigating human papillomavirus (HPV) and cervical neoplasia, many women will be HPV-negative at all time points and testing of all their cervical specimens is an inefficient use of laboratory resources. The aim of this pilot study was to evaluate whether pooling cervical specimens from the same woman might provide a useful pretest of specimens from women unlikely to have high-grade cervical neoplasia or significant HPV exposure. We selected women (n = 187) participating in the Guanacaste Project for whom we already had HPV testing data on all their specimens from multiple visits (median = 8 visits), who were HPV DNA-negative at enrollment and at their 5- to 7-year exit from the cohort, and had no evidence of high-grade cervical neoplasia. Equal aliquots of cervical specimens from these women were pooled to create a proportional pooled specimen. Aliquots of pooled specimens were tested in a masked fashion by MY09/11 L1 consensus primer PCR. Second aliquots of some pooled specimens (n = 83) were included to assess the reliability of pooled testing. Results were compared with the predicted (expected) results based on the obtained test results of the individual specimens collected at interim visits. There was good overall agreement between observed and expected HPV DNA positivity, with a kappa of 0.63 [95% confidence interval (95% CI), 0.51-0.75] and a percent agreement of 83.4% (95% CI, 77.3-88.5%) although the HPV DNA positivity in the pooled specimen was less than expected (P = 0.001). The agreement between observed and expected HPV DNA positivity was related to the number of aliquots pooled, suggesting that positivity was related to viral genome concentrations. The kappa and percent agreement for intra-batch reliability of testing pooled specimens were 0.68 (95% CI, 0.53-0.84) and 84.3% (95% CI, 74.7-91.4%), respectively. We conclude that pooling specimens and testing by PCR may be useful for discriminating HPV DNA-positive from completely negative specimen sets in women who are likely to have been HPV DNA-negative.>


The Study of Platelet Receptors Using Artificial Lipid Bilayers.
Artificial lipid bilayers are powerful tools that can be used to model the interactions between platelets and membrane-bound ligands. To mimic the interaction of platelets with membrane-bound ligands, biotinylated lipids can be used to couple monobiotinylated recombinant ligands to the upper leaflet of an artificial lipid bilayer using streptavidin to bridge the two. Artificial lipid bilayers are generated by preparing liposomes, treating glass coverslips to make them hydrophilic and by assembling the bilayer in a specialized flow chamber. Finally platelets can be added to the flow chamber and the localization of fluorescently labeled molecules followed using microscopy.


An essential role for SRC-activated STAT-3 in 14,15-EET-induced VEGF expression and angiogenesis.
To understand the molecular mechanisms underlying 14,15-epoxyeicosatrienoic acid (14,15-EET)-induced angiogenesis, here we have studied the role of signal transducer and activator of transcription-3 (STAT-3). 14,15-EET stimulated the tyrosine phosphorylation of STAT-3 and its translocation from the cytoplasm to the nucleus in human dermal microvascular endothelial cells (HDMVECs). Adenovirus-mediated delivery of dominant negative STAT-3 substantially inhibited 14,15-EET-induced HDMVEC migration, and tube formation and Matrigel plug angiogenesis. 14,15-EET activated Src, as measured by its tyrosine phosphorylation and blockade of its activation by adenovirus-mediated expression of its dominant negative mutant, significantly attenuated 14,15-EET-induced STAT-3 phosphorylation in HDMVECs and the migration and tube formation of these cells and Matrigel plug angiogenesis. 14,15-EET induced the expression of vascular endothelial cell growth factor (VEGF) in a time- and Src-STAT-3-dependent manner in HDMVECs. Transfac analysis of VEGF promoter revealed the presence of STAT-binding elements and 14,15-EET induced STAT-3 binding to this promoter in vivo, and this interaction was inhibited by suppression of Src-STAT-3 signaling. Neutralizing anti-VEGF antibodies completely blocked 14,15-EET-induced HDMVEC migration and tube formation and Matrigel plug angiogenesis. These results reveal that Src-dependent STAT-3-mediated VEGF expression is a major mechanism of 14,15-EET-induced angiogenesis.


