Phantom and clinical evaluation of the effect of full Monte Carlo collimator modelling in post-SIRT yttrium-90 Bremsstrahlung SPECT imaging.
Post-therapy SPECT/CT imaging of 90Y microspheres delivered to hepatic malignancies is difficult, owing to the continuous, high-energy Bremsstrahlung spectrum emitted by 90Y. This study aimed to evaluate the utility of a commercially available software package (HybridRecon, Hermes Medical Solutions AB) which incorporates full Monte Carlo collimator modelling. Analysis of image quality was performed on both phantom and clinical images in order to ultimately provide a recommendation of an optimum reconstruction for post-therapy 90Y microsphere SPECT/CT imaging. A 3D-printed anthropomorphic liver phantom was filled with 90Y with a sphere-to-background ratio of 4:1 and imaged on a GE Discovery 670 SPECT/CT camera. Datasets were reconstructed using ordered-subsets expectation maximization (OSEM) 1-7 iterations in order to identify the optimal OSEM reconstruction (5 iterations, 15 subsets). Quantitative analysis was subsequently carried out on phantom datasets obtained using four reconstruction algorithms: the default OSEM protocol (2 iterations, 10 subsets) and the optimised OSEM protocol, both with and without full Monte Carlo collimator modelling. The quantitative metrics contrast recovery (CR) and background variability (BV) were calculated. The four algorithms were then used to retrospectively reconstruct 10 selective internal radiation therapy (SIRT) patient datasets which were subsequently blind scored for image quality by a consultant radiologist. The optimised OSEM reconstruction (5 iterations, 15 subsets with full MC collimator modelling) increased the CR by 42% (p < 0.001) compared to the default OSEM protocol (2 iterations, 10 subsets). The use of full Monte Carlo collimator modelling was shown to further improve CR by 14% (30 mm sphere, CR = 90%, p < 0.05). The consultant radiologist had a significant preference for the optimised OSEM over the default OSEM protocol (p < 0.001), with the optimised OSEM being the favoured reconstruction in every one of the 10 clinical cases presented. OSEM (5 iterations, 15 subsets) with full Monte Carlo collimator modelling is quantitatively the optimal image reconstruction for post-SIRT 90Y Bremsstrahlung SPECT/CT imaging. The use of full Monte Carlo collimator modelling for correction of image-degrading effects significantly increases contrast recovery without degrading clinical image quality.


Inconsistent reproductive isolation revealed by interactions between Catostomus fish species.
Interactions between species are central to evolution and ecology, but we do not know enough about how outcomes of interactions between species vary across geographic locations, in heterogeneous environments, or over time. Ecological dimensions of interactions between species are known to vary, but evolutionary interactions such as the establishment and maintenance of reproductive isolation are often assumed to be consistent across instances of an interaction between species. Hybridization among Catostomus fish species occurs over a large and heterogeneous geographic area and across taxa with distinct evolutionary histories, which allows us to assess consistency in species interactions. We analyzed hybridization among six Catostomus species across the Upper Colorado River basin (US mountain west) and found extreme variation in hybridization across locations. Different hybrid crosses were present in different locations, despite similar species assemblages. Within hybrid crosses, hybridization varied from only first generation hybrids to extensive hybridization with backcrossing. Variation in hybridization outcomes might result from uneven fitness of hybrids across locations, polymorphism in genetic incompatibilities, chance, unidentified historical contingencies, or some combination thereof. Our results suggest caution in assuming that one or a few instances of hybridization represent all interactions between the focal species, as species interactions vary substantially across locations.


A mixed methods study to compare models of spirometry delivery in primary care for patients at risk of COPD.
To increase recognition of airflow obstruction in primary care, we compared two models of spirometry delivery in a target group at risk of chronic obstructive pulmonary disease (COPD). A 6 month qualitative/quantitative cluster randomised study in eight practices compared opportunistic spirometry by "visiting trained nurses" (TN) with optimised "usual care" (UC) from general practitioners (GPs) for smokers and ex-smokers, aged over 35 years. Outcomes were: spirometry uptake and quality, new diagnoses of COPD and GPs' experiences of spirometry. In the eligible target population, 531/904 (59%) patients underwent spirometry in the TN model and 87/1130 (8%) patients in the UC model (p < 0.0001). ATS spirometry standards for acceptability and reproducibility were met by 76% and 44% of tests in the TN and UC models, respectively (p < 0.0001). 125 (24%) patients tested with the TN model and 38 (44%) with the UC model reported a pre-existing respiratory diagnosis (p < 0.0001). Three months after spirometry, when the ratio of forced expiratory volume in 1 s/forced vital capacity (FEV(1)/FVC) was < 0.7 and no prior COPD diagnosis was reported, nine (8%) participants had a new doctor recorded COPD diagnosis in practices with the TN model and two (8%) participants in practices with the UC model. Mislabelling of participants with a diagnosis of COPD when FEV(1)/FVC was > or = 0.7 was present in both models prior to and after spirometry. GPs valued high quality spirometry and increased testing of patients at risk of COPD in the TN model. They identified limitations, including the need for better systematic follow-up of abnormal spirometry and support with interpretation, which may explain persisting underdiagnosis of COPD in practice records. Although opportunistic testing by visiting trained nurses substantially increased and improved spirometry performance compared with usual care, translating increased detection of airflow obstruction into diagnosis of COPD requires further development of the model. Australian Clinical Trials Registry: registration No 12605000019606.


TNF Lectin-Like Domain Restores Epithelial Sodium Channel Function in Frameshift Mutants Associated with Pseudohypoaldosteronism Type 1B.
Previous in vitro studies have indicated that tumor necrosis factor (TNF) activates amiloride-sensitive epithelial sodium channel (ENaC) current through its lectin-like (TIP) domain, since cyclic peptides mimicking the TIP domain (e.g., solnatide), showed ENaC-activating properties. In the current study, the effects of TNF and solnatide on individual ENaC subunits or ENaC carrying mutated glycosylation sites in the α-ENaC subunit were compared, revealing a similar mode of action for TNF and solnatide and corroborating the previous assumption that the lectin-like domain of TNF is the relevant molecular structure for ENaC activation. Accordingly, TNF enhanced ENaC current by increasing open probability of the glycosylated channel, position N511 in the α-ENaC subunit being identified as the most important glycosylation site. TNF significantly increased Na+ current through ENaC comprising only the pore forming subunits α or δ, was less active in ENaC comprising only β-subunits, and showed no effect on ENaC comprising γ-subunits. TNF did not increase the membrane abundance of ENaC subunits to the extent observed with solnatide. Since the α-subunit is believed to play a prominent role in the ENaC current activating effect of TNF and TIP, we investigated whether TNF and solnatide can enhance αβγ-ENaC current in α-ENaC loss-of-function frameshift mutants. The efficacy of solnatide has been already proven in pathological conditions involving ENaC in phase II clinical trials. The frameshift mutations αI68fs, αT169fs, αP197fs, αE272fs, αF435fs, αR438fs, αY447fs, αR448fs, αS452fs, and αT482fs have been reported to cause pseudohypoaldosteronism type 1B (PHA1B), a rare, life-threatening, salt-wasting disease, which hitherto has been treated only symptomatically. In a heterologous expression system, all frameshift mutants showed significantly reduced amiloride-sensitive whole-cell current compared to wild type αβγ-ENaC, whereas membrane abundance varied between mutants. Solnatide restored function in α-ENaC frameshift mutants to current density levels of wild type ENaC or higher despite their lacking a binding site for solnatide, previously located to the region between TM2 and the C-terminus of the α-subunit. TNF similarly restored current density to wild type levels in the mutant αR448fs. Activation of βγ-ENaC may contribute to this moderate current enhancement, but whatever the mechanism, experimental data indicate that solnatide could be a new strategy to treat PHA1B.


PD-1/PD-L1, but not PD-1/PD-L2, interactions regulate the severity of experimental autoimmune encephalomyelitis.
Interactions between PD-1 and its two differentially expressed ligands, PD-L1 and PD-L2, attenuate T cell activation and effector function. To determine the role of these molecules in autoimmune disease of the CNS, PD-1-/-, PD-L1-/- and PD-L2-/- mice were generated and immunized to induce experimental autoimmune encephalomyelitis (EAE). PD-1-/- and PD-L1-/- mice developed more severe EAE than wild type and PD-L2-/- mice. Consistent with this, PD-1-/- and PD-L1-/- cells produced elevated levels of the pro-inflammatory cytokines IFN-gamma, TNF, IL-6 and IL-17. These results demonstrate that interactions between PD-1/PD-L1, but not PD-1/PDL-2, are crucial in attenuating T cell responses in EAE.


Genetic Features of HIV-1 Integrase Sub-Subtype A6 Predominant in Russia and Predicted Susceptibility to INSTIs.
The increasing use of the integrase strand transfer inhibitor (INSTI) class for the treatment of HIV-infection has pointed to the importance of analyzing the features of HIV-1 subtypes for an improved understanding of viral genetic variability in the occurrence of drug resistance (DR). In this study, we have described the prevalence of INSTI DR in a Russian cohort and the genetic features of HIV-1 integrase sub-subtype A6. We included 408 HIV infected patients who were not exposed to INSTI. Drug resistance mutations (DRMs) were detected among 1.3% of ART-naïve patients and among 2.7% of INSTI-naïve patients. The prevalence of 12 polymorphic mutations was significantly different between sub-subtypes A6 and A1. Analysis of the genetic barriers determined two positions in which subtype A (A1 and A6) showed a higher genetic barrier (G140C and V151I) compared with subtype B, and one position in which subtypes A1 and B displayed a higher genetic barrier (L74M and L74I) than sub-subtype A6. Additionally, we confirmed that the L74I mutation was selected at the early stage of the epidemic and subsequently spread as a founder effect in Russia. Our data have added to the overall understanding of the genetic features of sub-subtype A6 in the context of drug resistance.


