The influence of neighbourhood green space on children's physical activity and screen time: findings from the longitudinal study of Australian children.
It is often hypothesised that neighbourhood green space may help prevent well-known declines in physical activity and increases in sedentary behaviour that occur across childhood. As most studies in this regard are cross-sectional, the purpose of our study was to use longitudinal data to examine whether green space promotes active lifestyles as children grow older. Data came from participants (n = 4983; age = 4-5) of the Longitudinal Study of Australian Children, a nationally representative study on health and child development. Physical activity and screen time were measured biennially (2004-2012) using questionnaires and time use diaries. Quantity of neighbourhood green space was objectively measured using Australian Bureau of Statistics mesh block data for each participant's statistical area level 2. Multilevel regression was used to test for associations between physical activity and screen time with green space quantity, adjusting for socio-economic confounders. Boys living in areas with 10% more neighbourhood green space had a: 7% (95% CI = 1.02, 1.13) greater odds of choosing physically active pastimes; 8% (95 % CI = 0.85, 1.00) lower odds of not enjoying physical activity; 2.3 min reduction in weekend television viewing (95% CI = -4.00, -0.69); and 7% (95% CI = 1.02; 1.12) and 9% (95% CI = 1.03; 1.15) greater odds of meeting physical activity guidelines on weekdays and weekends, respectively. No statistically (or practically) significant results were observed for girls. Current provisions of neighbourhood green space may be more amenable to promoting active lifestyles among boys than girls. Research is needed to explore what types of green space promote active lifestyles in all children.


Is Pornography Really about "Making Hate to Women"? Pornography Users Hold More Gender Egalitarian Attitudes Than Nonusers in a Representative American Sample.
According to radical feminist theory, pornography serves to further the subordination of women by training its users, males and females alike, to view women as little more than sex objects over whom men should have complete control. Composite variables from the General Social Survey were used to test the hypothesis that pornography users would hold attitudes that were more supportive of gender nonegalitarianism than nonusers of pornography. Results did not support hypotheses derived from radical feminist theory. Pornography users held more egalitarian attitudes--toward women in positions of power, toward women working outside the home, and toward abortion--than nonusers of pornography. Further, pornography users and pornography nonusers did not differ significantly in their attitudes toward the traditional family and in their self-identification as feminist. The results of this study suggest that pornography use may not be associated with gender nonegalitarian attitudes in a manner that is consistent with radical feminist theory.


Influence of the operative treatment of leiomyomas on lipid profile.
The aim of this study was to asses the influence of operative treatment of leiomyomas on lipid profile. The study was conducted from April 1, 2000, through April 30, 2002 in The Department of Septic Gynecology and Obstetrics at Collegium Medicum of the Jagiellonian University. Most hysterectomies are performed because of leiomyomas, which are the most common benign tumors of the female reproductive organ. Pathogenesis and evolution of uterine leiomyomas are not well understood. Treatment of leiomyomas is divided into operative and inoperative. Operative methods include generally laparoscopic myomectomy, conservative myomectomy and hysterectomy. 130 women with diagnosed leiomyomas were analyzed in four groups. Regardless of the type of performed surgery, decrease in cholesterol, HDL and LDL are observed 10 days after operation, with return to preoperative values at 6 months after surgical procedure. The highest level of cholesterol and LDL (6 moths from surgery) is observed in patients who underwent hysterectomy with bilateral oophorectomy.


Control of mitochondrial physiology and cell death by the Bcl-2 family proteins Bax and Bok.
Neuronal cell death is often triggered by events that involve intracellular increases in Ca2+. Under resting conditions, the intracellular Ca2+ concentration is tightly controlled by a number of extrusion and sequestering mechanisms involving the plasma membrane, mitochondria, and ER. These mechanisms act to prevent a disruption of neuronal ion homeostasis. As these processes require ATP, excessive Ca2+ overloading may cause energy depletion, mitochondrial dysfunction, and may eventually lead to Ca2+-dependent cell death. Excessive Ca2+ entry though glutamate receptors (excitotoxicity) has been implicated in several neurologic and chronic neurodegenerative diseases, including ischemic stroke, epilepsy, and Alzheimer's disease. Recent evidence has revealed that excitotoxic cell death is regulated by the B-cell lymphoma-2 (Bcl-2) family of proteins. Bcl-2 proteins, comprising of both pro-apoptotic and anti-apoptotic members, have been shown to not only mediate the intrinsic apoptosis pathway by controlling mitochondrial outer membrane (MOM) integrity, but to also control neuronal Ca2+ homeostasis and energetics. In this review, the role of Bcl-2 family proteins in the regulation of apoptosis, their expression in the central nervous system and how they control Ca2+-dependent neuronal injury are summarized. We review the current knowledge on Bcl-2 family proteins in the regulation of mitochondrial function and bioenergetics, including the fusion and fission machinery, and their role in Ca2+ homeostasis regulation at the mitochondria and ER. Specifically, we discuss how the 'pro-apoptotic' Bcl-2 family proteins, Bax and Bok, physiologically expressed in the nervous system, regulate such 'non-apoptotic/daytime' functions.


Isolation, cultivation and characterization of adult murine prostate stem cells.
The successful isolation and cultivation of prostate stem cells will allow us to study their unique biological properties and their application in therapeutic approaches. Here we describe step-by-step procedures on the basis of previous work in our laboratory for the harvesting of primary prostate cells from adolescent male mice by a modified enzymatic procedure; the isolation of an enriched population of prostate stem cells through cell sorting; and the cultivation of prostate stem cells in vitro and characterization of these cells and their stem-like activity, including in vivo tubule regeneration. Normally, it will take approximately 8 h to harvest prostate cells, isolate the stem cell-enriched population and set up the in vitro sphere assay. It will take up to 8 weeks to analyze the unique properties of the stem cells, including their regenerative capacity in vivo.


Social behavior and peer relationships of victims, bully-victims, and bullies in kindergarten.
Although the prevalence of bully/victim problems in school-age children and adolescents has been investigated in many countries, only a few studies have been carried out among younger children. This study examines social behaviors and peer relationships of children involved in bully/victim problems in kindergarten. Three hundred and forty-four five- to seven-year-old children participated. Children were categorized as victims, bully-victims, bullies, and non-involved by means of teacher ratings and peer nominations. Teachers completed questionnaires on children's social behavior patterns. Peer relationships were assessed by means of peer nominations and social cluster mapping. Compared to non-involved children, victims were more submissive, had fewer leadership skills, were more withdrawn, more isolated, less cooperative, less sociable, and frequently had no playmates. As expected, bullies and bully-victims were generally more aggressive than their peers. In addition, bully-victims were less cooperative, less sociable, and more frequently had no playmates than non-involved children. Bullies were less prosocial, and had more leadership skills than non-involved children. Bullies belonged to larger social clusters and were frequently affiliated with other bullies or bully-victims. We were able to establish distinct behavior patterns for bullies, bully-victims, and victims. Some of these social behaviors may be considered as risk factors for being victimized or becoming a bully. Our findings also emphasize the significance of peer relationships in bully/victim problems. On the one hand, victimized children's lack of friends might render them psychologically and socially vulnerable, and thus more prone to becoming easy targets. On the other hand, bullies seemed to be preferred playmates, particularly for other aggressive boys. This affiliation of aggressive children might lead to an increase in bullying behavior. Our understanding of the social and interactional nature of bullying and victimization has practical implications for prevention and intervention against bully/victim problems.


Edge disturbance drives liana abundance increase and alteration of liana-host tree interactions in tropical forest fragments.
Closed-canopy forests are being rapidly fragmented across much of the tropical world. Determining the impacts of fragmentation on ecological processes enables better forest management and improves species-conservation outcomes. Lianas are an integral part of tropical forests but can have detrimental and potentially complex interactions with their host trees. These effects can include reduced tree growth and fecundity, elevated tree mortality, alterations in tree-species composition, degradation of forest succession, and a substantial decline in forest carbon storage. We examined the individual impacts of fragmentation and edge effects (0-100-m transect from edge to forest interior) on the liana community and liana-host tree interactions in rainforests of the Atherton Tableland in north Queensland, Australia. We compared the liana and tree community, the traits of liana-infested trees, and determinants of the rates of tree infestation within five forest fragments (23-58 ha in area) and five nearby intact-forest sites. Fragmented forests experienced considerable disturbance-induced degradation at their edges, resulting in a significant increase in liana abundance. This effect penetrated to significantly greater depths in forest fragments than in intact forests. The composition of the liana community in terms of climbing guilds was significantly different between fragmented and intact forests, likely because forest edges had more small-sized trees favoring particular liana guilds which preferentially use these for climbing trellises. Sites that had higher liana abundances also exhibited higher infestation rates of trees, as did sites with the largest lianas. However, large lianas were associated with low-disturbance forest sites. Our study shows that edge disturbance of forest fragments significantly altered the abundance and community composition of lianas and their ecological relationships with trees, with liana impacts on trees being elevated in fragments relative to intact forests. Consequently, effective control of lianas in forest fragments requires management practices which directly focus on minimizing forest edge disturbance.


Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice.
Autophagy increases the lifespan of model organisms; however, its role in promoting mammalian longevity is less well-established1,2. Here we report lifespan and healthspan extension in a mouse model with increased basal autophagy. To determine the effects of constitutively increased autophagy on mammalian health, we generated targeted mutant mice with a Phe121Ala mutation in beclin 1 (Becn1F121A/F121A) that decreases its interaction with the negative regulator BCL2. We demonstrate that the interaction between beclin 1 and BCL2 is disrupted in several tissues in Becn1 F121A/F121A knock-in mice in association with higher levels of basal autophagic flux. Compared to wild-type littermates, the lifespan of both male and female knock-in mice is significantly increased. The healthspan of the knock-in mice also improves, as phenotypes such as age-related renal and cardiac pathological changes and spontaneous tumorigenesis are diminished. Moreover, mice deficient in the anti-ageing protein klotho 3 have increased beclin 1 and BCL2 interaction and decreased autophagy. These phenotypes, along with premature lethality and infertility, are rescued by the beclin 1(F121A) mutation. Together, our data demonstrate that disruption of the beclin 1-BCL2 complex is an effective mechanism to increase autophagy, prevent premature ageing, improve healthspan and promote longevity in mammals.


