Clinical correlates of first episode early onset psychosis in KwaZulu-Natal, South Africa.
The study of first episode early onset psychosis can yield many clues to understanding the early development of psychosis and guide interventions to decrease psychosis risk and improve outcome. The aim of the study was to investigate the socio-demographic profile and clinical correlates in early onset psychosis. Forty-five adolescents with first episode early onset psychosis were assessed by a clinical interview, socio-demographic questionnaire, the Positive and Negative Syndrome Scale (PANSS), Symptom Onset in Schizophrenia (SOS) score, the World Health Organization Alcohol, Smoking and Substance Involvement Screening Test (WHO ASSIST) questionnaire for substance misuse and a urine cannabis level. The mean age of the respondents was 15.9 years (SD 1.8, range 10-18 years). Thirty-one (69%) were male. There was a poor recognition of the prodromal period in 22 (49%) patients and caregivers. The mean duration of untreated psychosis (DUP) was 27.2 weeks (SD 56.7). There was a negative correlation between DUP and age of onset (p<0.05). Mean age at onset of psychosis (males 15.7 years, SD 2.2, and females 15.3 years, SD 2.6) and mean age of presentation (males 16.0 years, SD 1.8, and females 15.5 years, SD 1.7) was slightly younger in the females than males, but not statistically significant. A total of 25 (56%) adolescents reported lifetime cannabis use and 24 (96%) were male. Symptoms of the prodromal period were poorly recognised. The mean DUP suggests a significant delay in treatment and younger children had a longer DUP. The gender differences in presentation (marginal) and substance use (highly significant) suggests that there may be different environmental risk factors for males and females in early onset psychosis or that early onset psychosis is more genetically homogenous and less dependent on environmental triggers.


Cetuximab and Radiotherapy in Laryngeal Preservation for Cancers of the Larynx and Hypopharynx: A Secondary Analysis of a Randomized Clinical Trial.
The appropriate use of surgery or radiotherapy-based approaches for organ preservation has been the subject of much debate. Unfortunately, there has been a lack of improvement in overall survival for patients with laryngeal carcinoma in the last 30 years. To assess the rates of laryngeal preservation and laryngectomy-free survival in patients receiving cetuximab and radiotherapy (CRT) and patients receiving radiotherapy alone. Patients were enrolled in a multicenter, open-label, stratified, randomized, phase 3 study from April 1, 1999, through March 31, 2002, from 73 centers in the United States and 14 other countries. A secondary subgroup analysis of patients with hypopharyngeal and laryngeal carcinoma was undertaken. Rates of laryngeal preservation and laryngectomy-free survival were estimated by the Kaplan-Meier method. The hazard ratios (HRs) were calculated using a Cox proportional hazards regression model. Quality of life was evaluated using the European Organization for Research and Treatment of Cancer core questionnaire and head and neck module. Laryngeal preservation and laryngectomy-free survival. Of the 424 patients included in the trial, 168 treated patients with cancer of the larynx or hypopharynx were included in this analysis (90 in the CRT group and 78 in the radiotherapy alone group). The median (range) age of the patients was 59 (40-80) years in the CRT group and 61 (35-81) years in the radiotherapy alone group. In the CRT group, 72 patients (80.0%) were male and 18 (20.0%) were female. In the radiotherapy alone group, 62 (79.5%) were male and 16 (20.5%) were female. The rates of laryngeal preservation at 2 years were 87.9% for CRT vs 85.7% for radiotherapy alone, with an HR of 0.57 (95% CI, 0.23-1.42; P = .22). Similarly, the HR for laryngectomy-free survival comparing CRT vs radiotherapy alone was 0.78 (95% CI, 0.54-1.11; P = .17). This study was not powered to assess organ preservation. Median overall survival was 27 (95% CI, 20-45) vs 21 (95% CI, 17-35) months for the CRT and radiotherapy alone groups, respectively, with an HR of 0.87 (95% CI, 0.60-1.27). No differences between treatments were reported regarding overall quality of life, need for a feeding tube, or speech. The results of a possible cetuximab-related laryngeal preservation benefit for patients with hypopharyngeal or laryngeal cancer are intriguing; these results need to be interpreted in the context of a retrospective subset analysis with limited sample size. clinicaltrials.gov Identifier: NCT00004227.


In situ observation of graphene sublimation and multi-layer edge reconstructions.
We induced sublimation of suspended few-layer graphene by in situ Joule-heating inside a transmission electron microscope. The graphene sublimation fronts consisted of mostly {1100} zigzag edges. Under appropriate conditions, a fractal-like "coastline" morphology was observed. Extensive multiple-layer reconstructions at the graphene edges led to the formation of unique carbon nanostructures, such as sp(2)-bonded bilayer edges (BLEs) and nanotubes connected to BLEs. Flat fullerenes/nanopods and nanotubes tunneling multiple layers of graphene sheets were also observed. Remarkably, >99% of the graphene edges observed during sublimation are BLEs rather than monolayer edges (MLEs), indicating that BLEs are the stable edges in graphene at high temperatures. We reproduced the "coastline" sublimation morphologies by kinetic Monte Carlo (kMC) simulations. The simulation revealed geometrical and topological features unique to quasi-2-dimensional (2D) graphene sublimation and reconstructions. These reconstructions were enabled by bending, which cannot occur in first-order phase transformations of 3D bulk materials. These results indicate that substrate of multiple-layer graphene can offer unique opportunities for tailoring carbon-based nanostructures and engineering novel nano-devices with complex topologies.


Occurrence and ecological risk assessment of pharmaceuticals and personal care products in Taihu Lake, China: a review.
The rationale behind this paper was to review the available data regarding the current knowledge on the levels and trends of pharmaceuticals and personal care products (PPCPs) in Taihu Lake. The ecological risk associated with some of the PPCPs was also assessed. 36 PPCPs have been detected in the water, sediment and biota of Taihu Lake. These contaminants primarily emanate from anthropogenic activities in and around the lake. The northern part of the lake is highly polluted as compared to other parts because it receives most effluents from wastewater treatment plants (WWTPs), and domestic and industrial waste discharge from developed cities nearby. Based on the risk quotient (RQ) values, ciprofloxacin, ofloxacin, 17β-estradiol, roxithromycin and tetracycline may present a high ecological risk to organisms living in Taihu Lake. Regular monitoring is required to check the levels of PPCPs as they are regularly released into the lake. Investigations into the joint toxicities of PPCPs to aquatic organisms and the spread of antibiotic-resistant bacteria and genes in Taihu Lake are highly recommended. Special attention in terms of policy and research should be given to the northern part of the lake.


NCCN Task Force Report: Specialty Pharmacy.
The use of specialty pharmacies is expanding in oncology pharmacy practice. Specialty pharmacies provide a channel for distributing drugs that, from the payor perspective, creates economies of scale and streamlines the delivery of expensive drugs. Proposed goals of specialty pharmacy include optimization of pharmaceutical care outcomes through ensuring appropriate medication use and maximizing adherence, and optimization of economic outcomes through avoiding unwarranted drug expenditure. In oncology practice, specialty pharmacies have become a distribution channel for various agents. The use of a specialty pharmacy, and the addition of the pharmacist from the specialty pharmacy to the health care team, may not only provide benefits for care but also present challenges in oncology practice. The NCCN Specialty Pharmacy Task Force met to identify and examine the impact of specialty pharmacy practice on the care of people with cancer, and to provide recommendations regarding issues discussed. This report provides recommendations within the following categories: education and training of specialty pharmacy practitioners who care for individuals with cancer, coordination of care, and patient safety. Areas for further evaluation are also identified.


QRStream: A Secure and Convenient Method for Text Healthcare Data Transferring.
With the increasing of health awareness, the users become more and more interested in their daily health information and healthcare activities results from healthcare organizations. They always try to collect them together for better usage. Traditionally, the healthcare data is always delivered by paper format from the healthcare organizations, and it is not easy and convenient for data usage and management. They would have to translate these data on paper to digital version which would probably introduce mistakes into the data. It would be necessary if there is a secure and convenient method for electronic health data transferring between the users and the healthcare organizations. However, for the security and privacy problems, almost no healthcare organization provides a stable and full service for health data delivery. In this paper, we propose a secure and convenient method, QRStream, which splits original health data and loads them onto QR code frame streaming for the data transferring. The results shows that QRStream can transfer text health data smoothly with an acceptable performance, for example, transferring 10K data in 10 seconds.


Correlational effect size benchmarks.
Effect size information is essential for the scientific enterprise and plays an increasingly central role in the scientific process. We extracted 147,328 correlations and developed a hierarchical taxonomy of variables reported in Journal of Applied Psychology and Personnel Psychology from 1980 to 2010 to produce empirical effect size benchmarks at the omnibus level, for 20 common research domains, and for an even finer grained level of generality. Results indicate that the usual interpretation and classification of effect sizes as small, medium, and large bear almost no resemblance to findings in the field, because distributions of effect sizes exhibit tertile partitions at values approximately one-half to one-third those intuited by Cohen (1988). Our results offer information that can be used for research planning and design purposes, such as producing better informed non-nil hypotheses and estimating statistical power and planning sample size accordingly. We also offer information useful for understanding the relative importance of the effect sizes found in a particular study in relationship to others and which research domains have advanced more or less, given that larger effect sizes indicate a better understanding of a phenomenon. Also, our study offers information about research domains for which the investigation of moderating effects may be more fruitful and provide information that is likely to facilitate the implementation of Bayesian analysis. Finally, our study offers information that practitioners can use to evaluate the relative effectiveness of various types of interventions.


Point-of-care laboratory testing in critical care.
Critical care practitioners are searching for ways to improve the quality and outcomes of care while decreasing cost and length of stay. One technological advance that may facilitate meeting these objectives is bedside or point-of-care laboratory equipment. Evaluation of point-of-care testing for application in each institution requires information about the devices available; knowledge of the advantages and disadvantages of the technologies, the clinical impact, and cost of the process change; and strategies for successful implementation. To review the literature on point-of-care testing and the experience of healthcare professionals who have already successfully implemented this type of testing. A total of 81 relevant published articles were reviewed, and 21 critical care units in 8 facilities that use point-of-care testing were visited. Open-ended interviews were conducted with 83 subjects: 56 nurses, 14 laboratory personnel, 9 respiratory therapists, and 4 others. Point-of-care testing is a technological innovation with the potential for improving patients' care without increasing costs. It most likely will soon become part of the standard of care.