Retropatellar technique for intramedullary nailing of proximal tibia fractures: a cadaveric assessment.
To investigate if the radiographically correct and anatomically safe starting point and the appropriate sagittal plane vector could be obtained using a retropatellar technique for proximal tibia fractures treated with an intramedullary device. We performed a cadaveric and radiographic study utilizing 16 limbs. We performed a retropatellar approach via longitudinal quadriceps split, passed a specialized trocar through the patellofemoral joint and onto the superior aspect of the tibia, and inserted Kirschner wires into the anatomic safe zone of the tibial plateau at 0, 10, 20, 30, 40, and 50 degrees of knee flexion utilizing biplanar fluoroscopy. We recorded knee flexion with a goniometer and the entrance vector of the Kirschner wire in relation to the anterior tibial cortex. University-affiliated cadaver and anatomy laboratory. There was a progressive increase in the ability to obtain the correct anatomical start site from 1 of 16 (6.25%) at full extension to 12 of 16 (75%) at 50 degrees of knee flexion (P = 0.00098). A statistically significant decrease in the average sagittal plane entrance vector in relation to the anterior tibial cortex was found from 23.1 degrees at full extension to -0.41 degrees at 50 degrees of knee flexion (P < 0.0001). The retropatellar technique allows the radiographically defined correct start site to be localized, particularly at higher degrees of knee flexion. More favorable intramedullary nail insertion angles were possible with the retropatellar technique, particularly with knee flexion angles greater than 20 degrees. The retropatellar technique demands further investigations to further delineate its advantages, limitations, and possible risks to local anatomy.


Integrating ecosystem services analysis into scenario planning practice: accounting for street tree benefits with i-Tree valuation in Central Texas.
Scenario planning continues to gain momentum in the United States as an effective process for building consensus on long-range community plans and creating regional visions for the future. However, efforts to integrate more sophisticated information into the analytical framework to help identify important ecosystem services have lagged in practice. This is problematic because understanding the tradeoffs of land consumption patterns on ecological integrity is central to mitigating the environmental degradation caused by land use change and new development. In this paper we describe how an ecosystem services valuation model, i-Tree, was integrated into a mainstream scenario planning software tool, Envision Tomorrow, to assess the benefits of public street trees for alternative future development scenarios. The tool is then applied to development scenarios from the City of Hutto, TX, a Central Texas Sustainable Places Project demonstration community. The integrated tool represents a methodological improvement for scenario planning practice, offers a way to incorporate ecosystem services analysis into mainstream planning processes, and serves as an example of how open source software tools can expand the range of issues available for community and regional planning consideration, even in cases where community resources are limited. The tool also offers room for future improvements; feasible options include canopy analysis of various future land use typologies, as well as a generalized street tree model for broader U.S. application.


Validation of a 15-gene hypoxia classifier in head and neck cancer for prospective use in clinical trials.
In head and neck squamous cell carcinomas (HNSCC) hypoxic radioresistance can be reduced by use of the hypoxic modifier nimorazole, as shown in the DAHANCA 5 trial. Recently, a 15-gene hypoxia classifier has shown predictive impact for the effect of nimorazole by identifying 'more' and 'less' hypoxic tumors in the DAHANCA 5 cohort. A prospective multicentre EORTC-1219 study is initiated, where nimorazole and prospective use of the classifier as a predictor is tested in relation to the most recent accelerated chemoradiotherapy treatment. Validation of the gene expression classification procedures is described here. Formalin-fixed paraffin-embedded (FFPE) tumor material from three recent HNSCC cohorts [DAHANCA 18 (n = 96), 24 (n = 40), and IAEA Hypo (n = 55)] was used to establish and validate procedures for prospective classification of patients. Repeatability was tested for the different steps in the gene expression analysis, and reproducibility was tested with xenograft tumors (FaDuDD, UTSCC33), where gene expression in complementary sections was compared after fixation and embedding locally and at international institutions, respectively. Intra-tumor heterogeneity was addressed by classifying biopsy samples from HNSCC tumors, where 2-4 biopsies from each tumor was accessible. Procedures were successfully established for individual classification of HNSCC patients in retrospective and prospective cohorts. Measurements of gene expression levels were reproducible between different international institutions. Technical validation of the 15-gene hypoxia classifier demonstrated that it is suitable for implementation in prospective clinical trials.


Directed Markovnikov hydroarylation and hydroalkenylation of alkenes under nickel catalysis.
We report a full account of our research on nickel-catalyzed Markovnikov-selective hydroarylation and hydroalkenylation of non-conjugated alkenes, which has yielded a toolkit of methods that proceed under mild conditions with alkenyl sulfonamide, ketone, and amide substrates. Regioselectivity is controlled through catalyst coordination to the native Lewis basic functional groups contained within these substrates. To maximize product yield, reaction conditions were fine-tuned for each substrate class, reflecting the different coordination properties of the directing functionality. Detailed kinetic and computational studies shed light on the mechanism of this family of transformations, pointing to transmetalation as the turnover-limiting step.


Factors associated with non-utilisation of postnatal care services in Indonesia.
Postnatal care helps prevent neonatal deaths. This study aims to examine factors associated with non-utilisation of postnatal care in Indonesia. A cross-sectional analytic study was conducted using data from the 2002-3 Indonesia Demographic and Health Survey (IDHS), which used multistage cluster random sampling. Contingency table and logistic regression analyses were used to determine the factors associated with non-utilisation of postnatal care services. The population attribution risk percentage (PAR%) for non-utilisation of postnatal care services was also calculated. Data were available for 15,553 singleton live-born infants. The prevalence of non-attendance at postnatal care services was consistently higher in rural areas than in urban areas. Maternal factors associated with lack of postnatal care included low household wealth index, low education levels, lack of knowledge of pregnancy-related complications or where distance from health services was a problem. Infants of high birth rank and those reported to be smaller than average were less likely to receive postnatal care. Other indicators of access to healthcare services which were associated with non-utilisation of postnatal care services included few antenatal care checks, use of untrained birth attendants and births outside healthcare facilities. Public health interventions to increase the utilisation of postnatal care services should target women who are poor, less educated, from rural areas and who use untrained birth attendants. Strategies to improve the availability and accessibility of antenatal care services and skilled birth attendance including focused financial support and health promotion programmes, particularly in the rural areas, should increase utilisation of postnatal care services in Indonesia.


Lanthanide ions as spectral converters for solar cells.
The use of lanthanide ions to convert photons to different, more useful, wavelengths is well-known from a wide range of applications (e.g. fluorescent tubes, lasers, white light LEDs). Recently, a new potential application has emerged: the use of lanthanide ions for spectral conversion in solar cells. The main energy loss in the conversion of solar energy to electricity is related to the so-called spectral mismatch: low energy photons are not absorbed by a solar cell while high energy photons are not used efficiently. To reduce the spectral mismatch losses both upconversion and downconversion are viable options. In the case of upconversion two low energy infrared photons that cannot be absorbed by the solar cell, are added up to give one high energy photon that can be absorbed. In the case of downconversion one high energy photon is split into two lower energy photons that can both be absorbed by the solar cell. The rich and unique energy level structure arising from the 4f(n) inner shell configuration of the trivalent lanthanide ions gives a variety of options for efficient up- and downconversion. In this perspective an overview will be given of recent work on photon management for solar cells. Three topics can be distinguished: (1) modelling of the potential impact of spectral conversion on the efficiency of solar cells; (2) research on up- and downconversion materials based on lanthanides; and (3) proof-of-principle experiments. Finally, an outlook will be given, including issues that need to be resolved before wide scale application of up- and downconversion materials can be anticipated.


Secondary serological response of patients with chronic hepatosplenic suppurative brucellosis.
Chronic hepatosplenic suppurative brucellosis (CHSB) is a local reactivation of a previous brucellosis, coursing with an immunoglobulin G (IgG) and IgA secondary immunological response. The observation of two cases of CHSB with an apparent IgM response gave rise to a detailed serological study of three of our patients. We studied the first sample from all three patients and successive samples from two of them. In cases 1 and 2, we found samples with positive IgM lateral flow and IgM enzyme-linked immunosorbent assay results concomitantly with rheumatoid factor (RF); after absorption with anti-RF serum, these results were rendered negative. In patients 2 and 3 the diagnosis of brucellosis was delayed, because none of the test results were initially very significant. However, a clear seroconversion of IgG antibodies was observed in subsequent months; titers of the Brucellacapt and Coombs tests increased in similar ways, although Brucellacapt decreased more rapidly than Coombs, which persisted at high titers for years. In patient 3 a relapse was observed in the fourth year of follow-up, detected by Coombs and also by IgG lateral flow and counterimmunoelectrophoresis (CIEP), although not by the rose bengal, agglutination, or Brucellacapt tests. Serological changes in CHSB may sometimes be mild and are detected mainly by the Coombs test. Brucellacapt does not offer additional information, although IgG lateral flow and CIEP may be of some use. Careful surveillance of titer changes in the Coombs test is the best marker of infection activity. As the disease progresses, an intense IgG response may develop and RF sometimes appears, simulating an IgM response.


Addiction-related effects of DOV 216,303 and cocaine: A comparative study in the mouse.
DOV 216,303, an inhibitor of serotonin, noradrenaline and dopamine reuptake, belongs to a new line of drugs called 'triple reuptake inhibitors' that have been proposed for treatment of depression. The addictive drug cocaine has similar mechanism of action and exerts rewarding effects by blocking reuptake of dopamine, leading to increased extracellular concentrations of dopamine in the nucleus accumbens. Thus, DOV 216,303 and other triple reuptake inhibitors might be speculated to exhibit abuse potential, limiting their future therapeutic use. To further elucidate potential addictive properties of DOV 216,303, we conducted a comparative study of addiction-related effects of DOV 216,303 and cocaine in mice using acute self-administration, conditioned place preference (CPP) and drug-induced hyperlocomotion. Effects on accumbal extracellular dopamine levels were determined using microdialysis, and we measured monoamine receptor occupancy as well as brain and plasma exposure. DOV 216,303 was self-administered acutely in the same dose range as cocaine. However, in the CPP model, DOV 216,303 did not induce place preference at doses where cocaine caused place preference. Higher doses of DOV 216,303 than cocaine were needed to induce hyperlocomotion and increase extracellular accumbal dopamine with effective doses being higher than effective doses used in depression models. Moreover, DOV 216,303 displayed a pharmacokinetic profile with lower potential for addiction than cocaine. Thus, high levels of DAT occupancy were reached slower and decayed more slowly after DOV 216,303 than cocaine administration. The present study shows that acute administration of DOV 216,303 displays some addictive-like properties in mice, but these were less pronounced than cocaine, most likely due to different pharmacokinetic profiles.


