The interactions between the stimulatory effect of follicle-stimulating hormone and the inhibitory effect of estrogen on mouse primordial folliculogenesis.
The murine primordial follicle pool develops largely within 3 days after birth through germline nest breakdown and enclosure of oocytes within pregranulosa cells. The mechanisms that trigger primordial follicle formation likely are influenced by a transition from the maternal to fetal hormonal milieu at the time of birth. High levels of maternal estrogen maintain intact germline nest in fetal ovary, and decrease of estrogen after birth is permissive of follicle formation. In the present study, we measured an increase in neonatal serum follicle-stimulating hormone (FSH), which corresponded to falling estradiol (E(2)) levels during the critical window of primordial follicle formation (Postnatal Days 1-3). To determine whether fetal hormones contribute in an active manner to primordial follicle formation, mouse fetal ovaries (17.5 days postcoitus) were cultured in vitro at two concentrations of E(2) (meant to reflect maternal and fetal levels of E(2)) and FSH for 6 days. High levels of E(2) (10(-6) M) inhibited germline nest breakdown, and this effect was significantly reduced when fetal ovaries were cultured in the low E(2) concentration (10(-10) M). FSH facilitated germline nest breakdown and primordial follicle formation under both high and low E(2) culture conditions. Low E(2) was identified as being more permissive for the effects of FSH on primordial follicle formation by stimulating the up-regulation of Fshr and activin beta A subunit (Inhba) expression, pregranulosa cell proliferation, and oocyte survival. The decrease of E(2) plus the presence of FSH after birth are critical for primordial follicle formation and the expression of oocyte-specific transcription factors (Figla and Nobox) in that inappropriate exposure to FSH or E(2) during follicle formation resulted in premature or delayed primordial folliculogenesis. In conclusion, with the drop of E(2) level after birth, FSH promotes primordial follicle formation in mice by stimulating local activin signaling pathways and the expression of oocyte-specific transcription factors.


The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility.
Segmental duplications in the human genome are selectively enriched for genes involved in immunity, although the phenotypic consequences for host defense are unknown. We show that there are significant interindividual and interpopulation differences in the copy number of a segmental duplication encompassing the gene encoding CCL3L1 (MIP-1alphaP), a potent human immunodeficiency virus-1 (HIV-1)-suppressive chemokine and ligand for the HIV coreceptor CCR5. Possession of a CCL3L1 copy number lower than the population average is associated with markedly enhanced HIV/acquired immunodeficiency syndrome (AIDS) susceptibility. This susceptibility is even greater in individuals who also possess disease-accelerating CCR5 genotypes. This relationship between CCL3L1 dose and altered HIV/AIDS susceptibility points to a central role for CCL3L1 in HIV/AIDS pathogenesis and indicates that differences in the dose of immune response genes may constitute a genetic basis for variable responses to infectious diseases.


Skeletal muscle metaboreceptor stimulation opposes peak metabolic vasodilation in humans.
The total blood flow requirements of a large muscle mass can exceed the maximal cardiac output generated by the heart during exercise. Therefore, to maintain blood pressure, muscle vasodilation must be opposed by sympathetic vasoconstriction. The primary neural signal that increases sympathetic outflow is unclear. In an effort to isolate the vasoconstricting mechanism that opposes vasodilation, we measured the peak forearm vascular conductance response after the release of 10 minutes of forearm circulatory arrest under five separate study conditions: 1) no leg exercise, 2) low-level supine leg exercise, 3) low-level supine leg exercise with leg circulatory arrest after exercise, 4) high-level supine leg exercise, and 5) high-level supine leg exercise with leg circulatory arrest after exercise. We found that both high-workload conditions reduced peak forearm conductance below the no-leg exercise condition (a 34% reduction during leg exercise and a 52% reduction during leg exercise followed by leg circulatory arrest). In addition, at each workload, leg circulatory arrest after exercise, which isolated the skeletal muscle metaboreceptor contribution to vasoconstriction, reduced forearm conductance by approximately 20% below the values noted for leg exercise alone (combined central command and metaboreceptor stimulation). In a separate group of subjects, peak forearm blood flow was measured during lower-body negative pressure to levels up to -40 mm Hg, a maneuver that unloads high- and low-pressure baroreceptors. This intervention did not affect peak forearm blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)


Osseointegration of titanium implants with SLAffinity treatment: a histological and biomechanical study in miniature pigs.
Electrochemical oxidation following sandblasting and acid-etching (SLA) treatment has received interest as a surface modification procedure for titanium (Ti) implants (denoted as an SLAffinity surface); however, little information is available on its impacts on the in vivo performance of SLAffinity-Ti implants. The present study evaluated the osseointegration and biomechanical bone-tissue response to SLAffinity-Ti implants with micro- and nanoporous oxide layers. The interaction between blood and the tested implants was examined. In total, 144 implants with the following surfaces were used: a standard machined (M-Ti), an SLA-Ti, and an SLAffinity-Ti surface. For each animal, four implants (one M-Ti, one SLA-Ti, and two SLAffinity-Ti) were inserted into the mandibular canine-premolar area for histomorphometric observations and another four implants were inserted into the flat surface on the anteromedial aspect of the rear tibia for removal torque (RT) tests. After 2, 4, and 8 weeks of implantation, histomorphometric and RT tests were conducted. Interactions between blood and implants were better for implants with the SLAffinity-Ti surface. RT tests showed a significant improvement in fixation strength for SLAffinity-Ti implants (84.5 ± 8.7 N-cm) after 8 weeks compared to M-Ti (62.95 ± 11.5 N-cm) and SLAffinity-Ti (76.1 ± 6.6 N-cm) implants. A histological evaluation showed that osseous integration had occurred with all implants after 8 weeks. SLAffinity-Ti implants exhibited 28.5 ± 6.2 % bone-to-implant contact (BIC) at 2 weeks and 84.3 ± 8.1 % at 8 weeks. M-Ti implants exhibited BIC levels of 17.0 ± 5.4 and 76.5 ± 6.3 %, whereas SLA-Ti implants exhibited BIC levels of 28.5 ± 6.2 and 81.1 ± 8.4 % at corresponding time intervals. In terms of the peri-implant bone area (BA), values for SLAffinity-Ti implants ranged from 29.5 ± 4.1 to 88.3 ± 3.0 %. For M-Ti implants, values ranged from 20.3 ± 5.5 to 81.7 ± 4.2 %. For SLA-Ti implants, values ranged from 23.0 ± 3.5 to 84.0 ± 3.6 %. Electrochemical oxidation increased the oxide layers and improved the blood interaction with SLAffinity-Ti implants, resulting in significantly higher bone apposition with the SLAffinity-Ti implants after 2 and 8 weeks of healing. An increase in resistance for the RT of SLAffinity-Ti implants over the 8-week healing period was also observed. The use of SLAffinity-Ti implants has potential for improvement of early osseointegration.


Highly active macromolecular prodrugs inhibit expression of the hepatitis C virus genome in the host cells.
Efficacious, potent, and at the same time nontoxic macromolecular prodrugs of ribavirin are designed taking advantage over prodrug activation by the intracellular milieu. Activity of these prodrugs is illustrated in the cells hosting hepatitis C virus replication and also in the cells implicated in the inflammatory response to the viral infection.


Large-scale production of graphene nanoribbons from electrospun polymers.
Graphene nanoribbons (GNRs) are promising building blocks for high-performance electronics due to their high electron mobility and dimensionality-induced bandgap. Despite many past efforts, direct synthesis of GNRs with controlled dimensions and scalability remains challenging. Here we report the scalable synthesis of GNRs using electrospun polymer nanofiber templates. Palladium-incorporated poly(4-vinylphenol) nanofibers were prepared by electrospinning with controlled diameter and orientation. Highly graphitized GNRs as narrow as 10 nm were then synthesized from these templates by chemical vapor deposition. A transport gap can be observed in 30 nm-wide GNRs, enabling them to function as field-effect transistors at room temperature. Our results represent the first success on the scalable synthesis of highly graphitized GNRs from polymer templates. Furthermore, the generality of this method allows various polymers to be explored, which will lead to understanding of growth mechanism and rational control over crystallinity, feature size and bandgap to enable a new pathway for graphene electronics.


Paraoxonase (PON1) polymorphisms Q192R and L55M are not associated with human longevity: A meta-analysis.
Genetic mutations in the paraoxonase 1 (PON1) encoding gene have been considered to affect mortality and of these the functional promoter region polymorphisms Q192R and L55M are among the most widely studied. The aim of this study was to determine whether the Q192R and L55M polymorphisms of PON1 can increase susceptibility to longevity. A meta-analysis was performed to obtain a comprehensive estimation of the association between Q192R and L55M and longevity in long-lived individuals (LLIs) aged 80 years or more. A search was carried out in the PubMed database (from January 2001 to May 2014) to obtain data on the role of PON1 polymorphisms in longevity and a pooled odds ratio (OR) with a 95% confidence interval (CI) was used to assess the associations. The meta-analysis was based on 9 studies of PON1 Q192R and 5 studies of PON1 L55M that covered a total of 5086 LLIs and 4494 controls. Overall, significantly increased risks were not observed for either Q192R or L55M. The results of the statistical calculations were as follows: R vs. Q (additive model): OR = 1.080, 95% CI = 0.989-1.179, p = 0.088 and RR + RQ vs. QQ (dominant model): OR = 1.099, 95% CI = 0.975-1.240, p = 0.124; M vs. L (additive model): OR = 0.946, 95% CI = 0.862-1.039, p = 0.245 and MM + ML vs. LL (dominant model): OR = 0.951, 95% CI = 0.836-1.081, p = 0.442 for Q192R and L55M, respectively. The results did not change with an age cut-off among the LLIs of ≥ 93 years. No evidence that the Q192R and L55M polymorphisms of PON1 impacted on the probability of reaching extreme ages was found although this cannot be completely ruled out; however, the possibility of population-specific effects due to the influence of and interaction between different genes or environmental factors could not be ruled out.