N-Acetylcysteine amide protects against methamphetamine-induced oxidative stress and neurotoxicity in immortalized human brain endothelial cells.
Oxidative stress plays an important role in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Methamphetamine (METH) is an amphetamine analog that causes degeneration of the dopaminergic system in mammals and subsequent oxidative stress. In our present study, we have used immortalized human brain microvascular endothelial (HBMVEC) cells to test whether N-acetylcysteine amide (NACA), a novel antioxidant, prevents METH-induced oxidative stress in vitro. Our studies showed that NACA protects against METH-induced oxidative stress in HBMVEC cells. NACA significantly protected the integrity of our blood brain barrier (BBB) model, as shown by permeability and trans-endothelial electrical resistance (TEER) studies. NACA also significantly increased the levels of intracellular glutathione (GSH) and glutathione peroxidase (GPx). Malondialdehyde (MDA) levels increased dramatically after METH exposure, but this increase was almost completely prevented when the cells were treated with NACA. Generation of reactive oxygen species (ROS) also increased after METH exposure, but was reduced to control levels with NACA treatment, as measured by dichlorofluorescin (DCF). These results suggest that NACA protects the BBB integrity in vitro, which could prevent oxidative stress-induced damage; therefore, the effectiveness of this antioxidant should be evaluated for the treatment of neurodegenerative diseases in the future.


Longitudinal changes in free-water within the substantia nigra of Parkinson's disease.
There is a clear need to develop non-invasive markers of substantia nigra progression in Parkinson's disease. We previously found elevated free-water levels in the substantia nigra for patients with Parkinson's disease compared with controls in single-site and multi-site cohorts. Here, we test the hypotheses that free-water levels in the substantia nigra of Parkinson's disease increase following 1 year of progression, and that baseline free-water levels in the substantia nigra predict the change in bradykinesia following 1 year. We conducted a longitudinal study in controls (n = 19) and patients with Parkinson's disease (n = 25). Diffusion imaging and clinical data were collected at baseline and after 1 year. Free-water analyses were performed on diffusion imaging data using blinded, hand-drawn regions of interest in the posterior substantia nigra. A group effect indicated free-water values were increased in the posterior substantia nigra of patients with Parkinson's disease compared with controls (P = 0.003) and we observed a significant group × time interaction (P < 0.05). Free-water values increased for the Parkinson's disease group after 1 year (P = 0.006), whereas control free-water values did not change. Baseline free-water values predicted the 1 year change in bradykinesia scores (r = 0.74, P < 0.001) and 1 year change in Montreal Cognitive Assessment scores (r = -0.44, P = 0.03). Free-water in the posterior substantia nigra is elevated in Parkinson's disease, increases with progression of Parkinson's disease, and predicts subsequent changes in bradykinesia and cognitive status over 1 year. These findings demonstrate that free-water provides a potential non-invasive progression marker of the substantia nigra.


Cyclin D3 drives inertial cell cycling in dark zone germinal center B cells.
During affinity maturation, germinal center (GC) B cells alternate between proliferation and somatic hypermutation in the dark zone (DZ) and affinity-dependent selection in the light zone (LZ). This anatomical segregation imposes that the vigorous proliferation that allows clonal expansion of positively selected GC B cells takes place ostensibly in the absence of the signals that triggered selection in the LZ, as if by "inertia." We find that such inertial cycles specifically require the cell cycle regulator cyclin D3. Cyclin D3 dose-dependently controls the extent to which B cells proliferate in the DZ and is essential for effective clonal expansion of GC B cells in response to strong T follicular helper (Tfh) cell help. Introduction into the Ccnd3 gene of a Burkitt lymphoma-associated gain-of-function mutation (T283A) leads to larger GCs with increased DZ proliferation and, in older mice, clonal B cell lymphoproliferation, suggesting that the DZ inertial cell cycle program can be coopted by B cells undergoing malignant transformation.


Antibodies Reactive to Commensal Streptococcus mitis Show Cross-Reactivity With Virulent Streptococcus pneumoniae Serotypes.
Current vaccines against Streptococcus pneumoniae, a bacterial species that afflicts people by causing a wide spectrum of diseases, do not protect against all pneumococcal serotypes. Thus, alternative vaccines to fight pneumococcal infections that target common proteins are under investigation. One promising strategy is to take advantage of immune cross-reactivity between commensal and pathogenic microbes for cross-protection. In this study, we examined the antibody-mediated cross-reactivity between S. pneumoniae and Streptococcus mitis, a commensal species closely related to S. pneumoniae. Western blot analysis showed that rabbit antisera raised against S. mitis reacted with multiple proteins of virulent S. pneumoniae strains (6B, TIGR4, and D39). Rabbit anti-S. pneumoniae IgG antibodies also showed binding to S. mitis antigens. Incubation of rabbit antisera raised against S. mitis with heterologous or homologous bacterial lysates resulted in marked inhibition of the developments of bands in the Western blots. Furthermore, plasma IgG antibodies from adult human volunteers intranasally inoculated with S. pneumoniae 6B revealed enhanced S. mitis-specific IgG titers compared with the pre-inoculation samples. Using an on-chip protein microarray representing a number of selected membrane and extracellular S. pneumoniae proteins, we identified choline-binding protein D (CbpD), cell division protein (FtsH), and manganese ABC transporter or manganese-binding adhesion lipoprotein (PsaA) as common targets of the rabbit IgG antibodies raised against S. mitis or S. pneumoniae. Cumulatively, these findings provide evidence on the antibody-mediated cross-reactivity of proteins from S. mitis and S. pneumoniae, which may have implications for development of effective and wide-range pneumococcal vaccines.


The impact of impairment on kinematic and kinetic variables in Va'a paddling: Towards a sport-specific evidence-based classification system for Para Va'a.
Para Va'a is a new Paralympic sport in which athletes with trunk and/or leg impairment compete over 200 m. The purpose of this study was to examine the impact of impairment on kinematic and kinetic variables during Va'a ergometer paddling. Ten able-bodied and 44 Para Va'a athletes with impairments affecting: trunk and legs (TL), legs bilaterally (BL) or leg unilaterally (UL) participated. Differences in stroke frequency, mean paddling force, and joint angles and correlation of the joint angles with paddling force were examined. Able-bodied demonstrated significantly greater paddling force as well as knee and ankle flexion ranges of movement (ROM) on the top hand paddling side compared to TL, BL and UL. Able-bodied, BL and UL demonstrated greater paddling force and trunk flexion compared to TL, and UL demonstrated larger bottom hand paddling side knee and ankle flexion ROM compared to BL. Significant positive correlations were observed for both male and female athletes between paddling force and all trunk flexion angles and ROM in the trunk and pelvis rotation and bottom hand paddling side hip, knee and ankle flexion. The results of this study are important for creating an evidence-based classification system for Para Va'a.


Altered community flammability in Florida's Apalachicola ravines and implications for the persistence of the endangered conifer Torreya taxifolia.
Plant species and communities often reflect historic fire regimes via ecological and evolutionary responses to recurrent fires. Plant communities of the southeastern USA experience a wide array of fire regimes, perhaps nowhere more marked than the juxtaposition of fire-prone uplands and adjacent mesic ravines along Florida's Apalachicola River. The ravines contain many endemic and disjunct species, most notably the endangered endemic conifer Torreya taxifolia. A rapid decline in T. taxifolia over the past 60 years has been associated with widespread replacement by other tree species. To understand the changes accompanying the shift in ravine composition, we compared leaf litter flammability of nine historic and contemporary species. We measured maximum flame height, flame duration, smoldering duration, mass loss, absorptive capacity, and drying rate. Ordination and perMANOVA suggest the nine species segregated into three distinct groups: the fire-impeding T. taxifolia and Taxus floridana; an intermediate group of three deciduous angiosperms; and a mixed cluster of four flammable species. Results suggest T. taxifolia and T. floridana were fire-impeding species in these communities, while contemporary dominants burn similarly to the upslope pyric species. The increasing presence of fire-facilitating species may portend a shifting fire regime that further imperils T. taxifolia and other rare species in the formerly fire-safe ravines.


Probing the Origin of Challenge of Realizing Metallaphosphabenzenes: Unfavorable 1,2-Migration in Metallapyridines Becomes Feasible in Metallaphosphabenzenes.
Metallabenzenes have attracted considerable interest of both theoretical and experimental chemists. However, metallaphosphabenzene has never been synthesized. Thus, understanding the origin of the challenge of synthesizing metallaphosphabenzene is particularly urgent for experimentalists. Now density functional theory (DFT) calculations have been carried out to examine this issue. Our results reveal that the 1,2-migration in metallapyridines is unfavorable whereas such a 1,2-migration in metallaphosphabenzenes is feasible, which can be rationalized by the reluctance of phosphorus to participate in π bonding. In addition, π-donor ligands and the 5d transition metals can stabilize metallaphosphabenzenes. Compared with hydride and methyl migration, the chloride migration has a relatively lower activation barrier due to the polarization of the M=P bond. CO ligand could further decrease the reaction barrier of the migration due to the reduction of the interaction between the metal centre and the phosphorus atom. All of these findings could help synthetic chemists to realize the first metallaphosphabenzene.


Functional analysis of human cytochrome P450 21A2 variants involved in congenital adrenal hyperplasia.
Cytochrome P450 (P450, CYP) 21A2 is the major steroid 21-hydroxylase, converting progesterone to 11-deoxycorticosterone and 17α-hydroxyprogesterone (17α-OH-progesterone) to 11-deoxycortisol. More than 100 CYP21A2 variants give rise to congenital adrenal hyperplasia (CAH). We previously reported a structure of WT human P450 21A2 with bound progesterone and now present a structure bound to the other substrate (17α-OH-progesterone). We found that the 17α-OH-progesterone- and progesterone-bound complex structures are highly similar, with only some minor differences in surface loop regions. Twelve P450 21A2 variants associated with either salt-wasting or nonclassical forms of CAH were expressed, purified, and analyzed. The catalytic activities of these 12 variants ranged from 0.00009% to 30% of WT P450 21A2 and the extent of heme incorporation from 10% to 95% of the WT. Substrate dissociation constants (Ks) for four variants were 37-13,000-fold higher than for WT P450 21A2. Cytochrome b5, which augments several P450 activities, inhibited P450 21A2 activity. Similar to the WT enzyme, high noncompetitive intermolecular kinetic deuterium isotope effects (≥ 5.5) were observed for all six P450 21A2 variants examined for 21-hydroxylation of 21-d3-progesterone, indicating that C-H bond breaking is a rate-limiting step over a 104-fold range of catalytic efficiency. Using UV-visible and CD spectroscopy, we found that P450 21A2 thermal stability assessed in bacterial cells and with purified enzymes differed among salt-wasting- and nonclassical-associated variants, but these differences did not correlate with catalytic activity. Our in-depth investigation of CAH-associated P450 21A2 variants reveals critical insight into the effects of disease-causing mutations on this important enzyme.