Mutations in the SMAD4/DPC4 gene in juvenile polyposis.
Familial juvenile polyposis is an autosomal dominant disease characterized by a predisposition to hamartomatous polyps and gastrointestinal cancer. Here it is shown that a subset of juvenile polyposis families carry germ line mutations in the gene SMAD4 (also known as DPC4), located on chromosome 18q21.1, that encodes a critical cytoplasmic mediator in the transforming growth factor-beta signaling pathway. The mutant SMAD4 proteins are predicted to be truncated at the carboxyl-terminus and lack sequences required for normal function. These results confirm an important role for SMAD4 in the development of gastrointestinal tumors.


Promotion of NEDD-CUL1 conjugate cleavage by COP9 signalosome.
SCF ubiquitin ligases control various processes by marking regulatory proteins for ubiquitin-dependent proteolysis. To illuminate how SCF complexes are regulated, we sought proteins that interact with the human SCF component CUL1. The COP9 signalosome (CSN), a suppressor of plant photomorphogenesis, associated with multiple cullins and promoted cleavage of the ubiquitin-like protein NEDD8 from Schizosaccharomyces pombe CUL1 in vivo and in vitro. Multiple NEDD8-modified proteins uniquely accumulated in CSN-deficient S. pombe cells. We propose that the broad spectrum of activities previously attributed to CSN subunits--including repression of photomorphogenesis, activation of JUN, and activation of p27 nuclear export--underscores the importance of dynamic cycles of NEDD8 attachment and removal in biological regulation.


[Health and quality of life of medical residents].
This article highlights the relationship between health and quality of life among the resident medical staff. A review was carried out to analyze the content of the relationship under study. Sources for this search were the Virtual Health Library (VHL), by BIREME (Centro Latino-American and Caribbean Center on Health Sciences Information), the Electronic databases Medline (Medical Literature Analysis and Retrieval System On-Line) Lilacs (Literatura Latino-American and Caribbean Health Sciences), SciELO (Scientific Electronic Library Online) and the email address scholar.google.com.br. Descriptors used were: Quality of life, Burnout, Internship and Residency. Planning and analysis of scientific literature, was performed to evaluate and discuss issues presented in the studies related to the subject, considering the distribution of publications according to country of origin, date of publication, source and title, focus of study and main conclusions. Studies published point to high rates of burnout, stress, depression, fatigue and insomnia among medical residents; moreover a lack of coping strategies, the relationship between workload and quality of life, require a change of medical legislation regarding work-based learning. Studies have shown that an adequate training program is needed not only to increase professional qualification and personal quality of life, but also to provide safety during patient treatment. It is known that residency training is stressful; it is nevertheless a process required to prepare for a solid career and personal growth of the young medical staff.


Silver nanoscale antisense drug delivery system for photoactivated gene silencing.
The unique photophysical properties of noble metal nanoparticles contribute to their potential as photoactivated drug delivery vectors. Here we demonstrate the synthesis and characterization of 60-80 nm silver nanoparticles (SNPs) decorated with thiol-terminated photolabile DNA oligonucleotides. In vitro assays and fluorescent confocal microscopy of treated cell cultures show efficient UV-wavelength photoactivation of surface-tethered caged ISIS2302 antisense oligonucleotides possessing internal photocleavable linkers. As a demonstration of the advantages of these novel nanocarriers, we investigate properties including: enhanced stability to nucleases, increased hybridization activity upon photorelease, and efficient cellular uptake as compared to commercial transfection vectors. Their potential as multicomponent delivery agents for oligonucleotide therapeutics is shown through regulation of ICAM-1 (Intracellular Adhesion Molecule-1) silencing. Our results suggest a means to achieve light-triggered, spatiotemporally controlled gene silencing via nontoxic silver nanocarriers, which hold promise as tailorable platforms for nanomedicine, gene expression studies, and genetic therapies.


Satellite Assessment of Bio-Optical Properties of Northern Gulf of Mexico Coastal Waters Following Hurricanes Katrina and Rita.
The impacts of major tropical storms events on coastal waters include sediment resuspension, intense water column mixing, and increased delivery of terrestrial materials into coastal waters. We examined satellite imagery acquired by the Moderate Resolution Imaging Spectroradiometer (MODIS) ocean color sensor aboard the Aqua spacecraft following two major hurricane events: Hurricane Katrina, which made landfall on 29 August 2005, and Hurricane Rita, which made landfall on 24 September. MODIS Aqua true color imagery revealed high turbidity levels in shelf waters immediately following the storms indicative of intense resuspension. However, imagery following the landfall of Katrina showed relatively rapid return of shelf water mass properties to pre-storm conditions. Indeed, MODIS Aqua-derived estimates of diffuse attenuation at 490 nm (K_490) and chlorophyll (chlor_a) from mid-August prior to the landfall of Hurricane Katrina were comparable to those observed in mid-September following the storm. Regions of elevated K_490 and chlor_a were evident in offshore waters and appeared to be associated with cyclonic circulation (cold-core eddies) identified on the basis of sea surface height anomaly (SSHA). Imagery acquired shortly after Hurricane Rita made landfall showed increased water column turbidity extending over a large area of the shelf off Louisiana and Texas, consistent with intense resuspension and sediment disturbance. An interannual comparison of satellite-derived estimates of K_490 for late September and early October revealed relatively lower levels in 2005, compared to the mean for the prior three years, in the vicinity of the Mississippi River birdfoot delta. In contrast, levels above the previous three year mean were observed off Texas and Louisiana 7-10 d after the passage of Rita. The lower values of K_490 near the delta could be attributed to relatively low river discharge during the preceding months of the 2005 season. The elevated levels off Texas and Louisiana were speculated to be due to the presence of fine grain sediment or dissolved materials that remained in the water column following the storm, and may also have been associated with enhanced phytoplankton biomass stimulated by the intense vertical mixing and offshore delivery of shelf water and associated nutrients. This latter view was supported by observations of high chlor_a in association with regions of cyclonic circulation.


Evaluation of Antioxidant Activity of R. Slooffiae, R. Mucilaginosa Extracts.
Antioxidants are health beneficial compounds that can protect cells and macromolecules from the damage of reactive oxygen species (ROS). The aims of this study were to compare the total antioxidant and carotenoid production in R. Slooffiae and R. Mucilaginosa. To isolate the carotenoid pigment, cells were suspended in acetone and broken using a homogenizer, followed by centrifugation, and supernatant was separated. For analytical method, pigments were measured spectrophotometrically at 450 nm. The B-carotene bleaching and 1, 1-diphenyl-2-picrylhdrazyl (DPPH) assay were used to determine antioxidant properties of R. Slooffiae and R. Mucilaginosa by measuring the decrease in absorbance at 470 and 517 nm. The results showed that the content of total carotenoid in R. Slooffiae was higher than R. Mucilaginosa and it presented higher ability to show antioxidant activity. The mean total antioxidant activity of ascorbic acid was the highest (97.11 ± 6.11%), followed by BHT (64.71 ± 5.41%), R. sloofias extract (57.91 ± 7.34%) and R. Mucilaginosa (39.32 ± 5.85%). The EC50 of ascorbic acid was the strongest (0.252 ± 0.000 mg/ml), followed by BHT (0.612 ± 0.009 mg/ml) and R. Slooffiae (0.658 ± 0.033 mg/ml). There was significant difference observed between the EC50 of R. Slooffiae and BHT. It was found that both strains have ability to produce carotenoid and show antioxidant ability; however, R. Slooffiae had more potential in producing carotenoid and showing antioxidant ability than R. Mucilaginosa. Further study is required, in order to utilize this strain in the food, pharmaceuticals and cosmetics industries.


Assessment of multiparametric MRI in a human glioma model to monitor cytotoxic and anti-angiogenic drug effects.
Early imaging or blood biomarkers of tumor response is needed to customize anti-tumor therapy on an individual basis. This study evaluates the sensitivity and relevance of five potential MRI biomarkers. Sixty nude rats were implanted with human glioma cells (U-87 MG) and randomized into three groups: one group received an anti-angiogenic treatment (Sorafenib), a second a cytotoxic drug [1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU (Carmustine)] and a third no treatment. The tumor volume, apparent diffusion coefficient (ADC) of water, blood volume fraction (BVf), microvessel diameter (vessel size index, VSI) and vessel wall integrity (contrast enhancement, CE) were monitored before and during treatment. Sorafenib reduced tumor CE as early as 1 day after treatment onset. By 4 days after treatment onset, tumor BVf was reduced and tumor VSI was increased. By 14 days after treatment onset, ADC was increased and the tumor growth rate was reduced. With BCNU, ADC was increased and the tumor growth rate was reduced 14 days after treatment onset. Thus, the estimated MRI parameters were sensitive to treatment at different times after treatment onset and in a treatment-dependent manner. This study suggests that multiparametric MR monitoring could allow the assessment of new anti-tumor drugs and the optimization of combined therapies.


Cities' Role in Mitigating United States Food System Greenhouse Gas Emissions.
Current trends of urbanization, population growth, and economic development have made cities a focal point for mitigating global greenhouse gas (GHG) emissions. The substantial contribution of food consumption to climate change necessitates urban action to reduce the carbon intensity of the food system. While food system GHG mitigation strategies often focus on production, we argue that urban influence dominates this sector's emissions and that consumers in cities must be the primary drivers of mitigation. We quantify life cycle GHG emissions of the United States food system through data collected from literature and government sources producing an estimated total of 3800 kg CO2e/capita in 2010, with cities directly influencing approximately two-thirds of food sector GHG emissions. We then assess the potential for cities to reduce emissions through selected measures; examples include up-scaling urban agriculture and home delivery of grocery options, which each may achieve emissions reductions on the order of 0.4 and ∼1% of this total, respectively. Meanwhile, changes in waste management practices and reduction of postdistribution food waste by 50% reduce total food sector emissions by 5 and 11%, respectively. Consideration of the scale of benefits achievable through policy goals can enable cities to formulate strategies that will assist in achieving deep long-term GHG emissions targets.