Acute dyskerin depletion triggers cellular senescence and renders osteosarcoma cells resistant to genotoxic stress-induced apoptosis.
Dyskerin is a conserved, nucleolar RNA-binding protein implicated in an increasing array of fundamental cellular processes. Germline mutation in the dyskerin gene (DKC1) is the cause of X-linked dyskeratosis congenita (DC). Conversely, wild-type dyskerin is overexpressed in sporadic cancers, and high-levels may be associated with poor prognosis. It was previously reported that acute loss of dyskerin function via siRNA-mediated depletion slowed the proliferation of transformed cell lines. However, the mechanisms remained unclear. Using human U2OS osteosarcoma cells, we show that siRNA-mediated dyskerin depletion induced cellular senescence as evidenced by proliferative arrest, senescence-associated heterochromatinization and a senescence-associated molecular profile. Senescence can render cells resistant to apoptosis. Conversely, chromatin relaxation can reverse the repressive effects of senescence-associated heterochromatinization on apoptosis. To this end, genotoxic stress-induced apoptosis was suppressed in dyskerin-depleted cells. In contrast, agents that induce chromatin relaxation, including histone deacetylase inhibitors and the DNA intercalator chloroquine, sensitized dyskerin-depleted cells to apoptosis. Dyskerin is a core component of the telomerase complex and plays an important role in telomere homeostasis. Defective telomere maintenance resulting in premature senescence is thought to primarily underlie the pathogenesis of X-linked DC. Since U2OS cells are telomerase-negative, this leads us to conclude that loss of dyskerin function can also induce cellular senescence via mechanisms independent of telomere shortening.


Nanoring structure, spacing, and local dielectric sensitivity for plasmonic resonances in Fano resonant square lattices.
Lattices of plasmonic nanorings with particular geometries exhibit singular, tunable resonance features in the infrared. This work examined effects of nanoring inner radius, wall thickness, and lattice constant on the spectral response of single nanorings and in Fano resonant square lattices, combining use of the discrete and coupled dipole approximations. Increasing nanoring inner radius red-shifted and broadened the localized surface plasmon resonance (LSPR), while wall thickness modulated the LSPR wavelength and decreased absorption relative to scattering. The square lattice constant was tuned to observe diffractively-coupled lattice resonances, which increased resonant extinction 4.3-fold over the single-ring LSPR through Fano resonance. Refractive index sensitivities of 760 and 1075 nm RIU(-1) were computed for the plasmon and lattice resonances of an optimized nanoring lattice. Sensitivity of an optimal nanoring lattice to a local change in dielectric, useful for sensing applications, was 4 to 5 times higher than for isolated nanorings or non-coupling arrays. This was attributable to the Fano line-shape in far-field diffractive coupling with near-field LSPR.


Effects of kinematic complexity and number of muscles on musculoskeletal model robustness to muscle dysfunction.
The robustness of motor outputs to muscle dysfunction has been investigated using musculoskeletal modeling, but with conflicting results owing to differences in model complexity and motor tasks. Our objective was to systematically study how the number of kinematic degrees of freedom, and the number of independent muscle actuators alter the robustness of motor output to muscle dysfunction. We took a detailed musculoskeletal model of the human leg and systematically varied the model complexity to create six models with either 3 or 7 kinematic degrees of freedom and either 14, 26, or 43 muscle actuators. We tested the redundancy of each model by quantifying the reduction in sagittal plane feasible force set area when a single muscle was removed. The robustness of feasible force set area to the loss of any single muscle, i.e. general single muscle loss increased with the number of independent muscles and decreased with the number of kinematic degrees of freedom, with the robust area varying from 1% and 52% of the intact feasible force set area. The maximum sensitivity of the feasible force set to the loss of any single muscle varied from 75% to 26% of the intact feasible force set area as the number of muscles increased. Additionally, the ranges of feasible muscle activation for maximum force production were largely unconstrained in many cases, indicating ample musculoskeletal redundancy even for maximal forces. We propose that ratio of muscles to kinematic degrees of freedom can be used as a rule of thumb for estimating musculoskeletal redundancy in both simulated and real biomechanical systems.


Correspondence between simple 3-D MRI-based computer models and in-vivo EP measurements in swine with chronic infarctions.
The aim of this paper was to compare several in-vivo electrophysiological (EP) characteristics measured in a swine model of chronic infarct, with those predicted by simple 3-D MRI-based computer models built from ex-vivo scans (voxel size <1 mm(3)). Specifically, we recorded electroanatomical voltage maps (EAVM) in six animals, and ECG waves during induction of arrhythmia in two of these cases. The infarct heterogeneities (dense scar and border zone) as well as fiber directions were estimated using diffusion weighted DW-MRI. We found a good correspondence (r = 0.9) between scar areas delineated on the EAVM and MRI maps. For theoretical predictions, we used a simple two-variable macroscopic model and computed the propagation of action potential after application of a train of stimuli, with location and timing replicating the stimulation protocol used in the in-vivo EP study. Simulation results are exemplified for two hearts: one with noninducible ventricular tachycardia (VT), and another with a macroreentrant VT (for the latter, the average predicted VT cycle length was 273 ms, compared to a recorded VT of 250 ms).


Antigenic differences between AS03 adjuvanted influenza A (H1N1) pandemic vaccines: implications for pandemrix-associated narcolepsy risk.
Narcolepsy results from immune-mediated destruction of hypocretin secreting neurons in hypothalamus, however the triggers and disease mechanisms are poorly understood. Vaccine-attributable risk of narcolepsy reported so far with the AS03 adjuvanted H1N1 vaccination Pandemrix has been manifold compared to the AS03 adjuvanted Arepanrix, which contained differently produced H1N1 viral antigen preparation. Hence, antigenic differences and antibody response to these vaccines were investigated. Increased circulating IgG-antibody levels to Pandemrix H1N1 antigen were found in 47 children with Pandemrix-associated narcolepsy when compared to 57 healthy children vaccinated with Pandemrix. H1N1 antigen of Arepanrix inhibited poorly these antibodies indicating antigenic difference between Arepanrix and Pandemrix. High-resolution gel electrophoresis quantitation and mass spectrometry identification analyses revealed higher amounts of structurally altered viral nucleoprotein (NP) in Pandemrix. Increased antibody levels to hemagglutinin (HA) and NP, particularly to detergent treated NP, was seen in narcolepsy. Higher levels of antibodies to NP were found in children with DQB1*06:02 risk allele and in DQB1*06:02 transgenic mice immunized with Pandemrix when compared to controls. This work identified 1) higher amounts of structurally altered viral NP in Pandemrix than in Arepanrix, 2) detergent-induced antigenic changes of viral NP, that are recognized by antibodies from children with narcolepsy, and 3) increased antibody response to NP in association of DQB1*06:02 risk allele of narcolepsy. These findings provide a link between Pandemrix and narcolepsy. Although detailed mechanisms of Pandemrix in narcolepsy remain elusive, our results move the focus from adjuvant(s) onto the H1N1 viral proteins.


The lipid moiety 7-ketocholesteryl-9-carboxynonanoate mediates binding interaction of oxLDL to LOX-1 and upregulates ABCA1 expression through PPARγ.
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a specific membrane receptor for oxidized low-density lipoprotein (oxLDL), plays a crucial role in atherosclerosis progression. The aim of this study was to elucidate the role of 7-ketocholesteryl-9-carboxynonanoate (oxLig-1), a lipid component of oxLDL, in the binding of oxLDL to LOX-1 and to determine whether oxLig-1 binding to LOX-1 is involved in the upregulation of ABCA1 expression. OxLig-1 binding to LOX-1 was analysed by AutoDock 4.2.6 and confirmed by fluorescence immunocytochemistry and enzyme-linked immunosorbent assays (ELISAs). LOX-1, LXRα and ABCA1 protein expression induced by oxLig-1 or methylated oxLig-1 was measured by western blotting. In addition, PPARγ activation was investigated using a dual-luciferase reporter system. Furthermore, the signalling cascade involved in oxLig-1-induced ABCA1 expression was assessed using inhibitors for PPARγ and LXRα and specific siRNAs against LOX-1, PPARγ and LXRα. Docking, fluorescence immunocytochemistry and ELISA analyses showed that oxLig-1 bound LOX-1 and that the ω-carboxyl group was critical for this binding. Moreover, oxLig-1, but not methylated oxLig-1, increased LOX-1, LXRα, and ABCA1 expression. Luciferase reporter assays indicated that oxLig-1 activated PPARγ in the presence of LOX-1. Additionally, the inhibitor and siRNA experiments showed that oxLig-1 triggered the PPARγ-LXRα signalling pathway, leading to upregulation of ABCA1, and that this process required the participation of LOX-1. Our observations indicate that oxLig-1 is a critical epitope of oxLDL that mediates the binding of oxLDL to LOX-1 and initiates PPARγ signal transduction to upregulate the expression of ABCA1.


The economic impact of malignant catarrhal fever on pastoralist livelihoods.
This study is the first to partially quantify the potential economic benefits that a vaccine, effective at protecting cattle against malignant catarrhal fever (MCF), could accrue to pastoralists living in East Africa. The benefits would result from the removal of household resource and management costs that are traditionally incurred avoiding the disease. MCF, a fatal disease of cattle caused by a virus transmitted from wildebeest calves, has plagued Maasai communities in East Africa for generations. The threat of the disease forces the Maasai to move cattle to less productive grazing areas to avoid wildebeest during calving season when forage quality is critical. To assess the management and resource costs associated with moving, we used household survey data. To estimate the costs associated with changes in livestock body condition that result from being herded away from wildebeest calving grounds, we exploited an ongoing MCF vaccine field trial and we used a hedonic price regression, a statistical model that allows estimation of the marginal contribution of a good's attributes to its market price. We found that 90 percent of households move, on average, 82 percent of all cattle away from home to avoid MCF. In doing so, a herd's productive contributions to the household was reduced, with 64 percent of milk being unavailable for sale or consumption by the family members remaining at the boma (the children, women, and the elderly). In contrast cattle that remained on the wildebeest calving grounds during the calving season (and survived MCF) remained fully productive to the family and gained body condition compared to cattle that moved away. This gain was, however, short-lived. We estimated the market value of these condition gains and losses using hedonic regression. The value of a vaccine for MCF is the removal of the costs incurred in avoiding the disease.