A synthesis of genetic connectivity in deep-sea fauna and implications for marine reserve design.
With anthropogenic impacts rapidly advancing into deeper waters, there is growing interest in establishing deep-sea marine protected areas (MPAs) or reserves. Reserve design depends on estimates of connectivity and scales of dispersal for the taxa of interest. Deep-sea taxa are hypothesized to disperse greater distances than shallow-water taxa, which implies that reserves would need to be larger in size and networks could be more widely spaced; however, this paradigm has not been tested. We compiled population genetic studies of deep-sea fauna and estimated dispersal distances for 51 studies using a method based on isolation-by-distance slopes. Estimates of dispersal distance ranged from 0.24 km to 2028 km with a geometric mean of 33.2 km and differed in relation to taxonomic and life-history factors as well as several study parameters. Dispersal distances were generally greater for fishes than invertebrates with the Mollusca being the least dispersive sampled phylum. Species that are pelagic as adults were more dispersive than those with sessile or sedentary lifestyles. Benthic species from soft-substrate habitats were generally less dispersive than species from hard substrate, demersal or pelagic habitats. As expected, species with pelagic and/or feeding (planktotrophic) larvae were more dispersive than other larval types. Many of these comparisons were confounded by taxonomic or other life-history differences (e.g. fishes being more dispersive than invertebrates) making any simple interpretation difficult. Our results provide the first rough estimate of the range of dispersal distances in the deep sea and allow comparisons to shallow-water assemblages. Overall, dispersal distances were greater for deeper taxa, although the differences were not large (0.3-0.6 orders of magnitude between means), and imbalanced sampling of shallow and deep taxa complicates any simple interpretation. Our analyses suggest the scales of dispersal and connectivity for reserve design in the deep sea might be comparable to or slightly larger than those in shallow water. Deep-sea reserve design will need to consider the enormous variety of taxa, life histories, hydrodynamics, spatial configuration of habitats and patterns of species distributions. The many caveats of our analyses provide a strong impetus for substantial future efforts to assess connectivity of deep-sea species from a variety of habitats, taxonomic groups and depth zones.


Effectiveness and cost-effectiveness of a group-based pain self-management intervention for patients undergoing total hip replacement: feasibility study for a randomized controlled trial.
Total hip replacement (THR) is a common elective surgical procedure and can be effective for reducing chronic pain. However, waiting times can be considerable. A pain self-management intervention may provide patients with skills to more effectively manage their pain and its impact during their wait for surgery. This study aimed to evaluate the feasibility of conducting a randomized controlled trial to assess the effectiveness and cost-effectiveness of a group-based pain self-management course for patients undergoing THR. Patients listed for a THR at one orthopedic center were posted a study invitation pack. Participants were randomized to attend a pain self-management course plus standard care or standard care only. The lay-led course was delivered by Arthritis Care and consisted of two half-day sessions prior to surgery and one full-day session after surgery. Participants provided outcome and resource-use data using a diary and postal questionnaires prior to surgery and one month, three months and six months after surgery. Brief telephone interviews were conducted with non-participants to explore barriers to participation. Invitations were sent to 385 eligible patients and 88 patients (23%) consented to participate. Interviews with 57 non-participants revealed the most common reasons for non-participation were views about the course and transport difficulties. Of the 43 patients randomized to the intervention group, 28 attended the pre-operative pain self-management sessions and 11 attended the post-operative sessions. Participant satisfaction with the course was high, and feedback highlighted that patients enjoyed the group format. Retention of participants was acceptable (83% of recruited patients completed follow-up) and questionnaire return rates were high (72% to 93%), with the exception of the pre-operative resource-use diary (35% return rate). Resource-use completion rates allowed for an economic evaluation from the health and social care payer perspective. This study highlights the importance of feasibility work prior to a randomized controlled trial to assess recruitment methods and rates, barriers to participation, logistics of scheduling group-based interventions, acceptability of the intervention and piloting resource use questionnaires to improve data available for economic evaluations. This information is of value to researchers and funders in the design and commissioning of future research. Current Controlled Trials ISRCTN52305381.


LKB1 tumor suppressor protein regulates actin filament assembly through Rho and its exchange factor Dbl independently of kinase activity.
Germline mutations in LKB1 result in Peutz-Jeghers Syndrome characterized by intestinal hamartomas and increased incidence of epithelial cancers. LKB1 encodes a serine/threonine kinase that plays an important role in regulating energy metabolism through the AMPK/mTOR signaling pathway. In addition, LKB1 is homologous to PAR-4, a polarity protein first described in C. elegans, while activation of LKB1 in mammalian epithelial cells induces the polarized assembly of actin filaments. To explore the mechanism by which LKB1 interacts with the actin cytoskeleton, we introduced LKB1 into HeLa cells that lack endogenous LKB1. This results in activation of the small GTPase Rho and the assembly of linear actin filaments associated with focal adhesions. These effects on the actin cytoskeleton are attenuated by siRNA-mediated depletion of the guanine nucleotide exchange factor Dbl. Co-expression of the LKB1 with the adaptor protein STRAD induces actin filament puncta associated with phospho-ezrin. This study reveals that LKB1 regulates the actin cytoskeleton through a Dbl/Rho pathway.


Amorphous silicon nanocone array solar cell.
In the hydrogenated amorphous silicon [a-Si:H]-thin film solar cell, large amounts of traps reduce the carrier's lifetime that limit the photovoltaic performance, especially the power conversion efficiency. The nanowire structure is proposed to solve the low efficiency problem. In this work, we propose an amorphous silicon [a-Si]-solar cell with a nanocone array structure were implemented by reactive-ion etching through a polystyrene nanosphere template. The amorphous-Si nanocone exhibits absorption coefficient around 5 × 105/cm which is similar to the planar a-Si:H layer in our study. The nanostructure could provide the efficient carrier collection. Owing to the better carrier collection efficiency, efficiency of a-Si solar cell was increased from 1.43% to 1.77% by adding the nanocone structure which has 24% enhancement. Further passivation of the a-Si:H surface by hydrogen plasma treatment and an additional 10-nm intrinsic-a-Si:H layer, the efficiency could further increase to 2.2%, which is 54% enhanced as compared to the planar solar cell. The input-photon-to-current conversion efficiency spectrum indicates the efficient carrier collection from 300 to 800 nm of incident light.


Promoting Independent Sleep Onset in Young Children: Examination of the Excuse Me Drill.
Background: There is compelling evidence to support behavioral interventions as the first-line approach for bedtime resistance in young children. Among the behavioral treatment options, extinction ("cry it out") has the most extensive empirical support and tends to produce the most rapid gains. There are well known problems with the use of extinction, however, including side effects (extinction burst, spontaneous recovery) and poor acceptance, not to mention that extinction fails to teach children appropriate replacement behaviors (what "to do"). This study introduces a new behavioral sleep intervention, the Excuse Me Drill, designed to address some of the limitations of extinction. The EMD was formally evaluated for the first time using a multiple-baseline research design across four participants with sleep disturbance.Participants: Participants included four children who were clinically referred to outpatient pediatric psychology clinics for the treatment of behavioral insomnia of childhood, and included one 2-year-old female, two 7-year-old females, and one 7-year-old male. All participants had a history of dependent sleep onset at bedtime (i.e., parents remained in the child's bedroom upon sleep onset). Methods: A non-concurrent multiple baseline design across participants was used to experimentally evaluate the effectiveness of the EMD. During baseline, parents collected data on independent sleep onset and disruptive bedtime behaviors, but conducted the bedtime routine as usual. Immediately following baseline, parents implemented the EMD protocol until data indicated that children were consistently initiating sleep independently. Follow-up data were collected to determine the extent to which children continued to initiate sleep independently at bedtime in absence of the EMD. Results: Outcomes were promising as the EMD successfully taught all four children to initiate sleep independently and produced notable decreases in disruptive bedtime behavior. Results were maintained at follow-up for three of four participants. In addition, parents rated the EMD to be a socially acceptable procedure for their children. Conclusions: Results of this study indicate that the EMD was effective in promoting independent sleep onset and reducing disruptive bedtime behavior that maintained over time. The EMD should be considered to be a viable alternative to traditional extinction procedures for pediatric sleep disturbance. Implications for practice, limitations, and direction for future research are discussed.


A compilation and classification of DNA binding sites for protein transcription factors from vertebrates.
The field of protein transcription regulators and their DNA sequence specificity has been the most rapidly expanding in the last few years. The concerted interplay of protein transcription factors on the regulatory regions of eukaryotic genes (promoters, enhancers, origins of replication, silencers, and matrix-attached regions) regulates transcription levels; the differential activity of genes during development and the cell cycle, between cell types, and in response to physiological stimuli results from interdigitation of regulatory circuits controlling transcription initiation, finely tuned by the relative amounts of protein factors synthesized in a cell type, their phosphorylation, isoforms within factor families, the way protein regulators are brought in contact with one another through the patchwork of their cognate sites on the regulatory regions of genes, and by regulation of their nuclear import. The varying affinity of the same factor for its cognate DNA in different promoters can also be modulated by the type of proteins it is brought into contact with, by one or more nucleotide changes in its binding sites among promoters, and by the chromatin structure. The classification of protein transcriptional regulators attempted here according to their DNA binding specificity into those that bind AT-, GC-, GA, TG-rich and mixed motif has one obvious advantage: different protein factors that bind to the same DNA sequence will be found within the same class. In addition, this classification has allowed us to discern a class of transcriptional regulators whose binding site consists of a GA- and a CT-rich moiety; no other two pairs of dinucleotides compose a major class of factor sites.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of D1 and D2 agonists and antagonists on dyskinesia produced by L-dopa in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys.
A group of five cynomolgus monkeys was rendered parkinsonian by the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and then treated daily with levodopa until all animals developed evident dyskinesia in the limbs after each dose. At this point, levodopa was replaced by selective D2 and D1 dopamine receptor agonists. All D2 agonists including quinpirole, (+)-4-propyl-9-hydroxynaphthoxazine, bromocriptine, terguride and (-)-3-(3-hydroxyphenyl)-N-n-propylpiperone reproduced the same dyskinesia, the intensity and duration of which was dose-dependent and paralleled the therapeutic effect. One D1 agonist, SFK-38393, was without effect (antiparkinsonian and dyskinetic) whereas another, CY-208243, induced antiparkinsonian at a low dose but also a dyskinetic effect at a higher dose. The effect of the selective agonists were antagonized completely by their corresponding antagonist but partially by the noncorresponding one. The effect of either D1 and D2 agonist was totally suppressed by the dopamine depleting agent alpha-methyl-p-tyrosine, but the effect was restored by a small subthreshold dose of the other (complementary) agonist. Our results thus indicate that dyskinesia cannot be ascribed solely to the D2 or the D1 receptor and that some cooperation between the two receptors appears necessary for their manifestation.