How humans drive speciation as well as extinction.
A central topic for conservation science is evaluating how human activities influence global species diversity. Humanity exacerbates extinction rates. But by what mechanisms does humanity drive the emergence of new species? We review human-mediated speciation, compare speciation and known extinctions, and discuss the challenges of using net species diversity as a conservation objective. Humans drive rapid evolution through relocation, domestication, hunting and novel ecosystem creation-and emerging technologies could eventually provide additional mechanisms. The number of species relocated, domesticated and hunted during the Holocene is of comparable magnitude to the number of observed extinctions. While instances of human-mediated speciation are known, the overall effect these mechanisms have upon speciation rates has not yet been quantified. We also explore the importance of anthropogenic influence upon divergence in microorganisms. Even if human activities resulted in no net loss of species diversity by balancing speciation and extinction rates, this would probably be deemed unacceptable. We discuss why, based upon 'no net loss' conservation literature-considering phylogenetic diversity and other metrics, risk aversion, taboo trade-offs and spatial heterogeneity. We conclude that evaluating speciation alongside extinction could result in more nuanced understanding of biosphere trends, clarifying what it is we actually value about biodiversity.


High prevalence of schistosomiasis in Mbita and its adjacent islands of Lake Victoria, western Kenya.
Intestinal schistosomiasis continues to be a significant cause of morbidity among communities located around Lake Victoria and on its islands. Although epidemiological surveys have been conducted in other areas bordering the lake in western Kenya, Mbita district and its adjacent islands have never been surveyed, largely due to logistical challenges in accessing these areas. Consequently, there is a paucity of data on prevalence of schistosomiasis and soil-transmitted helminth (STH) infections that are endemic in this region. This cross-sectional study determined the prevalence, intensity of infection and geographical distribution of schistosome and STH infections among 4,065 children aged 5-19 years in 84 primary schools in Mbita and nearby islands of Lake Victoria (Mfangano, Ringiti, Rusinga and Takawiri), in western Kenya. Single stool samples were collected and examined for eggs of Schistosoma mansoni and STHs (Hookworms, Ascaris lumbricoides and Trichuris trichiura) using the Kato-Katz technique. Primary schools were mapped using geographical information system data on PDAs and prevalence maps generated using ArcView GIS software. Overall, 65.6% (95% CI = 64.2-67.1%) of children were infected with one or more helminth species; 12.4% (95% CI = 11.4-13.4%) of children were infected with one or more STH species. Mean school prevalence of S. mansoni infection was 60.5% (95% CI = 59.0-62.0%), hookworms 8.4% (95% CI = 7.6-9.3%), A. lumbricoides 3.3% (95% CI = 2.7-3.8%), and T. trichiura 1.6% (95% CI = 1.2-2.0%). Interestingly, the mean S. mansoni prevalence was 2-fold higher on the islands (82%) compared to the mainland (41%) (z = 5.8755, P < 0.0001). Similarly, intensity of infection was 54% higher on the islands (217.2 ± 99.3) compared to the mainland (141.3 ± 123.7) (z = 3.9374, P < 0.0001). Schools in closest proximity to Lake Victoria had the highest S. mansoni prevalence while prevalence of STHs was more homogenously distributed. The very high prevalence of schistosomiasis in Mbita and the 4 islands is quite alarming, and indicates an urgent and critical need for control interventions. Findings from this survey indicate the need to implement treatment in remote areas not previously covered by mass drug administration programs.


Severely altered guanidino compound levels, disturbed body weight homeostasis and impaired fertility in a mouse model of guanidinoacetate N-methyltransferase (GAMT) deficiency.
We generated a knockout mouse model for guanidinoacetate N-methyltransferase (GAMT) deficiency (MIM 601240), the first discovered human creatine deficiency syndrome, by gene targeting in embryonic stem cells. Disruption of the open reading frame of the murine GAMT gene in the first exon resulted in the elimination of 210 of the 237 amino acids present in mGAMT. The creation of an mGAMT null allele was verified at the genetic, RNA and protein levels. GAMT knockout mice have markedly increased guanidinoacetate (GAA) and reduced creatine and creatinine levels in brain, serum and urine, which are key findings in human GAMT patients. In vivo (31)P magnetic resonance spectroscopy showed high levels of PGAA and reduced levels of creatine phosphate in heart, skeletal muscle and brain. These biochemical alterations were comparable to those found in human GAMT patients and can be attributed to the very similar GAMT expression patterns found by us in human and mouse tissues. We provide evidence that GAMT deficiency in mice causes biochemical adaptations in brain and skeletal muscle. It is associated with increased neonatal mortality, muscular hypotonia, decreased male fertility and a non-leptin-mediated life-long reduction in body weight due to reduced body fat mass. Therefore, GAMT knockout mice are a valuable creatine deficiency model for studying the effects of high-energy phosphate depletion in brain, heart, skeletal muscle and other organs.


Blockade of glucagon signaling prevents or reverses diabetes onset only if residual β-cells persist.
Glucagon secretion dysregulation in diabetes fosters hyperglycemia. Recent studies report that mice lacking glucagon receptor (Gcgr(-/-)) do not develop diabetes following streptozotocin (STZ)-mediated ablation of insulin-producing β-cells. Here, we show that diabetes prevention in STZ-treated Gcgr(-/-) animals requires remnant insulin action originating from spared residual β-cells: these mice indeed became hyperglycemic after insulin receptor blockade. Accordingly, Gcgr(-/-) mice developed hyperglycemia after induction of a more complete, diphtheria toxin (DT)-induced β-cell loss, a situation of near-absolute insulin deficiency similar to type 1 diabetes. In addition, glucagon deficiency did not impair the natural capacity of α-cells to reprogram into insulin production after extreme β-cell loss. α-to-β-cell conversion was improved in Gcgr(-/-) mice as a consequence of α-cell hyperplasia. Collectively, these results indicate that glucagon antagonism could i) be a useful adjuvant therapy in diabetes only when residual insulin action persists, and ii) help devising future β-cell regeneration therapies relying upon α-cell reprogramming.


The evaluation of efficacy and safety of methotrexate and pioglitazone in psoriasis patients: A randomized, open-labeled, active-controlled clinical trial.
Psoriasis is a chronic inflammatory disease showing co-existence with metabolic syndrome (MS), as has been confirmed by numerous epidemiologic studies in recent times. In this study, the aim was to ascertain the beneficial effects of pioglitazone in psoriasis, simultaneously targeting the improvement of MS parameters. We conducted a prospective randomized open-labeled parallel-group interventional study in patients of moderate-to-severe chronic plaque psoriasis. A total of 90 patients were inducted in study and divided into three groups of standard treatment (methotrexate 7.5 mg/week for 12 weeks), active treatment (pioglitazone 15 mg tablets once daily for 12 weeks), and their combination. Primary outcome was taken as percentage Psoriasis Area and Severity Index (PASI) improvement from baseline; secondary outcomes were PASI-75, safety profile, and MS parameters. Intergroup evaluation of PASI score showed that standard treatment methotrexate and active treatment pioglitazone were comparable. Combination of methotrexate and pioglitazone proved superior in efficacy from both standard and active treatment in 8 and 12 weeks. Adverse drug reactions were mild and treated symptomatically. Pioglitazone and combination group also demonstrated beneficial efficacy in parameter of MS hence establishing it as a potential therapy in psoriasis with MS. Pioglitazone alone or in combination with standard treatment may be a safe alternative drug for psoriasis coexisting with MS proving beneficial for both.


Renal tissue thawed for 30 minutes is still suitable for gene expression analysis.
Some biosamples obtained from biobanks may go through thawing before processing. We aim to evaluate the effects of thawing at room temperature for different time periods on gene expression analysis. A time course study with four time points was conducted to investigate the expression profiling on 10 thawed normal mice renal tissue samples through Affymetrix GeneChip mouse gene 2.0 st array. Microarray results were validated by quantitative real time polymerase chain reactions (qPCR) on 6 candidate reference genes and 11 target genes. Additionally, we used geNorm plus and NormFinder to identify the most stably expressed reference genes over time. The results showed RNA degraded more after longer incubation at room temperature. However, microarray results showed only 240 genes (0.91%) altered significantly in response to thawing at room temperature. The signal of majority altered probe sets decreased with thawing time, and the crossing point (Cp) values of all candidate reference genes correlated positively with the thawing time (p<0.05). The combination of B2M, ACTB and PPIA was identified as the best choice for qPCR normalization. We found most target genes were stable by using this normalization method. However, serious gene quantification errors were resulted from improper reference genes. In conclusion, thirty minutes of thawing at room temperature has a limited impact on microarray and qPCR analysis, gene expression variations due to RNA degradation in early period after thawing can be largely reduced by proper normalization.


Achieving open access to conservation science.
Conservation science is a crisis discipline in which the results of scientific enquiry must be made available quickly to those implementing management. We assessed the extent to which scientific research published since the year 2000 in 20 conservation science journals is publicly available. Of the 19,207 papers published, 1,667 (8.68%) are freely downloadable from an official repository. Moreover, only 938 papers (4.88%) meet the standard definition of open access in which material can be freely reused providing attribution to the authors is given. This compares poorly with a comparable set of 20 evolutionary biology journals, where 31.93% of papers are freely downloadable and 7.49% are open access. Seventeen of the 20 conservation journals offer an open access option, but fewer than 5% of the papers are available through open access. The cost of accessing the full body of conservation science runs into tens of thousands of dollars per year for institutional subscribers, and many conservation practitioners cannot access pay-per-view science through their workplace. However, important initiatives such as Research4Life are making science available to organizations in developing countries. We urge authors of conservation science to pay for open access on a per-article basis or to choose publication in open access journals, taking care to ensure the license allows reuse for any purpose providing attribution is given. Currently, it would cost $51 million to make all conservation science published since 2000 freely available by paying the open access fees currently levied to authors. Publishers of conservation journals might consider more cost effective models for open access and conservation-oriented organizations running journals could consider a broader range of options for open access to nonmembers such as sponsorship of open access via membership fees.


Erectile dysfunction, metabolic syndrome, and cardiovascular risks: facts and controversies.
Erectile dysfunction (ED) is the most common male sexual dysfunction, and shares many risk factors with systemic conditions including cardiovascular disease (CVD) and the metabolic syndrome (MetS). ED is considered to be an independent risk factor for CVD and can be a harbinger of future cardiovascular events. Given this relationship, each encounter for ED should be viewed by healthcare providers as an opportunity to screen for CVD and other comorbid conditions, including the MetS, that can significantly affect a man's overall health. While universally accepted screening guidelines are lacking, expert panels do recommend an approach to risk stratification in men with ED. In this review, we discuss the current state of understanding of the relationship between ED, the MetS, and CV risk, and how this impacts the approach to the patient presenting with ED.


[Preventive health examinations of pregnant women in Denmark. Education, supervision and postgraduate education].
A questionnaire about the content of a concrete antenatal examination and their own qualifications was sent to a random sample consisting of 1/3 of general practitioners in Denmark, all of the midwives who had antenatal consultations, the medical staffs of 26 departments of obstetrics and gynaecology and 26 surgical departments with more than 100 deliveries in 1985. The medical staffs could describe three different types of antenatal examinations depending upon the place and function. The percentages of replies received were 62 for general practice, 86 for midwives and 63, 69 and 55 for the medical staffs of the institutions involved. 49% of the general practitioners had worked in departments of obstetrics and gynaecology for at least six months. 62% of the doctors who described antenatal examination in week 16-18 were house officers or registrars and 28% were specialists. Among the medical staff who described an antenatal examination of a woman with an at risk pregnancy, 61% were consultants or senior registrars and 49% were specialists. The commonest goal for postgraduate training where non-specialists were concerned was general practice. Supervision in one form or another was possible in all of the departments participating, as a rule because an experienced colleague was present in the outpatient department. Supervision may be improved by alterations in the working arrangements.


The evaluation of the acute toxicity and long term safety of hydroalcoholic extract of Sapthaparna (Alstonia scholaris) in mice and rats.
The acute and sub-acute toxic effects of various doses of hydroalcoholic extract of Alstonia scholaris (ASE) was studied in mice and rats. The acute toxicity in mice depended on the season of collection of plant. The highest acute toxicity was observed in the ASE prepared from the summer collection followed by winter. The least toxicity was observed in the extract prepared from the bark of A. scholaris collected in the monsoon season. The administration of different doses of ASE showed a dose dependent increase in the toxicity in all species of mice. The Swiss albino mice were found to be the most sensitive followed by the DBA and C(57)BL. The crossbred mice were resistant when compared to the pure inbred strains. The oral administration of ASE was non-toxic up to a dose of 2000 mg/kg b. wt., while maximum number of animals succumbed to death after administration of 1100 mg/kg ASE by intraperitoneal route. The rats were more sensitive than the mice as the LD(50) dose of ASE was lesser for the former than the latter. The sub-acute toxicity in the rats was carried out with 120 and 240 mg/kg b. wt. ASE (1/10th and 1/5th of the LD(50) dose of ASE). The 240 mg was observed to be more toxic than 120 mg/kg ASE since it caused mortality and deformity in various organs of the recipient animals. The various biochemical parameters like AST, ALT, ACP, ALP, CK, LDH, creatinine, urea, ammonia, glucose and LPx were higher at 240 mg/kg ASE when compared with the 120 mg and the non-drug treated animals. In contrast, the total protein, albumin, DNA, RNA, cholesterol, glucose, glutathione, total thiols declined in the 240 mg/kg ASE treated animals when compared with non-drug treated controls. The hematological analysis showed a dose dependent decrease in the RBC, WBC, hemoglobin, neutrophils and monocytes, while a significant increase in the lymphocytes, eosinophils and basophils was observed. The observed toxic effect of ASE may be due to the presence of echitamine. Our studies shows that at high doses, A. scholaris exhibited marked damage to all the major organs of the body.


High-dose eicosapentaenoic acid and docosahexaenoic acid supplementation reduces bone resorption in postmenopausal breast cancer survivors on aromatase inhibitors: a pilot study.
Postmenopausal breast cancer survivors are living longer; however, a common class of drugs, aromatase inhibitors (AI), depletes estrogen levels, promotes bone loss, and heightens fracture risk. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may offset AI effects to bone because of the known effects on cellular processes of bone turnover. Therefore, we hypothesized that 4 g of EPA and DHA daily for 3 mo would decrease bone turnover in postmenopausal breast cancer survivors on AI therapy in a randomized, double-blind, placebo controlled pilot study that included 38 women. At baseline and 3 mo, serum fatty acids, bone turnover, and inflammatory markers were analyzed. Serum EPA and DHA, total and long-chain (LC) omega (n)-3 polyunsaturated fatty acids (PUFA) increased, whereas arachidonic acid, total and LC n-6 PUFA, and the LC n-6:n-3 PUFA ratio decreased compared to placebo (all P < .05). Bone resorption was inhibited in the fish oil responders compared to placebo (P < .05). Inflammatory markers were not altered. This short-term, high-dose fish oil supplementation study's findings demonstrate that fish oil can reduce bone resorption; however, longer-term studies are needed to assess bone density preservation and to explore mechanistic pathways in this population at high risk for bone loss.


Carcinoma ex pleomorphic adenoma originating from ectopic salivary gland in the neck region: case report.
Carcinoma ex pleomorphic adenoma (CEPA) is the malignant salivary gland tumor originating from primary (de novo) or recurrent pleomorphic adenoma. Although parotid gland is the most common site, it can also be seen in submandibular gland or minor salivary glands. It can be seen rarely in head and neck region, such as oral cavity, trachea, nasal cavity and lacrimal gland. Although pleomorphic adenoma cases originating from ectopic salivary gland tissue in the neck region are present in the English literature, there is no published pleomorphic adenoma ex carcinoma case. In this case report we presented a CEPA as a 7.5 cm long neck mass in a 72-year-old woman originating from the submandibular region apart from submandibular gland. Difficulties in diagnosis and way to appropriate treatment are discussed with current literature.


Personal and professional values grading among midwifery students.
The purpose of this study was to determine the professional and personal values among midwifery students in Turkey and to identify whether the years of study affected these values. A total of 192 participants were asked to prioritize 16 professional and 36 personal values. The relationship between the year of study and value ranking was analyzed by Kruskal-Wallis test. The first three of the professional values were justice, equality, and human dignity. Equality ranked sixth among the personal terminal values, and it increased with the years of study. Of personal instrumental values, responsibility and cleanliness ranked second and fifth, which are of central importance for the profession of midwifery. However, the other two important values, privacy and preventing unnecessary suffering, ranked lower when the years of study increased, in other words when the students confront clinics. Since these values are important for midwifery, ethics courses should be given throughout the midwifery education to prepare students for the challenges they face in the clinical environment.


Cytotoxic epipolythiodioxopiperazine alkaloids from filamentous fungi of the Bionectriaceae.
Bioactivity-directed fractionation of the organic extracts of two filamentous fungi of the Bionectriaceae, strains MSX 64546 and MSX 59553 from the Mycosynthetix library, led to the isolation of a new dimeric epipolythiodioxopiperazine alkaloid, verticillin H (1), along with six related analogs, Sch 52900 (2), verticillin A (3), gliocladicillin C (4), Sch 52901 (5), 11'-deoxyverticillin A (6) and gliocladicillin A (7). The structures of compounds 1-7 were determined by extensive NMR and HRMS analyses, as well as by comparisons to the literature. All compounds (1-7) were evaluated for cytotoxicity against a panel of human cancer cell lines, displaying IC(50) values ranging from 1.2 μM to 10 nM. Compounds 1-5 were examined for activity in the NF-κB assay, where compounds 2 and 3 revealed activity in the sub-micromolar range. Additionally, compounds 1, 3 and 4 were tested for EGFR inhibition using an enzymatic assay, while compound 3 was examined against an overexpressing EGFR(+ve) cancer cell line.


Relationship between contrast adaptation and orientation tuning in V1 and V2 of cat visual cortex.
Previous studies investigating the response properties of neurons in the primary visual cortex of cats and primates have shown that prolonged exposure to optimally oriented, high-contrast gratings leads to a reduction in responsiveness to subsequently presented test stimuli. We recorded from 119 neurons in cat V1 and V2 and found that in a high proportion of cells contrast adaptation also occurs for gratings oriented orthogonal to a neuron's preferred orientation, even though this stimulus did not elicit significant increases in spiking activity. Approximately 20% of neurons adapted equally to all orientations tested and a further 46% showed at least some adaptation to orthogonally oriented gratings, whereas 20% of neurons did not adapt to orthogonal gratings. The magnitude of contrast adaptation was positively correlated with adapting contrast, but was not related to the spiking activity of the cells. Highly direction selective neurons produced stronger adaptation to orthogonally oriented gratings than other neurons. Orientation-related adaptation was correlated with the rate of change of orientation tuning in consecutive cells along electrode penetrations that traveled parallel to the cortical layers. Nonoriented adaptation was most common in areas where orientation preference changed rapidly, whereas orientation-selective adaptation was most common in areas where orientation preference changed slowly. A minority of neurons did not show contrast adaptation (14%). No major differences were found between units in different cortical layers, V1 and V2, or between complex and simple cells. The relevance of these findings to the current understanding of adaptation within the context of orientation column architecture is discussed.


Effects of tamoxifen on cell cycle progression of synchronous MCF-7 human mammary carcinoma cells.
The effects of tamoxifen on cell cycle progression and clonogenic survival have been examined using synchronized cultures of MCF-7 human mammary carcinoma cells. Cell synchrony was induced by mitotic selection. Subsequent cell cycle analyses, using DNA flow cytometry, showed that 85% of synchronized cells had a mean cell cycle time of 21.3 hr with mean phase durations of 9 hr for G0-G1, 9.3 hr for S, and 3 hr for G2 + M. A slowly cycling or noncycling subpopulation comprising 15% of the total population was also observed. Exposure to tamoxifen (5 to 12.5 microM) resulted in a dose-dependent reduction in the number of cells progressing through G0-G1 and entering S phase. Those cells which were not retained in G0-G1, however, appeared to traverse G0-G1 and the remainder of the cell cycle at a rate only slightly less than that of untreated controls. Further experiments demonstrated that the major sensitivity to tamoxifen in terms of both inhibition of cell cycle progression and drug cytotoxicity was restricted to a short interval in the middle of G0-G1. This 2- to 4-hr period of maximum drug sensitivity began approximately 4 hr after mitotic selection, with drug exposures outside this time frame having markedly fewer effects. The significance of these observations in the light of previous studies with asynchronous populations of MCF-7 cells is discussed.


Anabolic-androgenic steroids and the risk of imprisonment.
The use of Anabolic-Androgenic Steroids (AAS) has been associated with increased aggressiveness and violent behavior. We therefore investigated the proposed correlation between the use of AAS and criminality while controlling for important socio-economics covariates and for psychiatric comorbidity. The primary endpoints were prison sentences, and time to first prison sentence. A retrospective matched cohort study design consisting of 545 males, who tested positive for AAS in Danish gyms during the period January 3, 2006 to January 31, 2017. They were matched with 5450 randomly chosen male controls. Data were cross-referenced with national register information on education, employment status, substance abuse and psychiatric comorbidity. In addition, 638 males sanctioned because they rejected to participate in the doping control and 6380 controls were used as a replication cohort. Already at baseline, 20.6% of the AAS users had a previous prison sentence whereas the rate was 3.7% in the control cohort (p < 0.0001). During the follow-up period the cumulative prevalence increased to 29.5% and 4.9%, respectively (unadjusted HR 9.15, 95% CI 6.33-13.20). The associations remained highly significant after controlling for socio-economic factors, drug abuse and psychiatric comorbidity. The results could be replicated in a similar cohort. Our study shows that AAS users have a 9-fold increased risk of being convicted of a crime compared to matched controls, randomly chosen from the general population. This association could not be explained by common socioeconomic factors or by psychiatric comorbidity.


Changing Brain Networks Through Non-invasive Neuromodulation.
Background/Objective: Non-invasive neuromodulation techniques, such as repetitive Transcranial Magnetic Stimulation (rTMS) and transcranial Direct Current Stimulation (tDCS), have increasingly been investigated for their potential as treatments for neurological and psychiatric disorders. Despite widespread dissemination of these techniques, the underlying therapeutic mechanisms and the ideal stimulation site for a given disorder remain unknown. Increasing evidence support the possibility of non-invasive neuromodulation affecting a brain network rather than just the local stimulation target. In this article, we present evidence in a clinical setting to support the idea that non-invasive neuromodulation changes brain networks. Method: This article addresses the idea that non-invasive neuromodulation modulates brain networks, rather than just the local stimulation target, using neuromodulation studies in tinnitus and major depression as examples. We present studies that support this hypothesis from different perspectives. Main Results/Conclusion: Studies stimulating the same brain region, such as the dorsolateral prefrontal cortex (DLPFC), have shown to be effective for several disorders and studies using different stimulation sites for the same disorder have shown similar results. These findings, as well as results from studies investigating brain network connectivity on both macro and micro levels, suggest that non-invasive neuromodulation affects a brain network rather than just the local stimulation site targeted. We propose that non-invasive neuromodulation should be approached from a network perspective and emphasize the therapeutic potential of this approach through the modulation of targeted brain networks.


The influence of comorbidities on overall survival among older women diagnosed with breast cancer.
Previous studies have shown that summary measures of comorbid conditions are associated with decreased overall survival in breast cancer patients. However, less is known about associations between specific comorbid conditions on the survival of breast cancer patients. The Surveillance, Epidemiology, and End Results-Medicare database was used to identify primary breast cancers diagnosed from 1992 to 2000 among women aged 66 years or older. Inpatient, outpatient, and physician visits within the Medicare system were searched to determine the presence of 13 comorbid conditions present at the time of diagnosis. Overall survival was estimated using age-specific Kaplan-Meier curves, and mortality was estimated using Cox proportional hazards models adjusted for age, race and/or ethnicity, tumor stage, cancer prognostic markers, and treatment. All statistical tests were two-sided. The study population included 64,034 patients with breast cancer diagnosed at a median age of 75 years. None of the selected comorbid conditions were identified in 37,306 (58%) of the 64,034 patients in the study population. Each of the 13 comorbid conditions examined was associated with decreased overall survival and increased mortality (from prior myocardial infarction, adjusted hazard ratio [HR] of death = 1.11, 95% CI = 1.03 to 1.19, P = .006; to liver disease, adjusted HR of death = 2.32, 95% CI = 1.97 to 2.73, P < .001). When patients of age 66-74 years were stratified by stage and individual comorbidity status, patients with each comorbid condition and a stage I tumor had similar or poorer overall survival compared with patients who had no comorbid conditions and stage II tumors. In a US population of older breast cancer patients, 13 individual comorbid conditions were associated with decreased overall survival and increased mortality.


Phase I/II study of combination therapy with S-1 and CPT-11 for metastatic colorectal cancer.
We conducted a Phase I/II study of combination therapy using CPT-11 and S-1 as a first-line treatment for metastatic colorectal cancer. The 28-day treatment cycle consisted of S-1 administered orally from day 1 to 21 and CPT-11 administered intravenously on days 1 and 15. In the Phase I portion, the dose of S-1 was fixed at 80 mg/m2/day, while CPT-11 was administered at a starting dose of 60 mg/m2 then stepped up in 20 mg/m2 increments. The maximum-tolerated dose was achieved at 80 mg/m2 of CPT-11, and the recommended dose was determined to be 60 mg/m2 of CPT-11. In the Phase II portion, this therapy exhibited a response rate of 58%, a median progression-free survival of 8.4 months, and a median overall survival of 18.7 months. Toxicity was generally mild and manageable. No patient showed grade 4 toxicity, and grade 3 toxicity was observed in only 18% of patients. The most frequently observed grade 3 toxicity was diarrhea, at a rate of 6%. The mean relative dose intensity of CPT-11 and S-1 was as high as 98 and 97%, respectively. In conclusion, combination therapy with CPT-11 and S-1 according to our treatment schedule is effective, safe and highly feasible for metastatic colorectal cancer patients. These data suggest that assessing this combination therapy in a Phase III study would be worthwhile.


A general framework for analyzing sustainability of social-ecological systems.
A major problem worldwide is the potential loss of fisheries, forests, and water resources. Understanding of the processes that lead to improvements in or deterioration of natural resources is limited, because scientific disciplines use different concepts and languages to describe and explain complex social-ecological systems (SESs). Without a common framework to organize findings, isolated knowledge does not cumulate. Until recently, accepted theory has assumed that resource users will never self-organize to maintain their resources and that governments must impose solutions. Research in multiple disciplines, however, has found that some government policies accelerate resource destruction, whereas some resource users have invested their time and energy to achieve sustainability. A general framework is used to identify 10 subsystem variables that affect the likelihood of self-organization in efforts to achieve a sustainable SES.


Grip force control is dependent on task constraints in children with and without developmental coordination disorder.
Excessive grip force (GF) is often found in children with developmental coordination disorder (DCD). However, their GF control may vary when task constraints are imposed upon their motor performance. This study aimed to investigate how their GF control changes in response to task demands, and to examine their tactile sensitivity. Twenty-one children with DCD and 17 controls participated in the study. The instrument used to measure GF was a cylindrical cup equipped with a load cell. The children were asked to hold and transport three cups with varying physical properties as quickly as possible. For tactile function, static and moving two-point discrimination senses were recorded. Data were analyzed using repeated-measures analysis of covariance. Children with DCD displayed slower rate of GF generation, which might be related to their lower sensitivity of two-point dynamic discrimination. Given the slow rate of GF generation and time constraint, the peak GF for children with DCD was lower than that for the control children, but the peak GF of both the groups depended on the time allowed for the performance and the task demand. Both the groups of children cautiously modulated the grip when the cup was filled with water, and graded GF according to the physical property of the cup. We conclude that GF control in children with or without DCD was task dependent.


Lipid Droplet Motility Increases Following Viral Immune Stimulation.
Lipid droplets (LDs) have traditionally been thought of as solely lipid storage compartments for cells; however, in the last decade, they have emerged as critical organelles in health and disease. LDs are highly dynamic within cells, and their movement is critical in organelle-organelle interactions. Their dynamics are known to change during cellular stress or nutrient deprivation; however, their movement during pathogen infections, especially at very early timepoints, is under-researched. This study aimed to track LD dynamics in vitro, in an astrocytic model of infection. Cells were either stimulated with a dsRNA viral mimic, poly I:C, or infected with the RNA virus, Zika virus. Individual LDs within infected cells were analysed to determine displacement and speed, and average LD characteristics for multiple individual cells calculated. Both LD displacement and mean speed were significantly enhanced in stimulated cells over a time course of infection with an increase seen as early as 2 h post-infection. With the emerging role for LDs during innate host responses, understanding their dynamics is critical to elucidate how these organelles influence the outcome of viral infection.


The characteristics of acute non-fatal medication-related events attended by ambulance services in the Melbourne Metropolitan Area 1998-2002.
To describe the characteristics of non-fatal medication-related ambulance attendances in Melbourne. A retrospective analysis of 16 705 patient care records completed by ambulance paramedics in Melbourne where medications had a causal role in the attendance. A single medication only was implicated in 11 765 cases (70% of the total). Of these, 85% involved one of six types of medication: benzodiazepines (52%), paracetamol (15%), selective serotonin re-uptake inhibitors (6.5%), combination paracetamol and opioids (4%), phenothiazines (3.4%) and tricyclic antidepressants (TCA) (3.7%). Cases involving benzodiazepines were significantly (P < 0.001) older (Average = 37 years) than those involving paracetamol (Average = 30 years). Thirty-four per cent of cases involved concurrent alcohol use, and this varied according to drug type (paracetamol 26%, benzodiazepines 40%, selective serotonin re-uptake inhibitors 35%, paracetamol and opioids 35%). An abnormal Glasgow Coma Scale score was found in 19% of cases, again varying according to drug type (paracetamol 10%, TCA 39%, benzodiazepines 21%, paracetamol and opioids 17%, phenothiazines 15%). Ten per cent of cases were not transported to hospital ranging from 3% for TCA to 13% for benzodiazepines. The majority of non-fatal medication events attended by ambulance paramedics involve one of six substances. Benzodiazepines were most commonly implicated and, as management may require only simple supportive treatment, significant numbers are not transported to hospital. The unique clinical population is identified in this study and the ongoing medical and psychiatric treatment of these patients not transported to hospital in the study period needs to be considered.


Histone H3 N-terminal mimicry drives a novel network of methyl-effector interactions.
The reader ability of PHD fingers is largely limited to the recognition of the histone H3 N-terminal tail. Distinct subsets of PHDs bind either H3K4me3 (a transcriptional activator mark) or H3K4me0 (a transcriptional repressor state). Structural studies have identified common features among the different H3K4me3 effector PHDs, including (1) removal of the initiator methionine residue of H3 to prevent steric interference, (2) a groove where arginine-2 binds, and (3) an aromatic cage that engages methylated lysine-4. We hypothesize that some PHDs might have the ability to engage with non-histone ligands, as long as they adhere to these three rules. A search of the human proteome revealed an enrichment of chromatin-binding proteins that met these criteria, which we termed H3 N-terminal mimicry proteins (H3TMs). Seven H3TMs were selected, and used to screen a protein domain microarray for potential effector domains, and they all had the ability to bind H3K4me3-interacting effector domains. Furthermore, the binding affinity between the VRK1 peptide and the PHD domain of PHF2 is ∼3-fold stronger than that of PHF2 and H3K4me3 interaction. The crystal structure of PHF2 PHD finger bound with VRK1 K4me3 peptide provides a molecular basis for stronger binding of VRK1 peptide. In addition, a number of the H3TMs peptides, in their unmethylated form, interact with NuRD transcriptional repressor complex. Our findings provide in vitro evidence that methylation of H3TMs can promote interactions with PHD and Tudor domain-containing proteins and potentially block interactions with the NuRD complex. We propose that these interactions can occur in vivo as well.


The impact of risk-averse operation on the likelihood of extreme events in a simple model of infrastructure.
A simple dynamic model of agent operation of an infrastructure system is presented. This system evolves over a long time scale by a daily increase in consumer demand that raises the overall load on the system and an engineering response to failures that involves upgrading of the components. The system is controlled by adjusting the upgrading rate of the components and the replacement time of the components. Two agents operate the system. Their behavior is characterized by their risk-averse and risk-taking attitudes while operating the system, their response to large events, and the effect of learning time on adapting to new conditions. A risk-averse operation causes a reduction in the frequency of failures and in the number of failures per unit time. However, risk aversion brings an increase in the probability of extreme events.


Neuron-astrocyte interactions, pyruvate carboxylation and the pentose phosphate pathway in the neonatal rat brain.
Glucose and acetate metabolism and the synthesis of amino acid neurotransmitters, anaplerosis, glutamate-glutamine cycling and the pentose phosphate pathway (PPP) have been extensively investigated in the adult, but not the neonatal rat brain. To do this, 7 day postnatal (P7) rats were injected with [1-(13)C]glucose and [1,2-(13)C]acetate and sacrificed 5, 10, 15, 30 and 45 min later. Adult rats were injected and sacrificed after 15 min. To analyse pyruvate carboxylation and PPP activity during development, P7 rats received [1,2-(13)C]glucose and were sacrificed 30 min later. Brain extracts were analysed using (1)H- and (13)C-NMR spectroscopy. Numerous differences in metabolism were found between the neonatal and adult brain. The neonatal brain contained lower levels of glutamate, aspartate and N-acetylaspartate but similar levels of GABA and glutamine per mg tissue. Metabolism of [1-(13)C]glucose at the acetyl CoA stage was reduced much more than that of [1,2-(13)C]acetate. The transfer of glutamate from neurons to astrocytes was much lower while transfer of glutamine from astrocytes to glutamatergic neurons was relatively higher. However, transport of glutamine from astrocytes to GABAergic neurons was lower. Using [1,2-(13)C]glucose it could be shown that despite much lower pyruvate carboxylation, relatively more pyruvate from glycolysis was directed towards anaplerosis than pyruvate dehydrogenation in astrocytes. Moreover, the ratio of PPP/glucose-metabolism was higher. These findings indicate that only the part of the glutamate-glutamine cycle that transfers glutamine from astrocytes to neurons is operating in the neonatal brain and that compared to adults, relatively more glucose is prioritised to PPP and pyruvate carboxylation. Our results may have implications for the capacity to protect the neonatal brain against excitotoxicity and oxidative stress.


Canary Prostate Active Surveillance Study: design of a multi-institutional active surveillance cohort and biorepository.
Active surveillance is a management plan for localized prostate cancer that offers selective delayed intervention on indication of disease progression, allowing patients to delay or avoid treatment and associated side-effects. Outcomes from centers that promote active surveillance are favorable, with high rates of disease-specific survival. However, there remains a need for prognostic variables or biomarkers that distinguish with high specificity the aggressive cancers that progress on surveillance from the indolent cancers. The Canary Prostate Active Surveillance Study is a multicenter study and a biorepository that will discover and confirm biomarkers of aggressive disease as defined by histologic, prostate-specific antigen, or clinical criteria.


Ellipsometry using imperfect polarizers.
Recent work in which reflection polarizers were used to make ellipsometric measurements in the far uv employed the tacit assumption that the incident light was in a coherent state of polarization. However, since the most general state of light is that of partial polarization, i.e., a mixture of polarized and unpolarized components, a significant modification to the experimental techniques used hitherto is shown to be necessary.


Relation between circulating leptin concentrations and appetite during a prolonged, moderate energy deficit in women.
On the basis of observations in rodents, leptin is thought to play a key role in the regulation of energy expenditure and food intake, but less is known of its influence on ingestive behavior and energy balance in humans. We examined the effect in women of a chronic energy deficit on plasma leptin concentrations and self-reported appetite and explored possible relations between leptin and appetite sensations. Twelve healthy women (body mass index, in kg/m2: 23-37) participated in a metabolic ward study in which 3 wk of neutral energy balance was followed by 12 wk of energy deficit (energy intake reduced by 2 MJ/d and energy expenditure increased by 0.8 MJ/d). Body weight and composition were monitored, fasting leptin concentrations were measured 4 times, and feelings of hunger, fullness, desire to eat, and prospective consumption were monitored hourly throughout the day on 7 selected days. Adiposity-adjusted leptin decreased by 54% after 1 wk of a moderate energy deficit and remained low after 6 and 12 wk. Leptin was associated with self-reported hunger, desire to eat, and prospective consumption (range of r: -0.6 to -0.7, P < 0.01). The greatest hunger increase coincided with the largest percentage drop in circulating leptin and the lowest final leptin concentration. The relation between leptin and hunger was not influenced by amount of weight or body fat loss. These findings support the idea that leptin is a physiologic regulator of hunger during energy deficits in humans; the role of leptin in the long-term regulation of food intake warrants further study.


An induced rebinding model of antigen discrimination.
T cells have to detect rare high-affinity 'foreign' peptide MHC (pMHC) ligands among abundant low-affinity 'self'-peptide MHC ligands. It remains unclear how this remarkable discrimination is achieved. Kinetic proofreading mechanisms can provide the required specificity but only at the expense of much reduced sensitivity. A number of recent observations suggest that pMHC engagement of T cell receptors (TCRs) induces changes such as clustering and/or conformational alterations that enhance subsequent rebinding. We show that inclusion of induced rebinding to the same pMHC in kinetic proofreading models enhances the sensitivity of TCR recognition while retaining specificity. Moreover, induced rebinding is able to reproduce the striking, and hitherto unexplained, 2D membrane-binding properties recently reported for the TCR.


Embedding covariate adjustments in tree-based automated machine learning for biomedical big data analyses.
A typical task in bioinformatics consists of identifying which features are associated with a target outcome of interest and building a predictive model. Automated machine learning (AutoML) systems such as the Tree-based Pipeline Optimization Tool (TPOT) constitute an appealing approach to this end. However, in biomedical data, there are often baseline characteristics of the subjects in a study or batch effects that need to be adjusted for in order to better isolate the effects of the features of interest on the target. Thus, the ability to perform covariate adjustments becomes particularly important for applications of AutoML to biomedical big data analysis. We developed an approach to adjust for covariates affecting features and/or target in TPOT. Our approach is based on regressing out the covariates in a manner that avoids 'leakage' during the cross-validation training procedure. We describe applications of this approach to toxicogenomics and schizophrenia gene expression data sets. The TPOT extensions discussed in this work are available at https://github.com/EpistasisLab/tpot/tree/v0.11.1-resAdj . In this work, we address an important need in the context of AutoML, which is particularly crucial for applications to bioinformatics and medical informatics, namely covariate adjustments. To this end we present a substantial extension of TPOT, a genetic programming based AutoML approach. We show the utility of this extension by applications to large toxicogenomics and differential gene expression data. The method is generally applicable in many other scenarios from the biomedical field.


The Effects of Early Antibiotic Administration on Bacterial Culture Growth From Hand Abscesses.
Traditional management of hand abscesses consists of withholding antibiotics prior to drainage to optimize bacterial culture growth and outcome. The purpose of this study was to determine the effect of preoperative empiric antibiotics on the rate of culture growth and rate of adverse events in patients with acute hand abscesses. We performed a retrospective review of prospectively collected data on 88 consecutive hand abscesses that received empiric antibiotics prior to incision and drainage from 2012 to 2013 at an urban academic institution. We analyzed patient demographics, bacteriology, culture growth results, time to surgery, and frequency of adverse events. The overall rate of positive culture growth was 90% (n = 79) despite running the antibiotics for a mean of 31 hours prior to debridement. Furthermore, 96% of the isolates were given a susceptible antibiotic during that time. The mean number of debridements was 1.5 per patient, but 4 re-operations were necessary for wound complications. No patients required an amputation or were upgraded to intensive care. Preoperative empiric antibiotic administration does not appear to greatly reduce bacterial culture growth from hand abscesses. The adverse events are relatively few for simple abscesses treated with pre-surgical antibiotics and decompression within 24 hours.


Primary sequence of paxillin contains putative SH2 and SH3 domain binding motifs and multiple LIM domains: identification of a vinculin and pp125Fak-binding region.
Paxillin is a cytoskeletal protein involved in actin-membrane attachment at sites of cell adhesion to the extracellular matrix. Extensive tyrosine phosphorylation of this protein occurs during integrin-mediated cell adhesion, embryonic development, fibroblast transformation and following stimulation of cells by mitogens that operate through the family of seven membrane-spanning G-protein-coupled receptors. Paxillin binds in vitro to the focal adhesion protein vinculin as well as to the SH3 domain of c-src and, when tyrosine phosphorylated, to the SH2 domain of v-crk. Here, we report the complementary DNA, and derived amino acid sequence, that codes for approximately 90% of the paxillin protein. We have identified a region in the amino-terminal half of the protein that supports the binding of both vinculin and the focal adhesion tyrosine kinase, pp125Fak. Although there is no significant overall homology with other identified proteins, the carboxyl third of paxillin contains one LIM domain and three LIM-like sequences. The LIM motif is common to a number of transcription factors and to two other focal adhesion proteins, zyxin and cysteine-rich protein. In addition to several potential tyrosine phosphorylation sites there are five tyrosine-containing sequences that conform to SH2-binding motifs. The protein also contains a short proline-rich region indicative of a SH3-binding domain. Taken together, these data suggest that paxillin is a unique cytoskeletal protein capable of interaction with a variety of intracellular signalling, and structural, molecules important in growth control and the regulation of cytoskeletal organization.(ABSTRACT TRUNCATED AT 250 WORDS)


Biochemical characterization of the 44G4 antigen from the HOON pre-B leukemic cell line.
The 44G4 antigen is expressed in high amounts on human endothelial cells and at low levels on leukemic cells of pre-B and myelomonocytic origin. Its level of expression on the pre-B leukemic HOON cell line used for derivation of the corresponding mAb is intermediate but sufficient to permit the purification of the Ag. The molecule isolated by immunoaffinity from HOON is a glycoprotein since it bound to Ricinus communis agglutinin, wheat germ agglutinin, and peanut agglutinin lectins. The Ag was purified 2400-fold from a soluble taurocholate extract of HOON cells by affinity to wheat germ agglutinin-agarose and 44G4-IgG-Sepharose. The purified glycoprotein is likely a homodimer as it migrated on SDS-PAGE with an apparent m.w. of 170,000, nonreduced, and 95,000, reduced. Removal of N-linked oligosaccharides by endoglycosidase F led to a decrease in m.w. of 25,000; if neuraminidase and O-glycanase were also present, the total decrease in m.w. was 33,000 suggesting a polypeptide chain of 62,000 and 8,000 in O-linked substitutions. The glycoprotein digested with N-glycanase, neuraminidase, or O-glycanase could still be immunoprecipitated with the 44G4 mAb indicating that the antigenic epitope resides in the polypeptide. By Western blot analysis, the dissociated but nonreduced protein was reactive with 44G4, whereas the reduced and alkylated protein was not. Therefore, the epitope is dependent on the presence of intact disulfide bond(s). Sequential immunoprecipitation with OKT9 and 44G4 antibodies indicated that these epitopes are present on two distinct molecules and that 44G4 is distinct from the transferrin receptor despite a similar subunit structure.


Non-sedation versus sedation with a daily wake-up trial in critically ill patients receiving mechanical ventilation (NONSEDA Trial): study protocol for a randomised controlled trial.
Through many years, the standard care has been to use continuous sedation of critically ill patients during mechanical ventilation. However, preliminary randomised clinical trials indicate that it is beneficial to reduce the sedation level. No randomised trial has been conducted comparing sedation with no sedation, a priori powered to have all-cause mortality as primary outcome.The objective is to assess the benefits and harms of non-sedation versus sedation with a daily wake-up trial in critically ill patients. The non-sedation (NONSEDA) trial is an investigator-initiated, randomised, clinical, parallel-group, multinational trial designed to include 700 patients from at least six ICUs in Denmark, Norway and Sweden.Inclusion criteria are mechanically ventilated patients with expected duration of mechanical ventilation >24 hours.Exclusion criteria are non-intubated patients, patients with severe head trauma, coma at admission or status epilepticus, patients treated with therapeutic hypothermia, patients with PaO2/FiO2 < 9 where sedation might be necessary to ensure sufficient oxygenation or place the patient in prone position.Experimental intervention is non-sedation supplemented with pain management during mechanical ventilation.Control intervention is sedation with a daily wake-up trial.The primary outcome will be all cause mortality at 90 days after randomization. Secondary outcomes will be: days until death throughout the total observation period; coma- and delirium-free days; highest RIFLE score; days until discharge from the intensive care unit (within 28 days); days until the participant is without mechanical ventilation (within 28 days); and proportion of patients with a major cardiovascular outcome. Explorative outcomes will be: all cause mortality at 28 days after randomisation; days until discharge from the intensive care unit; days until the participant is without mechanical ventilation; days until discharge from the hospital; organ failure.Trial size: we will include 700 participants (2 × 350) in order to detect or reject 25% relative risk reduction in mortality with a type I error risk of 5% and a type II error risk of 20% (power at 80%). The trial investigates potential benefits of non-sedation. This might have large impact on the future treatment of mechanically ventilated critically ill patients. ClinicalTrials.gov NCT0196768, 09.01.2014.


The short-term effect of a lymphatic pump protocol on blood cell counts in nursing home residents with limited mobility: a pilot study.
Lymphatic pump techniques have the potential to alter blood cell counts and thus enhance immune function in elderly adults with diminished mobility. To test whether an osteopathic manipulative treatment (OMT) protocol designed to enhance immune function will have an effect on lymphocyte and lymphocyte subset counts compared with a sham control group. The study design was a single-session, randomized, controlled clinical trial comparing a standardized lymphatic pump protocol with a light-touch protocol. Participants were assigned to 1 of 2 groups by using a 1:1 allocation ratio. The study was conducted in 2 rural long-term care facilities in Missouri. Residents in the long-term care facilities who were aged 60 years or older and who were confined to a bed or wheelchair for most of their waking hours. Twenty residents were recruited to participate in the study, and 10 were randomly assigned to each group. Baseline blood samples were obtained. Then each patient received a 6-minute study protocol treatment. Thirty minutes after completion, posttreatment blood samples were obtained. The OMT protocol consisted of 3 osteopathic techniques: myofascial release to the thoracic inlet, the splenic pump, and the pedal lymphatic pump. The light touch protocol was applied to the same body areas as the OMT protocol for 6 minutes. A pretreatment and posttreatment lymphocyte subset panel, complete blood cell count, and automated white blood cell count differential was obtained from each participant. There was a statistically significant between-group difference in mean change for platelet counts: counts in the OMT group decreased by a mean (standard deviation) of 15,400 (7947) platelets per microliter and the light touch group increased by 4,700 (17,857) platelets per microliter (P=.004). The between-group differences for the mean (standard deviation) absolute lymphocyte cell count, red blood cell count, hemoglobin level, and hematocrit measures all decreased, but the changes were not statistically significant relative to the control group. The OMT protocol used in this pilot study modestly reduced platelet counts in nursing home residents with limited mobility.


An Italian Retrospective Survey on Bone Metastasis in Melanoma: Impact of Immunotherapy and Radiotherapy on Survival.
We performed a multicenter retrospective observational study to investigate the impact of clinical-pathological features and therapeutic strategies on both the complications and survival of patients with bone metastases (BMs) from malignant melanoma. A total of 305 patients with melanoma and radiological evidence of BMs were retrospectively enrolled from 19 Italian centers. All patients received conventional treatments in accordance with each own treating physician's practice. Both univariate and multivariate models were used to explore the impact of melanoma features, including skeletal-related events (SREs), and different treatments on both overall survival (OS) and time-to-SREs. The chi-squared test evaluated the suitability of several parameters to predict the occurrence of SREs. Eighty-three percent of patients had metachronous BMs. The prevalent (90%) bone metastatic site was the spine, while 45% had involvement of the appendicular skeleton. Forty-seven percent experienced at least one SRE, including palliative radiotherapy (RT) in 37% of cases. No melanoma-associated factor was predictive of the development of SREs, although patients receiving early treatment with bone-targeted agents showed 62% lower risk and delayed time of SRE occurrence. Median OS from the diagnosis of bone metastasis was 10.7 months. The multivariate analysis revealed as independent prognostic factors the number of BMs, number of metastatic organs, baseline lactate dehydrogenase levels, and treatment with targeted therapy or immunotherapy. Subgroup analyses showed the best OS (median = 16.5 months) in the subset of patients receiving both immunotherapy and palliative RT. Based on our results, patients undergoing immunotherapy and palliative RT showed an OS benefit suggestive of a possible additive effect. The apparent protective role of bone targeting agent use on SREs observed in our analysis should deserve prospective evaluation.


Turing pattern dynamics in an activator-inhibitor system with superdiffusion.
The fractional operator is introduced to an activator-inhibitor system to describe species anomalous superdiffusion. The effects of the superdiffusive exponent on pattern formation and pattern selection are studied. Our linear stability analysis shows that the wave number of the Turing pattern increases with the superdiffusive exponent. A weakly nonlinear analysis yields a system of amplitude equations and the analysis of these amplitude equations predicts parameter regimes where hexagons, stripes, and their coexistence are expected. Numerical simulations of the activator-inhibitor model near the stability boundaries confirm our analytical results. Since diffusion rate manifests in both diffusion constant and diffusion exponent, we numerically explore their interactions on the emergence of Turing patterns. When the activator and inhibitor have different superdiffusive exponents, we find that the critical ratio of the diffusion rate of the inhibitor to the activator, required for the formation of the Turing pattern, increases monotonically with the superdiffusive exponent. We conclude that small ratio (than unity) of anomalous diffusion exponent between the inhibitor and activator is more likely to promote the emergence of the Turing pattern, relative to the normal diffusion.


Neuropsychological test performance in depressed and nondepressed collegiate athletes following concussion.
To examine neuropsychological test differences following concussion between collegiate athletes screening positive and negative for depression. Participants included 113 (91 male) college athletes, who were assessed at baseline and following diagnosis of sport-related concussion (SRC). The Beck Depression Inventory-Fast Screen was used as a screener for depression. Athletes were categorized as either depressed (≥4) or nondepressed (<4) following injury and compared on composites for memory and attention-processing speed. Groups were also compared on reliable change index scores from baseline, as well as on proportion of impaired scores. Depressed athletes performed significantly worse than did nondepressed athletes on the Memory Composite (p = .04, d = .51) but not on the Attention-Processing Speed Composite score (p = .15, d = .46). Chi-square tests indicated that, compared with nondepressed athletes, a significantly higher number of depressed athletes showed reliable decreases on the following test indices: Verbal Memory Composite of the Immediate Post-Concussion Assessment and Cognitive Testing (p = .03, φ = .21), Brief Visuospatial Memory Test-Revised Total (p = .02, φ = .22), and Hopkins Verbal Learning Test-Revised Total (p = .05, φ = .19). Chi-square test indicated that, compared with nondepressed athletes, a significantly higher proportion of depressed athletes met criteria for impairment (p = .02, φ = .23). Whether examining the data at the intraindividual or group level, there are memory deficits associated with the combination of an SRC and depression. The results highlight the importance of screening for depression to provide a more complete picture of an individual's functioning postconcussion. (PsycINFO Database Record (c) 2020 APA, all rights reserved).