The socioeconomic impact of human immunodeficiency virus / acquired immune deficiency syndrome in India and its relevance to eye care.
Human immunodeficiency virus (HIV) infection is aptly called the modern day 'plague' and has the potential to decimate people in the productive age group. On the other hand, the increasing life expectancy in developing countries spirals age-related blindness. One therefore reduces economic productivity while the other increases economic dependency. Both lead to increased expenditure of households though in different proportions. Human immunodeficiency virus and blindness are both associated with discrimination, stigma and long-term consequences. They impact the socioeconomic fabric of the affected individuals, communities and countries. The loss in productivity and the cost of support to the affected individuals are seen in both. Each is a potent problem on its own but together they spell disaster in geometric proportions rather than a simple additive effect. Strategies need to be evolved to provide solace and improve the quality of life of an HIV-positive blind individual.


Acute Illnesses, Use of Health Services, and Changes in Medication Among Parents After Infant or Child Death.
The death of an infant or child has been described as the most stressful life event, but few reports exist on the effects on parents' physical health in the year after the death. To examine acute illnesses, use of health services, and medication changes among parents from 3 racial/ethnic groups 1 to 13 months after the death of an infant or child in the neonatal intensive care unit or pediatric intensive care unit. In a longitudinal study, 96 parents (41% black, 32% Hispanic, 27% white) of deceased infants or children were recruited from 4 children's hospitals and death records. Parents reported demographic information, acute illnesses, health services used, and medication changes 1 to 13 months after the death. Descriptive statistics and 1-way analysis of variance were used to analyze the data. Seventy mothers (age, mean [SD], 35.9 [7.13] years) and 26 fathers (age, 39.0 [7.37] years) participated; 56% of mothers and 42% of fathers had preexisting health problems before the death. Morbidity was greatest in the first 6 months, was relatively quiescent in months 7 through 10, and increased in months 11 through 13. Mothers reported 363 acute illnesses, 16 hospitalizations, and 124 medication changes. Morbidity rates and medication changes for fathers followed similar patterns but with lower frequency. After the death of an infant or child, interventions for parents, especially parents with chronic health problems, are best targeted on illness prevention and mental health in months 1 to 6 and 11 to 13 following the death.


Expression and function of the epithelial sodium channel δ-subunit in human respiratory epithelial cells in vitro.
Using human airway epithelial cell lines (i.e. NCI-H441 and Calu-3) as well as human alveolar epithelial type I-like (ATI) cells in primary culture, we studied the contribution of the epithelial sodium channel δ-subunit (δ-ENaC) to transepithelial sodium transport in human lung in vitro. Endogenous δ-ENaC protein was present in all three cell types tested; however, protein abundance was low, and no expression was detected in the apical cell membrane of these cells. Similarly, known modulators of δ-ENaC activity, such as capsazepine and icilin (activators) and Evans blue (inhibitor), did not show effects on short-circuit current (I SC), suggesting that δ-ENaC is not involved in the modulation of transcellular sodium absorption in NCI-H441 cell monolayers. Over-expression of δ-ENaC in NCI-H441 cells resulted in detectable protein expression in the apical cell membrane, as well as capsazepine and icilin-stimulated increases in I SC that were effectively blocked by Evans blue and that were consistent with δ-ENaC activation and inhibition, respectively. Consequently, these observations suggest that δ-ENaC expression is low in NCI-H441, Calu-3, and ATI cells and does not contribute to transepithelial sodium absorption.


Genetic Dissection of Grain Yield and Agronomic Traits in Maize under Optimum and Low-Nitrogen Stressed Environments.
Understanding the genetic basis of maize grain yield and other traits under low-nitrogen (N) stressed environments could improve selection efficiency. In this study, five doubled haploid (DH) populations were evaluated under optimum and N-stressed conditions, during the main rainy season and off-season in Kenya and Rwanda, from 2014 to 2015. Identifying the genomic regions associated with grain yield (GY), anthesis date (AD), anthesis-silking interval (ASI), plant height (PH), ear height (EH), ear position (EPO), and leaf senescence (SEN) under optimum and N-stressed environments could facilitate the use of marker-assisted selection to develop N-use-efficient maize varieties. DH lines were genotyped with genotyping by sequencing. A total of 13, 43, 13, 25, 30, 21, and 10 QTL were identified for GY, AD ASI, PH, EH, EPO, and SEN, respectively. For GY, PH, EH, and SEN, the highest number of QTL was found under low-N environments. No common QTL between optimum and low-N stressed conditions were identified for GY and ASI. For secondary traits, there were some common QTL for optimum and low-N conditions. Most QTL conferring tolerance to N stress was on a different chromosome position under optimum conditions.


Adherence to diaphragm use for infection prevention: a prospective study of female sex workers in Kenya.
To assess adherence to and acceptability of the diaphragm among 140 female sex workers in Kenya in a 6-month prospective study. At baseline and bimonthly visits, participants were interviewed on diaphragm knowledge, attitude, and practices. We used principal component analysis and logistic regression to identify predictors of consistent use. At 50% of 386 bimonthly visits, women reported consistently using a diaphragm with all partners during the preceding 2 weeks. Consistent use was significantly higher at the 6-month than the 2-month visit. Women reported less covert use with "helping" (regular sex partners to whom she could go for help or support) than with "other" partners. Perceptions that diaphragms are easier to use than condoms and that their lack of coital interruption is important were associated with consistent diaphragm use with both partner types. Partner support of diaphragm use is correlated with consistent use with "helping" partners only while higher parity, consistent condom use, and perceived lack of need of condoms as a benefit of diaphragms were associated with consistent use with "other" partners. Diaphragm acceptance among female sex workers in Nairobi was high. Future studies should distinguish between partner types when evaluating diaphragm adherence.


A study on neural learning on manifold foliations: the case of the Lie group SU(3).
Learning on differential manifolds may involve the optimization of a function of many parameters. In this letter, we deal with Riemannian-gradient-based optimization on a Lie group, namely, the group of unitary unimodular matrices SU(3). In this special case, subalgebras of the associated Lie algebra su(3) may be individuated by computing pair-wise Gell-Mann matrices commutators. Subalgebras generate subgroups of a Lie group, as well as manifold foliation. We show that the Riemannian gradient may be projected over tangent structures to foliation, giving rise to foliation gradients. Exponentiations of foliation gradients may be computed in closed forms, which closely resemble Rodriguez forms for the special orthogonal group SO(3). We thus compare optimization by Riemannian gradient and foliation gradients.


Agriculture versus wastewater pollution as drivers of macroinvertebrate community structure in streams.
Water pollution is ubiquitous globally, yet how the effects of pollutants propagate through natural ecosystems remains poorly understood. This is because the interactive effects of multiple stressors are generally hard to predict. Agriculture and municipal wastewater treatment plants (WWTPs) are often major sources of contaminants for streams, but their relative importance and the role of different pollutants (e.g. nutrients or pesticides) are largely unknown. Using a 'real world experiment' with sampling locations up- and downstream of WWTPs, we studied how effluent discharges affected water quality and macroinvertebrate communities in 23 Swiss streams across a broad land-use gradient. Variation partitioning of community composition revealed that overall water quality explained approximately 30% of community variability, whereby nutrients and pesticides each independently explained 10% and 2%, respectively. Excluding oligochaetes (which were highly abundant downstream of the WWTPs) from the analyses, resulted in a relatively stronger influence (3%) of pesticides on the macroinvertebrate community composition, whereas nutrients had no influence. Generally, the macroinvertebrate community composition downstream of the WWTPs strongly reflected the upstream conditions, likely due to a combination of efficient treatment processes, environmental filtering and organismal dispersal. Wastewater impacts were most prominently by the Saprobic index, whereas the SPEAR index (a trait-based macroinvertebrate metrics reflecting sensitivity to pesticides) revealed a strong impact of arable cropping but only a weak impact of wastewater. Overall, our results indicate that agriculture can have a stronger impact on headwater stream macroinvertebrate communities than discharges from WWTP. Yet, effects of wastewater-born micropollutants were clearly quantifiable among all other influence factors. Improving our ability to further quantify the impacts of micropollutants requires highly-resolved water quality and taxonomic data with adequate spatial and temporal sampling. These improvements would help to better account for the underlying causal pathways that drive observed biological responses, such as episodic contaminant peaks and dispersal-related processes.


Stripes, topological order, and deconfinement in a planar t-Jz model.
We determine the quantum phase diagram of a two-dimensional bosonic t-Jz model as a function of the lattice anisotropy gamma, using a quantum Monte Carlo loop algorithm. We show analytically that the low-energy sectors of the bosonic and the fermionic t-Jz models become equivalent in the limit of small gamma. In this limit, the ground state represents a static stripe phase characterized by a nonzero value of a topological order parameter. This phase remains up to intermediate values of gamma, where there is a quantum phase transition to a phase-segregated state or a homogeneous superfluid with dynamic stripe fluctuations depending on the ratio Jz/t.


Array-based comparative genomic hybridization analysis identified cyclin D1 as a target oncogene at 11q13.3 in nasopharyngeal carcinoma.
Nasopharyngeal carcinoma is highly prevalent in Southern China and Southeast Asia. To unveil the molecular basis of this endemic disease, high-resolution comparative genomic hybridization arrays were used for systematic investigation of genomic abnormalities in 26 nasopharyngeal carcinoma samples. A comprehensive picture of genetic lesions associated with tumorigenesis of nasopharyngeal carcinoma was generated. Consistent chromosomal gains were frequently found on 1q, 3q, 8q, 11q, 12p, and 12q. High incidences of nonrandom losses were identified on chromosomes 3p, 9p, 11q, 14q, and 16q. In addition to previously characterized regions, we have identified several novel minimal regions of gains, including 3q27.3-28, 8q21-24, 11q13.1-13.3, and 12q13, which may harbor candidate nasopharyngeal carcinoma-associated oncogenes. In this study, gain of 11q13.1-13.3 was the most frequently detected chromosomal aberration and a 5.3-Mb amplicon was delineated at this region. Within this 11q13 amplicon, concordant amplification and overexpression of cyclin D1 (CCND1) oncogene was found in nasopharyngeal carcinoma cell lines, xenografts, and primary tumors. Knockdown of cyclin D1 by small interfering RNA in nasopharyngeal carcinoma cell lines led to significant decrease of cell proliferation. The findings suggest that cyclin D1 is a target oncogene at 11q13 in nasopharyngeal carcinoma and its activation plays a significant role in nasopharyngeal carcinoma tumorigenesis.