Idiopathic inflammatory myopathy: Interrater variability in muscle biopsy reading.
To determine interrater variability in diagnosing individual muscle biopsy abnormalities and diagnosis. We developed a scoring tool to analyze consensus in muscle biopsy reading of an ad hoc workgroup of international experts. Twenty-four samples from patients with suspected idiopathic inflammatory myopathy (IIM) were randomly selected, providing sections that were stained with standard histologic and immunohistochemical methods. Sections were made available on an online platform, and experts were queried about myopathologic features within 4 pathologic domains: muscle fibers, inflammation, connective tissue, and vasculature. A short clinical presentation of cases was included, and experts were asked to give a tentative diagnosis of polymyositis, dermatomyositis, inclusion-body myositis, antisynthetase syndrome-related myositis, immune-mediated necrotizing myopathy, nonspecific myositis, or other disease. Fleiss κ values, scoring interrater variability, showed the highest agreement within the muscle fiber and connective tissue domains. Despite overall low κ values, moderate agreement was achieved for tentative diagnosis, supporting the idea of using holistic muscle biopsy interpretation rather than adding up individual features. The assessment of individual pathologic features needs to be standardized and harmonized and should be measured for sensitivity and specificity for subgroup classification. Standardizing the process of diagnostic muscle biopsy reading would allow identification of more homogeneous patient cohorts for upcoming treatment trials.


Experience with livaditis circular myotomy in management of long gap TEF.
Management of long gap oesophageal atresia with tracheoesophageal fistula (OA TEF) is challenging. Various intra-operative and pre-operative manures have been described to tackle this challenge. We reviewed our experiences with livaditis circular myotomy. The aim of this study was to evaluate long-term outcomes in cases of long gap OA TEF managed primarily with livaditis circular myotomy. This is a cross-sectional study including cases of long gap oesophagus managed by livaditis circular myotomy between January 1998 and October 2012. Their case records were evaluated for operative and post-operative data. The anthropometric data of these cases were collected. All these cases were subjected to barium swallow and manometry. Those cases with other associated neurological anomalies, multiple congenital anomalies, parents refusing consent for the study, less than 6 months of follow up or incomplete data were excluded from the study. Out of the total of 109 patients of OA TEF managed, long gaps OA TEF were 37. Out of the 37 cases, 13 were managed by primary repair with livaditis circular myotomy. Of these 13 cases, 11 formed the study group. Mean age at evaluation was 36 ± 9 months. Mean age at primary surgery was 3 ± 2.5 days of life. Minor leak in the immediate post-operative period was present in 2/11 cases. Manometry was done in all the cases and revealed motility disorder in the form of un-coordinated contraction in 4/11 cases. Remaining 7/11 cases were normal. Livaditis circular myotomy is a viable option in the management of long gap OA TEF with good comparable long-term results.


Chimeric Antigen Receptor T-Cell Therapy for Cancer and Heart: JACC Council Perspectives.
Chimeric antigen receptor (CAR) T-cell therapy has significantly advanced the treatment of patients with relapsed and refractory hematologic malignancies and is increasingly investigated as a therapeutic option of other malignancies. The main adverse effect of CAR T-cell therapy is potentially life-threatening cytokine release syndrome (CRS). Clinical cardiovascular (CV) manifestations of CRS include tachycardia, hypotension, troponin elevation, reduced left ventricular ejection fraction, pulmonary edema, and cardiogenic shock. Although insults related to CRS toxicity might be transient and reversible in most instances in patients with adequate CV reserve, they can be particularly challenging in higher-risk, often elderly patients with pre-existing CV disease. As the use of CAR T-cell therapy expands to include a wider patient population, careful patient selection, pre-treatment cardiac evaluation, and CV risk stratification should be considered within the CAR T-cell treatment protocol. Early diagnosis and management of CV complications in patients with CRS require awareness and multidisciplinary collaboration.


Identification and characterization of three members of the human SR family of pre-mRNA splicing factors.
SR proteins have a characteristic C-terminal Ser/Arg-rich repeat (RS domain) of variable length and constitute a family of highly conserved nuclear phosphoproteins that can function as both essential and alternative pre-mRNA splicing factors. We have cloned a cDNA encoding a novel human SR protein designated SRp30c, which has an unusually short RS domain. We also cloned cDNAs encoding the human homologues of Drosophila SRp55/B52 and rat SRp40/HRS. Recombinant proteins expressed from these cDNAs are active in constitutive splicing, as shown by their ability to complement a HeLa cell S100 extract deficient in SR proteins. Additional cDNA clones reflect extensive alternative splicing of SRp40 and SRp55 pre-mRNAs. The predicted protein isoforms lack the C-terminal RS domain and might be involved in feedback regulatory loops. The ability of human SRp30c, SRp40 and SRp55 to modulate alternative splicing in vivo was compared with that of other SR proteins using a transient contransfection assay. The overexpression of individual SR proteins in HeLa cells affected the choice of alternative 5' splice sites of adenovirus E1A and/or human beta-thalassemia reporters. The resulting splicing patterns were characteristic for each SR protein. Consistent with the postulated importance of SR proteins in alternative splicing in vivo, we demonstrate complex changes in the levels of mRNAs encoding the above SR proteins upon T cell activation, concomitant with changes in the expression of alternatively spliced isoforms of CD44 and CD45.


Predicting island biosecurity risk from introduced fauna using Bayesian Belief Networks.
Around the globe, islands are the last refuge for many threatened and endemic species. Islands are frequently also important sites for recreation, cultural activities, and industrial development, all of which facilitate the establishment of invasive species. Surveillance is employed on islands to detect the establishment of invasive species after their arrival, leading to decisions about follow-up actions. Unless surveillance is prioritised according to risk of establishment of invasives, it may be infeasible to implement efficiently over large tracts of publicly accessible land, especially in data-deficient areas. The key biosecurity problem for many regions is one of prioritizing sites for surveillance activities and identifying invasive species most likely to disperse to, and establish, and proliferate on those sites. We created a series of Bayesian Belief Networks (BBNs), linked by Java computing code and the freely available GeNIe application to automate the creation and computation of species- and site-specific biosecurity BBNs. The BBNs require data on island attributes, recreational or industrial visitor load, infrastructure, habitat availability, and animal behaviour and dispersal via swimming, flying, human movement, land bridges, or flood plumes. We used this biosecurity BBN to estimate the risk of 11 invasive faunal species arriving and establishing on 600 islands along the Pilbara coastline, Western Australia. Sensitivity analyses were conducted to identify nodes within the BBNs that required refined data inputs. Propagule pressure was the node with the greatest influence over the number of arrivals. Other nodes such as the number of visitors to islands and swimming capabilities of invasive animals greatly influenced the model results. Across the 11 species studied, our models predicted one arrival per 300 visitors. The biosecurity BBN can be used to identify the islands at highest risk from establishment of invasive species within any archipelago/s, and the invasive species most likely to establish on each island.


The genome of the arapaima (Arapaima gigas) provides insights into gigantism, fast growth and chromosomal sex determination system.
We have sequenced the genome of the largest freshwater fish species of the world, the arapaima. Analysis of gene family dynamics and signatures of positive selection identified genes involved in the specific adaptations and unique features of this iconic species, in particular it's large size and fast growth. Genome sequences from both sexes combined with RAD-tag analyses from other males and females led to the isolation of male-specific scaffolds and supports an XY sex determination system in arapaima. Whole transcriptome sequencing showed that the product of the gland-like secretory organ on the head surface of males and females may not only provide nutritional fluid for sex-unbiased parental care, but that the organ itself has a more specific function in males, which engage more in parental care.


Screening of mammalian DNA polymerase and topoisomerase inhibitors from Garcinia mangostana L. and analysis of human cancer cell proliferation and apoptosis.
We purified and identified eight xanthones from mangosteen (Garcinia mangostana L.) and investigated whether these compounds inhibited the activities of mammalian DNA polymerases (Pols) and human DNA topoisomerases (Topos). β-Mangostin was the strongest inhibitor of both mammalian Pols and human Topos among the isolated xanthones, with 50% inhibitory concentration (IC50) values of 6.4-39.6 and 8.5-10 µM, respectively. Thermal transition analysis indicated that β-mangostin did not directly bind to double-stranded DNA, suggesting that this compound directly bound the enzyme protein rather than the DNA substrate. β-Mangostin showed the strongest suppression of human cervical cancer HeLa cell proliferation among the eight compounds tested, with a 50% lethal dose (LD50) of 27.2 µM. This compound halted cell cycle in S phase at 12-h treatment and induced apoptosis. These results suggest that decreased proliferation by β-mangostin may be a result of the inhibition of cellular Pols rather than Topos, and β-mangostin might be an anticancer chemotherapeutic agent.