Risk of first cervical HPV infection and pre-cancerous lesions after onset of sexual activity: analysis of women in the control arm of the randomized, controlled PATRICIA trial.
More information is needed about time between sexual initiation and human papillomavirus (HPV) infection and development of cervical precancer. The objectives were to investigate the time between first sexual activity and detection of first cervical HPV infection or development of first cervical intraepithelial neoplasia (CIN), and associated factors in women from the double-blind, multinational, 4-year PATRICIA trial. PATRICIA enroled women aged 15-25 years with no more than 6 lifetime sexual partners. Women were randomized 1:1 to the HPV-16/18 AS04-adjuvanted vaccine or to control, but only women from the control arm who began sexual intercourse during the study or within 6 months before enrolment, and had no HPV infection detected before the recorded date of their first sexual intercourse, were included in the present analysis. The time between onset of sexual activity and detection of the first cervical HPV infection or development of the first CIN lesion was analyzed using Kaplan-Meier and univariate and multivariable Cox proportional-hazards models. A total of 9337 women were enroled in the control arm of PATRICIA of whom 982 fulfilled the required inclusion criteria for analysis. A cumulative total of 28%, 44%, and 62% of the subjects had HPV infection within 12, 24, and 48 months, respectively. The overall incidence rate was 27.08 per 100 person-years. The most common oncogenic types associated with 6-month persistent infection were HPV-16 (incidence rate: 2.74 per 100 person-years), HPV-51 (2.70), HPV-52 (1.66), HPV-66 (1.14), and HPV-18 (1.09). Increased infection risk was associated with more lifetime sexual partners, being single, Chlamydia trachomatis history, and duration of hormone use. CIN1+ and CIN2+ lesions were most commonly associated with HPV-16, with an overall incidence rate of 1.87 and 1.07 per 100 person-years, respectively. Previous cervical HPV infection was most strongly associated with CIN development. More than 25% of women were infected with HPV within 1 year of beginning sexual activity. Without underestimating the value of vaccination at older ages, our findings emphasize its importance before sexual initiation. clinicaltrials.gov: NCT00122681 .


Evaluation of Extratropical Cyclone Precipitation in the North Atlantic Basin: An analysis of ERA-Interim, WRF, and two CMIP5 models.
The representation of extratropical cyclones (ETCs) precipitation in general circulation models (GCMs) and a weather research and forecasting (WRF) model is analyzed. This work considers the link between ETC precipitation and dynamical strength and tests if parameterized convection affects this link for ETCs in the North Atlantic Basin. Lagrangian cyclone tracks of ETCs in ERA-Interim reanalysis (ERAI), the GISS and GFDL CMIP5 models, and WRF with two horizontal resolutions are utilized in a compositing analysis. The 20-km resolution WRF model generates stronger ETCs based on surface wind speed and cyclone precipitation. The GCMs and ERAI generate similar composite means and distributions for cyclone precipitation rates, but GCMs generate weaker cyclone surface winds than ERAI. The amount of cyclone precipitation generated by the convection scheme differs significantly across the datasets, with GISS generating the most, followed by ERAI and then GFDL. The models and reanalysis generate relatively more parameterized convective precipitation when the total cyclone-averaged precipitation is smaller. This is partially due to the contribution of parameterized convective precipitation occurring more often late in the ETC life cycle. For reanalysis and models, precipitation increases with both cyclone moisture and surface wind speed, and this is true if the contribution from the parameterized convection scheme is larger or not. This work shows that these different models generate similar total ETC precipitation despite large differences in the parameterized convection, and these differences do not cause unexpected behavior in ETC precipitation sensitivity to cyclone moisture or surface wind speed.


Spalt-like 4 promotes posterior neural fates via repression of pou5f3 family members in Xenopus.
Amphibian neural development occurs as a two-step process: (1) induction specifies a neural fate in undifferentiated ectoderm; and (2) transformation induces posterior spinal cord and hindbrain. Signaling through the Fgf, retinoic acid (RA) and Wnt/β-catenin pathways is necessary and sufficient to induce posterior fates in the neural plate, yet a mechanistic understanding of the process is lacking. Here, we screened for factors enriched in posterior neural tissue and identify spalt-like 4 (sall4), which is induced by Fgf. Knockdown of Sall4 results in loss of spinal cord marker expression and increased expression of pou5f3.2 (oct25), pou5f3.3 (oct60) and pou5f3.1 (oct91) (collectively, pou5f3 genes), the closest Xenopus homologs of mammalian stem cell factor Pou5f1 (Oct4). Overexpression of the pou5f3 genes results in the loss of spinal cord identity and knockdown of pou5f3 function restores spinal cord marker expression in Sall4 morphants. Finally, knockdown of Sall4 blocks the posteriorizing effects of Fgf and RA signaling in the neurectoderm. These results suggest that Sall4, activated by posteriorizing signals, represses the pou5f3 genes to provide a permissive environment allowing for additional Wnt/Fgf/RA signals to posteriorize the neural plate.


AMPK-mediated GSK3beta inhibition by isoliquiritigenin contributes to protecting mitochondria against iron-catalyzed oxidative stress.
Isoliquiritigenin (ILQ), a flavonoid compound originated from Glycyrrhiza species, is known to activate SIRT1. Arachidonic acid (AA) in combination with iron (a catalyst of auto-oxidation) leads cells to produce excess reactive species with a change in mitochondrial permeability transition. In view of the importance of oxidative stress in cell death and inflammation, this study investigated the potential of ILQ to protect cells against the mitochondrial impairment induced by AA+iron and the underlying basis for this cytoprotection. Treatment with ILQ inhibited apoptosis induced by AA+iron, as evidenced by alterations in the levels of the proteins associated with cell viability: ILQ prevented a decrease in Bcl-x(L), and cleavage of poly(ADP-ribose)polymerase and procaspase-3. Moreover, ILQ inhibited the ability of AA+iron to elicit mitochondrial dysfunction. In addition, superoxide generation in mitochondria was attenuated by ILQ treatment. Consistently, ILQ prevented cellular H2O2 production increased by AA+iron, thereby enabling cells to restore GSH content. ILQ treatment enhanced inhibitory phosphorylation of glycogen synthase kinase-3beta (GSK3beta), and prevented a decrease in the GSK3beta phosphorylation elicited by AA+iron, which contributed to protecting cells and mitochondria. GSK3beta phosphorylation by ILQ was preceded by AMP-activated protein kinase (AMPK) activation, which was also responsible for mitochondrial protection, as shown by reversal of its effect in the experiments using a dominant negative mutant of AMPK and compound C. Moreover, the AMPK activation led to GSK3beta phosphorylation. These results demonstrate that ILQ has the ability to protect cells from AA+iron-induced H2O2 production and mitochondrial dysfunction, which is mediated with GSK3beta phosphorylation downstream of AMPK.


Subjamming transition in binary sphere mixtures.
We study the influence of particle-size asymmetry on structural evolution of randomly jammed binary sphere mixtures with varying large-sphere and small-sphere composition. Simulations of jammed packings are used to assess the transition from large-sphere dominant to small-sphere dominant mixtures. For weakly asymmetric particle sizes, packing properties evolve smoothly, but not monotonically, with increasing small-sphere composition, f. Our simulations reveal that at high values of ratio α of large- to small-sphere radii (α≥α_{c}≈5.75), evolution of structural properties, such as packing density, fraction of jammed spheres, and contact statistics with f, exhibit features that suggest a sharp transition, either through discontinuities in structural measures or their derivatives. We argue that this behavior is related to the singular, composition dependence of close-packing fraction predicted in infinite aspect ratio mixtures α→∞ by the Furnas model, but occurring for finite valued range of α above a critical value, α_{c}≈5.75. The existence of a sharp transition from small- to large-f values for α≥α_{c} can be attributed to the existence of a subjamming transition of small spheres within the interstices of jammed large spheres along the line of compositions f_{sub}(α). We argue that the critical value of finite-size asymmetry α_{c}≃5.75 is consistent with the geometric criterion for the transmission of small-sphere contacts between neighboring tetrahedrally close-packed interstices of large spheres, facilitating a cooperative subjamming transition of small spheres confined within the disjoint volumes.


Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation.
Inflammation is a beneficial host response to infection but can contribute to inflammatory disease if unregulated. The Th17 lineage of T helper (Th) cells can cause severe human inflammatory diseases. These cells exhibit both instability (they can cease to express their signature cytokine, IL-17A) and plasticity (they can start expressing cytokines typical of other lineages) upon in vitro re-stimulation. However, technical limitations have prevented the transcriptional profiling of pre- and post-conversion Th17 cells ex vivo during immune responses. Thus, it is unknown whether Th17 cell plasticity merely reflects change in expression of a few cytokines, or if Th17 cells physiologically undergo global genetic reprogramming driving their conversion from one T helper cell type to another, a process known as transdifferentiation. Furthermore, although Th17 cell instability/plasticity has been associated with pathogenicity, it is unknown whether this could present a therapeutic opportunity, whereby formerly pathogenic Th17 cells could adopt an anti-inflammatory fate. Here we used two new fate-mapping mouse models to track Th17 cells during immune responses to show that CD4(+) T cells that formerly expressed IL-17A go on to acquire an anti-inflammatory phenotype. The transdifferentiation of Th17 into regulatory T cells was illustrated by a change in their signature transcriptional profile and the acquisition of potent regulatory capacity. Comparisons of the transcriptional profiles of pre- and post-conversion Th17 cells also revealed a role for canonical TGF-β signalling and consequently for the aryl hydrocarbon receptor (AhR) in conversion. Thus, Th17 cells transdifferentiate into regulatory cells, and contribute to the resolution of inflammation. Our data suggest that Th17 cell instability and plasticity is a therapeutic opportunity for inflammatory diseases.


Structural investigation of donor age effect on human bone marrow mesenchymal stem cells: FTIR spectroscopy and imaging.
Stem cell studies hold enormous potential for development of new therapies for tissue regeneration and repair. Bone marrow mesenchymal stem cells (BM-MSCs) can differentiate into a variety of non-hematopoietic tissues and contribute maintenance of healthy hematopoiesis by providing supportive cellular microenvironment into BM. Here, we investigated age-related differences in BM-MSCs by using attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy and FTIR imaging together with hierarchical clustering as a novel methods to clarify global alterations in the structure and function of macromolecules in characterized BM-MSCs of different aged donors. The results may contribute to identification of age-related new molecular marker(s) to determine the effects of donor age on MSCs. The spectral results reflected that there were significant increases in the concentration of saturated lipids, proteins, glycogen, and nucleic acids in children and adolescent group BM-MSCs when compared to the infants and early and mid adults. The concentration of mentioned macromolecules in adult (early and mid) BM-MSCs were significantly lower than the concentrations in the children and adolescents. These results were attributed to the increase in the proliferation activity in younger BM-MSCs. The distribution of macromolecules into the cells was shown as in the form of chemical maps by FTIR imaging, and the results are in agreement with the ATR-FTIR spectroscopy results. The cellular activity degree was determined by the thiazolyl blue tetrazolium bromide (MTT) proliferation assay to support ATR-FTIR spectroscopy results. BM-MSCs of five different age groups were discriminated by making the hierarchical cluster analysis where the spectral data according to alterations in structure and composition of macromolecules were considered.


Vascular mimicry in glioblastoma following anti-angiogenic and anti-20-HETE therapies.
Glioblastoma (GBM) is one hypervascular and hypoxic tumor known among solid tumors. Antiangiogenic therapeutics (AATs) have been tested as an adjuvant to normalize blood vessels and control abnormal vasculature. Evidence of relapse exemplified in the progressive tumor growth following AAT reflects development of resistance to AATs. Here, we identified that GBM following AAT (Vatalanib) acquired an alternate mechanism to support tumor growth, called vascular mimicry (VM). We observed that Vatalanib induced VM vessels are positive for periodic acid-Schiff (PAS) matrix but devoid of any endothelium on the inner side and lined by tumor cells on the outer-side. The PAS+ matrix is positive for basal laminae (laminin) indicating vascular structures. Vatalanib treated GBM displayed various stages of VM such as initiation (mosaic), sustenance, and full-blown VM. Mature VM structures contain red blood cells (RBC) and bear semblance to the functional blood vessel-like structures, which provide all growth factors to favor tumor growth. Vatalanib treatment significantly increased VM especially in the core of the tumor, where HIF-1α was highly expressed in tumor cells. VM vessels correlate with hypoxia and are characterized by co-localized MHC-1+ tumor and HIF-1α expression. Interestingly, 20-HETE synthesis inhibitor HET0016 significantly decreased GBM tumors through decreasing VM structures both at the core and at periphery of the tumors. In summary, AAT induced resistance characterized by VM is an alternative mechanism adopted by tumors to make functional vessels by transdifferentiation of tumor cells into endothelial-like cells to supply nutrients in the event of hypoxia. AAT induced VM is a potential therapeutic target of the novel formulation of HET0016. Our present study suggests that HET0016 has a potential to target therapeutic resistance and can be combined with other antitumor agents in preclinical and clinical trials.


RNA-binding protein Musashi1 modulates glioma cell growth through the post-transcriptional regulation of Notch and PI3 kinase/Akt signaling pathways.
Musashi1 (MSI1) is an RNA-binding protein that plays critical roles in nervous-system development and stem-cell self-renewal. Here, we examined its role in the progression of glioma. Short hairpin RNA (shRNA)-based MSI1-knock down (KD) in glioblastoma and medulloblastoma cells resulted in a significantly lower number of self renewing colony on day 30 (a 65% reduction), compared with non-silencing shRNA-treated control cells, indicative of an inhibitory effect of MSI1-KD on tumor cell growth and survival. Immunocytochemical staining of the MSI1-KD glioblastoma cells indicated that they ectopically expressed metaphase markers. In addition, a 2.2-fold increase in the number of MSI1-KD cells in the G2/M phase was observed. Thus, MSI1-KD caused the prolongation of mitosis and reduced the cell survival, although the expression of activated Caspase-3 was unaltered. We further showed that MSI1-KD glioblastoma cells xenografted into the brains of NOD/SCID mice formed tumors that were 96.6% smaller, as measured by a bioluminescence imaging system (BLI), than non-KD cells, and the host survival was longer (49.3±6.1 days vs. 33.6±3.6 days; P<0.01). These findings and other cell biological analyses suggested that the reduction of MSI1 in glioma cells prolonged the cell cycle by inducing the accumulation of Cyclin B1. Furthermore, MSI1-KD reduced the activities of the Notch and PI(3) kinase-Akt signaling pathways, through the up-regulation of Numb and PTEN, respectively. Exposure of glioma cells to chemical inhibitors of these pathways reduced the number of spheres and living cells, as did MSI1-KD. These results suggest that MSI1 increases the growth and/or survival of certain types of glioma cells by promoting the activation of both Notch and PI(3) kinase/Akt signaling.


Determination of autoantibodies to annexin XI in systemic autoimmune diseases.
Annexin XI, a calcyclin-associated protein, has been shown to be identical to a 56,000 Da antigen recognized by antibodies found in sera from patients suffering from systemic autoimmune diseases. In this work hexahistidine-tagged recombinant annexin XI (His6- rAnn XI) was used as antigen in ELISA experiments for determination of autoantibodies to annexin XI in sera of patients with systemic rheumatic autoimmune diseases. Immunoblotting with HeLa cell extract and with His6-rAnn XI as antigen was used for confirmation of positive ELISA results. We found eleven anti-annexin XI positive sera (3.9%) out of 282 sera from patients with systemic rheumatic diseases. The highest number of annexin XI positive sera were found in primary antiphospholipid syndrome (3/17), and in subacute lupus erythematosus (1/6), while lower frequencies of positive sera were found in patients with systemic sclerosis (5/137), rheumatoid arthritis (1/21), and systemic lupus erythematosus (1/58). Sera from healthy donors and patients with chronic infections were negative, except for one Salmonella typhimurium antibody positive serum. Autoantibodies to annexin XI were found to relate to thrombosis, but not to other clinical or laboratory features. A relation between antibodies to annexins and thrombosis has so far only been known for annexin V.


mHealth Application Areas and Technology Combinations*. A Comparison of Literature from High and Low/Middle Income Countries.
With the continuous and enormous spread of mobile technologies, mHealth has evolved as a new subfield of eHealth. While eHealth is broadly focused on information and communication technologies, mHealth seeks to explore more into mobile devices and wireless communication. Since mobile phone penetration has exceeded other infrastructure in low and middle-income countries (LMICs), mHealth is seen as a promising component to provide pervasive and patient-centered care. The aim of our research work for this paper is to examine the mHealth literature to identify application areas, target diseases, and mHealth service and technology types that are most appropriate for LMICs. Based on the 2011 WHO mHealth report, a combination of search terms, all including the word "mHealth", was identified. A literature review was conducted by searching the PubMed and IEEE Xplore databases. Articles were included if they were published in English, covered an mHealth solution/ intervention, involved the use of a mobile communication device, and included a pilot evaluation study. Articles were excluded if they did not provide sufficient detail on the solution covered or did not focus on clinical efficacy/effectiveness. Cross-referencing was also performed on included articles. 842 articles were retrieved and analyzed, 255 of which met the inclusion criteria. North America had the highest number of applications (n=74) followed by Europe (n=50), Asia (n=44), Africa (n=25), and Australia (n=9). The Middle East (n=5) and South America (n=3) had the least number of studies. The majority of solutions addressed diabetes (n=51), obesity (n=25), CVDs (n=24), HIV (n=18), mental health (n=16), health behaviors (n=16), and maternal and child's health (MCH) (n=11). Fewer solutions addressed asthma (n=7), cancer (n=5), family health planning (n=5), TB (n=3), malaria (n=2), chronic obtrusive pulmonary disease (COPD) (n=2), vision care (n=2), and dermatology (n=2). Other solutions targeted stroke, dental health, hepatitis vaccination, cold and flu, ED prescribed antibiotics, iodine deficiency, and liver transplantation (n=1 each). The remainder of solutions (n=14) did not focus on a certain disease. Most applications fell in the areas of health monitoring and surveillance (n=93) and health promotion and raising awareness (n=88). Fewer solutions addressed the areas of communication and reporting (n=11), data collection (n=6), telemedicine (n=5), emergency medical care (n=3), point of care support (n=2), and decision support (n=2). The majority of solutions used SMS messaging (n=94) or mobile apps (n=71). Fewer used IVR/phone calls (n=8), mobile website/email (n=5), videoconferencing (n=2), MMS (n=2), or video (n=1) or voice messages (n=1). Studies were mostly RCTs, with the majority suffering from small sample sizes and short study durations. Problems addressed by solutions included travel distance for reporting, self-management and disease monitoring, and treatment/medication adherence. SMS and app solutions are the most common forms of mHealth applications. SMS solutions are prevalent in both high and LMICs while app solutions are mostly used in high income countries. Common application areas include health promotion and raising awareness using SMS and health monitoring and surveillance using mobile apps. Remaining application areas are rarely addressed. Diabetes is the most commonly targeted medical condition, yet remains deficient in LMICs.


Pyruvate Dehydrogenase and Tricarboxylic Acid Cycle Enzymes Are Sensitive Targets of Traumatic Brain Injury Induced Metabolic Derangement.
Using a closed-head impact acceleration model of mild or severe traumatic brain injury (mTBI or sTBI, respectively) in rats, we evaluated the effects of graded head impacts on the gene and protein expressions of pyruvate dehydrogenase (PDH), as well as major enzymes of mitochondrial tricarboxylic acid cycle (TCA). TBI was induced in anaesthetized rats by dropping 450 g from 1 (mTBI) or 2 m height (sTBI). After 6 h, 12 h, 24 h, 48 h, and 120 h gene expressions of enzymes and subunits of PDH. PDH kinases and phosphatases (PDK1-4 and PDP1-2, respectively), citrate synthase (CS), isocitrate dehydrogenase (IDH), oxoglutarate dehydrogenase (OGDH), succinate dehydrogenase (SDH), succinyl-CoA synthase (SUCLG), and malate dehydrogenase (MDH) were determined in whole brain extracts (n = 6 rats at each time for both TBI levels). In the same samples, the high performance liquid chromatographic (HPLC) determination of acetyl-coenzyme A (acetyl-CoA) and free coenzyme A (CoA-SH) was performed. Sham-operated animals (n = 6) were used as controls. After mTBI, the results indicated a general transient decrease, followed by significant increases, in PDH and TCA gene expressions. Conversely, permanent PDH and TCA downregulation occurred following sTBI. The inhibitory conditions of PDH (caused by PDP1-2 downregulations and PDK1-4 overexpression) and SDH appeared to operate only after sTBI. This produced almost no change in acetyl-CoA and free CoA-SH following mTBI and a remarkable depletion of both compounds after sTBI. These results again demonstrated temporary or steady mitochondrial malfunctioning, causing minimal or profound modifications to energy-related metabolites, following mTBI or sTBI, respectively. Additionally, PDH and SDH appeared to be highly sensitive to traumatic insults and are deeply involved in mitochondrial-related energy metabolism imbalance.