Low-dose protocol for head CT in monitoring hydrocephalus in children.
Children with hydrocephalus and increased intracranial pressure are treated with ventricular shunts. Multiple head CT is used to assess shunt malfunction and changes in ventricular size (volume). Because of the naturally high contrast of the head structures in CT imaging, a low-dose protocol for hydrocephalic pediatric patients was proposed. The aim of the study was to assess the implemented protocol in categories of radiation risk to the patients. Head CT examinations were performed using the fourth-generation single-slice scanner PQ-2000 (Picker). Exposure parameters of the routine head procedure stored in the scanner software were the starting point for the investigation. The acceptable ranges of the modified parameters were found on the basis of earlier published results. The effect of the new protocol on image quality was tested using a CATPHAN phantom. The organ doses were evaluated experimentally. The clinical images were evaluated by two experienced and independent radiologists. Head CT examinations were performed in 380 children with hydrocephalus during a 10-year period at the Department of Diagnostic Imaging Polish Mother's Memorial Hospital. Until 2005 these children were examined according to the routine protocol of the scanner, i.e. 10 mm contiguous axial, 120 kVp, and 225 mAs. Then the protocol was modified to 10 mm contiguous axial, 100 kVp, and 150 mAs. Reductions in patient doses to 70% were found while the clinical images maintained sufficient diagnostic value. The low-dose protocol for head CT can be recommended for the monitoring of pediatric hydrocephalus patients.


Does blood rheology revert to normal after myocardial infarction?
After myocardial infarction there is an acute deterioration of the flow properties of blood. The present study was designed to test whether the abnormality persists. Blood and plasma viscosity, red cell aggregation and deformability, haematocrit, erythrocyte sedimentation rate, white cell count, cholesterol, and triglycerides were measured in 51 patients who had had a myocardial infarction 5.4 (mean) years before. Results in patients and controls were compared and matched pairs with identical cardiovascular risk factors were also selected. Blood viscosity and red cell aggregation were increased and red cell deformability was decreased in the 51 patients. The abnormalities were independent of the interval since infarction and persisted for years. The rheological abnormalities present after myocardial infarction are at least partly independent of the acute event and acute phase reactions. They contribute to the reduced perfusion of the microcirculation of the heart.


Kernelized Z' factor in multiparametric screening technology.
RNA interference (RNAi) high-content screening (HCS) enables massive parallel gene silencing and is increasingly being used to reveal novel connections between genes and disease-relevant phenotypes. The application of genome-scale RNAi relies on the development of high quality HCS assays. The Z' factor statistic provides a way to evaluate whether or not screening run conditions (reagents, protocols, instrumentation, kinetics, and other conditions not directly related to the test compounds) are optimized. Z' factor, introduced by Zhang et al. (1), is a dimensionless value that represents both the variability and the dynamic range between two sets of sample control data. This paper describes a new extension of the Z' factor, which integrates multiple readouts for screening quality assessment. Currently presented multivariate Z' factor is based on linear projection, which may not be suitable for data with nonlinear structure. This paper proposes an algorithm which extends existing algorithm to deal with nonlinear data by using the kernel function. Using kernel methods for projections, multiple readouts are condensed to a single parameter, based on which the screening run quality is monitored.


Pilot Test of an Adapted Intervention to Improve Timeliness of Referrals to Hospice and Palliative Care for Eligible Home Health Patients.
Background: Casarett et al. tested an intervention to improve timeliness of referrals to hospice. Although efficacious in the nursing home setting, it was not tested in other settings of care for seriously ill patients. We, therefore, adapted Casarett's intervention for use in home health (HH). Objective: To assess feasibility, acceptability, and patient outcomes of the adapted intervention. Design: We conducted a nine-week observational pilot test. Setting/Subjects: We conducted our pilot study with two HH agencies. Eligible patients included those who were high risk or frail (identified by the agencies' analytic software as being moderate to high risk for hospitalization or a candidate for hospice referral). Clinical managers identified eligible patients and registered nurses then delivered the intervention, screening patients for hospice appropriateness by asking about care goals, needs, and preferences and initiating appropriate follow-up for patients who screened positive. Measurements: We collected quantitative data on patient enrollment rates and outcomes (election of hospice and/or palliative care). We collected qualitative data on pilot staff experience with the intervention and suggestions for improvement. Results: Pilot HH agencies were able to implement the intervention with high fidelity with minimal restructuring of workflows; 14% of patients who screened positive for hospice appropriateness elected hospice or palliative care. Conclusions: Our findings suggest the adapted intervention was feasible and acceptable to enhance timeliness of hospice and palliative care referral in the HH setting. Additional adaptations suggested by pilot participants could improve impact of the intervention.


The effect of different types of insoles or shoe modifications on medial loading of the knee in persons with medial knee osteoarthritis: a randomised trial.
Many conservative treatments exist for medial knee osteoarthritis (OA) which aims to reduce the external knee adduction moment (EKAM). The objective of this study was to determine the difference between different shoes and lateral wedge insoles on EKAM, knee adduction angular impulse (KAAI), external knee flexion moment, pain, and comfort when walking in individuals with medial knee OA. Seventy individuals with medial knee OA underwent three-dimensional walking gait analysis in five conditions (barefoot, control shoe, typical wedge, supported wedge, and mobility shoe) with pain and comfort recorded concurrently. The change in EKAM, KAAI, external knee flexion moment, pain, and comfort were assessed using multiple linear regressions and pairwise comparisons. Compared with the control shoe, lateral wedge insoles and barefoot walking significantly reduced early stance EKAM and KAAI. The mobility shoe showed no effect. A significant reduction in latter stance EKAM was seen in the lateral wedge insoles compared to the other conditions, with only the barefoot condition reducing the external knee flexion moment. However, the mobility shoe showed significant immediate knee pain reduction and improved comfort scores. Different lateral wedge insoles show comparable reductions in medial knee loading and in our study, the mobility shoe did not affect medial loading.


The first three years of buprenorphine in the United States: experience to date and future directions.
Buprenorphine, primarily as the buprenorphine/naloxone combination, has been available in the United States for office and specialty treatment program-based care since 2003. The existing evidence, collected primarily from federal sources, indicates that access to this type of treatment has expanded, that more than 50% of the 12,000 physicians able to provide this care are not addiction specialists, that buprenorphine diversion is low, that physician scrutiny by federal agents is infrequent, and among those receiving treatment patient acceptance is high. Implementation has been slowed because of physician training and support needs, reimbursement, and limits on the number of patients each physician can treat. As a result there are geographic variations in access and unmet treatment needs. The United States Congress has moved twice to loosen numerical limitations, now allowing each physician to treat up to 100 patients. Future research and evaluation are needed to ensure that opioid-dependent patients receive optimal care with buprenorphine.


Prognostic Value of Stress CMR Perfusion Imaging in Patients With Reduced Left Ventricular Function.
The aim of this study was to investigate the prognostic value of stress cardiac magnetic resonance imaging (CMR) in patients with reduced left ventricular (LV) systolic function. Patients with ischemic cardiomyopathy are at risk from both myocardial ischemia and heart failure. Invasive testing is often used as the first-line investigation, and there is limited evidence as to whether stress testing can effectively provide risk stratification. In this substudy of a multicenter registry from 13 U.S. centers, patients with reduced LV ejection fraction (<50%), referred for stress CMR for suspected myocardial ischemia, were included. The primary outcome was cardiovascular death or nonfatal myocardial infarction. The secondary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, hospitalization for unstable angina or congestive heart failure, and unplanned late coronary artery bypass graft surgery. Among 582 patients (mean age 62 ± 12 years, 34% women), 40% had a history of congestive heart failure, and the median LV ejection fraction was 39% (interquartile range: 28% to 45%). At median follow-up of 5.0 years, 97 patients had experienced the primary outcome, and 182 patients had experienced the secondary outcome. Patients with no CMR evidence of ischemia or late gadolinium enhancement (LGE) experienced an annual primary outcome event rate of 1.1%. The presence of ischemia, LGE, or both was associated with higher event rates. In a multivariate model adjusted for clinical covariates, ischemia and LGE were independent predictors of the primary (hazard ratio [HR]: 2.63; 95% confidence interval [CI]: 1.68 to 4.14; p < 0.001; and HR: 1.86; 95% CI: 1.05 to 3.29; p = 0.03) and secondary (HR: 2.14; 95% CI: 1.55 to 2.95; p < 0.001; and HR 1.70; 95% CI: 1.16 to 2.49; p = 0.007) outcomes. The addition of ischemia and LGE led to improved model discrimination for the primary outcome (change in C statistic from 0.715 to 0.765; p = 0.02). The presence and extent of ischemia were associated with higher rates of use of downstream coronary angiography, revascularization, and cost of care spent on ischemia testing. Stress CMR was effective in risk-stratifying patients with reduced LV ejection fractions. (Stress CMR Perfusion Imaging in the United States [SPINS] Study; NCT03192891).


A functional genomics approach to establish the complement of carbohydrate transporters in Streptococcus pneumoniae.
The aerotolerant anaerobe Streptococcus pneumoniae is part of the normal nasopharyngeal microbiota of humans and one of the most important invasive pathogens. A genomic survey allowed establishing the occurrence of twenty-one phosphotransferase systems, seven carbohydrate uptake ABC transporters, one sodium:solute symporter and a permease, underlining an exceptionally high capacity for uptake of carbohydrate substrates. Despite high genomic variability, combined phenotypic and genomic analysis of twenty sequenced strains did assign the substrate specificity only to two uptake systems. Systematic analysis of mutants for most carbohydrate transporters enabled us to assign a phenotype and substrate specificity to twenty-three transport systems. For five putative transporters for galactose, pentoses, ribonucleosides and sulphated glycans activity was inferred, but not experimentally confirmed and only one transport system remains with an unknown substrate and lack of any functional annotation. Using a metabolic approach, 80% of the thirty-two fermentable carbon substrates were assigned to the corresponding transporter. The complexity and robustness of sugar uptake is underlined by the finding that many transporters have multiple substrates, and many sugars are transported by more than one system. The present work permits to draw a functional map of the complete arsenal of carbohydrate utilisation proteins of pneumococci, allows re-annotation of genomic data and might serve as a reference for related species. These data provide tools for specific investigation of the roles of the different carbon substrates on pneumococcal physiology in the host during carriage and invasive infection.


Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.
Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P<10-6). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.


Maternal health-related quality of life after induction of labor or expectant monitoring in pregnancy complicated by intrauterine growth retardation beyond 36 weeks.
Pregnancies complicated by intrauterine growth retardation (IUGR) beyond 36 weeks of gestation are at increased risk of neonatal morbidity and mortality. Optimal treatment in IUGR at term is highly debated. Results from the multicenter DIGITAT (Disproportionate Intrauterine Growth Intervention Trial At Term) trial show that induction of labor and expectant monitoring result in equal neonatal and maternal outcomes for comparable cesarean section rates. We report the maternal health-related quality of life (HR-QoL) that was measured alongside the trial at several points in time. Both randomized and non-randomized women were asked to participate in the HR-QoL study. Women were asked to fill out written validated questionnaires, covering background characteristics, condition-specific issues and the Short Form (SF-36), European Quality of Life (EuroQoL 6D3L), Hospital Anxiety and Depression scale (HADS), and Symptom Check List (SCL-90) at baseline, 6 weeks postpartum and 6 months postpartum. We compared the difference scores of all summary measures between the two management strategies by ANOVA. A repeated measures multivariate mixed model was defined to assess the effect of the management strategies on the physical (PCS) and mental (MCS) components of the SF-36. Analysis was by intention to treat. We analyzed data of 361 randomized and 198 non-randomized patients. There were no clinically relevant differences between the treatments at 6 weeks or 6 months postpartum on any summary measures; e.g., on the SF-36 (PCS: P = .09; MCS: P = .48). The PCS and the MCS were below norm values at inclusion. The PCS improved over time but stayed below norm values at 6 months, while the MCS did not improve. In pregnancies complicated by IUGR beyond 36 weeks, induction of labor does not affect the long-term maternal quality of life.


Clinical presentation of atopic dermatitis by filaggrin gene mutation status during the first 7 years of life in a prospective cohort study.
Filaggrin null mutations result in impaired skin barrier functions, increase the risk of early onset atopic dermatitis and lead to a more severe and chronic disease. We aimed to characterize the clinical presentation and course of atopic dermatitis associated with filaggrin mutations within the first 7 years of life. The COPSAC cohort is a prospective, clinical birth cohort study of 411 children born to mothers with a history of asthma followed during their first 7 years of life with scheduled visits every 6 months, as well as visits for acute exacerbations of dermatitis. Atopic dermatitis was defined in accordance with international guidelines and described at every visit using 35 predefined localizations and 10 different characteristics. A total of 170 (43%) of 397 Caucasian children developed atopic dermatitis. The R501X and/or 2282del4 filaggrin null mutations were present in 26 (15%) of children with atopic dermatitis and were primarily associated with predilection to exposed skin areas (especially the cheeks and back of the hands) and an up-regulation of both acute and chronic dermatitis. Furthermore, we found the filaggrin mutations to be associated with a higher number of unscheduled visits (3.6 vs. 2.7; p=0.04) and more severe (moderate-severe SCORAD 44% vs. 31%; p=0.14), and widespread dermatitis (10% vs. 6% of the body area, p<0.001) with an earlier age at onset (246 vs. 473 days, p<0.0001) compared to wild-type. In children, filaggrin mutations seem to define a specific endotype of atopic dermatitis primarily characterized by predilection to exposed areas of the body, in particular hands and cheeks, and an up-regulation in both acute and chronic morphological markers. Secondary, this endotype is characterized by an early onset of dermatitis and a more severe course, with more generalized dermatitis resulting in more frequent medical consultations.


Cleavage of rRNA ensures translational cessation in sperm at fertilization.
Intact ribosomal RNAs (rRNAs) comprise the majority of somatic transcripts, yet appear conspicuously absent in spermatozoa, perhaps reflecting cytoplasmic expulsion during spermatogenesis. To discern their fate, total RNA retained in mature spermatozoa from three fertile donors was characterized by Next Generation Sequencing. In all samples, >75% of total sequence reads aligned to rRNAs. The distribution of reads along the length of these transcripts exhibited a high degree of non-uniformity that was reiterated between donors. The coverage of sequencing reads was inversely correlated with guanine-cytosine (GC)-richness such that sequences greater than ∼70% GC were virtually absent in all sperm RNA samples. To confirm the loss of sequence, the relative abundance of specific regions of the 28S transcripts in sperm was established by 7-Deaza-2'-deoxy-guanosine-5'-triphosphate RT-PCR. The inability to amplify specific regions of the 28S sequence from sperm despite the abundant representation of this transcript in the sequencing libraries demonstrates that approximately three-quarters of RNA retained in the mature male gamete are products of rRNA fragmentation. Hence, cleavage (not expulsion of the RNA component of the translational machinery) is responsible for preventing spurious translation following spermiogenesis. These results highlight the potential importance of those transcripts, including many mRNAs, which evade fragmentation and remain intact when sperm are delivered at fertilization. Sequencing data are deposited in GEO as: GSE29160.


Onychomatricoma: an unusual case of ungual pathology. Case report and review of the literature.
Onychomatricoma represents a rare fibro-epithelial nail bed tumour. Numerous clinical variants of the condition have been described, and explicit diagnostic criteria have been recently developed. In this article, we outline the clinical and histopathological features of a case of onychomatricoma and review the literature with regards to the clinical presentation, differential diagnosis and management.


Functional morphology and developmental biology of zebrafish: reciprocal illumination from an unlikely couple.
Functional morphology has benefited greatly from the input of techniques and thinking from other disciplines. This has been especially productive in situations where each discipline has made significant contributions to a particular research topic. A combination of methodologies from functional morphology and developmental biology has allowed us to characterize feeding mechanics of first-feeding larval zebrafish (Danio rerio). Contrary to kinematic patterns commonly seen in adult teleosts, larval zebrafish showed no lateral abduction during the expansive phase of a suction-feeding event. Instead, dorsoventral expansion of the buccal chamber, more typical of patterns seen in primitive fishes, characterized the expansive phase. Moreover, a pronounced preparatory phase during which the buccal chamber is constricted by the protractor hyoideus was consistently seen in first-feeding larval kinematics. Key kinematic variables associated with first feeding correlated significantly with the hydrodynamic regime as measured by the Reynolds number. Using the tools of both functional morphology and developmental biology we have not only determined which cranial muscles are important for successful feeding but also uncovered important physiological differences in muscle structure. Muscles necessary for the rapid dorsoventral expansion of the head are composed primarily of fast-twitch fibers while those involved in more tonic contractions such as hyoid protraction have more slow-twitch muscle fibers. While most evolutionary developmental studies have examined mechanisms responsible for large evolutionary changes in morphology, we propose that the type of data uncovered in functional studies can lead to the generation of hypotheses concerning the developmental mechanisms responsible for smaller intra- and/or interspecific changes.


Trade-offs between public and private coverage for low-income children have implications for future policy debates.
Much of the discussion around the Affordable Care Act has focused on likely changes in coverage and access to care for adults. However, the law also alters coverage options for many low-income children. We used data from the new Health Reform Monitoring Survey Child Supplement to examine access to care and related outcomes for low-income publicly and privately insured children. We found that over 90 percent of low-income insured children had a usual source of care and had parents who were confident that their children could get the health care they need, regardless of their type of coverage. However, on a variety of cost-related measures, including difficulty paying the child's medical bills, out-of-pocket expenses, and satisfaction with health insurance premiums and copayments, children with Medicaid or the Children's Health Insurance Program (CHIP) fared better than those with employer-sponsored insurance. These results have implications for debates about the future of CHIP and other policies that affect public and private coverage options available to children and families.


AAA domains and organization of the dynein motor unit.
Dyneins contain one-three microtubule motor units that are each derived from the C-terminal globular head of a heavy chain. The N-terminal regions of the heavy chains form stems that are required for intra-dynein associations. The microtubule-binding sites are located at the terminus of a short stalk that emanates from each globular head. Recent electron microscopic analysis indicates that the dynein head has a heptameric toroidal organization. This finding is echoed by the identification of six AAA (ATPases associated with cellular activities) domains and a seventh unrelated unit within this heavy chain region. At least two of these AAA domains can bind nucleotide, although only one appears able to hydrolyze ATP. Several other AAA domain proteins exhibit a similar annular organization of six AAA units. Detailed structural information is available for several AAA proteins, including N-ethylmaleimide-sensitive vesicle-fusion protein and the RuvB motor involved in DNA migration and resolution of Holliday junctions. The resulting structural parallels allow intriguing predictions to be made concerning dynein organization and motor function.


Domestic violence: diurnal mismatch between need and availability of services.
To determine whether a diurnal discordance exists between need and availability of services for victims of domestic violence. A consecutive sample of women presenting to a municipal hospital ED with physical injuries suspected to be related to domestic violence were entered into a registry. Date and time of presentation and perceived need for services information were collected from all patients who answered affirmatively a screening question for domestic violence and whose conditions did not preclude administration of the data collection instrument. The Social Service Departments of all of the 53 911-receiving hospitals in New York City were contacted to ascertain availability of social services for victims of domestic violence by time of day. Twenty-eight of 32 (88%; 95% CI: 71%, 97%) victims of domestic violence presented to the ED during hours other than weekday 9 AM to 5 PM. Of these, 63% desired counseling, 32% lacked a safe place to go, and 82% had children. Of those who had children, 48% were concerned for the children's safety. In-hospital social services were universally available weekday daytime (9 AM to 5 PM) but were available in only 11% of hospital (95% CI: 4%, 23%) at other times. Approximately nine of ten victims of domestic violence presented to the ED during hours when only about one hospital in ten can provide the special services these patients require. A marked diurnal mismatch appears to exist between availability of domestic violence services in New York City and the need for these services as measured by a representative sample drawn from an ED population.