Comprehensive exploration of novel chimeric transcripts in clear cell renal cell carcinomas using whole transcriptome analysis.
The aim of this study was to clarify the participation of expression of chimeric transcripts in renal carcinogenesis. Whole transcriptome analysis (RNA sequencing) and exploration of candidate chimeric transcripts using the deFuse program were performed on 68 specimens of cancerous tissue (T) and 11 specimens of non-cancerous renal cortex tissue (N) obtained from 68 patients with clear cell renal cell carcinomas (RCCs) in an initial cohort. As positive controls, two RCCs associated with Xp11.2 translocation were analyzed. After verification by reverse transcription (RT)-PCR and Sanger sequencing, 26 novel chimeric transcripts were identified in 17 (25%) of the 68 clear cell RCCs. Genomic breakpoints were determined in five of the chimeric transcripts. Quantitative RT-PCR analysis revealed that the mRNA expression levels for the MMACHC, PTER, EPC2, ATXN7, FHIT, KIFAP3, CPEB1, MINPP1, TEX264, FAM107A, UPF3A, CDC16, MCCC1, CPSF3, and ASAP2 genes, being partner genes involved in the chimeric transcripts in the initial cohort, were significantly reduced in 26 T samples relative to the corresponding 26 N samples in the second cohort. Moreover, the mRNA expression levels for the above partner genes in T samples were significantly correlated with tumor aggressiveness and poorer patient outcome, indicating that reduced expression of these genes may participate in malignant progression of RCCs. As is the case when their levels of expression are reduced, these partner genes also may not fully function when involved in chimeric transcripts. These data suggest that generation of chimeric transcripts may participate in renal carcinogenesis by inducing dysfunction of tumor-related genes.


Fatal fulminant necrotizing pneumonia: a case report.
Here we present the case of a patient with fatal pulmonary histoplasmosis who presented with extensive necrotizing and cavitating pneumonia. To the best of our knowledge, this case report is the first to describe this presentation in a patient with no known immunosuppression. A 45-year-old Caucasian woman, a smoker from southeastern Minnesota, presented to our hospital with progressive dyspnea, fatigue and weight loss over the course of several months. Her medical history included type 2 diabetes mellitus, systemic hypertension and chronic opioid use for back pain. She did not have any recent travel history, and she had no unusual hobbies or risk factors for human immunodeficiency virus. When she was admitted to our intensive care unit, she was in hypoxic respiratory failure, thus we intubated her and placed her on mechanical ventilation. A computed tomographic scan of the chest revealed extensive areas of pulmonary necrosis with diffuse bilateral cavitation and lung destruction, which were especially prominent in the upper and middle lung fields. Bronchoalveolar lavage confirmed growth of Histoplasma capsulatum as the sole isolated pathogen. No other infectious agents were identified in blood, bronchoalveolar lavage, sputum or urine samples. Her condition worsened over the next 24 to 48 hours, with progressive multi-organ failure in spite of aggressive antibiotic and antifungal therapy. Her family elected to withdraw supportive care, and she died shortly thereafter. This case demonstrates a novel manifestation of histoplasmosis associated with extensive lung necrosis and cavitation. This report is of particular interest to pulmonologists and intensivists and underscores the importance of maintaining suspicion for mycotic disease in patients who have atypical presentations but live in an endemic area.


Cafestol overcomes ABT-737 resistance in Mcl-1-overexpressed renal carcinoma Caki cells through downregulation of Mcl-1 expression and upregulation of Bim expression.
Although ABT-737, a small-molecule Bcl-2/Bcl-xL inhibitor, has recently emerged as a novel cancer therapeutic agent, ABT-737-induced apoptosis is often blocked in several types of cancer cells with elevated expression of Mcl-1. Cafestol, one of the major compounds in coffee beans, has been reported to have anti-carcinogenic activity and tumor cell growth-inhibitory activity, and we examined whether cafestol could overcome resistance against ABT-737 in Mcl-1-overexpressed human renal carcinoma Caki cells. ABT-737 alone had no effect on apoptosis, but cafestol markedly enhanced ABT-737-mediated apoptosis in Mcl-1-overexpressed Caki cells, human glioma U251MG cells, and human breast carcinoma MDA-MB231 cells. By contrast, co-treatment with ABT-737 and cafestol did not induce apoptosis in normal human skin fibroblast. Furthermore, combined treatment with cafestol and ABT-737 markedly reduced tumor growth compared with either drug alone in xenograft models. We found that cafestol inhibited Mcl-1 protein expression, which is important for ABT-737 resistance, through promotion of protein degradation. Moreover, cafestol increased Bim expression, and siRNA-mediated suppression of Bim expression reduced the apoptosis induced by cafestol plus ABT-737. Taken together, cafestol may be effectively used to enhance ABT-737 sensitivity in cancer therapy via downregulation of Mcl-1 expression and upregulation of Bim expression.


Emerging HIV-1 drug resistance after roll-out of antiretroviral therapy in sub-Saharan Africa.
This review provides an update of recent data on the development of HIV-1 drug resistance during treatment and its transmission in sub-Saharan Africa after the scale-up of antiretroviral therapy (ART). Evidence is accumulating of a rising prevalence of transmitted HIV drug resistance (TDR), predominantly associated with nonnucleoside reverse transcriptase inhibitors (NNRTIs), in east and southern Africa. Pretherapy resistance is associated with first-line therapy failure. Accumulation of resistance mutations during first-line failure can be prevented by early detection and timely switching to second-line ART. Important gaps in service delivery and programme performance, associated with resistance development, affect a considerable proportion of ART programmes, particularly with respect to inadequate supply systems and patient retention. The reduction in new HIV infections associated with earlier use of ART is predicted to outweigh the risk of increasing TDR. Future levels of TDR are estimated to be diminished by improving switching practices to second-line regimens. TDR is on the rise after the recent scale-up of ART in Africa. To prevent the development and spread of drug resistance and sustain the effectiveness of ART programmes, there is a need to improve drug supply systems, patient retention and access to routine viral load monitoring. Enhanced resistance monitoring is warranted in Africa.


Loss of dermatan-4-sulfotransferase 1 function results in adducted thumb-clubfoot syndrome.
Adducted thumb-clubfoot syndrome is an autosomal-recessive disorder characterized by typical facial appearance, wasted build, thin and translucent skin, congenital contractures of thumbs and feet, joint instability, facial clefting, and coagulopathy, as well as heart, kidney, or intestinal defects. We elucidated the molecular basis of the disease by using a SNP array-based genome-wide linkage approach that identified distinct homozygous nonsense and missense mutations in CHST14 in each of four consanguineous families with this disease. The CHST14 gene encodes N-acetylgalactosamine 4-O-sulfotransferase 1 (D4ST1), which catalyzes 4-O sulfation of N-acetylgalactosamine in the repeating iduronic acid-alpha1,3-N-acetylgalactosamine disaccharide sequence to form dermatan sulfate. Mass spectrometry of glycosaminoglycans from a patient's fibroblasts revealed absence of dermatan sulfate and excess of chondroitin sulfate, showing that 4-O sulfation by CHST14 is essential for dermatan sulfate formation in vivo. Our results indicate that adducted thumb-clubfoot syndrome is a disorder resulting from a defect specific to dermatan sulfate biosynthesis and emphasize roles for dermatan sulfate in human development and extracellular-matrix maintenance.


Three-dimensional assessment of the influence of juvenile pubic symphysiodesis on the pelvic geometry of dogs.
OBJECTIVE To evaluate the 3-D geometry of canine pelves and to characterize the long-term effects of juvenile pubic symphysiodesis (JPS) on pelvic geometry by comparing the pelvic configuration between littermates that did and did not undergo the procedure. ANIMALS 24 Labrador Retriever, Golden Retriever, or Labrador Retriever-Golden Retriever crossbred service dogs from 13 litters. PROCEDURES At 16 weeks old, puppies with a hip joint distraction index ≥ 0.5 were randomly assigned to undergo thermal JPS (n = 9), mechanical JPS (7), or a sham (control) surgical procedure (8). Ten years later, each dog underwent a CT scan of the pelvic region. Modeling software was used to create 3-D reconstructions from the CT scans, and various pelvic measurements were made and compared among the 3 treatments. RESULTS Compared with the control treatment, thermal and mechanical JPS increased the hemipelvis acetabular angle by 4°, the acetabular angle of lateral opening by 5°, and the orientation of the medial acetabular wall in a transverse plane by 6°, which indicated that JPS increased dorsal femoral head coverage by the acetabulum. Both JPS procedures decreased the pelvic canal area by approximately 20% and acetabular inclination by 6° but did not alter acetabular retroversion. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that thermal and mechanical JPS were equally effective in altering the 3-D pelvic geometry of dogs. These findings may help guide future studies of alternatives for optimizing canine pelvic anatomy to minimize the risk of hip dysplasia and associated osteoarthritis.


Urokinase plasminogen activator receptor is expressed in invasive cells in gastric carcinomas from high- and low-risk countries.
Gastric cancer is the second cancer causing death worldwide. Both incidence and mortality rates vary according to geographical regions. The receptor for urokinase plasminogen activator (uPAR) is involved in extracellular matrix degradation by mediating cell surface associated plasminogen activation, and its presence on gastric cancer cells is linked to micro-metastasis and poor prognosis. Immunohistochemical analyses of a set of 44 gastric cancer lesions from Costa Rica showed expression of uPAR in cancer cells in both intestinal subtype (14 of 27) and diffuse subtype (10 of 17). We compared the expression pattern of uPAR in gastric cancers from a high-risk country (Costa Rica) with a low-risk country (Norway). We found uPAR on gastric cancer cells in 24 of 44 cases (54%) from Costa Rica and in 13 of 23 cases (56%) from Norway. uPAR was seen in macrophages and neutrophils in all cases. We also examined the nonneoplastic mucosa and found that uPAR was more frequently seen in epithelial cells located at the luminal edge of the crypts in cases with Helicobacter pylori infection than in similar epithelial cells in noninfected mucosa (p = 0.033; chi(2) = 4.54). In conclusion, the expression of uPAR in cancer cells in more than half of the gastric cancer cases suggests that their uPAR-positivity do not contribute to explain the different mortality rates between the 2 countries, however, the actual prevalence of uPAR-positive cancer cells in the gastric cancers may still provide prognostic information.