Characteristics of antrochoanal polyps in the pediatric age group.
To evaluate and compare the clinical and the pathological characteristics of antrochoanal polyps (ACPS) in adults and children. Medical records of 35 patients (19 children, 16 adults) operated upon for ACPS between 1995 and 2005 at an academic tertiary center were reviewed retrospectively. Demographic characteristics, clinical presentation, surgical management, histological findings and recurrence rate were compared. Of the 35 patients, 19 (54%) were children (mean age, 12.6 years) and 16 (46%) were adults (mean age, 31.4 years). Nasal obstruction was the most common presenting symptom in both groups. The incidence of snoring and/or obstructive sleep apnea was statistically significant, more common among the pediatric age group as compared to the adult group (P =.001). Epistaxis was also found to be more common among the pediatric age group (P =.027), while sinusitis was noted to be significantly more common among the adult group (P =.019). Transnasal endoscopic removal of ACPS was performed in 12 (63.1%) children and 11 (68.7%) adults. A combined open/endoscopic approach was required in 36.9% of children and 31.3% of adults. On histologic examination, allergic ACPS (the mucosal surface is respiratory epithelium, no mucus glands, abundant eosinophils) was more common than inflammatory ACPS (the mucosal surface is respiratory epithelium, no mucus glands, abundant neutrophils) in children (2.8:1) as compared to adults (0.8:1) (P =.045). All of our patients were followed with endoscopic examination for a period ranging from 9 to 42 months (mean, 24 months). Recurrence of ACPS was identified in 2 children and 1 adult. Antrochoanal polyps are a rare clinical entity. Children have unique clinical and pathological features as compared to adults. Endoscopic excision is safe and effective in the pediatric age group and has the capability to ensure complete removal and lower recurrence rate.


Tomato root microbiota and Phytophthora parasitica-associated disease.
Interactions between pathogenic oomycetes and microbiota residing on the surface of the host plant root are unknown, despite being critical to inoculum constitution. The nature of these interactions was explored for the polyphagous and telluric species Phytophthora parasitica. Composition of the rhizospheric microbiota of Solanum lycopersicum was characterized using deep re-sequencing of 16S rRNA gene to analyze tomato roots either free of or partly covered with P. parasitica biofilm. Colonization of the host root surface by the oomycete was associated with a shift in microbial community involving a Bacteroidetes/Proteobacteria transition and Flavobacteriaceae as the most abundant family. Identification of members of the P. parasitica-associated microbiota interfering with biology and oomycete infection was carried out by screening for bacteria able to (i) grow on a P. parasitica extract-based medium (ii), exhibit in vitro probiotic or antibiotic activity towards the oomycete (iii), have an impact on the oomycete infection cycle in a tripartite interaction S. lycopersicum-P. parasitica-bacteria. One Pseudomonas phylotype was found to exacerbate disease symptoms in tomato plants. The lack of significant gene expression response of P. parasitica effectors to Pseudomonas suggested that the increase in plant susceptibility was not associated with an increase in virulence. Our results reveal that Pseudomonas spp. establishes commensal interactions with the oomycete. Bacteria preferentially colonize the surface of the biofilm rather than the roots, so that they can infect plant cells without any apparent infection of P. parasitica. The presence of the pathogenic oomycete P. parasitica in the tomato rhizosphere leads to a shift in the rhizospheric microbiota composition. It contributes to the habitat extension of Pseudomonas species mediated through a physical association between the oomycete and the bacteria.


Regional myocardial volume perfused by the coronary artery branch: estimation in vivo.
Seven closed-chest dogs were anesthetized with intramuscular Innovar and a N2O/O2 gas mixture. Maximal coronary vasodilation was induced by intra-aortic injection of nitroglycerin (200 micrograms/kg) and continuous infusion of adenosine (1 mg/kg/min) into the main pulmonary artery. Superselective coronary arteriograms were obtained at varying distances along the left circumflex and left anterior descending coronary arteries during scans using the dynamic spatial reconstructor rapid tomographic x-ray scanner. At end-diastole the images of the coronary arteries and opacified myocardium were analyzed for cross-sectional area (CSA) of the coronary artery lumen and regional myocardial volume (Vdsr) perfused by that coronary artery. Postmortem regional myocardial volume (Vpath) was related to the volume perfused by the same artery measured in vivo by the dynamic spatial reconstructor as follows: Vdsr = 4.56 + 0.93 Vpath (r = .98, p less than .001). In addition, the cross-sectional area of the coronary artery supplying a volume of myocardium was related to that volume as follows: Vdsr = - 1.95 + 6.34 CSAmax (r = .88, p less than .001). This suggests that a maximally dilated coronary artery luminal cross-sectional area is linearly related to the volume of muscle it perfuses. We speculate that this relationship may be useful in expressing the physiologic significance of coronary arterial narrowing.