Ascaridia galli in chickens: intestinal localization and comparison of methods to isolate the larvae within the first week of infection.
This study was conducted to observe the localization and to compare methods for isolation of minute Ascaridia galli larvae in chicken intestine. Firstly, six 7-week-old layer pullets were orally infected with 2,000 embryonated A. galli eggs and necropsied either at 3, 5 or 7 days post infection (dpi). More than 95 % of the recovered larvae were obtained from the anterior half of the jejunoileum, suggesting this part as the initial predilection site for A. galli larvae. Secondly, the intestinal wall of one layer pullet infected with 20,000 A. galli eggs 3 days earlier was digested in pepsin-HCl for 90 min. The initial 10 min of digestion released 51 % of the totally recovered larvae and the last 30 min of continuous digestion yielded only 5 %. This indicates that the majority of larvae were located superficially in the intestinal mucosa. Thirdly, 48 7-week-old layer pullets were infected with 500 A. galli eggs and necropsied at 3 dpi to compare three different larval isolation methods from the intestinal wall, viz., EDTA incubation, agar-gel incubation and pepsin-HCl digestion, resulting in mean percentages of the recovered larvae: 14.4, 18.2 and 20.0 %, respectively (P = 0.15). As conclusion, we recommended Pepsin-HCl digestion as the method of choice for larval recovery from the intestinal wall in future population dynamics study due to high efficiency and quick and simple detection. The agar-gel method was considered to be a prerequisite for molecular and immunological investigations as the larvae were more active and fully intact.


Synaptic long-term potentiation and depression in the rat medial vestibular nuclei depend on neural activation of estrogenic and androgenic signals.
Estrogenic and androgenic steroids can be synthesised in the brain and rapidly modulate synaptic transmission and plasticity through direct interaction with membrane receptors for estrogens (ERs) and androgens (ARs). We used whole cell patch clamp recordings in brainstem slices of male rats to explore the influence of ER and AR activation and local synthesis of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) on the long-term synaptic changes induced in the neurons of the medial vestibular nucleus (MVN). Long-term depression (LTD) and long-term potentiation (LTP) caused by different patterns of high frequency stimulation (HFS) of the primary vestibular afferents were assayed under the blockade of ARs and ERs or in the presence of inhibitors for enzymes synthesizing DHT (5α-reductase) and E2 (P450-aromatase) from testosterone (T). We found that LTD is mediated by interaction of locally produced androgens with ARs and LTP by interaction of locally synthesized E2 with ERs. In fact, the AR block with flutamide prevented LTD while did not affect LTP, and the blockade of ERs with ICI 182,780 abolished LTP without influencing LTD. Moreover, the block of P450-aromatase with letrozole not only prevented the LTP induction, but inverted LTP into LTD. This LTD is likely due to the local activation of androgens, since it was abolished under blockade of ARs. Conversely, LTD was still induced in the presence of finasteride the inhibitor of 5α-reductase demonstrating that T is able to activate ARs and induce LTD even when DHT is not synthesized. This study demonstrates a key and opposite role of sex neurosteroids in the long-term synaptic changes of the MVN with a specific role of T-DHT for LTD and of E2 for LTP. Moreover, it suggests that different stimulation patterns can lead to LTD or LTP by specifically activating the enzymes involved in the synthesis of androgenic or estrogenic neurosteroids.


Analysis of Iterative Screening with Stepwise Compound Selection Based on Novartis In-house HTS Data.
With increased automation and larger compound collections, the development of high-throughput screening (HTS) started replacing previous approaches in drug discovery from around the 1980s onward. However, even today it is not always appropriate, or even feasible, to screen large collections of compounds in a particular assay. Here, we present an efficient method for iterative screening of small subsets of compound libraries. With this method, the retrieval of active compounds is optimized using their structural information and biological activity fingerprints. We validated this approach retrospectively on 34 Novartis in-house HTS assays covering a wide range of assay biology, including cell proliferation, antibacterial activity, gene expression, and phosphorylation. This method was employed to retrieve subsets of compounds for screening, where selected hits from any given round of screening were used as starting points to select chemically and biologically similar compounds for the next iteration. By only screening ∼1% of the full screening collection (∼15 000 compounds), the method consistently retrieves diverse compounds belonging to the top 0.5% of the most active compounds for the HTS campaign. For most of the assays, over half of the compounds selected by the method were found to be among the 5% most active compounds of the corresponding full-deck HTS. In addition, the stringency of the iterative method can be modified depending on the number of compounds one can afford to screen, making it a flexible tool to discover active compounds efficiently.


Improvement of Light Extraction Efficiency in Flip-Chip Light Emitting Diodes on SiC Substrate via Transparent Haze Films with Morphology-Controlled Collapsed Alumina Nanorods.
We demonstrate GaN-based flip-chip light emitting diodes (FC-LEDs) on SiC substrate achieving high extraction efficiency by simply attaching the optically transparent haze films consisting of collapsed alumina nanorods. Through controlled etching time of alumina nanorods, we obtain four types of films that have different morphologies with different optical transmittance and haze properties. We show that the light output power of the FC-LEDs with film, which has 95.6% transmittance and 62.7% haze, increases by 20.4% in comparison to the bare LEDs. The angular radiation pattern of the LEDs also follows the Lambertian emission pattern without deteriorating the electrical properties of the device. The improvement of light extraction is mainly attributed to the reduced total internal reflection (TIR) via efficient out-coupling of guided light from SiC substrate to air by collapsed alumina nanorod structures in the film. The high transparency of film and reduced Fresnel reflection via graded refractive index transition between the film and SiC substrate also contribute to the extraction enhancement of the device. We systematically investigate the influence of haze film's geometrical or optical properties on the extraction efficiency of FC-LEDs, and this study will provide a novel approach to enhance the performance of various optoelectronic devices.


BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma.
Melanoma is the most lethal form of skin cancer, and the incidence and mortality rates are rapidly rising. Epidemiologically, high numbers of nevi (moles) are associated with higher risk of melanoma . The majority of melanomas exhibit activating mutations in the serine/threonine kinase BRAF . BRAF mutations may be critical for the initiation of melanoma ; however, the direct role of BRAF in nevi and melanoma has not been tested in an animal model. To directly test the role of activated BRAF in nevus and melanoma development, we have generated transgenic zebrafish expressing the most common BRAF mutant form (V600E) under the control of the melanocyte mitfa promoter. Expression of mutant, but not wild-type, BRAF led to dramatic patches of ectopic melanocytes, which we have termed fish (f)-nevi. Remarkably, in p53-deficient fish, activated BRAF induced formation of melanocyte lesions that rapidly developed into invasive melanomas, which resembled human melanomas and could be serially transplanted. These data provide direct evidence that BRAF activation is sufficient for f-nevus formation, that BRAF activation is among the primary events in melanoma development, and that the p53 and BRAF pathways interact genetically to produce melanoma.


Nonmedical information seeking amid conflicting health information: negative and positive effects on prostate cancer screening.
This study investigates the impact of seeking information about the prostate-specific antigen (PSA) test on men's PSA test use during a period of conflicting recommendations. Analyses used longitudinal survey data collected in 2005 and 2006 from a nationally representative sample of U.S. males aged 40-70 years (n = 777). Cross-sectionally, nonmedical information seeking was significantly associated with increased odds of having a PSA test in the past year (Time 1 odds ratio [OR] = 9.74, p < .01, 95% confidence interval [CI] = 4.37, 21.70; Time 2 OR = 5.78, p < .01, 95% CI = 3.17, 10.55). However, lagged analyses showed that among men who had a PSA at Time 1, active seeking is associated with reduced odds of later having a PSA test (OR = 0.33, p < .05, 95% CI = 0.13, 0.85). Participants who had not had a PSA test in the past year very rarely sought information about PSA tests. Information acquisition in an environment of conflicting recommendations may influence adoption of cancer screening behaviors.


Characterization of a Dopamine Transporter and Its Splice Variant Reveals Novel Features of Dopaminergic Regulation in the Honey Bee.
Dopamine is an important neuromodulator involved in reward-processing, movement control, motivational responses, and other aspects of behavior in most animals. In honey bees (Apis mellifera), the dopaminergic system has been implicated in an elaborate pheromonal communication network between individuals and in the differentiation of females into reproductive (queen) and sterile (worker) castes. Here we have identified and characterized a honey bee dopamine transporter (AmDAT) and a splice variant lacking exon 3 (AmDATΔex3). Both transcripts are present in the adult brain and antennae as well as at lower levels within larvae and ovaries. When expressed separately in the Xenopus oocyte system, AmDAT localizes to the oocyte surface whereas the splice variant is retained at an internal membrane. Oocytes expressing AmDAT exhibit a 12-fold increase in the uptake of [3H]dopamine relative to non-injected oocytes, whereas the AmDATΔex3-expressing oocytes show no change in [3H]dopamine transport. Electrophysiological measurements of AmDAT activity revealed it to be a high-affinity, low-capacity transporter of dopamine. The transporter also recognizes noradrenaline as a major substrate and tyramine as a minor substrate, but does not transport octopamine, L-Dopa, or serotonin. Dopamine transport via AmDAT is inhibited by cocaine in a reversible manner, but is unaffected by octopamine. Co-expression of AmDAT and AmDATΔex3 in oocytes results in a substantial reduction in AmDAT-mediated transport, which was also detected as a significant decrease in the level of AmDAT protein. This down-regulatory effect is not attributable to competition with AmDATΔex3 for ER ribosomes, nor to a general inhibition of the oocyte's translational machinery. In vivo, the expression of both transcripts shows a high level of inter-individual variability. Gene-focused, ultra-deep amplicon sequencing detected methylation of the amdat locus at ten 5'-C-phosphate-G-3' dinucleotides (CpGs), but only in 5-10% of all reads in whole brains or antennae. These observations, together with the localization of the amdat transcript to a few clusters of dopaminergic neurons, imply that amdat methylation is positively linked to its transcription. Our findings suggest that multiple cellular mechanisms, including gene splicing and epigenomic communication systems, may be adopted to increase the potential of a conserved gene to contribute to lineage-specific behavioral outcomes.


The triheme cytochrome PpcF from Geobacter metallireducens exhibits distinct redox properties.
Electrogenic bacteria, such as Geobacter, can couple the oxidation of carbon sources to the reduction of extracellular electron acceptors; such acceptors include toxic and radioactive metals, as well as electrode surfaces, making Geobacter a suitable candidate for applied use in bioremediation and bioenergy generation. Geobacter metallireducens is more promising in this regard than the better studied Geobacter sulfurreducens, as it has more efficient Fe (III) reduction rates and can convert nitrate to ammonia. The operon responsible for nitrate reductase activity in G. metallireducens includes the gene encoding the cytochrome PpcF, which was proposed to exchange electrons with nitrate reductase. In the present work, we perform a biochemical and a biophysical characterization of PpcF. Spectroscopic techniques, including circular dichroism (CD), UV-visible, and nuclear magnetic resonance (NMR), revealed that the cytochrome is very stable (T m > 85 °C), contains three low-spin hemes, and is diamagnetic (S = 0) and paramagnetic (S = 1/2) in the reduced and oxidized states, respectively. The NMR chemical shifts of the heme substituents were assigned and used to determine the heme core architecture of PpcF. Compared to the PpcA-family from G. sulfurreducens, the spatial disposition of the hemes is conserved, but the functional properties are clearly distinct. In fact, potentiometric titrations monitored by UV-visible absorption reveal that the reduction potential values of PpcF are significantly less negative (-56 and -64 mV, versus the normal hydrogen electrode at pH 7.0 and 8.0, respectively). NMR redox titrations showed that the order of oxidation of the hemes is IV-I-III, a feature not observed for G. sulfurreducens. The different redox properties displayed by PpcF, including the small redox-Bohr effect and low reduction potential value of heme IV, were structurally rationalized and attributed to the lower number of positively charged residues located in the vicinity of heme IV. Overall, the redox features of PpcF suggest that biotechnological applications of G. metallireducens may require less negative working functional redox windows than those using by G. sulfurreducens.


Representation of pitch chroma by multi-peak spectral tuning in human auditory cortex.
Musical notes played at octave intervals (i.e., having the same pitch chroma) are perceived as similar. This well-known perceptual phenomenon lays at the foundation of melody recognition and music perception, yet its neural underpinnings remain largely unknown to date. Using fMRI with high sensitivity and spatial resolution, we examined the contribution of multi-peak spectral tuning to the neural representation of pitch chroma in human auditory cortex in two experiments. In experiment 1, our estimation of population spectral tuning curves from the responses to natural sounds confirmed--with new data--our recent results on the existence of cortical ensemble responses finely tuned to multiple frequencies at one octave distance (Moerel et al., 2013). In experiment 2, we fitted a mathematical model consisting of a pitch chroma and height component to explain the measured fMRI responses to piano notes. This analysis revealed that the octave-tuned populations-but not other cortical populations-harbored a neural representation of musical notes according to their pitch chroma. These results indicate that responses of auditory cortical populations selectively tuned to multiple frequencies at one octave distance predict well the perceptual similarity of musical notes with the same chroma, beyond the physical (frequency) distance of notes.


Surgery of intradural extramedullary tumors: retrospective analysis of 107 cases.
Intradural extramedullary tumors (IDEMTs) are uncommon lesions that cause pain and neurological deficits. To evaluate the effects of surgery for IDEMTs. This cohort study recruited all patients operated on for IDEMTs at the Department of Neurology and Psychiatry of Sapienza University of Rome from January 2003 to January 2013. The analysis was conducted on clinical records evaluation over a 1-year follow-up. The Graphic Rating Scale was used to assess pain. Neurological deficits were detected through neurological examination. Quality of life was evaluated with the EuroQol (EQ-5D). Statistical interpretation of the data was performed with SPSS version 19 software. One hundred seven patients were recruited. Three were lost to follow-up. Patients reported lower level of pain 1 year after surgery (before surgery, 6.05; after surgery, 3.65). Mean comparison showed a significant decrease of -2.400 (P < .001). Ninety-two patients (88.5%) were neurologically asymptomatic 1 year after surgery. Only 12 patients (11.5%) presented with a deficit, with a global decrease of 39% (χ(2) = 27.6; P < .005). The quality of life in patients was middle to high (mean rating of EQ-5D visual analog score, 61.78%). The lowest levels of quality of life were found in patients with sphincter dysfunctions (mean, 33.4). Surgery for IDEMTs has a good outcome. Patients reported lower levels of pain and a drastic reduction in neurological symptoms 1 year after surgery. The quality of life is middle to high. It is influenced mainly by the neurological outcome.


Association of circulating transcriptomic profiles with mortality in sickle cell disease.
Sickle cell disease (SCD) complications are associated with increased morbidity and risk of mortality. We sought to identify a circulating transcriptomic profile predictive of these poor outcomes in SCD. Training and testing cohorts consisting of adult patients with SCD were recruited and prospectively followed. A pathway-based signature derived from grouping peripheral blood mononuclear cell transcriptomes distinguished 2 patient clusters with differences in survival in the training cohort. These findings were validated in a testing cohort in which the association between cluster 1 molecular profiling and mortality remained significant in a fully adjusted model. In a third cohort of West African children with SCD, cluster 1 differentiated SCD severity using a published scoring index. Finally, a risk score composed of assigning weights to cluster 1 profiling, along with established clinical risk factors using tricuspid regurgitation velocity, white blood cell count, history of acute chest syndrome, and hemoglobin levels, demonstrated a higher hazard ratio for mortality in both the training and testing cohorts compared with clinical risk factors or cluster 1 data alone. Circulating transcriptomic profiles are a powerful method to risk-stratify severity of disease and poor outcomes in both children and adults, respectively, with SCD and highlight potential associated molecular pathways.


Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clones.
The effect of progesterone (P) on the cytokine production profile of Ag-specific human CD4+ T cell lines and clones was investigated. T cell lines specific for purified protein derivative or streptokinase (SK) derived in the presence of P exhibited significant increased ability to produce IL-5 in comparison with T cell lines derived in the absence of P. Moreover, IL-4 was significantly increased in SK-specific T cell lines derived in the presence of P in comparison with SK-specific T cell lines derived in the absence of this hormone. In addition, SK-specific T cell lines generated in the presence of P developed into T cell clones showing a Th0-, instead of Th1-like, cytokine profile. Furthermore, SK-specific T cell clones with an established Th1 profile of cytokine secretion did express mRNA for, and produced detectable amounts of, IL-4 when stimulated with P in combination with insoluble anti-CD3 mAb. Combined stimulation with P and insoluble anti-CD3 mAb also enabled Th1 clones to express CD30 on their surface membrane. These results indicate that P can favor the development of Th cells producing Th2-type cytokines and is an inducer of both transient IL-4 production and CD30 expression in established Th1 cells. Thus, P production at the placental level may be responsible, at least in part, for increased production of Th2-type cytokines which have been implied in fetal allograft survival and maintenance of successful pregnancy.


Anti-inflammatory and renal protective actions of stanniocalcin-1 in a model of anti-glomerular basement membrane glomerulonephritis.
We have previously shown that stanniocalcin-1 (STC1) inhibits the transendothelial migration of macrophages and T cells, suppresses superoxide generation in macrophages, and attenuates macrophage responses to chemoattractants. To study the effects of STC1 on inflammation, in this study we induced a macrophage- and T-cell-mediated model of anti-glomerular basement membrane disease in STC1 transgenic mice, which display elevated serum STC1 levels and preferentially express STC1 in both endothelial cells and macrophages. We examined the following parameters both at baseline and after anti-glomerular basement membrane antibody treatment: blood pressure; C(3a) levels; urine output; proteinuria; blood urea nitrogen; and kidney C(3) deposition, fibrosis, histological changes, cytokine expression, and number of T cells and macrophages. Compared with wild-type mice, after anti-glomerular basement membrane treatment STC1 transgenic mice exhibited: i) diminished infiltration of inflammatory macrophages in the glomeruli; ii) marked reduction in crescent formation and sclerotic glomeruli; iii) decreased interstitial fibrosis; iv) preservation of kidney function and lower blood pressure; v) diminished C(3) deposition in the glomeruli; and vi) reduced expression of macrophage inhibitory protein-2 and transforming growth factor-beta2 in the kidney. Compared with baseline, wild-type mice, but not STC1 transgenic mice, had higher proteinuria and a marked reduction in urine output. STC1 had minimal effects, however, on both T-cell number in the glomeruli and interstitium and on cytokine expression characteristic of either TH1 or TH2 activation. These data suggest that STC1 is a potent anti-inflammatory and renal protective protein.


Prediction of serum ionized calcium concentration by use of serum total calcium concentration in dogs.
To determine whether total serum calcium (tCa) or adjusted tCa concentrations accurately predict ionized calcium (iCa) status in dogs. 1,633 canine serum samples. The tCa concentration was adjusted for total protein (TP) or albumin concentration by use of published equations. Correlations between iCa and tCa or adjusted tCa, tCa and TP, and tCa and albumin were calculated. Diagnostic discordance between tCa or adjusted tCa and iCa was determined. Diagnostic discordance in predicting iCa was also determined for 490 dogs with chronic renal failure (CRF). Sensitivity, specificity, positive and negative predictive values, and positive and negative diagnostic likelihood ratios were calculated for tCa, tCa adjusted forTP, and tCa adjusted for albumin. Diagnostic discordance was 27% when tCa concentration was used to predict iCa status. Use of adjusted tCa increased diagnostic discordance to approximately 37% for all dogs and 55% for dogs with CRF. Positive predictive value and positive diagnostic likelihood ratios were poor when tCa concentration was used to predict iCa status. The tCa concentration overestimated normocalcemia and underestimated hypocalcemia. Adjusted tCa overestimated hypercalcemia and underestimated hypocalcemia. Adjusted tCa or tCa concentrations are unacceptable for predicting iCa status in dogs. Use of adjustment equations is not recommended. Direct measurement of iCa concentration is necessary for accurate assessment of calcium status. Use of tCa or adjusted tCa concentrations to predict iCa status in dogs could cause serious mistakes in diagnosis and case management, especially in dogs with CRF.


The ion pathway through the opened Na(+),K(+)-ATPase pump.
P-type ATPases pump ions across membranes, generating steep electrochemical gradients that are essential for the function of all cells. Access to the ion-binding sites within the pumps alternates between the two sides of the membrane to avoid the dissipation of the gradients that would occur during simultaneous access. In Na(+),K(+)-ATPase pumps treated with the marine agent palytoxin, this strict alternation is disrupted and binding sites are sometimes simultaneously accessible from both sides of the membrane, transforming the pumps into ion channels (see, for example, refs 2, 3). Current recordings in these channels can monitor accessibility of introduced cysteine residues to water-soluble sulphydryl-specific reagents. We found previously that Na(+),K(+) pump-channels open to the extracellular surface through a deep and wide vestibule that emanates from a narrower pathway between transmembrane helices 4 and 6 (TM4 and TM6). Here we report that cysteine scans from TM1 to TM6 reveal a single unbroken cation pathway that traverses palytoxin-bound Na(+),K(+) pump-channels from one side of the membrane to the other. This pathway comprises residues from TM1, TM2, TM4 and TM6, passes through ion-binding site II, and is probably conserved in structurally and evolutionarily related P-type pumps, such as sarcoplasmic- and endoplasmic-reticulum Ca(2+)-ATPases and H(+),K(+)-ATPases.


Lead Repositioning Guided by Both Physiology and Atlas Based Targeting in Tourette Deep Brain Stimulation.
The centromedian (CM) region of the thalamus is a common target for deep brain stimulation (DBS) treatment for Tourette Syndrome (TS). However, there are currently no standard microelectrode recording or macrostimulation methods to differentiate CM thalamus from other nearby structures and nuclei. Here we present a case of failed conventional stereotactic targeting in TS DBS. Postoperative local field potential recordings (LFPs) showed features including beta power desynchronization during voluntary movement and thalamo-cortical phase amplitude coupling at rest. These findings suggested that the DBS lead was suboptimally placed in the ventral intermediate (VIM) nucleus of the thalamus rather than the intended CM region. Due to a lack of clinical improvement in tic severity scales three months following the initial surgery, the patient underwent lead revision surgery. Slight repositioning of the DBS leads resulted in a remarkably different clinical outcome. Afterwards, LFPs revealed less beta desynchronization and disappearance of the thalamo-cortical phase amplitude coupling. Follow-up clinical visits documented improvement of the patient's global tic scores. This case provides preliminary evidence that combining physiology with atlas based targeting may possibly enhance outcomes in some cases of Tourette DBS. A larger prospective study will be required to confirm these findings. This report demonstrates a case of failed centromedian nucleus region deep brain stimulation (DBS). We observed suboptimal tic improvement several months following DBS surgery and subsequent lead revision improved the outcome. The neurophysiology provided an important clue suggesting the possibility of suboptimally placed DBS leads. Repeat LFPs during lead revision revealed less beta desynchronization and disappearance of the thalamo-cortical phase amplitude coupling. There was improvement in tic outcome following slight repositioning during bilateral DBS lead revision. This case provides preliminary evidence supporting the use of physiology to augment the atlas based targeting of Tourette DBS cases.


Greater Efficiency Observed 12 Months Post-Implementation of an Automatic Tube Sorting and Registration System in a Core Laboratory.
Sample classification and registration have been recognized as important and time-consuming processes in laboratories. There is increasing pressure on laboratories to automate processes due to intense workload and reduce manual procedures and errors. The aim of the present study was to evaluate the positive effects of an automatic tube registration and sorting system on specimen processing. An automatic tube registration and sorting system (HCTS2000 MK2, m-u-t AG, Wedel, Germany) was evaluated. Turnaround time (TAT), rate of sample rejection and unrealized tests were examined 12 months pre- and post-implementation of the automatic tube sorting and registration system. The mean TAT of routine chemistry immunoassay, complete blood cell count (CBC) and coagulation samples were significantly improved (P<0.001). The number of rejected samples and unrealized tests was insignificantly decreased post-implementation of the system (0.4% to 0.2% and 4.5% to 1.4%, respectively) (P>0.05). By reducing delays and errors in the preanalytical processing and sorting of samples, significant improvements in specimen processing were observed after implementation of the system. These results suggest that an automatic tube registration and sorting system may also be used to improve specimen processing in a higher-volume core laboratory.


An instant multi-responsive porous polymer actuator driven by solvent molecule sorption.
Fast actuation speed, large-shape deformation and robust responsiveness are critical to synthetic soft actuators. A simultaneous optimization of all these aspects without trade-offs remains unresolved. Here we describe porous polymer actuators that bend in response to acetone vapour (24 kPa, 20 °C) at a speed of an order of magnitude faster than the state-of-the-art, coupled with a large-scale locomotion. They are meanwhile multi-responsive towards a variety of organic vapours in both the dry and wet states, thus distinctive from the traditional gel actuation systems that become inactive when dried. The actuator is easy-to-make and survives even after hydrothermal processing (200 °C, 24 h) and pressing-pressure (100 MPa) treatments. In addition, the beneficial responsiveness is transferable, being able to turn 'inert' objects into actuators through surface coating. This advanced actuator arises from the unique combination of porous morphology, gradient structure and the interaction between solvent molecules and actuator materials.


Temporal contrast sensitivity loss in primary open-angle glaucoma and glaucoma suspects.
The need for more sensitive tests for the early detection of compromised visual function in glaucoma is established by anatomic and psychophysical evidence of damage occurring to optic nerve fibers in eyes with normal visual fields. The results are reported of temporal frequency testing on 51 glaucoma suspects without visual field loss in either eye, 52 glaucoma patients with visual field deficits in the tested eye, and 11 normal subjects. Modulation transfer functions were obtained using a sinusoidally flickering 5 degrees spatially uniform white field viewed with central fixation and plotted at six frequencies from 5-30 Hz. The results showed a frequency-specific sensitivity loss centered at 15 Hz and a nonfrequency-specific mean sensitivity loss, that was greater, on average, in glaucoma patients than in suspects. Sensitivity losses of both kinds were seen in most glaucoma patients, but only in a minority of glaucoma suspects. About 12% of suspects were indistinguishable from the lowest performing one third of these glaucoma patients. A smaller number of suspects appeared to form a second mode in the frequency distribution for temporal sensitivity at 15 and 25 Hz. In patients with glaucoma, age was found to be a significant factor associated with the magnitude of mean sensitivity loss. Age was not a significant factor contributing to sensitivity loss in individual suspect data as measured by regression analysis, but it contributed to a small and consistent sensitivity loss across frequency for group-averaged data in those older than 55 years of age.


Repeat convection-enhanced delivery for diffuse intrinsic pontine glioma.
While the safety and efficacy of convection-enhanced delivery (CED) have been studied in patients receiving single-dose drug infusions, agents for oncological therapy may require repeated or chronic infusions to maintain therapeutic drug concentrations. Repeat and chronic CED infusions have rarely been described for oncological purposes. Currently available CED devices are not approved for extended indwelling use, and the only potential at this time is for sequential treatments through multiple procedures. The authors report on the safety and experience in a group of pediatric patients who received sequential CED into the brainstem for the treatment of diffuse intrinsic pontine glioma. Patients in this study were enrolled in a phase I single-center clinical trial using 124I-8H9 monoclonal antibody (124I-omburtamab) administered by CED (clinicaltrials.gov identifier NCT01502917). A retrospective chart and imaging review were used to assess demographic data, CED infusion data, and postoperative neurological and surgical outcomes. MRI scans were analyzed using iPlan Flow software for volumetric measurements. Target and catheter coordinates as well as radial, depth, and absolute error in MRI space were calculated with the ClearPoint imaging software. Seven patients underwent 2 or more sequential CED infusions. No patients experienced Clinical Terminology Criteria for Adverse Events grade 3 or greater deficits. One patient had a persistent grade 2 cranial nerve deficit after a second infusion. No patient experienced hemorrhage or stroke postoperatively. There was a statistically significant decrease in radial error (p = 0.005) and absolute tip error (p = 0.008) for the second infusion compared with the initial infusion. Sequential infusions did not result in significantly different distribution capacities between the first and second infusions (volume of distribution determined by the PET signal/volume of infusion ratio [mean ± SD]: 2.66 ± 0.35 vs 2.42 ± 0.75; p = 0.45). This series demonstrates the ability to safely perform sequential CED infusions into the pediatric brainstem. Past treatments did not negatively influence the procedural workflow, technical application of the targeting interface, or distribution capacity. This limited experience provides a foundation for using repeat CED for oncological purposes.


The dischargeable cut-off score of Oswestry Disability Index (ODI) in the inpatient care for low back pain with disability.
The admission due to low back pain (LBP) became prevalent cause of international economic losses. Since LBP patients with disability are often subject to inpatient care, it is important to determine the appropriate time of discharge. The purpose of this study is to set the cut-off value of appropriate Oswestry Disability Index (ODI) at the time of discharge. Of 1,394 LBP patients admitted in hospital specialized in spinal disease, 774 eligible patients with disability were included in this study. And several clinical variables including numerical rating score, ODI, satisfaction level were observed during the hospital stay. We considered satisfaction level as an important factor for discharge, categorized patients into satisfied group and dissatisfied group. Through the statistical analysis, appropriate factor for determining dischargeable patients satisfied with their current condition and its cut-off value of ODI were found. And proper predictors for the cut-off value were extracted statistically and logically from a pool of several clinical indexes. The ODI at the time of discharge was most accurate in determining dischargeable patients. The cut-off value of ODI was 30. Predictors were ODI questions 4 and 6. We set the cut-off value of dischargeable ODI for LBP inpatient with disability and found its predictor.