Antibiotic therapy in Lyme disease.
We studied antibiotic efficacy in 113 patients with erythema chronicum migrans, the first manifestation of Lyme disease. Erythema chronicum migrans and its associated symptoms resolved faster in patients given penicillin or tetracycline (median duration, 4 and 2 days, respectively) than in untreated patients (10 days; P less than 0.001 and P = 0.005, respectively). Erythromycin had no significant effect. Although the frequency of subsequent neurologic and cardiac abnormalities was similar in all four groups, significantly fewer patients given penicillin developed arthritis than did untreated patients (P = 0.001). Among 15 patients with arthritis who were followed for at least 29 months, the total duration of joint involvement was shorter in penicillin-treated patients (median, 4 weeks) than in untreated patients (17 weeks; P = 0.019). Although the clinical manifestations of the disease may fluctuate in frequency from year to year and influence apparent antibiotic effect, we conclude that penicillin therapy shortens the duration of erythema chronicum migrans and may prevent or attenuate subsequent arthritis.


A network-based approach to modelling bluetongue spread in France.
Bluetongue virus serotype 8 (BTV-8) was reported for the first time in Europe in 2006, causing the largest bluetongue outbreak ever recorded. France was mostly impacted in 2007/09. Trade restrictions were implemented all along. Vaccination became available from 2008: a limited number of doses was first administered in an emergency vaccination campaign, followed by two nationwide compulsory vaccination campaigns in 2009 and 2010. France regained a disease-free status in December 2012, but BTV may have kept circulating undetected as infected herds have been reported again since August 2015. We developed a stochastic dynamic compartmental model of BTV transmission in cattle and sheep to analyze the relative importance of vector active flight and host movements in disease spread, and assess the effectiveness of control measures. We represented BTV transmission both within and between French administrative subdivisions called cantons, during the 2007/09 outbreak and until the end of 2010, when compulsory vaccination was interrupted. Within-canton transmission was vector-borne, and between canton transmission could occur through three contact networks that accounted for movements of: (i) vectors between pastures located at close distance; (ii) cattle and sheep between pastures of the same farm; (iii) traded cattle. We estimated the model parameters by approximate Bayesian computation, using data from the 2007 French outbreak. With this framework, we were able to reproduce the BTV-8 epizootic wave. Host movements between distant pastures of the same farm were found to have a major contribution to BTV spread to disease-free areas, thus raising practical questions about herd management during outbreaks. We found that cattle trade restrictions had been well complied with; without them, the whole French territory would have been infected by winter 2007. The 2008 emergency vaccination campaign had little impact on disease spread as almost half vaccine doses had likely been administered to already immune cattle. Alternatively, establishing a vaccination buffer zone would have allowed a better control of BTV in 2008: limiting its spatial expansion and decreasing the number of infected cattle and sheep. We also showed a major role of compulsory vaccination in controlling the outbreak in 2009 and 2010, though we predicted a possible low-level circulation after the last detection.


A Comparison of EORTC And CUETO Risk Tables in Terms of the Prediction of Recurrence and Progression in All Non-Muscle-Invasive Bladder Cancer Patients.
To compare the prediction accuracy of the European Organization for Research and Treatment of Cancer (EORTC) and the Spanish Urology Association for Oncological Treatment (CUETO) risk tables in all non-muscle invasive bladder cancer patients. Recurrence and progression-free survival of all patients were assessed according to the EORTC and the CUETO risk tables for each patient and the concordance index was used to indicate discriminative ability. Statistical analyses were performed, at 1 and 5 years, to the whole group and separately to those treated or not treated with bacillus Calmette-Guerin (BCG) . The study included 400 patients. One-year BCG maintenance therapy was applied to 181 patients (45.3%). The recurrence rate was higher than in CUETO, and similar to EORTC. The EORTC was determined to provide better discrimination than CUETO in the whole patient group and in those treated or not treated with BCG. The concordance indices for these groups were 0.777, 0.705; 0.773, 0.669; and 0.823, 0.758, respectively . The progression rate was similar in this study to the rate defined in both risk tables. The discrimination power was similarin EORTC and CUETO for all the groups. The concordance indices were 0.801, 0.881; 0.915, 0.930; and 0.832, 0.806, respectively. The EORTC has more power than CUETO to discriminate each recurrence risk group and both risk tables can successfully discriminate progression risk groups in all patients.


microRNA-199a/b-5p enhance imatinib efficacy via repressing WNT2 signaling-mediated protective autophagy in imatinib-resistant chronic myeloid leukemia cells.
Imatinib (IM) is a first-line therapeutic drug for chronic myeloid leukemia (CML), a hematological disease. Mutations in the BCR-ABL domain increase formation of IM resistance in CML. However, not all patients are BCR-ABL domain-mutant dependent. Investigating non-mutant mechanisms in the development of acquired IM resistance is a critical issue. We explored the mechanisms which influence IM efficacy and resistance in CML. Higher protective autophagy was identified in IM-resistant K562 (K562R) cells. Inhibition of autophagy by the inhibitors, chloroquine and 3-methyladenine, enhanced IM's efficacy in K562R cells. In addition, microRNA (miR)-199a/b-5p were downregulated in K562R cells compared to parent cells. Overexpression of miR-199a/b-5p reduced autophagy and induced cell apoptosis, resulting in enhanced IM's efficacy in K562R cells. Moreover, expression levels of the Wingless-type MMTV integration site family member 2 (WNT2), a positive regulator of autophagy, were significantly higher in K562R cells, and it was validated as a direct target gene of miR-199a/b-5p. Overexpressions of miR-199a/b-5p inhibited WNT2 downstream signaling. Furthermore, overexpression and knockdown of WNT2 influenced autophagy formation and CML drug sensitivity to IM. Overexpression of WNT2 could also reverse miR-199a/b-5p-enhanced IM efficacy in K562R cells. These results emphasized that miR-199a/b-5p inhibited autophagy via repressing WNT2 signaling and might provide novel therapeutic strategies for future IM-resistant CML therapy and drug development.


Hepatoprotective effects of methanol extract of Carissa opaca leaves on CCl4-induced damage in rat.
Carissa opaca (Apocynaceae) leaves possess antioxidant activity and hepatoprotective effects, and so may provide a possible therapeutic alternative in hepatic disorders. The effect produced by methanolic extract of Carissa opaca leaves (MCL) was investigated on CCl4-induced liver damages in rat. 30 rats were divided into five groups of six animals of each, having free access to food and water ad libitum. Group I (control) was given olive oil and DMSO, while group II, III and IV were injected intraperitoneally with CCl4 (0.5 ml/kg) as a 20% (v/v) solution in olive oil twice a week for 8 weeks. Animals of group II received only CCl4. Rats of group III were given MCL intragastrically at a dose of 200 mg/kg bw while that of group IV received silymarin at a dose of 50 mg/kg bw twice a week for 8 weeks. However, animals of group V received MCL only at a dose of 200 mg/kg bw twice a week for 8 weeks. The activities of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and γ-glutamyltransferase (γ-GT) were determined in serum. Catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), glutathione-S-transferase (GST), glutathione peroxidase (GSH-Px), glutathione reductase (GSR) and quinone reductase (QR) activity was measured in liver homogenates. Lipid peroxidation (thiobarbituric acid reactive substances; TBARS), glutathione (GSH) and hydrogen peroxide (H2O2) concentration was also assessed in liver homogenates. Phytochemicals in MCL were determined through qualitative and high performance liquid chromatography (HPLC) analysis. Hepatotoxicity induced with CCl4 was evidenced by significant increase in lipid peroxidation (TBARS) and H2O2 level, serum activities of AST, ALT, ALP, LDH and γ-GT. Level of GSH determined in liver was significantly reduced, as were the activities of antioxidant enzymes; CAT, POD, SOD, GSH-Px, GSR, GST and QR. On cirrhotic animals treated with CCl4, histological studies showed centrilobular necrosis and infiltration of lymphocytes. MCL (200 mg/kg bw) and silymarin (50 mg/kg bw) co-treatment prevented all the changes observed with CCl4-treated rats. The phytochemical analysis of MCL indicated the presence of flavonoids, tannins, alkaloids, phlobatannins, terpenoids, coumarins, anthraquinones, and cardiac glycosides. Isoquercetin, hyperoside, vitexin, myricetin and kaempherol was determined in MCL. These results indicate that MCL has a significant protective effect against CCl4 induced hepatotoxicity in rat, which may be due to its antioxidant and membrane stabilizing properties.


A model for damage load and its implications for the evolution of bacterial aging.
Deleterious mutations appearing in a population increase in frequency until stopped by natural selection. The ensuing equilibrium creates a stable frequency of deleterious mutations or the mutational load. Here I develop the comparable concept of a damage load, which is caused by harmful non-heritable changes to the phenotype. A damage load also ensues when the increase of damage is opposed by selection. The presence of a damage load favors the evolution of asymmetrical transmission of damage by a mother to her daughters. The asymmetry is beneficial because it increases fitness variance, but it also leads to aging or senescence. A mathematical model based on microbes reveals that a cell lineage dividing symmetrically is immortal if lifetime damage rates do not exceed a threshold. The evolution of asymmetry allows the lineage to persist above the threshold, but the lineage becomes mortal. In microbes with low genomic mutation rates, it is likely that the damage load is much greater than the mutational load. In metazoans with higher genomic mutation rates, the damage and the mutational load could be of the same magnitude. A fit of the model to experimental data shows that Escherichia coli cells experience a damage rate that is below the threshold and are immortal under the conditions examined. The model estimates the asymmetry level of E. coli to be low but sufficient for persisting at higher damage rates. The model also predicts that increasing asymmetry results in diminishing fitness returns, which may explain why the bacterium has not evolved higher asymmetry.


Can Public Housing Decrease Segregation? Lessons and Challenges From Non-European Immigration in France : Can Public Housing Decrease Segregation?
Recent decades have seen a rapid increase in the share of non-European immigrants in public housing in Europe, which has led to concern regarding the rise of ghettos in large cities. Using French census data over three decades, we examine how this increase in public housing participation has affected segregation. While segregation levels have increased moderately, on average, the number of immigrant enclaves has grown. The growth of enclaves is being driven by the large increase in non-European immigrants in the census tracts where the largest housing projects are located, both in the housing projects and the surrounding nonpublic dwellings. As a result, contemporary differences in segregation levels across metropolitan areas are being shaped by the concentration of public housing within cities, in particular the share of non-European immigrants in large housing projects constructed before the 1980s. Nevertheless, the overall effect of public housing on segregation has been ambiguous. While large projects have increased segregation, the inflows of non-European immigrants into small projects have brought many immigrants into census tracts where they have previously been rare and, thus, diminished segregation levels.