Footprints pull origin and diversification of dinosaur stem lineage deep into Early Triassic.
The ascent of dinosaurs in the Triassic is an exemplary evolutionary radiation, but the earliest phase of dinosaur history remains poorly understood. Body fossils of close dinosaur relatives are rare, but indicate that the dinosaur stem lineage (Dinosauromorpha) originated by the latest Anisian (ca 242-244 Ma). Here, we report footprints from the Early-Middle Triassic of Poland, stratigraphically well constrained and identified using a conservative synapomorphy-based approach, which shifts the origin of the dinosaur stem lineage back to the Early Olenekian (ca 249-251 Ma), approximately 5-9 Myr earlier than indicated by body fossils, earlier than demonstrated by previous footprint records, and just a few million years after the Permian/Triassic mass extinction (252.3 Ma). Dinosauromorph tracks are rare in all Polish assemblages, suggesting that these animals were minor faunal components. The oldest tracks are quadrupedal, a morphology uncommon among the earliest dinosauromorph body fossils, but bipedality and moderately large body size had arisen by the Early Anisian (ca 246 Ma). Integrating trace fossils and body fossils demonstrates that the rise of dinosaurs was a drawn-out affair, perhaps initiated during recovery from the Permo-Triassic extinction.


Elevation of Non-Classical (CD14+/lowCD16++) Monocytes Is Associated with Increased Albuminuria and Urine TGF-β1 in HIV-Infected Individuals on Stable Antiretroviral Therapy.
High rates of albuminuria are observed among HIV-infected individuals on stable antiretroviral therapy (ART). Though pro-inflammatory and pro-fibrotic responses are described as components of albuminuria in the general population, it is unclear how these responses are associated to albuminuria in ART-treated chronic HIV. We investigated the relationship of monocyte subsets and urine inflammatory and fibrotic biomarkers to albuminuria in ART-treated HIV-infected participants. Cross-sectional analyses were performed on Hawaii Aging with HIV-cardiovascular disease study cohort participants who were required at entry to be ≥40 years old and on ART ≥3 months. Monocyte subpopulations were determined in banked peripheral blood mononuclear cells (PBMC) using multi-parametric flow-cytometry. Entry random urine samples were assessed for albumin-to-creatinine ratios (UACR). Urine samples were measured for inflammatory and fibrotic biomarkers using Luminex technology. Among 96 HIV-infected subjects with measured UACR (87% male, 59% Caucasian, and 89% undetectable HIV RNA with median CD4 of 495.5 cells/μL), 18 patients (19%) had albuminuria. Non-classical (CD14low/+CD16++) monocytes were significantly elevated in subjects with albuminuria (p = 0.034) and were correlated to UACR (r = 0.238, p = 0.019). Elevated non-classical monocyte counts were significant predictors of worsening albuminuria, independent of traditional- and ART-associated risk factors (β = 0.539, p = 0.007). Urine TGF-β1 and collagen-IV were significantly higher in albuminuric compared to non-albuminuric participants (TGF-β1; p = 0.039 and collagen-IV; p = 0.042). Urine TGF-β1 was significantly correlated with non-classical monocyte counts (r = 0.464, p = 0.017). Alterations in monocyte subpopulations and urine pro-fibrotic factors may play a role in kidney dysfunction during chronic HIV infection and warrants further study.


Attentional Access to Multiple Target Objects in Visual Search.
Most investigations of visual search have focused on the discrimination between a search target and other task-irrelevant distractor objects (selection). The attentional limitations that arise when multiple target objects in the same display have to be processed simultaneously (access) remain poorly understood. Here, we employed behavioral and electrophysiological measures to investigate the factors that determine whether multiple target objects can be accessed in parallel. Performance and N2pc components were measured for search displays that contained either a single target or two target objects. When two target objects were present, they either had the same or different target-defining features. Participants reported whether search displays contained a single target, two targets with shared features, or two targets with different features. There were performance costs as well as reduced N2pc amplitudes for two-target/different relative to two-target/same displays, suggesting that access to multiple target objects defined by different features was impaired. These behavioral and electrophysiological costs were also observed in a task where all search display objects were physically different, but not during color or shape singleton search, confirming that they do not reflect a low-level perceptual grouping of physically identical targets. These results demonstrate strong feature-specific limitations of visual access, as proposed by the Boolean map theory of visual attention. They suggest that multiple target objects can be accessed in parallel only when they share task-relevant features and demonstrate that mechanisms of visual access can be studied with electrophysiological markers.


Optical space-time wave packets having arbitrary group velocities in free space.
Controlling the group velocity of an optical pulse typically requires traversing a material or structure whose dispersion is judiciously crafted. Alternatively, the group velocity can be modified in free space by spatially structuring the beam profile, but the realizable deviation from the speed of light in vacuum is small. Here we demonstrate precise and versatile control over the group velocity of a propagation-invariant optical wave packet in free space through sculpting its spatio-temporal spectrum. By jointly modulating the spatial and temporal degrees of freedom, arbitrary group velocities are unambiguously observed in free space above or below the speed of light in vacuum, whether in the forward direction propagating away from the source or even traveling backwards towards it.


The mechanism of mitochondrial superoxide production by the cytochrome bc1 complex.
Production of reactive oxygen species (ROS) by the mitochondrial respiratory chain is considered to be one of the major causes of degenerative processes associated with oxidative stress. Mitochondrial ROS has also been shown to be involved in cellular signaling. It is generally assumed that ubisemiquinone formed at the ubiquinol oxidation center of the cytochrome bc(1) complex is one of two sources of electrons for superoxide formation in mitochondria. Here we show that superoxide formation at the ubiquinol oxidation center of the membrane-bound or purified cytochrome bc(1) complex is stimulated by the presence of oxidized ubiquinone indicating that in a reverse reaction the electron is transferred onto oxygen from reduced cytochrome b(L) via ubiquinone rather than during the forward ubiquinone cycle reaction. In fact, from mechanistic studies it seems unlikely that during normal catalysis the ubisemiquinone intermediate reaches significant occupancies at the ubiquinol oxidation site. We conclude that cytochrome bc(1) complex-linked ROS production is primarily promoted by a partially oxidized rather than by a fully reduced ubiquinone pool. The resulting mechanism of ROS production offers a straightforward explanation of how the redox state of the ubiquinone pool could play a central role in mitochondrial redox signaling.


Treating asthma with omega-3 fatty acids: where is the evidence? A systematic review.
Considerable interest exists in the potential therapeutic value of dietary supplementation with the omega-3 fatty acids. Given the interplay between pro-inflammatory omega-6 fatty acids, and the less pro-inflammatory omega-3 fatty acids, it has been thought that the latter could play a key role in treating or preventing asthma. The purpose was to systematically review the scientific-medical literature in order to identify, appraise, and synthesize the evidence for possible treatment effects of omega-3 fatty acids in asthma. Medline, Premedline, Embase, Cochrane Central Register of Controlled Trials, CAB Health, and, Dissertation Abstracts were searched to April 2003. We included randomized controlled trials (RCT's) of subjects of any age that used any foods or extracts containing omega-3 fatty acids as treatment or prevention for asthma. Data included all asthma related outcomes, potential covariates, characteristics of the study, design, population, intervention/exposure, comparators, and co interventions. Ten RCT's were found pertinent to the present report. Given the largely inconsistent picture within and across respiratory outcomes, it is impossible to determine whether or not omega-3 fatty acids are an efficacious adjuvant or monotherapy for children or adults. Based on this systematic review we recommend a large randomized controlled study of the effects of high-dose encapsulated omega-3 fatty acids on ventilatory and inflammatory measures of asthma controlling diet and other asthma risk factors. This review was limited because Meta-analysis was considered inappropriate due to missing data; poorly or heterogeneously defined populations, interventions, intervention-comparator combinations, and outcomes. In addition, small sample sizes made it impossible to meaningfully assess the impact on clinical outcomes of co-variables. Last, few significant effects were found.


Expression of the interleukin-21 and phosphorylated extracellular signal regulated kinase 1/2 in Kimura disease.
To investigate the expressions of interleukin (IL)-21 and phosphorylated extracellular signal regulated kinase 1/2 (pERK1/2) in Kimura disease (KD) and to correlate the findings with clinical and prognostic variables. Immunohistochemical analysis of IL-21 and pERK1/2 was performed in 18 cases of KD and five gender- and age-matched control samples. Clinical data were extracted and patients followed up for a mean period of 32.1 months. After a mean follow-up period of 32.1 months (range 1-102 months), recurrence was diagnosed as the end point for seven patients-that is, a 44% (7/16) cumulative recurrence rate. In comparison with gender- and age-matched controls, patients showed strong in situ expressions of IL-21 and pERK1/2, respectively (p<0.05). Patients with strong IL-21 staining intensity and overexpression of pERK1/2 had a lower recurrence rate than those with moderate staining intensity (p=0.049, p=0.019, respectively). However, differences were not statistically significant by gender, age, eosinophils, location, multiplicity, laterality, size, duration and primary outbreak. pERK1/2 was the independent prognostic factor (p=0.020), while age, gender, eosinophils, multiplicity, laterality, size, duration, primary outbreak and expression of IL-21 were not. This study suggests that the IL-21/pERK1/2 pathway is activated in KD, and pERK1/2 might be considered as a potential prognostic indicator in KD.


Indications and selection of MR enterography vs. MR enteroclysis with emphasis on patients who need small bowel MRI and general anaesthesia: results of a survey.
To survey the perceived indications for magnetic resonance imaging of the small bowel (MRE) by experts, when MR enteroclysis (MREc) or MR enterography (MREg) may be chosen, and to determine how the approach to MRE is modified when general anaesthesia (GA) is required. Selected opinion leaders in MRE completed a questionnaire that included clinical indications (MREg or MREc), specifics regarding administration of enteral contrast, and how the technique is altered to accommodate GA. Fourteen responded. Only the diagnosis and follow-up of Crohn's disease were considered by over 80 % as a valid MRE indication. The remaining indications ranged between 35.7 % for diagnosis of caeliac disease and unknown sources of gastrointestinal bleeding to 78.6 % for motility disorders. The majority chose MREg over MREc for all indications (from 100 % for follow-up of caeliac disease to 57.7 % for tumour diagnosis). Fifty per cent of responders had needed to consider MRE under GA. The most commonly recommended procedural change was MRI without enteral distention. Three had experience with intubation under GA (MREc modification). Views were variable. Requests for MRE under GA are not uncommon. Presently most opinion leaders suggest standard abdominal MRI when GA is required. • Experts are using MRE for various indications. • Requests for MRE under general anaesthesia are not uncommon. • Some radiologists employ MREc under general anaesthesia; others do not distend the small bowel.


Comparison of diffraction patterns exposed by pulsed and CW lasers on positive-tone photoresist.
Two different grating formation geometries for recording onto the positive-tone photoresist with pulsed laser and continuous-wave sources are analyzed and compared. Diffraction efficiency measurements and atomic force microscopy (AFM) examination have been performed in order to investigate the optical and topographical properties of the recorded structures. Gratings patterned by a continuous-wave laser and by a pulsed laser working in the single pulse and multipulse regimes showed different surface roughness and optical properties. The possible reasons for surface roughness and effective exposure differences between gratings created with pulsed and continuous-wave laser radiations are discussed. The processing schemes for diffractive structures patterned by pulsed laser onto positive-tone photoresist for commercial hologram production are analyzed and presented in this work.


GCUNC-45 is a novel regulator for the progesterone receptor/hsp90 chaperoning pathway.
The hsp90 chaperoning pathway is a multiprotein system that is required for the production or activation of many cell regulatory proteins, including the progesterone receptor (PR). We report here the identity of GCUNC-45 as a novel modulator of PR chaperoning by hsp90. GCUNC-45, previously implicated in the activities of myosins, can interact in vivo and in vitro with both PR-A and PR-B and with hsp90. Overexpression and knockdown experiments show GCUNC-45 to be a positive factor in promoting PR function in the cell. GCUNC-45 binds to the ATP-binding domain of hsp90 to prevent the activation of its ATPase activity by the cochaperone Aha1. This effect limits PR chaperoning by hsp90, but this can be reversed by FKBP52, a cochaperone that is thought to act later in the pathway. These findings reveal a new cochaperone binding site near the N terminus of hsp90, add insight on the role of FKBP52, and identify GCUNC-45 as a novel regulator of the PR signaling pathway.


Email for clinical communication between healthcare professionals.
Email is one of the most widely used methods of communication, but its use in healthcare is still uncommon. Where email communication has been utilised in health care, its purposes have included clinical communication between healthcare professionals, but the effects of using email in this way are not well known. We updated a 2012 review of the use of email for two-way clinical communication between healthcare professionals. To assess the effects of email for clinical communication between healthcare professionals on healthcare professional outcomes, patient outcomes, health service performance, and service efficiency and acceptability, when compared to other forms of communicating clinical information. We searched: the Cochrane Consumers and Communication Review Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 9 2013), MEDLINE (OvidSP) (1946 to August 2013), EMBASE (OvidSP) (1974 to August 2013), PsycINFO (1967 to August 2013), CINAHL (EbscoHOST) (1982 to August 2013), and ERIC (CSA) (1965 to January 2010). We searched grey literature: theses/dissertation repositories, trials registers and Google Scholar (searched November 2013). We used additional search methods: examining reference lists and contacting authors. Randomised controlled trials, quasi-randomised trials, controlled before and after studies, and interrupted time series studies examining interventions in which healthcare professionals used email for communicating clinical information in the form of: 1) unsecured email, 2) secure email, or 3) web messaging. All healthcare professionals, patients and caregivers in all settings were considered. Two authors independently assessed studies for inclusion, assessed the included studies' risk of bias, and extracted data. We contacted study authors for additional information and have reported all measures as per the study report. The previous version of this review included one randomised controlled trial involving 327 patients and 159 healthcare providers at baseline. It compared an email to physicians containing patient-specific osteoporosis risk information and guidelines for evaluation and treatment versus usual care (no email). This study was at high risk of bias for the allocation concealment and blinding domains. The email reminder changed health professional actions significantly, with professionals more likely to provide guideline-recommended osteoporosis treatment (bone density measurement or osteoporosis medication, or both) when compared with usual care. The evidence for its impact on patient behaviours or actions was inconclusive. One measure found that the electronic medical reminder message impacted patient behaviour positively (patients had a higher calcium intake), and two found no difference between the two groups. The study did not assess health service outcomes or harms.No new studies were identified for this update. Only one study was identified for inclusion, providing insufficient evidence for guiding clinical practice in regard to the use of email for clinical communication between healthcare professionals. Future research should aim to utilise high-quality study designs that use the most recent developments in information technology, with consideration of the complexity of email as an intervention.


Replication of ribonucleotide-containing DNA templates by yeast replicative polymerases.
The major replicative DNA polymerases of S. cerevisiae (Pols α, δ, and ɛ) incorporate substantial numbers of ribonucleotides into DNA during DNA synthesis. When these ribonucleotides are not removed in vivo, they reside in the template strand used for the next round of replication and could potentially reduce replication efficiency and fidelity. To examine if the presence of ribonucleotides in a DNA template impede DNA synthesis, we determined the efficiency with which Pols α, δ, and ɛ copy DNA templates containing a single ribonucleotide. All three polymerases can replicate past ribonucleotides. Relative to all-DNA templates, bypass of ribo-containing templates is slightly reduced, to extents that depend on the identity of the ribo and the sequence context in which it resides. Bypass efficiencies for Pols δ and ɛ were increased by increasing the dNTP concentrations to those induced by cellular stress, and in the case of Pol ɛ, by inactivating the 3'-exonuclease activity. Overall, ribonucleotide bypass efficiencies are comparable to, and usually exceed, those for the common oxidative stress-induced lesion 8-oxo-guanine.


Signal transducer and activator of transcription 1 in breast cancer: analysis with tissue microarray.
Constitutively activated signal transducer and activator of transcription (STAT) proteins are found in various types of tumors. However, there is still very limited information about the role of STATs in breast cancer. The power of the tissue microarray analysis (TMA) technique is the capability of performing a series of analyses of thousands of specimens in a parallel fashion with minimal damage to the original blocks. This study was designed to use TMA in determing the STAT1 status in breast cancer tissues. Archival tissue specimens from 102 patients with primary invasive breast cancer were selected and STAT1 expression was analyzed using immunohistochemical staining with tissue microarray. The data of primary tumor staging, age, estrogen receptor status, lymph node status, histological grading and TNM staging were also collected. There were 18 patients (17.6%) with 0 expression in STAT1, 29 patients (28.4%) with 1 expression in STAT1, 21 patients (20.6%) with 2 expression in STAT1 and 34 patients (33.4%) with 3 expression in STAT1. There was no significant relationship between STAT1 expression and age (p = 0.203), estrogen receptor status (p = 0.221), histological grading (p = 0.861), primary tumor staging (p = 0.918), lymph node status (p = 0.53), or TNM staging (p = 0.826). There was no survival difference noted among the four groups with different STAT1 expression (p = 0.859). Immuno-histochemical staining with tissue microarray analysis was convenient and feasible for the analysis of STAT1 expression status in breast cancer. STAT1 expression did not show significant correlation with the overall survival rate.


New-onset incontinence and markers of frailty: data from the Hispanic Established Populations for Epidemiologic Studies of the Elderly.
Urinary incontinence in older adults has many distinct etiologies and is associated with lower self-reported health. However, it is unclear whether the new onset of urinary incontinence marks newly emergent frailty. Using a longitudinal population-based survey of older Mexican Americans (N = 2660) across five south-western states, this study compared the strength of association between markers of physical frailty such as activities of daily living (ADLs), instrumental activities of daily living (IADLs), and performance (timed walk, timed chair rise, and tandem balance) with baseline incontinence (prevalent disease) and new-onset incontinence (incident disease). We found that 14.1% of the participants (n = 329) were incontinent at baseline (prevalent cases) and 11.6% (n = 208) were newly incontinent 2 years later (incident cases). Controlling for other covariates, prevalent incontinence was only associated with a 60% increased risk of having difficulty walking 8 ft. Incident incontinence was associated with a twofold increased risk of impairment in ADLs and IADLs, and poor performance on all three physical measures. Incident incontinence is associated with an increased risk of more global functional impairment. Thus, incident disease may be an important early marker for signaling the onset of frailty among persons who become incontinent after the age of 65 years.


Adjusting for Publication Bias in Meta-Analysis: An Evaluation of Selection Methods and Some Cautionary Notes.
We review and evaluate selection methods, a prominent class of techniques first proposed by Hedges (1984) that assess and adjust for publication bias in meta-analysis, via an extensive simulation study. Our simulation covers both restrictive settings as well as more realistic settings and proceeds across multiple metrics that assess different aspects of model performance. This evaluation is timely in light of two recently proposed approaches, the so-called p-curve and p-uniform approaches, that can be viewed as alternative implementations of the original Hedges selection method approach. We find that the p-curve and p-uniform approaches perform reasonably well but not as well as the original Hedges approach in the restrictive setting for which all three were designed. We also find they perform poorly in more realistic settings, whereas variants of the Hedges approach perform well. We conclude by urging caution in the application of selection methods: Given the idealistic model assumptions underlying selection methods and the sensitivity of population average effect size estimates to them, we advocate that selection methods should be used less for obtaining a single estimate that purports to adjust for publication bias ex post and more for sensitivity analysis-that is, exploring the range of estimates that result from assuming different forms of and severity of publication bias.


Identification of a molecular recognition feature in the E1A oncoprotein that binds the SUMO conjugase UBC9 and likely interferes with polySUMOylation.
Hub proteins have central roles in regulating cellular processes. By targeting a single cellular hub, a viral oncogene may gain control over an entire module in the cellular interaction network that is potentially comprised of hundreds of proteins. The adenovirus E1A oncoprotein is a viral hub that interacts with many cellular hub proteins by short linear motifs/molecular recognition features (MoRFs). These interactions transform the architecture of the cellular protein interaction network and virtually reprogram the cell. To identify additional MoRFs within E1A, we screened portions of E1A for their ability to activate yeast pseudohyphal growth or differentiation. This identified a novel functional region within E1A conserved region 2 comprised of the sequence EVIDLT. This MoRF is necessary and sufficient to bind the N-terminal region of the SUMO conjugase UBC9, which also interacts with SUMO noncovalently and is involved in polySUMOylation. Our results suggest that E1A interferes with polySUMOylation, but not with monoSUMOylation. These data provide the first insight into the consequences of the interaction of E1A with UBC9, which was initially described in 1996. We further demonstrate that polySUMOylation regulates pseudohyphal growth and promyelocytic leukemia body reorganization by E1A. In conclusion, the interaction of the E1A oncogene with UBC9 mimics the normal binding between SUMO and UBC9 and represents a novel mechanism to modulate polySUMOylation.


Intraspinal rewiring of the corticospinal tract requires target-derived brain-derived neurotrophic factor and compensates lost function after brain injury.
Brain injury that results in an initial behavioural deficit is frequently followed by spontaneous recovery. The intrinsic mechanism of this functional recovery has never been fully understood. Here, we show that reorganization of the corticospinal tract induced by target-derived brain-derived neurotrophic factor is crucial for spontaneous recovery of motor function following brain injury. After destruction of unilateral sensorimotor cortex, intact-side corticospinal tract formed sprouting fibres into the specific lamina of the denervated side of the cervical spinal cord, and made new contact with two types of spinal interneurons-segmental and propriospinal neurons. Anatomical and electrophysiological analyses revealed that this rewired corticospinal tract functionally linked to motor neurons and forelimb muscles. This newly formed corticospinal circuit was necessary for motor recovery, because transection of the circuit led to impairment of recovering forelimb function. Knockdown of brain-derived neurotrophic factor in the spinal neurons or its receptor in the intact corticospinal neurons diminished fibre sprouting of the corticospinal tract. Our findings establish the anatomical, functional and molecular basis for the intrinsic capacity of neurons to form compensatory neural network following injury.


Melamine Impairs Renal and Vascular Function in Rats.
Melamine incident, linked to nephrotoxicity and kidney stone in infants previously exposed to melamine-contaminated milk products, was unprecedentedly grave in China in 2008 as little was known about the mechanistic process leading to renal dysfunction in affected children. This study investigates whether neonatal ingestion of melamine leads to renal and vascular dysfunction in adulthood; and whether ingestion of melamine in pregnant rats leads to renal dysfunction in their offspring. A combination of approaches employed includes functional studies in rat renal arteries, renal blood flow measurement by functional magnetic resonance imaging, assay for pro-inflammatory and fibrotic biomarkers, immunohistochemistry, and detection of plasma and renal melamine. We provide mechanistic evidence showing for the first time that melamine reduces renal blood flow and impairs renal and vascular function associated with overexpression of inflammatory markers, transforming growth factor-β1, bone morphogenic protein 4 and cyclooxygenase-2 in kidney and renal vasculature. Melamine also induces renal inflammation and fibrosis. More importantly, melamine causes nephropathies in offsprings from pregnant rat exposed to melamine during pregnancy, as well as in neonatal rat exposed to melamine afterbirth, thus supporting the clinical observations of kidney stone and acute renal failure in infants consuming melamine-contaminated milk products.


Uterine involution and progesterone level during the postpartum period in Barbary ewes in north Libya.
The objectives of the present study were to determine the time of uterine involution and ovarian activity using ultrasound examination and progesterone assay. Weekly progesterone levels were measured starting one week postpartum until two weeks after the 1(st) postpartum estrus in Barbary ewes lambed during winter in AL-Bayda city, north of Libya. A total of 15 Barbary ewes were used in the present study distributed in three groups according to the month of lambing as group 1 (lambed in January), group 2 (lambed in February) and group 3 (lambed in March). Ewes were examined weekly by trans-rectal ultrasound to check involution of the uterus starting one week after lambing until complete uterine involution. Blood samples were collected from the jugular vein, and serum was separated and stored at -20 °C until measuring progesterone using ELISA. Results showed that uterine involution completed at day 35 postpartum in groups 1 and 2, while it occurred at day 28 in group 3. The mean progesterone level was basal (less than 1 ng/ml) for a long period and started to increase at days 119, 99 and 77 postpartum in group 1, 2 and 3, respectively. One ewe did not show estrus at all during the period of study in group 2 and there were no growing follicles on their ovaries. The obtained results indicate that, uterine involution as determined by ultrasound completed earlier in ewes lambed in March than those lambed in February or January. Also, progesterone level and ultrasound examination showed that there was no ovarian activity for a longtime after parturition indicating that reproduction in Barbary ewes tends to be seasonal in AL-Bayda city, north Libya.


Nap1 links transcription elongation, chromatin assembly, and messenger RNP complex biogenesis.
Chromatin remodeling is central to the regulation of transcription elongation. We demonstrate that the conserved Saccharomyces cerevisiae histone chaperone Nap1 associates with chromatin. We show that Nap1 regulates transcription of PHO5, and the increase in transcript level and the higher phosphatase activity plateau observed for Deltanap1 cells suggest that the net function of Nap1 is to facilitate nucleosome reassembly during transcription elongation. To further our understanding of histone chaperones in transcription elongation, we identified factors that regulate the function of Nap1 in this process. One factor investigated is an essential mRNA export and TREX complex component, Yra1. Nap1 interacts directly with Yra1 and genetically with other TREX complex components and the mRNA export factor Mex67. Additionally, we show that the recruitment of Nap1 to the coding region of actively transcribed genes is Yra1 dependent and that its recruitment to promoters is TREX complex independent. These observations suggest that Nap1 functions provide a new connection between transcription elongation, chromatin assembly, and messenger RNP complex biogenesis.


Cell cycle regulatory markers in uterine atypical leiomyoma and leiomyosarcoma: immunohistochemical study of 68 cases with clinical follow-up.
Cell cycle regulatory protein expression by immunohistochemical assay may have diagnostic utility in the distinction of uterine leiomyosarcoma from leiomyoma variants. p16, p21, p27, and p53 protein expression was evaluated by immunohistochemistry on 44 atypical leiomyomas (mean follow-up, 50.8 mo), 16 leiomyosarcomas (mean follow-up, 29.7 mo), and 8 cellular leiomyomas (mean follow-up, 22.6 mo). Nuclear staining was semiquantitatively scored on 1 representative section per case as negative (0%), focal (>0% to 33%), patchy (>33% to 66%), or diffuse (>66%). In addition, staining intensity was noted as weak, moderate, or strong. Proliferative index was gauged by Ki-67 and PHH3 immunohistochemical staining. One of 35 atypical leiomyoma patients with follow-up data developed an extrauterine recurrence 25.7 months after hysterectomy, whereas a second had intrauterine recurrence 24.9 months after myomectomy. Seven of 8 patients with leiomyosarcoma with follow-up had recurrence within the follow-up period, whereas there were no recurrences in patients with cellular leiomyoma. The Ki-67 proliferation index ranged from 0% to 25% in atypical leiomyoma (mean, 2%) and 6% to 50% in leiomyosarcoma (mean, 25%) with 0% to 10% in cellular leiomyoma (mean, 3%), whereas the PHH3 proliferation index ranged from 0% to 3% in atypical leiomyoma (mean, <1%) and 0% to 10% in leiomyosarcoma (mean, 2%) with 0% to 2% in cellular leiomyoma (mean, <1%). The atypical leiomyoma with extrauterine recurrence was diffusely positive for p21, but showed only weak focal (<33%) staining for all other cell cycle markers. Uterine atypical leiomyomas, cellular leiomyomas, and leiomyosarcomas demonstrate a heterogenous pattern of cell cycle regulatory protein expression. Caution should be exercised in distinguishing leiomyosarcoma from atypical leiomyoma variants on the basis of cell cycle protein expression alone. In our study, cell cycle markers were not useful for predicting recurrence in atypical leiomyoma.


Short communication: Late refills during the first year of antiretroviral therapy predict mortality and program failure among HIV-infected adults in urban Zambia.
We evaluated the association of the number of late antiretroviral therapy (ART) refills with patient outcomes in a large public-sector human immunodeficiency virus treatment program in Lusaka, Zambia. Using pharmacy data routinely collected during 2004-2010, we calculated the number of late refills during the initial year of ART. We used multivariable Cox proportional hazard regression to examine the association between the number of late refills and death or program failure (i.e., death, loss to follow-up, or program withdrawal) >12 months after ART initiation, with and without stratification by the medication possession ratio (MPR) during the initial year of ART. Of 53,015 adults who received ART for ≥12 months (median follow-up duration, 86.1 months; interquartile range, 53.2-128.2 months), 26,847 (50.6%) had 0 late refills, 16,762 (31.6%) had 1, 6,505 (12.3%) had 2, and 2,901 (5.5%) had ≥3. Kaplan-Meier analysis revealed that ≥3 late refills was associated with a greater mortality risk than 1 and 2 late refills (p<0.001, by the log-rank test). The mortality risk was greater for patients with 2 late refills [adjusted hazard ratio (HR), 1.17; 95% confidence interval (CI), 0.99-1.38] or ≥3 late refills (adjusted HR, 1.51; 95% CI, 1.23-1.87), compared with that for patients with 0-1 late refills. Program failure was associated with ≥2 late refills. An MPR of <80% was associated with similar increases in mortality risk across late-refill strata. Monitoring late refills during the initial period of ART may help resource- and time-constrained clinics identify patients at risk for program failure.


Suppression of experimental lung colonization of a metastatic variant of murine colon adenocarcinoma 26 by a monoclonal antibody 8F11 inhibiting tumor cell-induced platelet aggregation.
We have previously established and characterized two monoclonal antibodies, 8F11 and 20A11, that recognize an Mr 44,000 membrane glycoprotein of metastatic murine colon 26 cells. Both monoclonal antibodies inhibit platelet aggregation induced by the tumor cells in vitro. In this report, the inhibitory effect of 8F11 on lung colonization of i.v.-inoculated tumor cells was examined. The i.v. administration of 8F11 suppressed lung colonization of NL-17, a highly metastatic variant of colon 26. Inhibition of NL-17 lung colonization by 8F11 was dose dependent with a maximum of 80% inhibition at a dose of 800 micrograms 8F11/mouse. 8F11 did not inhibit metastases at doses lower than 100 micrograms/mouse. Inhibition of pulmonary metastases by 8F11 was greatest when the antibody was administered 2 h before tumor inoculation. The effect was diminished when the antibody was given 2 h after tumor inoculation. The pulmonary retention of i.v.-inoculated radiolabeled NL-17 cells was decreased by 8F11. F(ab')2 fragments of 8F11 also effectively inhibited lung colonization by NL-17 cells, suggesting that mechanisms unrelated to immune-mediated destruction are involved. These results indicate that the monoclonal antibody 8F11 suppresses the lung colonization of NL-17 cells by interfering with the initial arrest of tumor cells in the lung vasculature through the inhibition of tumor cell-platelet interaction.


The incidence of spondylolysis and spondylolisthesis in children with osteogenesis imperfecta.
Spondylolysis and spondylolisthesis are common abnormalities of the lumbar spine. The incidence of these diagnoses is recognized in the healthy population. However, their incidence in osteogenesis imperfecta (OI) patients is less well defined. This is a retrospective radiographic review of patients treated in the OI clinic from a single institution. Lateral radiographs were reviewed on all available patients to assess the incidence of spondylolysis and spondylolisthesis in this patient population. The morphology of the pedicle and pars interarticularis was also evaluated to identify any abnormalities or dysplasia of these structures. One hundred ten of the 139 patients treated in the OI clinic met the inclusion criteria for this study. Of these patients, 79% (87 of 110) were ambulatory. The overall incidence of spondylolysis in this pediatric OI population was found to be 8.2% (9 of 110) at an average age of 7.5 years. The incidence of spondylolisthesis was 10.9% (12 of 110) at an average age of 6.5 years with 75% (3 of 12) being isthmic type and 25% (3 of 12) dysplastic. The combined incidence of spondylolysis and spondylolisthesis was 19.2%. Incidentally, the pedicle length was noted to be elongated in 40.0% (44 of 110) of this OI population. This study found that the incidence of spondylolysis in a group of children with OI was much higher than in the normal pediatric population, which has been reported to be 2.6% to 4.0%. This incidence was also found to be higher than previously reported incidence of spondylolysis in OI patients (5.3%). The incidence of spondylolisthesis was also found to be much higher than that of the normal pediatric population (4.2%). It is important to recognize this higher incidence of these abnormalities and to anticipate future associated symptoms and potential worsening listhesis that can clinically affect the lifestyles of these children and potentially require surgical treatment. The clinical significance of these findings will necessitate long-term follow-up.


Long-term treatment strategies in anxiety disorders.
Anxiety disorders are prevalent and associated with increased morbidity and mortality. Some chronic anxiety disorders, including generalized anxiety disorder (GAD), may be characterized by an underlying high level of anxiety on which exacerbations of symptoms are superimposed. Effective treatment of anxiety disorders should therefore strive to attain both an acute reduction in the symptoms of anxiety (a response) and sustained resolution of the symptoms of any underlying chronic anxiety (remission). This strategy may necessitate long-term treatment of these disorders by pharmacotherapy and/or psychotherapy. Studies using the serotonin and norepinephrine reuptake inhibitor (SNRI), venlafaxine extended release (XR), suggest that these aims may be achieved using this newer class of drugs. Studies with venlafaxine XR in patients with GAD have demonstrated robust anxiolytic efficacy over placebo, particularly regarding worry, cognitive dysfunction, and muscular tension, which are specific to GAD. Administration of venlafaxine XR over both short- (8-week) and long-term (6-month) periods resulted in a significantly greater number of patients achieving response and remission than obtained with placebo. Long-term treatment with venlafaxine XR in patients with GAD showed greater efficacy than that observed in short-term studies. This was achieved without any loss of short-term efficacy and patients' social functioning was also restored. While available data indicate that venlafaxine XR is an appropriate choice of agent in the long-term treatment of GAD, more studies are needed to determine how to further increase remission rates and to maintain remission beyond 6 months.


Adaptive chaos: mild disorder may help contain major disease.
We have qualitatively analyzed different cases of human disorders and displacement activities of animals and hypothesize that some of them are examples of low-dimensional dynamical chaos in biological organisms. We also considered a biological organism in the framework of the control system theory and found that chaotic regime in one subsystem may be compensating for the loss of chaos in another subsystem for the sake of stability of the whole system. According to the hypothesis chaotic behavior of different organs sets in a human body as an alternative to serious diseases or even death. The principle of compensation was applied to different physiological systems with chaotic regimes to explain the adaptive nature of chaos there. Implications of the mechanism of adaptive chaos for sleep diseases, e.g., enuresis, and other potentially life threatening disorders of humans, e.g., RLS, are discussed in connection with the possibility to use these ideas for improved treatment strategies. The main conclusion is that adaptive disorders with chaotic symptoms should not be aggressively treated; if adaptive disorders are over treated, the whole organism may be thrown into a more regular state, which eventually will lead to a chronic disease or even death.


Isolation and characterization of murine Cds (CDP-diacylglycerol synthase) 1 and 2.
Phototransduction in Drosophila is a phosphoinositide-mediated signalling pathway. Phosphatidylinositol 4,5-bisphosphate (PIP2) plays a central role in this process, and its levels are tightly regulated. A photoreceptor-specific form of the enzyme CDP-diacylglycerol synthase (CDS), which catalyzes the formation of CDP-diacylglycerol from phosphatidic acid, is a key regulator of the amount of PIP2 available for signalling. cds mutants develop light-induced retinal degeneration. We report here the isolation and characterization of two murine genes encoding this enzyme, Cds1 and Cds2. The genes encode proteins that are 73% identical and 92% similar but exhibit very different expression patterns. Cds1 shows a very restricted expression pattern but is expressed in the inner segments of the photoreceptors whilst Cds2 shows a ubiquitous pattern of expression. Using fluorescent in situ hybridization we have mapped Cds1 and Cds2 to chromosomes 5E3 and 2G1 respectively. These are regions of synteny with the corresponding human gene localization (4q21 and 20p13). Transient transfection experiments with epitope tagged proteins have also demonstrated that both are associated with the endoplasmic reticulum.


Vitamin C intake from diary recordings and risk of breast cancer in the UK Dietary Cohort Consortium.
Vitamin C intake has been inversely associated with breast cancer risk in case-control studies, but not in meta-analyses of cohort studies using Food Frequency Questionnaires, which can over-report fruit and vegetable intake, the main source of vitamin C. This is the first study to investigate associations between vitamin C intake and breast cancer risk using food diaries. Estimated dietary vitamin C intake was derived from 4-7 day food diaries pooled from five prospective studies in the UK Dietary Cohort Consortium. This nested case-control study of 707 incident breast cancer cases and 2144 matched controls examined breast cancer risk in relation to dietary vitamin C intake using conditional logistic regression adjusting for relevant covariates. Additionally, total vitamin C intake from supplements and diet was analysed in three cohorts. No evidence of associations was observed between breast cancer risk and vitamin C intake analysed for dietary vitamin C intake (odds ratios (OR)=0.98 per 60 mg/day, 95% confidence interval (CI): 0.88-1.09, P (trend)=0.7), dietary vitamin C density (OR=0.97 per 60 mg/day, 95% CI: 0.87-1.07, P (trend)=0.5 ) or total vitamin C intake (OR=1.01 per 60 mg/day, 95% CI: 0.99-1.03, P (trend)=0.3). Additionally, there was no significant association for post-menopausal women (OR=1.02 per 60 mg/day, 95% CI: 0.99-1.05, P (trend)=0.3). This pooled analysis of individual UK women found no evidence of significant associations between breast cancer incidence and dietary or total vitamin C intake derived uniquely from detailed diary recordings.


[Interterritorial inequalities in compensation for occupational diseases in Spain from 1990-2007].
To determine the reporting pattern and trends for occupational diseases by autonomous communities in Spain between 1990 and 2007. Cases were obtained from the Ministry of Labor and Social Affairs, and the number of workers was obtained from the National Institute of Statistics. A principal components analysis was used to explain the data structure. Adjusted annual incidence rates were computed and relative risk is shown in maps. The number of reported occupational diseases remained constant from 1990 to 2005 in all the autonomous communities, except for minor occupational diseases not leading to sick leave (accounting for 99% of the total), which increased. From 2006-07, reported rates decreased to almost half: 17,061 cases in 2007 versus 30,030 in 2005. Both the increase and the decrease in incidence were observed in all autonomous communities, but with distinct values and slopes. As revealed by the principal components analysis, all the autonomous communities showed the same time pattern, except Asturias. Northern Spain showed the highest rates, which cannot be explained by factors such as age, sex, economic activity or occupation. The social security system is not compensating the complex and chronic diseases that are prevalent today. Despite improvements in disease reporting from 1990-2005, the decrease observed from 2006-07 and, above all, the gap among autonomous communities show that provision is not working with equity, generating inequality and lack of cohesion and posing a challenge for the definition of efficient prevention policies.


Multidisciplinary pulmonary embolism response teams and systems.
Pulmonary embolism (PE) is a complex diagnosis that encompasses a wide range of clinical presentations. Often patients who present with PE have complicated medical histories which can make their management challenging. Many novel therapeutic strategies and tools are emerging to improve the care and outcomes of patients with PE. Pulmonary embolism response teams (PERTs) are developing at multiple centers to improve the decision making, efficiency and orchestration of these clinical strategies. Concordantly with development of PERT programs is the design and implementation of systems to allow for numerous specialists to convene and discuss complex PE patients in real time. The mechanisms to engage a multidisciplinary approach are proving to be an invaluable resource in the decision making processes and treatment of high risk PE patients. Ultimately, other multi-disciplinary teams may adopt these methods to better address their clinical needs.


Socioeconomic vulnerability and adaptation to environmental risk: a case study of climate change and flooding in Bangladesh.
In this article we investigate the complex relationship between environmental risk, poverty, and vulnerability in a case study carried out in one of the poorest and most flood-prone countries in the world, focusing on household and community vulnerability and adaptive coping mechanisms. Based upon the steadily growing amount of literature in this field we develop and test our own analytical model. In a large-scale household survey carried out in southeast Bangladesh, we ask almost 700 floodplain residents living without any flood protection along the River Meghna about their flood risk exposure, flood problems, flood damage, and coping mechanisms. Novel in our study is the explicit testing of the effectiveness of adaptive coping strategies to reduce flood damage costs. We show that, households with lower income and less access to productive natural assets face higher exposure to risk of flooding. Disparity in income and asset distribution at community level furthermore tends to be higher at higher risk exposure levels, implying that individually vulnerable households are also collectively more vulnerable. Regarding the identification of coping mechanisms to deal with flood events, we look at both the ex ante household level preparedness for flood events and the ex post availability of community-level support and disaster relief. We find somewhat paradoxically that the people that face the highest risk of flooding are the least well prepared, both in terms of household-level ex ante preparedness and community-level ex post flood relief.


Fabrication and applications of complex-shaped microparticles via microfluidics.
Complex-shaped microparticles (MPs) have attracted extensive interest in a myriad of scientific and engineering fields in recent years for their distinct morphology and capability in combining different functions within a single particle. Microfluidic techniques offer an intriguing method for fabricating MPs with excellent monodispersity and complex morphology in parallel while controlling their number and size precisely and independently. To date, there are two notable microfluidics approaches for the synthesis of complex-shaped MPs, namely droplet based, and flow-lithography based microfluidics approaches. It is undoubted that the application of complex-shaped MPs via microfluidic fabrication will hold great promise in a variety of fields including microfabrication, analytical chemistry and biomedicine.


Modeling SSFP functional MRI contrast in the brain.
Steady-state free precession (SSFP) has recently been proposed for function MRI because of the potential for reducing image distortion and signal dropout. Several different contrast mechanisms have been suggested to explain the reported observations, but there has been limited work comparing theory with experiment in the brain. Moreover, the detailed work that has considered oxygen-dependent signal in SSFP outside the brain has focused on R(2) effects in the pass band, and largely neglected the signal contrast that occurs due to off-resonance effects. The article describes a model for SSFP functional contrast based on the convolution of the theoretical SSFP profile with the underlying frequency distribution. It is demonstrated that such a model must account for the effects of diffusion, which can alter the apparent R(2) and linespread. Monte Carlo simulations are used to calibrate corrections for these terms. This new model has the computational efficiency of the convolution model while encapsulating information from more time-consuming Monte Carlo simulations. This corrected convolution model is shown to agree well with experimental data, and model predictions and limitations are discussed.


Alpha-fetoprotein and beta-human chorionic gonadotropin: their clinical significance as tumour markers.
Tumour markers can aid in areas such as diagnosis, surveillance of recurrence, staging and prognosis. This article focuses on 2 tumour markers, alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (HCG). These tumour markers have been examined for their utility as prognostic indicators in 2 different manners. First, the marker level at diagnosis has been studied to determine if it is prognostic of outcome presumably because of its relation to tumour bulk or to the biological nature of the tumour. A more recent trend has been to investigate tumour marker decline. The finding of a delayed rate of decline suggests a poorer response of the malignancy to chemotherapy. The major focus of the article will be on marker decline of AFP and HCG as prognostic tools in peripheral and central nervous system (CNS) germ cell tumours (GCTs) and hepatic tumours (hepatoblastoma and hepatocellular carcinoma). The articles reviewed here suggest that HCG and AFP can correlate with survival if examined in specific ways, and could potentially be used to tailor treatment for individual patients. One group of authors presents data on patients with GCTs suggesting that satisfactory marker regression is an independent prognostic factor for survival. In a study of hepatoblastoma, data demonstrate that both the magnitude and rate of decline are associated with survival. Marker decline studies in hepatocellular carcinoma do not exist and marker levels at diagnosis do not appear to have a role in potential therapeutic changes. However, data on fucosylated subtype of AFP, Lens culinaris agglutinin A reactive AFP, has shown prognostic significance in hepatocellular carcinoma. The data for CNS GCTs are limited and studies examining serial cerebrospinal fluid HCG/AFP are ongoing. In some diseases, issues relating to timing of marker sampling when examining marker decline need to be studied in greater detail. Hopefully, marker decline studies can be duplicated in the other diseases, to document a potential role in determining outcome. Further studies are needed to test the ability to alter therapy in attempts to improve survival while decreasing toxicity to patients.


Non-invasive evaluation of liver fibrosis using transient elastography.
Transient elastography (TE, FibroScan) is a novel non-invasive method that has been proposed for the assessment of hepatic fibrosis in patients with chronic liver diseases, by measuring liver stiffness. TE is a rapid and user-friendly technique that can be easily performed at the bedside or in the outpatient clinic with immediate results and good reproducibility. Limitations include failure in around 5% of cases, mainly in obese patients. So far, TE has been mostly validated in chronic hepatitis C, with diagnostic performance equivalent to that of serum markers for the diagnosis of significant fibrosis. Combining TE with serum markers increases diagnostic accuracy and as a result, liver biopsy could be avoided for initial assessment in most patients with chronic hepatitis C. This strategy warrants further evaluation in other aetiological types of chronic liver diseases. TE appears to be an excellent tool for early detection of cirrhosis and may have prognostic value in this setting. As TE has excellent patient acceptance it could be useful for monitoring fibrosis progression and regression in the individual case, but more data are awaited for this application. Guidelines are needed for the use of TE in clinical practice.


Determinants of variations in self-reported barriers to colonoscopy among uninsured patients in a primary care setting.
Colorectal cancer (CRC) is the third most common type of cancer among both males and females in the United States and the second leading cause of cancer-related deaths. Although largely preventable through screening, early detection and removal of polyps, screening rates are considered sub-optimal. Perceived barriers to screening have been reported to influence screening rates. This paper examines variations in the extent to which uninsured patients identified barriers to CRC screening using colonoscopy based on race/ethnicity, educational attainment, age, gender, marital status and prior colonoscopy. Multivariate analyses showed that compared to Caucasians, African Americans had an increased likelihood of identifying lack of transportation as a barrier [odds ratio (OR) 2.68; 95 % confidence interval (CI) 1.35-5.32] while Hispanics were more likely to identify fear of finding cancer as a barrier (OR 2.09; 95 % CI 1.19-3.66). Compared to those with more than a high school education, there was increased likelihood of identifying lack of knowledge as a barrier among individuals with high school education (OR 3.51; 95 % CI 1.94-6.36) or less than a high school education (OR 2.16; 95 % CI 1.04-4.50). Our findings suggest that strategies aimed at increasing colonoscopy screening rates among underserved populations should take into consideration race/ethnicity, educational attainment, age, and prior colonoscopy experience when developing education and outreach plans to reduce barriers to colonoscopy.


Identification of a 60-kD tumor necrosis factor (TNF) receptor as the major signal transducing component in TNF responses.
We describe here a monoclonal antibody (H398) that immunoprecipitates a human 60-kD tumor necrosis factor (TNF) membrane receptor (p60) and competes with TNF binding to p60 but not to p85 TNF receptors. Despite partial inhibition of TNF binding capacity of cells coexpressing both TNF receptor molecules, H398 uniformly and completely inhibits very distinct TNF responses on a variety of cell lines. These data suggest a limited structural heterogeneity in those components actually contributing to TNF responsiveness and identify p60 as a common receptor molecule essential for TNF signal transduction. As H398 is a highly effective TNF antagonist in vitro, it might be useful as a therapeutic agent in the treatment of TNF-mediated acute toxicity.


Polarization-sensitive compositions of organic dyes.
We present the results of our investigation of photoanisotropy and photogyrotropy in the compositions of several dye mixtures in a polymer matrix. A variety of light-sensitive media are available today in which polarized light induces photophysical and photochemical processes that result in photoanisotropy and photogyrotropy. Among these media the materials on the basis of organic dyes in a polymer matrix are available. The photochemical behavior of single dyes usually differs from their behavior in mixtures; it is, therefore, natural to assume that photoanisotropic properties of dye mixtures will also differ. Based on these assumptions we created several compositions of organic dyes from different classes. The physical and chemical properties as well as the mechanisms responsible for anisotropy of the dyes used in this investigation differ significantly. A special technique was needed to make the most of their photoanisotropic properties.


The developmental dynamics of the maize leaf transcriptome.
We have analyzed the maize leaf transcriptome using Illumina sequencing. We mapped more than 120 million reads to define gene structure and alternative splicing events and to quantify transcript abundance along a leaf developmental gradient and in mature bundle sheath and mesophyll cells. We detected differential mRNA processing events for most maize genes. We found that 64% and 21% of genes were differentially expressed along the developmental gradient and between bundle sheath and mesophyll cells, respectively. We implemented Gbrowse, an electronic fluorescent pictograph browser, and created a two-cell biochemical pathway viewer to visualize datasets. Cluster analysis of the data revealed a dynamic transcriptome, with transcripts for primary cell wall and basic cellular metabolism at the leaf base transitioning to transcripts for secondary cell wall biosynthesis and C(4) photosynthetic development toward the tip. This dataset will serve as the foundation for a systems biology approach to the understanding of photosynthetic development.


Behavioral indicators for conserving mammal diversity.
Mammals are threatened with population decline and extinction. Numerous species require immediate conservation intervention. But our ability to identify species on the brink of decline, and to intervene successfully, depends on developing reliable leading indicators of population, community, and environmental change. Classic approaches, such as population and life history assessment, as well as indicator species, trail environmental change. Adaptive behaviors honed by natural selection to respond quickly to environmental changes represent true leading indicators that we can learn to apply to conservation and management. Excellent examples of useful behaviors for conservation include foraging behavior, patch use, and habitat selection. Comparisons among giving-up densities collected in artificial resource patches can effectively indicate the forager's predation costs, its habitat quality, mechanisms of coexistence, and environmental richness. Patterns of adaptive habitat use can similarly reveal the relative value of different types of habitat, the location, and amounts of source versus sink habitat in a landscape, the effects of human disturbance, and projections on future extinction risk. Each behavior is likely to change more quickly than population size. As useful as these and related indicators may be to managers and conservationists, similar behaviors can emerge from different causes, and immediate returns of behavior to fitness may cause rapid evolution of associated morphological and physiological traits. Conservation strategies will thereby often be most effective if they build on research programs targeting the processes influencing adaptive behaviors and that assess whether wild-type or novel behaviors are most likely to sustain populations into the future.