Landscape structure and live fences in Andes Colombian agrosystems: upper basin of the Cane-Iguaque River.
Changes in land use have generated a new landscape configuration in the Andino orobiome (mountain range) of the tropical Andes, resulting in a mosaic of cultivation and pastures interrupted by small fragments of forest and live fences. This has resulted in an ongoing decrease in the biodiversity of this biome. In the upper basin of the Cane-Iguaque River (Villa de Levya-Boyacá, Colombia), located 2,600-3,000 m above the Cordillera Oriental, over three time periods in 1960, 1984, and 2004, we characterized the structure, patterns, and evolution of the overall landscape and of the live fences (used as tools in biodiversity conservation and considered to be desirable alternatives to nonlive fences in farming production systems) within an agricultural landscape. To do this, we interpreted high-resolution satellite images using a landscape ecology approach and applied landscape map metrics. We found that the natural forests have been transformed by pastures and cultivation, and that although live fences cover only a small portion of the total landscape (4.6%), they have an important effect on landscape structure and biodiversity. There has been an increase in live fences, especially between 1960 and 1984, as well as an increase in their density. However, there has been a reduction in the average length of live fences over the periods that we studied. This could be due in part to changes in the types of agricultural products that have been cultivated in recent years, with an increase in potatoes and a decrease in other vegetables, and also by resource extraction of timber and fuel wood. In the studied area, agricultural production was sustained while biodiversity conservation was improved by the use of live fences. Therefore, live fences should be considered not only as part of an agriculturally productive area, but also as an important element of a multi-functional landscape that contributes to the maintenance of biodiversity and provides resources of economic and ecological interest, decreasing the pressure on natural forest. Improving the network of live fences constitutes an important strategy for the sustainable management of the rural landscape of the Andino orobiome of Colombia and similar areas in the tropics.


"Floating knee" injuries: ipsilateral fractures of the femur and tibia.
Ipsilateral fractures of the femur and tibia have been called "floating knee" injuries and may include combinations of diaphyseal, metaphyseal, and intra-articular fractures. These are often high-energy injuries and most frequently occur in the polytrauma patient. Many of these fractures are open, with associated vascular injuries. Surgical stabilization of both fractures and early mobilization of the patient and the extremity produce the best clinical outcomes. The use of a radiolucent operating room table and the introduction of retrograde intramedullary fixation of femoral fractures have facilitated surgical stabilization of some floating-knee fracture patterns. Although treatment planning for each fracture in the extremity should be considered individually to achieve the optimal result, the effect of that decision must be considered in light of the overall injury status of the entire extremity. Collateral ligament and meniscal injuries may also be associated with this fracture complex. Complications (such as compartment syndrome, loss of knee motion, failure to diagnose knee ligament injury, and the need for amputation) are not infrequent. Better results and fewer complications are observed when both fractures are diaphyseal than when one or both are intra-articular.


Leptomeningeal carcinomatosis: easy to miss.
Leptomeningeal carcinomatosis is a devastating condition with very poor prognosis. With advances in cancer treatment leading to improved survival in solid tumours, the incidence of ante-mortem diagnosis of leptomeningeal carcinomatosis is likely to rise. Without a high index of suspicion and appropriate imaging the diagnosis can be missed. We report two cases of leptomeningeal carcinomatosis secondary to metastatic breast disease with varied clinical presentation where the diagnosis was initially missed.


The inhibition of matrix metalloproteinase activity in chronic wounds by a polyacrylate superabsorber.
Excessive matrix metalloproteinase (MMP) levels have been observed in wound fluid of impaired healing wounds. This is thought to interfere with granulation tissue formation as newly formed extracellular matrix and cytokines are degraded and the wound becomes deadlocked, unable to progress to the next healing stages. In the cleansing phase, associated with high MMP activity levels, hydroactive wound dressings containing polyacrylate superabsorber particles are particularly effective. We tested whether these particles can block MMP activity in wound fluid obtained from chronic venous leg ulcers. Polyacrylate superabsorber particles inhibited MMP activity by more than 87% in a fluorogenic peptide substrate assay. Further analysis revealed two underlying molecular mechanisms. First, experiments showed direct binding of MMPs to the particles. Secondly, polyacrylate superabsorber particles can bind Ca2+ and Zn2+ ions competing with MMPs for divalent ions required for enzymatic activity. Furthermore, we provide the first evidence in vivo that MMPs bind effectively to polyacrylate superabsorber particles within the hostile environment of chronic wounds. We conclude that polyacrylate superabsorber particles can rescue the highly proteolytic microenvironment of non-healing wounds from MMP activity so that more conductive conditions allow healing to proceed.


Complex rearrangements and oncogene amplifications revealed by long-read DNA and RNA sequencing of a breast cancer cell line.
The SK-BR-3 cell line is one of the most important models for HER2+ breast cancers, which affect one in five breast cancer patients. SK-BR-3 is known to be highly rearranged, although much of the variation is in complex and repetitive regions that may be underreported. Addressing this, we sequenced SK-BR-3 using long-read single molecule sequencing from Pacific Biosciences and develop one of the most detailed maps of structural variations (SVs) in a cancer genome available, with nearly 20,000 variants present, most of which were missed by short-read sequencing. Surrounding the important ERBB2 oncogene (also known as HER2), we discover a complex sequence of nested duplications and translocations, suggesting a punctuated progression. Full-length transcriptome sequencing further revealed several novel gene fusions within the nested genomic variants. Combining long-read genome and transcriptome sequencing enables an in-depth analysis of how SVs disrupt the genome and sheds new light on the complex mechanisms involved in cancer genome evolution.


Having less, giving more: the influence of social class on prosocial behavior.
Lower social class (or socioeconomic status) is associated with fewer resources, greater exposure to threat, and a reduced sense of personal control. Given these life circumstances, one might expect lower class individuals to engage in less prosocial behavior, prioritizing self-interest over the welfare of others. The authors hypothesized, by contrast, that lower class individuals orient to the welfare of others as a means to adapt to their more hostile environments and that this orientation gives rise to greater prosocial behavior. Across 4 studies, lower class individuals proved to be more generous (Study 1), charitable (Study 2), trusting (Study 3), and helpful (Study 4) compared with their upper class counterparts. Mediator and moderator data showed that lower class individuals acted in a more prosocial fashion because of a greater commitment to egalitarian values and feelings of compassion. Implications for social class, prosocial behavior, and economic inequality are discussed.


MicroRNA-466 inhibits tumor growth and bone metastasis in prostate cancer by direct regulation of osteogenic transcription factor RUNX2.
MicroRNAs (miRNAs) have emerged as key players in cancer progression and metastatic initiation yet their importance in regulating prostate cancer (PCa) metastasis to bone has begun to be appreciated. We employed multimodal strategy based on in-house PCa clinical samples, publicly available TCGA cohorts, a panel of cell lines, in silico analyses, and a series of in vitro and in vivo assays to investigate the role of miR-466 in PCa. Expression analyses revealed that miR-466 is under-expressed in PCa compared to normal tissues. Reconstitution of miR-466 in metastatic PCa cell lines impaired their oncogenic functions such as cell proliferation, migration/invasion and induced cell cycle arrest, and apoptosis compared to control miRNA. Conversely, attenuation of miR-466 in normal prostate cells induced tumorigenic characteristics. miR-466 suppressed PCa growth and metastasis through direct targeting of bone-related transcription factor RUNX2. Overexpression of miR-466 caused a marked downregulation of integrated network of RUNX2 target genes such as osteopontin, osteocalcin, ANGPTs, MMP11 including Fyn, pAkt, FAK and vimentin that are known to be involved in migration, invasion, angiogenesis, EMT and metastasis. Xenograft models indicate that miR-466 inhibits primary orthotopic tumor growth and spontaneous metastasis to bone. Receiver operating curve and Kaplan-Meier analyses show that miR-466 expression can discriminate between malignant and normal prostate tissues; and can predict biochemical relapse. In conclusion, our data strongly suggests miR-466-mediated attenuation of RUNX2 as a novel therapeutic approach to regulate PCa growth, particularly metastasis to bone. This study is the first report documenting the anti-bone metastatic role and clinical significance of miR-466 in prostate cancer.


Intralysosomal hydrolysis of glycyl-L-phenylalanine 2-naphthylamide.
Glycyl-L-phenylalanine 2-naphthylamide (Gly-L-Phe-2-NNap), a cathepsin C substrate, induces an increase of the free and unsedimentable activities of this enzyme when incubated with a total mitochondrial fraction of rat liver. 1 mM-ZnSO4 considerably inhibits the cathepsin C total activity, measured with Gly-L-Phe-2-NNap as the substrate, in the presence of Triton X-100. The inhibition is markedly less pronounced when the free activity is determined; a high activity remains that depends on the integrity of the lysosomes; it decreases as the free activity of N-acetylglucosaminidase increases when lysosomes are subjected to treatments able to disrupt their membrane. Cathepsin C activity is reduced when thioethylamine hydrochloride is omitted from the incubation medium. Under these conditions at 37 degrees C, the free activity equals the total activity, although the lysosomes are intact, as indicated by the low free activity of N-acetylglucosaminidase. 1 mM-ZnSO4 strikingly inhibits the total activity, whereas more than 80% of the free activity remains. These observations are presented as evidence that Gly-L-Phe-2-NNap can possibly cause a disruption of the lysosomes as a result of its hydrolysis inside these organelles. In the presence of ZnSO4, intralysosomal hydrolysis becomes apparent, owing to a preferential inhibition by Zn2+ of extralysosomal hydrolysis; in the absence of thioethylamine hydrochloride, it is measurable because the disruption of lysosomes by Gly-L-Phe-2-NNap is delayed as a result of a slow-down of the reaction. The usefulness of Gly-L-Phe-2-NNap and related dipeptidyl naphthylamides in lysosomal-membrane-permeability studies is emphasized.


Neuromuscular control of prey capture in frogs.
While retaining a feeding apparatus that is surprisingly conservative morphologically, frogs as a group exhibit great variability in the biomechanics of tongue protraction during prey capture, which in turn is related to differences in neuromuscular control. In this paper, I address the following three questions. (1) How do frog tongues differ biomechanically? (2) What anatomical and physiological differences are responsible? (3) How is biomechanics related to mechanisms of neuromuscular control? Frog species use three non-exclusive mechanisms to protract their tongues during feeding: (i) mechanical pulling, in which the tongue shortens as its muscles contract during protraction; (ii) inertial elongation, in which the tongue lengthens under inertial and muscular loading; and (iii) hydrostatic elongation, in which the tongue lengthens under constraints imposed by the constant volume of a muscular hydrostat. Major differences among these functional types include (i) the amount and orientation of collagen fibres associated with the tongue muscles and the mechanical properties that this connective tissue confers to the tongue as a whole; and (ii) the transfer of intertia from the opening jaws to the tongue, which probably involves a catch mechanism that increases the acceleration achieved during mouth opening. The mechanisms of tongue protraction differ in the types of neural mechanisms that are used to control tongue movements, particularly in the relative importance of feed-forward versus feedback control, in requirements for precise interjoint coordination, in the size and number of motor units, and in the afferent pathways that are involved in coordinating tongue and jaw movements. Evolution of biomechanics and neuromuscular control of frog tongues provides an example in which neuromuscular control is finely tuned to the biomechanical constraints and opportunities provided by differences in morphological design among species.


New Terthiophene-Conjugated Porphyrin Donors for Highly Efficient Organic Solar Cells.
To mimic the natural photosynthetic systems utilizing chlorophylls to absorb light and store light energy, two new porphyrin-based small molecules of PTTR and PTTCNR have been developed for photovoltaic applications. The highest power conversion efficiency of 8.21% is achieved, corresponding to a short-circuit current of 14.30 mA cm-2, open-circuit voltage of 0.82 V, and fill factor of 70.01%. The excellent device performances can be ascribed to the engineering of molecule structure and film morphology. The horizontal conjugation of 3,3″-dihexyl-terthiophene to porphyrin-core with the vertical aliphatic 2-octylundecyl peripheral substitutions, can not only effectively increase the solar flux coverage between the conventional Soret and Q bands of porphyrin unit, but also optimize molecular packing through polymorphism associated with side-chains and the linear π-conjugated backbones. And the additive of 1,8-diiodooctane and subsequent chloroform solvent vapor annealing facilitate the formation of the blend films with [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM) characteristics of bicontinuous, interpenetrating networks required for efficient charge separation and transportation.


Why do some fathers become primary caregivers for their infants? A qualitative study.
Despite recent advances, research on father-infant relations is still relatively lacking. One hitherto neglected area is the subjective experience of primary caregiving (PCG) fathers, including their reasons for taking on a PCG role. Twenty-five PCG fathers, defined as those providing sole child care for their 1-year-old infant for at least 20 waking hours a week, completed semi-structured interviews as part of a large two-centre English study of child care. Interviews were tape-recorded, transcribed and analysed using emergent theme analysis. Themes with a bearing on the fathers' explicit and implicit reasons for providing relatively high levels of sole child care were grouped using an iterative process of independent analysis, comparison and rechecking. Reasons included mother's and father's employment situation and relative earning power, the absence of acceptable alternative child care, perceptions of societal values, maternal and paternal health, family history and ideological values. Flexibility of paternal employment, or its relative unimportance, and motivation or willingness on the part of the father to share in child care were invariably present. For some, the fact of one or other of their own parents having been emotionally distant or physically absent had led to a determination to do things differently with their own children. Fathers reported that they valued the increased time spent with their child, even if they had not been consciously motivated beforehand. Fathers describe a wide range of reasons for becoming primary caregivers for their infant, and generally experience themselves as being actively involved in that decision. If fathers are to take an increasing role in child care, societal values and financial pressure may need to be addressed.