Coherent terahertz photonics.
We present a review of recent developments in THz coherent systems based on photonic local oscillators. We show that such techniques can enable the creation of highly coherent, thus highly sensitive, systems for frequencies ranging from 100 GHz to 5 THz, within an energy efficient integrated platform. We suggest that such systems could enable the THz spectrum to realize its full applications potential. To demonstrate how photonics-enabled THz systems can be realized, we review the performance of key components, show recent demonstrations of integrated platforms, and give examples of applications.


Granulocyte heterochromatin: defining the epigenome.
Mammalian blood neutrophilic granulocytes are terminally differentiated cells, possessing extensive heterochromatin and lobulated (or ring-shaped) nuclei. Despite the extensive amount of heterochromatin, neutrophils are capable of increased gene expression, when activated by bacterial infection. Understanding the mechanisms of transcriptional repression and activation in neutrophils requires detailing the chromatin epigenetic markers, which are virtually undescribed in this cell type. Much is known about the heterochromatin epigenetic markers in other cell-types, permitting a basis for comparison with those of mature normal neutrophilic granulocytes. Immunostaining and immunoblotting procedures were employed to study the presence of repressive histone modifications and HP1 proteins in normal human and mouse blood neutrophils, and in vitro differentiated granulocytes of the mouse promyelocytic (MPRO) system. A variety of repressive histone methylation markers were detectable in these granulocytes (di- and trimethylated H3K9; mono-, di- and trimethyl H3K27; di- and trimethyl H4K20). However, a paucity of HP1 proteins was noted. These granulocytes revealed negligible amounts of HP1 alpha and beta, but exhibited detectable levels of HP1 gamma. Of particular interest, mouse blood and MPRO undifferentiated cells and granulocytes revealed clear co-localization of trimethylated H3K9, trimethylated H4K20 and HP1 gamma with pericentric heterochromatin. Mature blood neutrophils possess some epigenetic heterochromatin features that resemble those of well-studied cells, such as lymphocytes. However, the apparent paucity of HP1 proteins in neutrophils suggests that heterochromatin organization and binding to the nuclear envelope may differ in this cell-type. Future investigations should follow changes in epigenetic markers and levels of HP1 proteins during granulopoiesis and bacterial activation of neutrophils.


How Law 180 in Italy has reshaped psychiatry after 30 years: past attitudes, current trends and unmet needs.
Law 180 eliminated psychiatric hospitals for the care of people with chronic psychosis in Italy. After 30 years, we review the consequences for the practice of psychiatry in Italy and parallels for England and Wales. We argue that the substitution of legal/political direction for clinical leadership means psychiatrists may cease to merit the privileges and responsibilities of being doctors.


Structural basis for inhibition of Plasmodium vivax invasion by a broadly neutralizing vaccine-induced human antibody.
The most widespread form of malaria is caused by Plasmodium vivax. To replicate, this parasite must invade immature red blood cells through a process requiring interaction of the P. vivax Duffy binding protein (PvDBP) with its human receptor, the Duffy antigen receptor for chemokines. Naturally acquired antibodies that inhibit this interaction associate with clinical immunity, suggesting PvDBP as a leading candidate for inclusion in a vaccine to prevent malaria due to P. vivax. Here, we isolated a panel of monoclonal antibodies from human volunteers immunized in a clinical vaccine trial of PvDBP. We screened their ability to prevent PvDBP from binding to the Duffy antigen receptor for chemokines, and their capacity to block red blood cell invasion by a transgenic Plasmodium knowlesi parasite genetically modified to express PvDBP and to prevent reticulocyte invasion by multiple clinical isolates of P. vivax. This identified a broadly neutralizing human monoclonal antibody that inhibited invasion of all tested strains of P. vivax. Finally, we determined the structure of a complex of this antibody bound to PvDBP, indicating the molecular basis for inhibition. These findings will guide future vaccine design strategies and open up possibilities for testing the prophylactic use of such an antibody.


The use of silymarin in the treatment of liver diseases.
The high prevalence of liver diseases such as chronic hepatitis and cirrhosis underscores the need for efficient and cost-effective treatments. The potential benefit of silymarin (extracted from the seeds of Silybum marianum or milk thistle) in the treatment of liver diseases remains a controversial issue. Therefore, the objective of this review is to assess the clinical efficacy and safety of silymarin by application of systematic approach. 525 references were found in the databases, of which 84 papers were retained for closer examination and 36 were deemed suitable for detailed analysis. Silymarin has metabolic and cell-regulating effects at concentrations found in clinical conditions, namely carrier-mediated regulation of cell membrane permeability, inhibition of the 5-lipoxygenase pathway, scavenging of reactive oxygen species (ROS) of the R-OH type and action on DNA-expression, for example, via suppression of nuclear factor (NF)-kappaB. Pooled data from case record studies involving 452 patients with Amanita phalloides poisoning show a highly significant difference in mortality in favour of silibinin [the main isomer contained in silymarin] (mortality 9.8% vs 18.3% with standard treatment; p < 0.01). The available trials in patients with toxic (e.g. solvents) or iatrogenic (e.g. antispychotic or tacrine) liver diseases, which are mostly outdated and underpowered, do not enable any valid conclusions to be drawn on the value of silymarin. The exception is an improved clinical tolerance of tacrine. In spite of some positive results in patients with acute viral hepatitis, no formally valid conclusion can be drawn regarding the value of silymarin in the treatment of these infections. Although there were no clinical end-points in the four trials considered in patients with alcoholic liver disease, histological findings were reported as improved in two out of two trials, improvement of prothrombin time was significant (two trials pooled) and liver transaminase levels were consistently lower in the silymarin-treated groups. Therefore, silymarin may be of use as an adjuvant in the therapy of alcoholic liver disease. Analysis was performed on five trials with a total of 602 patients with liver cirrhosis. The evidence shows that, compared with placebo, silymarin produces a nonsignificant reduction of total mortality by -4.2% [odds ratio (OR) 0.75 (0.5 - 1.1)]; but that, on the other hand, the use of silymarin leads to a significant reduction in liver-related mortality of-7% [OR: 0.54 (0.3 - 0.9); p < 0.01]. An individual trial reported a reduction in the number of patients with encephalopathy of -8.7% (p = 0.06). In one study of patients with cirrhosis-related diabetes mellitus, the insulin requirement was reduced by -25% (p < 0.01). We conclude that available evidence suggests that silymarin may play a role in the therapy of (alcoholic) liver cirrhosis. Silymarin is has a good safety record and only rare case reports of gastrointestinal disturbances and allergic skin rashes have been published. This review does not aim to replace future prospective trials aiming to provide the 'final' evidence of the efficacy of silymarin.


GRA12, a Toxoplasma dense granule protein associated with the intravacuolar membranous nanotubular network.
The intracellular protozoan parasite Toxoplasma gondii develops within the parasitophorous vacuole (PV), an intracellular niche in which it secretes proteins from secretory organelles named dense granules and rhoptries. Here, we describe a new dense granule protein that should now be referred to as GRA12, and that displays no homology with other proteins. Immunofluorescence and immuno-electron microscopy showed that GRA12 behaves similarly to both GRA2 and GRA6. It is secreted into the PV from the anterior pole of the parasite soon after the beginning of invasion, transits to the posterior invaginated pocket of the parasite where a membranous tubulovesicular network is first assembled, and finally resides throughout the vacuolar space, associated with the mature membranous nanotubular network. GRA12 fails to localise at the parasite posterior end in the absence of GRA2. Within the vacuolar space, like the other GRA proteins, GRA12 exists in both a soluble and a membrane-associated form. Using affinity chromatography experiments, we showed that in both the parasite and the PV soluble fractions, GRA12 is purified with the complex of GRA proteins associated with a tagged version of GRA2 and that this association is lost in the PV membranous fraction.


Algorithm-guided empirical tuberculosis treatment for people with advanced HIV (TB Fast Track): an open-label, cluster-randomised trial.
Tuberculosis, which is often undiagnosed, is the major cause of death among HIV-positive people. We aimed to test whether the use of a clinical algorithm enabling the initiation of empirical tuberculosis treatment by nurses in primary health-care clinics would reduce mortality compared with standard of care for adults with advanced HIV disease. In this open-label cluster-randomised controlled trial, we recruited individuals from 24 primary health-care clinics in South Africa. The clinics were randomly assigned (1:1) to either deliver an intervention or routine care (control) using computer-generated random numbers. Eligible participants were HIV-positive adults (aged ≥18 years) with CD4 counts of 150 cells per μL or less, who had not had antiretroviral therapy (ART) in the past 6 months or tuberculosis treatment in the past 3 months, and did not require urgent hospital referral. In intervention clinics, study nurses assessed participants on the basis of tuberculosis symptoms, body-mass index, point-of-care haemoglobin concentrations, and urine lipoarabinomannan assay results. Participants classified by a study algorithm as having high probability of tuberculosis (positive urine lipoarabinomannan assay, body-mass index <18·5 kg/m2, or haemoglobin concentration <100 g/L) were recommended to start tuberculosis treatment immediately followed by ART 2 weeks later; participants classified as medium probability (tuberculosis symptoms, no high probability criteria) were recommended to have symptom-guided investigation; and participants classified as low probability (no tuberculosis symptoms or high probability criteria) were recommended to start ART immediately. In standard-of-care clinics, participants received treatment in accordance with South African guidelines. Investigators and participants were aware of treatment allocation. The primary outcome was all-cause mortality at 6 months, assessed in the intention-to-treat population. Safety was also analysed in the intention-to treat population. This trial is registered with the ISRCTN registry, ISRCTN35344604, and the South African National Clinical Trials Register, DOH-27-0812-3902. Between Dec 19, 2012, and Dec 18, 2014, 3091 individuals were screened for eligibility, of whom 3053 were recruited, and 3022 (1507 participants in the intervention group and 1515 participants in the control group) were analysed for the primary outcome. 930 (61·7%) of 1507 participants in the intervention group versus 172 (11·4%) of 1515 participants in the control group had started tuberculosis treatment by 2 months. At 6 months, the mortality rate was 19·0 deaths per 100 person-years for the intervention group versus 21·6 deaths per 100 person-years in the control group (unadjusted hazard ratio [HR] 0·92, 95% CI 0·67-1·26, p=0·58; adjusted HR 0·87, 0·61-1·24, p=0·41). 28 (1·9%) of 1507 participants in the intervention group and ten (0·7%) of 1515 participants in the control group reported serious or severe adverse events. Grade 3 or 4 nausea and vomiting was the most common adverse event (ten participants in the intervention group and four participants in the control group). Among participants with adverse events, eight participants (six participants in the intervention group and two participants in the control group) died; none of the six deaths in the intervention group were attributed to the study intervention. Our intervention substantially increased coverage of tuberculosis treatment in this high-risk population, but did not reduce mortality. Joint Global Health Trials (Medical Research Council, Department for International Development, Wellcome Trust).


Peripherally inserted central catheters in the treatment of children with cancer: Results of a multicenter study.
To review our experience with peripherally inserted central catheters in pediatric cancer patients. The analysis included 353 patients (3 months up to 17 years, mean age 11.2 years) with a variety of cancers diseases, which in 2011-2016, 354 peripherally inserted central catheters were placed. All settings are carried out using ultrasound guidance. In 138 (39%) patients, external anatomical landmarks were used and in 216 (61%) intraoperative fluoroscopy. Maximal duration of the line was 1.3 years, the lowest 1.5 months, and average 6.3 months. Among the technical difficulties during placement, most frequently have been the migration of the distal end of the catheter into the internal jugular vein against blood flow-32 (9%) patients. In one (0.3%) case, we were unable to catheterize the patient's vein. Among the most common complications of operation were marked peripherally inserted central catheter clot occlusion of the lumen-26 (7.3%) cases. Symptomatic catheter-related thrombosis was observed in 16 (4.5%) cases. Catheter-related blood stream infections were not reported. Removal of peripherally inserted central catheters related to the complications was performed in 30 (8.5%) patients who were later implanted venous ports. Peripherally inserted central catheters are recommend to use in the treatment of children with cancer. There should be trained nursing staff to minimize the risk of complications.


Intravenous needle-free injection devices: new information for compounding pharmacists.
By educating their clients (especially prescribing physicians, nurses, and home healthcare aides) about the advantages of using needle-free devices to administer intravenous medications, compounding pharmacists can help prevent complications associated with vascular access devices and needlestick injuries. Despite state and federal efforts to reduce the incidence of sharps injuries among healthcare workers, percutaneous needle-stick injuries remain a source of emotional stress, morbidity, and possible mortality in those individuals. According to the Centers for Disease Control and Prevention, 50% or more of surveyed healthcare personnel do not report their occupational percutaneous injuries, and an estimated 385,000 sharps-related injuries occur annually among healthcare workers in hospitals alone. Because sharps injuries are associated with the transmission of more than 20 pathogens, including hepatitis B and C viruses and the human immunodeficiency virus, the potential burden of disease is great. For the intgravenous administration of medications, however, devices safer than those requiring the use of needles are available, and pharmacists have a key role in educating caregivers about needle-free equipment and its use. In this article, we explain the types of intravenous needle-free devices of interest to compounding pharmacists and the clients they serve, and we answer frequently asked questions about that equipment. Compounders who understand the design features and capabilities of such products, their clients' intended use of those devices, patients' specific needs can improve treatment outcomes and protect healthcare workers against needlestick injury.


Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma.
This multi-institutional phase I trial was designed to determine the maximum-tolerated dose (MTD) of cilengitide (EMD 121974) and to evaluate the use of perfusion magnetic resonance imaging (MRI) in patients with recurrent malignant glioma. Patients received cilengitide twice weekly on a continuous basis. A treatment cycle was defined as 4 weeks. Treatment-related dose-limiting toxicity (DLT) was defined as any grade 3 or 4 nonhematologic toxicity or grade 4 hematologic toxicity of any duration. A total of 51 patients were enrolled in cohorts of six patients to doses of 120, 240, 360, 480, 600, 1,200, 1,800, and 2,400 mg/m2 administered as a twice weekly intravenous infusion. Three patients progressed early and were inevaluable for toxicity assessment. The DLTs observed were one thrombosis (120 mg/m2), one grade 4 joint and bone pain (480 mg/m2), one thrombocytopenia (600 mg/m2) and one anorexia, hypoglycemia, and hyponatremia (800 mg/m2). The MTD was not reached. Two patients demonstrated complete response, three patients had partial response, and four patients had stable disease. Perfusion MRI revealed a significant relationship between the change in tumor relative cerebral blood flow (rCBF) from baseline and area under the plasma concentration versus time curve after 16 weeks of therapy. Cilengitide is well tolerated to doses of 2,400 mg/m2, durable complete and partial responses were seen in this phase I study, and clinical response appears related to rCBF changes.


Application of an advanced maximum likelihood estimation restoration method for enhanced-resolution and contrast in second-harmonic generation microscopy.
Second-harmonic generation (SHG) microscopy has gained popularity because of its ability to perform submicron, label-free imaging of noncentrosymmetric biological structures, such as fibrillar collagen in the extracellular matrix environment of various organs with high contrast and specificity. Because SHG is a two-photon coherent scattering process, it is difficult to define a point spread function (PSF) for this modality. Hence, compared to incoherent two-photon processes like two-photon fluorescence, it is challenging to apply the various PSF-engineering methods to improve the spatial resolution to be close to the diffraction limit. Using a synthetic PSF and application of an advanced maximum likelihood estimation (AdvMLE) deconvolution algorithm, we demonstrate restoration of the spatial resolution in SHG images to that closer to the theoretical diffraction limit. The AdvMLE algorithm adaptively and iteratively develops a PSF for the supplied image and succeeds in improving the signal to noise ratio (SNR) for images where the SHG signals are derived from various sources such as collagen in tendon and myosin in heart sarcomere. Approximately 3.5 times improvement in SNR is observed for tissue images at depths of up to ∼480 nm, which helps in revealing the underlying helical structures in collagen fibres with an ∼26% improvement in the amplitude contrast in a fibre pitch. Our approach could be adapted to noisy and low resolution modalities such as micro-nano CT and MRI, impacting precision of diagnosis and treatment of human diseases.


A sialic acid binding site in a human picornavirus.
The picornaviruses coxsackievirus A24 variant (CVA24v) and enterovirus 70 (EV70) cause continued outbreaks and pandemics of acute hemorrhagic conjunctivitis (AHC), a highly contagious eye disease against which neither vaccines nor antiviral drugs are currently available. Moreover, these viruses can cause symptoms in the cornea, upper respiratory tract, and neurological impairments such as acute flaccid paralysis. EV70 and CVA24v are both known to use 5-N-acetylneuraminic acid (Neu5Ac) for cell attachment, thus providing a putative link between the glycan receptor specificity and cell tropism and disease. We report the structures of an intact human picornavirus in complex with a range of glycans terminating in Neu5Ac. We determined the structure of the CVA24v to 1.40 Å resolution, screened different glycans bearing Neu5Ac for CVA24v binding, and structurally characterized interactions with candidate glycan receptors. Biochemical studies verified the relevance of the binding site and demonstrated a preference of CVA24v for α2,6-linked glycans. This preference can be rationalized by molecular dynamics simulations that show that α2,6-linked glycans can establish more contacts with the viral capsid. Our results form an excellent platform for the design of antiviral compounds to prevent AHC.


African parasitoid fig wasp diversification is a function of Ficus species ranges.
Host specificity is a fundamental property implicit in obligate insect-plant associations. Rigid life history constraints exhibited by parasitoid fig wasps are believed to select for specialization directed at fig trees and this is supported by evidence of phenotypic adaptation to figs and partial co-speciation with the fig wasps they attack. Conversely, the ability to colonize such novel communities occurs under relaxed specificity, a behavior typified by more generalist groups such as parasitoids. The specificity directed towards Ficus species by Sycoryctinae parasitoid fig wasps is important in order to understand how this form of specialization influences their diversification and interactions with other fig wasp guilds. We use genetic distance analyses and reconstruct ancestral patterns of Ficus trait association with two genera of Sycoryctinae parasitoid fig wasps to identify evolutionary conservatism in Ficus species utilization. Ancestral state reconstructions of (i) affiliate Ficus subsection and (ii) syconia diameters of natal Ficus species indicate contrasting Ficus species ranges between Arachonia and Sycoryctes parasitoid genera. This work demonstrates that parasitoid speciation is not tightly constrained to Ficus speciation and rather a function of Ficus range limitations. Ficus evolution, ecology, and functional compatibility between parasitoid and Ficus traits appear to constrain parasitoid Ficus utilization. These results suggest that contrasting ecological settings and potential number of hosts available impose different ramifications for the evolution of parasitoid host specificity and so to the species interactions within the communities to which they belong.


Carcinogenesis Bioassay of Guar Gum (CAS No. 9000-30-0) in F344 Rats and B6C3F1 Mice (Feed Study).
A carcinogenesis bioassay of guar gum, a widely used food stabilizer, was conducted by feeding diets containing 25,000 or 50,000 ppm of the test substance from two batches having purities of 83.5% and 91.9% to 50 F344 rats and 50 B6C3F1 mice of either sex for 103 weeks. Groups of 50 untreated rats and mice of either sex served as controls. The rodents might have tolerated higher doses but 50,000 ppm (5% of diet) is the upper limit for chronic feeding studies in the Bioassay Program, and this level represented the maximum tolerated dose (MTD) for females of both species in the present study. After week 20 in mice and week 40 in rats, mean body weights of high-dose females were lower than those of the untreated controls. No compound-related clinical signs or adverse effects on survival were observed. Feed consumption by dosed rats and dosed mice of either sex was lower than that of the controls. There were increased incidences of adenomas of the pituitary (8/45, 18% controls; 17/46, 37% low dose; 17/43, 40% high dose) in male rats and pheochromocytomas of the adrenal (0/50, 0%; 5/50, 10%; 6/50, 12%) in female rats, but these differences (P<0.035) were considered to be unrelated to administration of guar gum. When pituitary adenomas or carcinomas and when pheochromocytomas or malignant pheochromocytomas are combined, the statistical differences disappear. Hepatocellular carcinomas (15/44, 34%; 6/50, 12%; 6/49, 12%) occurred in treated male mice at incidences significantly (P</=0.011) lower than that in controls. The combined incidence of male mice with either hepatocellular adenomas or carcinomas (16/44, 36%; 12/50, 24%; 7/49, 14%) was also significantly (P=0.013) lower in the high-dose group. Under the conditions of this bioassay, guar gum was not carcinogenic for F344 rats or B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative