Based on a multi-agent system for multi-scale simulation and application of household's LUCC: a case study for Mengcha village, Mizhi county, Shaanxi province.
Multi-Agent Systems (MAS) offer a conceptual approach to include multi-actor decision making into models of land use change. Through the simulation based on the MAS, this paper tries to show the application of MAS in the micro scale LUCC, and reveal the transformation mechanism of difference scale. This paper starts with a description of the context of MAS research. Then, it adopts the Nested Spatial Choice (NSC) method to construct the multi-scale LUCC decision-making model. And a case study for Mengcha village, Mizhi County, Shaanxi Province is reported. Finally, the potentials and drawbacks of the following approach is discussed and concluded. From our design and implementation of the MAS in multi-scale model, a number of observations and conclusions can be drawn on the implementation and future research directions. (1) The use of the LUCC decision-making and multi-scale transformation framework provides, according to us, a more realistic modeling of multi-scale decision making process. (2) By using continuous function, rather than discrete function, to construct the decision-making of the households is more realistic to reflect the effect. (3) In this paper, attempts have been made to give a quantitative analysis to research the household interaction. And it provides the premise and foundation for researching the communication and learning among the households. (4) The scale transformation architecture constructed in this paper helps to accumulate theory and experience for the interaction research between the micro land use decision-making and the macro land use landscape pattern. Our future research work will focus on: (1) how to rational use risk aversion principle, and put the rule on rotation between household parcels into model. (2) Exploring the methods aiming at researching the household decision-making over a long period, it allows us to find the bridge between the long-term LUCC data and the short-term household decision-making. (3) Researching the quantitative method and model, especially the scenario analysis model which may reflect the interaction among different household types.


Goniometry: is it a reliable tool to monitor passive joint range of motion in horses?
Simple objective assessment tools are essential to monitor the clinical efficacy of therapeutic interventions used in equine orthopaedics and rehabilitation. In human medicine, goniometry is a validated tool to quantify restrictions in joint range of motion (ROM); however, the technique is not validated in horses. To validate 2 different goniometry techniques for the measurement of passive flexion of the fetlock, carpus and hock by examining; 1) the intra- and inter-tester reliability; 2) the differences between 2 goniometry techniques and 3) differences between standing and anaesthetised horses. The study is composed of three parts: 1) the intra- and inter-tester reliability was examined on 10 horses, where each horse was assessed by 5 pairs of testers measuring ROM with a universal goniometer; 2) the differences between 2 goniometry techniques were examined on 14 horses, each assessed by 2 investigators (either working in pairs with one investigator holding the limb and the other measuring the joint angle, or working individually at the same time holding and measuring); 3) on 6 horses, the differences between standing and anaesthetised horses were assessed by 2 investigators with the same techniques as described above. Nonparametric tests (Mann-Whitney, Wilcoxon sign-rank) and Intraclass Correlation Coefficient (ICC) were used for statistical analysis (P < 0.05). 1) The intra-tester reliability was high to excellent (ICC 0.8-1) and the inter-tester reliability low to average (ICC 0.1-0.5); 2) significant differences in joint ROM were registered in carpus and hock when measuring in pairs compared to singly and 3) significant differences in joint ROM were registered measuring anaesthetised compared to standing horses. As shown in human studies, goniometry is a promising tool in documenting passive flexion of fetlock, carpus and hock, if used by the same investigator. However, additional studies are needed for further validation.


Annual plankton community metabolism in estuarine and coastal waters in Perth (Western Australia).
The planktonic metabolic balance that is the balance between gross primary production (GPP) and community respiration (CR) was determined in Matilda Bay (estuarine) and Woodman Point (coastal) in Perth, Western Australia. The rates of net community production (NCP = GPP - CR) and the ratio between GPP and CR (P/R) were assessed to evaluate whether the metabolic balance in the two coastal locations tends to be net autotrophic (production exceeding community respiration) or net heterotrophic (respiration exceeding production). We also analyzed environmental variability by measuring temperature, salinity, and nutrients and chlorophyll a concentration. Samples were collected biweekly from March 2014 to March 2015. During the study period the metabolic rates were three times higher in Matilda Bay than in Woodman Point. The predominant metabolism was net autotrophic at both sites with P/R ratios >1 in the majority of the sampling dates. In Matilda Bay, the metabolic rates were negatively correlated with salinity denoting river dynamics influence, and positively with chlorophyll a. In Woodman Point only the GPP was positively correlated with chlorophyll a. The positive correlation between P/R ratio and GPP in Matilda Bay and the positive correlations between the metabolic rates and chlorophyll a suggest that factors controlling autotrophic processes are modulating the planktonic metabolic balance in the coastal marine ecosystem in Perth. Significant correlations were found between CR and GPP-standardized to chlorophyll a and water temperature. The net autotrophic metabolic balance indicates that in both ecosystems planktonic communities are acting as a sink of CO2 and as a source of organic matter and oxygen to the system and are able to export organic matter to other ecosystems.


The influence of the conditions of hematopoietic cell transplantation on infectious complications.
The multitude of factors that influence the risk of infection after hematopoietic cell transplantation has been further complicated by the rapid evolution of this therapy in the past 5 years. The degree to which functional immune reconstitution has been achieved reflects the equilibrium reached by the immune systems of the recipient and donor in the context of host non-hematopoietic tissue. Thus immunomodulatory influences on the recipient and the transplanted graft, both before and after hematopoietic cell transplantation, have a profound influence on the incidence and severity of infection. This review of the recent literature contributes to our understanding of how the conditions of hematopoietic cell transplantation influence the timing and nature of infectious complications. The main themes of published primary research from 2004 to the present focus on non-myeloablative conditioning regimens and their effects on immune reconstitution after hematopoietic cell transplantation. A plethora of clinical trials are ongoing, focused on the outcome after conditioning regimens designed to result in less regimen-related toxicity while preserving or enhancing the graft-versus-tumor effect. Given the infancy of these new approaches, it is not possible to make definitive statements regarding the relative risk of serious infection with each therapy. It is clear that a reduction in regimen-related non-infectious complications or mortality does not necessarily ensure a reduction in clinically significant infections. Improvements in early diagnostic and therapeutic options for these infections now bring us to an era of understanding pathogens as probes of the functional reconstitution of immunity.


Pores in n-Type InP: A Model System for Electrochemical Pore Etching.
The growth mechanism of currentline-oriented pores in n-type InP has been studied by Fast-Fourier-Transform Impedance Spectroscopy (FFT IS) applied in situ during pore etching and by theoretical calculations. Several pore growth parameters could thus be extracted in situ that are otherwise not obtainable. These include the space-charge-region (SCR) width, the SCR potential, the capacitance at the pore tips, and the avalanche breakdown field strength. It could be demonstrated that the system adjusts itself in such a way that the potential across the space-charge-region at the pore tips is kept constant within a certain bandwidth of the applied potential. This provides for a constant field strength at the pore tips, ensuring that avalanche breakdown occurs, generating the necessary holes for the electrochemical dissolution of InP.


Integration of regulatory networks by NKX3-1 promotes androgen-dependent prostate cancer survival.
The NKX3-1 gene is a homeobox gene required for prostate tumor progression, but how it functions is unclear. Here, using chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq) we showed that NKX3-1 colocalizes with the androgen receptor (AR) across the prostate cancer genome. We uncovered two distinct mechanisms by which NKX3-1 controls the AR transcriptional network in prostate cancer. First, NKX3-1 and AR directly regulate each other in a feed-forward regulatory loop. Second, NKX3-1 collaborates with AR and FoxA1 to mediate genes in advanced and recurrent prostate carcinoma. NKX3-1- and AR-coregulated genes include those found in the "protein trafficking" process, which integrates oncogenic signaling pathways. Moreover, we demonstrate that NKX3-1, AR, and FoxA1 promote prostate cancer cell survival by directly upregulating RAB3B, a member of the RAB GTPase family. Finally, we show that RAB3B is overexpressed in prostate cancer patients, suggesting that RAB3B together with AR, FoxA1, and NKX3-1 are important regulators of prostate cancer progression. Collectively, our work highlights a novel hierarchical transcriptional regulatory network between NKX3-1, AR, and the RAB GTPase signaling pathway that is critical for the genetic-molecular-phenotypic paradigm in androgen-dependent prostate cancer.


Thyroid hormones in male hamsters with activated pineals or melatonin treatment.
Blinding resulted in gonadal and prostatic atrophy and reduced plasma thyroxine (T4), free T4 index (FT4I) and reverse triiodothyronine (rT3) levels in adult male hamsters housed in light-to-dark, 14:10 h. Similar effects were seen after daily evening injections of 25 microgram melatonin. Pinealectomy prevented the effects of blinding or melatonin injections. There were no pineal- or melatonin-induced decrements in T3 or thyrotrophin (TSH) concentrations. TSH was elevated by blinding in one experiment but not in another, despite suppression of T4 and FT4I in both. Orally administered melatonin (approximately 245 microgram daily in drinking water through the evening and night) reduced the weight of testes and prostates and slightly lowered plasma T4 and FT4I, indicating the effectiveness of melatonin by this route. The capability of the pineal and of melatonin to suppress plasma T4 is not a result of sex-steroid-induced alteration of plasma binding but is most likely a result of variable suppression of the pituitary-thyroid axis at the level of TSH regulation and also at the level of T4 secretion and/or metabolism. Reduced rT3, but not T3 levels after blinding, may reflect the pineal-induced deficit in T4 as a substrate for rT3 formation, altered peripheral conversion of T4 or altered disposal of thyroid hormones.


Gamma-vinyl GABA reduces paired pulse inhibition in the rat dentate gyrus in vivo and in vitro.
Gamma vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, has anticonvulsant effects. GVG increases GABA levels in the brain by blocking its degradation, and is presumed to enhance GABAergic inhibition, however, in some cases it exacerbates seizures. We investigated the effects of GVG in vivo and in vitro on paired pulse inhibition (PPI) recorded in the rat dentate gyrus (DG) evoked by perforant path stimulation. At 2.5 h and 24 h after administration of GVG (1 g/kg, i.p.), there was a loss of PPI at both 15- and 25-ms interpulse intervals (IPI). Activation of presynaptic GABA(B) autoreceptors could explain this in vivo effect. We therefore further investigated the effects of co-application of GVG with the GABA(B) antagonists 2-OH saclofen (saclofen) or CGP 35348 (CGP) on PPI in hippocampal slices by in vitro study. Bath application of GVG (400 and 500 microM) not only resulted in a loss of perforant path evoked PPI at a 15-ms IPI, but produced facilitation of the second population spike relative to the first. Co-application of saclofen (250 microM) with GVG (500 microM) prevented facilitation of the second response of a paired-pulse. The facilitation of the second stimulation response produced by GVG (400 microM) was converted to inhibition by bath application of CGP 35348 (400 microM). These results suggest that activation of presynaptic GABA(B) receptors by increased extracellular GABA may be one of the contributing factors to the apparent paradoxical effect of GVG on PPI in the DG.


Health Services Use and Costs for Americans With Intellectual and Developmental Disabilities: A National Analysis.
Health services and associated costs for adults with intellectual and developmental disabilities (IDD) were nationally profiled and the predictors of high expense users statistically modeled. Using linked data from the National Health Interview Survey and Medical Expenditure Panel Survey for the years 2002 through 2011, the study found a mixed pattern of differences in rates of service use and costs when compared to the general population depending upon personal characteristics, health status, and type of health care service. Prescription medication costs were the primary driver of total health care expenditures for Americans with IDD. The presence of secondary chronic health conditions and poor mental health status were the consistent predictors of high expense users across types of health care. Study results are discussed in terms of implications for more nuanced evaluations of health care costs and need for recurring surveillance of health care for Americans with IDD in the years following passage of the Patient Protection and Affordable Care Act.


Complete genome sequence of Cellulophaga algicola type strain (IC166).
Cellulophaga algicola Bowman 2000 belongs to the family Flavobacteriaceae within the phylum 'Bacteroidetes' and was isolated from Melosira collected from the Eastern Antarctic coastal zone. The species is of interest because its members produce a wide range of extracellular enzymes capable of degrading proteins and polysaccharides with temperature optima of 20-30°C. This is the first completed genome sequence of a member of the genus Cellulophaga. The 4,888,353 bp long genome with its 4,285 protein-coding and 62 RNA genes consists of one circular chromosome and is a part of the Genomic Encyclopedia of Bacteria and Archaea project.


Structure-activity relationships of GPR120 agonists based on a docking simulation.
GPR120 is a G protein-coupled receptor expressed preferentially in the intestinal tract and adipose tissue, that has been implicated in mediating free fatty acid-stimulated glucagon-like peptide-1 (GLP-1) secretion. To develop GPR120-specific agonists, a series of compounds (denoted as NCG compounds) derived from a peroxisome proliferator-activated receptor γ agonist were synthesized, and their structure-activity relationships as GPR120 agonists were explored. To examine the agonistic activities of these newly synthesized NCG compounds, and of compounds already shown to have GPR120 agonistic activity (grifolic acid and MEDICA16), we conducted docking simulation in a GPR120 homology model that was developed on the basis of a photoactivated model derived from the crystal structure of bovine rhodopsin. We calculated the hydrogen bonding energies between the compounds and the GPR120 model. These energies correlated well with the GPR120 agonistic activity of the compounds (R(2) = 0.73). NCG21, the NCG compound with the lowest calculated hydrogen bonding energy, showed the most potent extracellular signal-regulated kinase (ERK) activation in a cloned GPR120 system. Furthermore, NCG21 potently activated ERK, intracellular calcium responses and GLP-1 secretion in murine enteroendocrine STC-1 cells that express GPR120 endogenously. Moreover, administration of NCG21 into the mouse colon caused an increase in plasma GLP-1 levels. Taken together, our present study showed that a docking simulation using a GPR120 homology model might be useful to predict the agonistic activity of compounds.


Protective Effects of Quercetin Against Cadmium Chloride-Induced Oxidative Injury in Goat Sperm and Zygotes.
Quercetin, a plant-derived flavonoid, is frequently used as an antioxidant for efficient anti-oxidative capacity. However, whether quercetin has protective effects on goat sperm and preimplantation embryos against Cd2+-induced oxidative injury is still unclear. So, we researched the influence of quercetin on goat sperm and zygotes respectively under the oxidative stress induced by Cd2+. In our study, quercetin decreased the malonaldehyde (MDA) and reactive oxygen species (ROS) levels caused by Cd2+ in goat sperm (p < 0.05), which facilitated sperm characteristics including motility, survival rates, membrane integrity, and mitochondria activity during storage in vitro and subsequent embryo development (p < 0.05). Moreover, in goat zygotes, quercetin decreased peroxidation products including ROS, MDA, and carbonyl through preserving or maintaining mitochondrial function, gene expression, and anti-oxidative products such as glutathione peroxidase, superoxide dismutase, and catalase, which ameliorated subsequent embryo development and embryo quality (p < 0.05). Taken together, these results suggest that quercetin protects both goat sperm and preimplantation embryos from Cd2+-induced oxidative stress.


Relative dominance of physical versus chemical effects on the transport of adhesion-deficient bacteria in intact cores from South Oyster, Virginia.
Bacterial transport experiments were conducted using intact sediment cores collected from sites on the Delmarva Peninsula near South Oyster, VA, to delineate the relative importance of physical and chemical heterogeneity in controlling transport of an adhesion-deficient bacterial strain. Electron microscopy revealed that the sediments consisted of quartz and feldspar with a variable amount of clay and iron and aluminum hydroxide coatings on the grains. A nonmotile, gram-negative indigenous groundwater strain, designated as Comamonas sp. DA001, was injected into the cores along with a conservative tracer bromide (Br). DA001 cells were 1.2 x 0.6 microm in size with a hydrophilic surface and a slightly negative surface charge. Bacterial breakthrough preceded that of Br. This differential advection phenomenon can be accounted for by reduction of the effective porosity for the bacteria relative to Br. The distribution of cells remaining in the core as determined by scintillation counting and phosphor imaging techniques was variable, ranging from nearly uniform concentrations throughout the core to exponentially decreasing concentrations with distance from the point of injection. The fraction of bacterial retention in the core was positively correlated with the abundance of the metal hydroxides and negatively correlated with grain size. Because grain size was inversely correlated with the abundance of the metal hydroxide coatings, it was necessary to separate the effects of grain size and mineralogy. The fraction of the bacterial retention accounting for the effect of grain size, the collision efficiency, exhibited no correlation with the abundance of the metal hydroxides, indicating that the bacterial retention was primarily controlled by grain size. Reasons for the lack of influence of mineralogy on bacterial transport include (i) the slightly negatively charged bacterial surfaces; (ii) an insufficient heterogeneity of sediment surface properties; and (iii) the masking of the positive charge of the metal hydroxide surfaces by adsorbed organic carbon (up to 1180 ppm). This study demonstrates that the laboratory-based bacterial transport experiments are effective in delineating physical versus chemical controlling factors and provide an important link to field-based bacterial transport studies.


Contrasting patterns in crop domestication and domestication rates: recent archaeobotanical insights from the Old World.
Archaeobotany, the study of plant remains from sites of ancient human activity, provides data for studying the initial evolution of domesticated plants. An important background to this is defining the domestication syndrome, those traits by which domesticated plants differ from wild relatives. These traits include features that have been selected under the conditions of cultivation. From archaeological remains the easiest traits to study are seed size and in cereal crops the loss of natural seed dispersal. The rate at which these features evolved and the ordering in which they evolved can now be documented for a few crops of Asia and Africa. This paper explores this in einkorn wheat (Triticum monococcum) and barley (Hordeum vulgare) from the Near East, rice (Oryza sativa) from China, mung (Vigna radiata) and urd (Vigna mungo) beans from India, and pearl millet (Pennisetum glaucum) from west Africa. Brief reference is made to similar data on lentils (Lens culinaris), peas (Pisum sativum), soybean (Glycine max) and adzuki bean (Vigna angularis). Available quantitative data from archaeological finds are compiled to explore changes with domestication. The disjunction in cereals between seed size increase and dispersal is explored, and rates at which these features evolved are estimated from archaeobotanical data. Contrasts between crops, especially between cereals and pulses, are examined. These data suggest that in domesticated grasses, changes in grain size and shape evolved prior to non-shattering ears or panicles. Initial grain size increases may have evolved during the first centuries of cultivation, within perhaps 500-1000 years. Non-shattering infructescences were much slower, becoming fixed about 1000-2000 years later. This suggests a need to reconsider the role of sickle harvesting in domestication. Pulses, by contrast, do not show evidence for seed size increase in relation to the earliest cultivation, and seed size increase may be delayed by 2000-4000 years. This implies that conditions that were sufficient to select for larger seed size in Poaceae were not sufficient in Fabaceae. It is proposed that animal-drawn ploughs (or ards) provided the selection pressure for larger seeds in legumes. This implies different thresholds of selective pressure, for example in relation to differing seed ontogenetics and underlying genetic architecture in these families. Pearl millet (Pennisetum glaucum) may show some similarities to the pulses in terms of a lag-time before truly larger-grained forms evolved.


Use of desferoxamine and S-adenosylmethionine to treat hemochromatosis in a red ruffed lemur (Varecia variegata ruber).
Hemochromatosis was diagnosed in a 14-year-old, male, red ruffed lemur (Varecia variegata ruber) on the basis of abnormal results of serum biochemical analysis, including high serum ferritin and transferrin saturation values, and of liver biopsy. Therapy included chelation, using desferoxamine to remove excess iron and S-adenosylmethionine to improve liver function, and monthly peripheral blood removal by phlebotomy to reduce total body iron content. Response to treatment was assessed by changes in the lemur's attitude and appetite, as well as variations in serum biochemical and iron panel values. Initial improvement was associated with the onset of therapy. After 56 days of treatment, results of serum biochemical analysis indicated a decrease in iron panel values. Treatment was temporarily discontinued from days 56 to 65, and the lemur's condition worsened, so therapy was re-instituted. However, the lemur died of hepatocellular carcinoma on day 110 of treatment.


The Ectopic Overexpression of the Cotton Ve1 and Ve2-Homolog Sequences Leads to Resistance Response to Verticillium Wilt in Arabidopsis.
Verticillium wilt, caused by the Verticillium dahliae phytopathogen, is a devastating disease affecting many economically important crops. A receptor-like protein (RLP) gene, Ve1, has been reported to confer resistance to V. dahliae in tomato plants, but few genes have been found to be involved in cotton Verticillium wilt resistance. Here, we cloned two RLP gene homologs, Gossypium barbadense resistance gene to Verticillium dahliae 1 (GbaVd1) and GbaVd2, from the Verticillium wilt-resistant cultivar G. barbadense cv. Hai7124. GbaVd1 and GbaVd2 display sequence divergence, but both encode typical RLPs. Virus-induced gene silencing of GbaVd1 or GbaVd2 compromised the resistance of cotton to V. dahliae, and both genes conferred Verticillium wilt resistance after interfamily transfer into Arabidopsis. Microarray analysis revealed that GbaVd1 and GbaVd2 participate in Verticillium wilt resistance in Arabidopsis through activation of defense responses, including the endocytosis process, signaling factors, transcription factors and reinforcement of the cell wall, as demonstrated by lignification in Arabidopsis transgenic plants. In addition, microarray analysis showed that GbaVd1 and GbaVd2 differentially mediate resistance signaling and activation of defense responses after overexpression in Arabidopsis. Thus, GbaVd1 and GbaVd2 encode RLPs and act as disease resistance genes that mediate the defense response against V. dahliae in cotton.


Long acting octreotide in the treatment of advanced hepatocellular cancer and overexpression of somatostatin receptors: randomized placebo-controlled trial.
To estimate if and to what extent long acting octreotide (LAR) improves survival and quality of life in patients with advanced hepatocellular carcinoma (HCC). A total of 127 cirrhotics, stages A-B, due to chronic viral infections and with advanced HCC, were enrolled in the study. Scintigraphy with 111Indium labeled octreotide was performed in all cases. The patients with increased accumulation of radionuclear compound were randomized to receive either oral placebo only or octreotide/octreotide LAR only as follows: octreotide 0.5 mg s.c. every 8 h for 6 wk, at the end of wk 4-8 octreotide LAR 20 mg i.m. and at the end of wk 12 and every 4 wk octreotide LAR 30 mg i.m.. Follow-up was worked out monthly as well as the estimation of quality of life (QLQ-C30 questionnaire). Patients with negative somatostatin receptors (SSTR) detection were followed up in the same manner. Scintigraphy demonstrated SSTR in 61 patients. Thirty were randomized to receive only placebo and 31 only octreotide. A significantly higher survival time was observed for the octreotide group (49+/-6 wk) as compared to the control group (28+/-1 wk) and to the SSTR negative group (28+/-2 wk), LR=20.39, df=2, P<0.01. The octreotide group presented 68.5% lower hazard ratio [95% CI (47.4%-81.2%)]. During the first year, a 22%, 39% and 43% decrease in the QLQ-C30 score was observed in each group, respectively. The proposed therapeutic approach has shown to improve the survival and quality of life in SSTR positive patients with advanced HCC.


Patterns of progression in malignant glioma following anti-VEGF therapy: perceptions and evidence.
Antiangiogenic treatment has recently become an integral part of modern cancer therapy targeting the vasculature of numerous aggressive malignancies including glioblastoma. There is preclinical evidence that antiangiogenic therapies promote glioma cell invasiveness. In clinical series, upon progression on antiangiogenic therapy with the vascular endothelial growth factor-directed antibody bevacizumab (BEV), glioblastoma has been reported to display a more infiltrative pattern of recurrence. This distant spread at recurrence or progression and a gliomatosis cerebri-like growth pattern is best detectable on fluid-attenuated inversion recovery MRI. The frequency of up to 20% to 30% of such a pattern in BEV-treated patients is higher than expected to occur without BEV. Older reports and common clinical knowledge estimate the frequency of diffuse or distant spread in recurrent glioblastoma at 10%. This observation stimulated two streams of research. One is to overcome this often insidious adverse effect of antiangiogenic treatment, to optimize antiangiogenic therapies and to face this major challenge, integrating antiangiogenic with anti-invasive mechanisms into one combined treatment concept. The second is questioning a specific property of antiangiogenic therapy to induce diffuse or distant spread. Here, alternative hypotheses of increased awareness and better imaging as well as invasiveness being part of the natural course of the disease have been tested. Without doubt, migration and invasiveness are major obstacles to successful glioma therapy, notably local therapies, both in the natural course of the disease and in the concept of "evasive resistance." However, clinical analyses of case series, matched pairs analyses, and follow-up on the BRAIN trial (A Study to Evaluate Bevacizumab Alone or in Combination with Irinotecan for Treatment of Glioblastoma Multiforme), which led to accelerated approval of BEV for recurrent glioblastoma in the United States, have not supported a specific propensity of BEV to induce diffuse growth or distant spread at recurrence.


Wound healing trajectories in burn patients and their impact on mortality.
The rate of wound healing and its effect on mortality has not been well described. The objective of this article is to report wound healing trajectories in burn patients and analyze their effects on in-hospital mortality. The authors used software (WoundFlow) to depict burn wounds, surgical results, and healing progression at multiple time points throughout admission. Data for all patients admitted to the intensive care unit with ≥ 20% TBSA burned were collected retrospectively. The open wound size (OWS), which includes both unhealed burns and unhealed donor sites, was measured. We calculated the rate of wound closure (healing rate), which we defined as the change in OWS/time. We also determined the time delay (DAYS) from day of burn until day on which there was a reduction in OWS < 10%. Data are medians [interquartile range]. There were 38 patients with complete data; 25 had documentation of successful healing (H), and 13 did not (NH). H differed from NH on age (38 years [32-57] vs 63 [51-74]), body mass index (27 [21-28] vs 32 [19-52]), 24-hour fluid resuscitation (12 L [10-16] vs 18 [15-20]), pressors during first 48 hours (72% vs 100%), use of renal replacement therapy (32% vs 92%), and mortality (4% vs 100%). Repeated measures analysis of covariance showed a significant difference between survivors and nonsurvivors on OWS as a function of time (P<.001). Patients with a positive healing rate (+2%/day) after postburn day 20 had 100% survival whereas those with a negative healing rate (-2%/day) had 100% mortality. For H patients, median DAYS was 41 (28-54); median DAYS/TBSA was 1.3 (1.0-1.9). Survivors had a 0.62% drop in OWS/day, or 4.3%/week. In this cohort of patients with ≥ 20% TBSA, there was a difference in mortality after postburn day 20, between patients with a positive healing rate (+2%/day, 100% survival) and those with a negative healing rate (-2%/day, 100% mortality, P < .05).


Regulation of mating-type information in yeast. Negative control requiring sequences both 5' and 3' to the regulated region.
The genome of the yeast Saccharomyces cerevisiae contains three complete copies of the genetic information governing cell mating type. Normally, only the information in one of the copies (the MAT locus) is expressed; the other two copies (HML and HMR) are repressed and serve as donors of mating-type sequences that can be transposed to MAT in cells capable of switching mating type. We have mutagenized the silent HMR locus and have found that the repression of this locus requires two sites, one lying on each side of the mating-type sequences at HMR. The regulatory sites are positioned outside of the sequences that are included in the pair of divergent transcripts coded for by HMR, and lie about 1000 base-pairs to either side of the central promoter region of the locus. Deletion of one of the regulatory sites results phenotypically in complete loss of repression, whereas deletion of the other site gives only partial loss of control. Both of the sites are associated with an autonomous replication activity, though the relationship between this activity and the process of repression is unclear.


Delirium in older persons: evaluation and management.
Delirium is defined as an acute, fluctuating syndrome of altered attention, awareness, and cognition. It is common in older persons in the hospital and long-term care facilities and may indicate a life-threatening condition. Assessment for and prevention of delirium should occur at admission and continue throughout a hospital stay. Caregivers should be educated on preventive measures, as well as signs and symptoms of delirium and conditions that would indicate the need for immediate evaluation. Certain medications, sensory impairments, cognitive impairment, and various medical conditions are a few of the risk factors associated with delirium. Preventive interventions such as frequent reorientation, early and recurrent mobilization, pain management, adequate nutrition and hydration, reducing sensory impairments, and ensuring proper sleep patterns have all been shown to reduce the incidence of delirium, regardless of the care environment. Treatment of delirium should focus on identifying and managing the causative medical conditions, providing supportive care, preventing complications, and reinforcing preventive interventions. Pharmacologic interventions should be reserved for patients who are a threat to their own safety or the safety of others and those patients nearing death. In older persons, delirium increases the risk of functional decline, institutionalization, and death.


Digital Health Innovations, Tools, and Resources to Support Helping Babies Survive Programs.
The Helping Babies Survive (HBS) initiative features a suite of evidence-based curricula and simulation-based training programs designed to provide health workers in low- and middle-income countries (LMICs) with the knowledge, skills, and competencies to prevent, recognize, and manage leading causes of newborn morbidity and mortality. Global scale-up of HBS initiatives has been rapid. As HBS initiatives rolled out across LMIC settings, numerous bottlenecks, gaps, and barriers to the effective, consistent dissemination and implementation of the programs, across both the pre- and in-service continuums, emerged. Within the first decade of expansive scale-up of HBS programs, mobile phone ownership and access to cellular networks have also concomitantly surged in LMICs. In this article, we describe a number of HBS digital health innovations and resources that have been developed from 2010 to 2020 to support education and training, data collection for monitoring and evaluation, clinical decision support, and quality improvement. Helping Babies Survive partners and stakeholders can potentially integrate the described digital tools with HBS dissemination and implementation efforts in a myriad of ways to support low-dose high-frequency skills practice, in-person refresher courses, continuing medical and nursing education, on-the-job training, or peer-to-peer learning, and strengthen data collection for key newborn care and quality improvement indicators and outcomes. Thoughtful integration of purpose-built digital health tools, innovations, and resources may assist HBS practitioners to more effectively disseminate and implement newborn care programs in LMICs, and facilitate progress toward the achievement of Sustainable Development Goal health goals, targets, and objectives.


Preserving cognitive function for patients with overactive bladder: evidence for a differential effect with darifenacin.
Antimuscarinic agents used in the treatment of overactive bladder (OAB) differ in their potential to impair cognitive function. It is hypothesised that low brain concentrations and relatively low selectivity for the M(1) muscarinic receptor may reduce the potential for adverse central nervous system (CNS) effects with darifenacin, compared with other antimuscarinics, particularly oxybutynin. Cognitive function studies evaluating darifenacin, oxybutynin, tolterodine, solifenacin and/or trospium were identified from publications databases (Medline, Biosis and Embase) and congress abstracts. Preclinical studies and randomised controlled trials in adults were reviewed. Five randomised, double-blind, multiple-dose studies of cognitive function were identified. Oxybutynin was consistently associated with cognitive deficit (four studies), whereas darifenacin did not impair cognition (three studies). These findings were supported by data from sleep/attention and EEG studies. Tolterodine data were limited to one small study with each formulation. For solifenacin and trospium, there were no human studies evaluating memory, the cognitive function most vulnerable to CNS anticholinergics. There is compelling evidence of cognitive impairment with oxybutynin, whereas darifenacin stands out by demonstrating no impairment of memory or other cognitive functions in three randomised, controlled trials. This may be attributed to the differences in physicochemical properties, efflux mechanisms and relative M(1) muscarinic receptor sparing. The risk of CNS impairment is of particular concern for vulnerable populations such as the elderly (a substantial proportion of the OAB population), and CNS-compromised neurogenic bladder patients such as those with multiple sclerosis or Parkinson's disease.


Complement factor H in AMD: Bridging genetic associations and pathobiology.
Age-Related Macular Degeneration (AMD) is a complex multifactorial disease characterized in its early stages by lipoprotein accumulations in Bruch's Membrane (BrM), seen on fundoscopic exam as drusen, and in its late forms by neovascularization ("wet") or geographic atrophy of the Retinal Pigmented Epithelial (RPE) cell layer ("dry"). Genetic studies have strongly supported a relationship between the alternative complement cascade, in particular the common H402 variant in Complement Factor H (CFH) and development of AMD. However, the functional significance of the CFH Y402H polymorphism remains elusive. In this article, we critically review the literature surrounding the functional significance of this polymorphism. Furthermore, based on our group's studies we propose a model in which CFH H402 affects CFH binding to heparan sulfate proteoglycans leading to accelerated lipoprotein accumulation in BrM and drusen progression. We also review the literature on the role of other complement components in AMD pathobiologies, including C3a, C5a and the membrane attack complex (MAC), and on transgenic mouse models developed to interrogate in vivo the effects of the CFH Y402H polymorphism.


Short-term treatment with L-arginine prevents the smoking-induced impairment of endothelial function and vascular elastic properties in young individuals.
L-arginine, the substrate for endothelial nitric oxide synthase, is essential for normal endothelial function. Aim of the present study was to investigate in healthy smokers the effect of a short-term daily L-arginine administration on vascular function. We studied the effect of a 3-day oral administration of L-arginine in 10 healthy smokers (24.3+/-0.73 years old) on 3 occasions (day , day 1 and day 3). The study was carried out on two separate arms, one with L-arginine (7 gr/d) and one with placebo according to a randomized, placebo-controlled, double-blind, cross-over design. Measurements were carried out before, immediately after (Sm0) and 20 min after (Sm20) cigarette smoking. Endothelial function was evaluated by flow-mediated dilatation (FMD) of the brachial artery. Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness and augmentation index (AIx) as a measure of arterial wave reflections. Compared to placebo, L-arginine led to an increase of FMD (p<0.05 at day 2), indicating a favorable effect on endothelial function, which however lost significance at day 3. l-arginine induced a progressive decrease of PWV and AIx at both day 2 and day 3 (p<0.01 vs baseline for all). L-arginine blunted the acute smoking-induced increase of AIx at both day 1 (p<0.05) and day 3 (p<0.01), and there was a trend to protect the smoking-induced change of PWV at day 3 (p<0.1). Short-term daily administration of L-arginine improves arterial performance in healthy smokers and abrogates the smoking-induced increase in arterial stiffness and wave reflections in these individuals.


Conceptualizing community: a comparison of neighborhood characteristics of supportive housing for persons with psychiatric and developmental disabilities.
Housing and services for persons with developmental disabilities (DD) have been shaped by the normalization approach, a commitment to full integration within the general community. In contrast, housing and services for persons with psychiatric disabilities (PD) have had various and sometimes conflicting goals, including provision of custodial care, promotion of therapeutic community, and community integration. This cross-field study compares the neighborhood characteristics of publicly-funded housing for the PD and DD populations in a metropolitan community. The aim of the study was to examine whether the contrasting housing approaches are reflected at an ecological level and to consider how these findings relate to the goal of community integration for people with PD and DD. Administrative databases provided residential addresses of 1932 residents with PD living in 297 locations and 1716 residents with DD living in 749 locations in the city of Philadelphia. The 2000 U.S. Census and city's police department database provided information on neighborhood characteristics. Geographic information system (GIS) methodology generated maps displaying the distribution of housing locations in relation to spatial dispersion, distress, stability, safety, and race/ethnic diversity. Statistical analyses compared neighborhood characteristics of the DD and PD populations. Findings indicated that the DD population in supportive housing was more spatially dispersed, and lived in less distressed, less unstable, more secure, but equally racially/ethnically diverse neighborhoods when compared to the PD population in supportive housing. Greater geographic dispersal among persons with DD may be the result of more emphasis on normalization within policies and programs determining the location of their housing. The higher funding levels for housing and residential support for persons with DD also provided programs with the option of placing people in higher income neighborhoods. Given that community integration has emerged as an organizing principle within mental health services over other models, policymakers in the field of psychiatric disabilities may have much to learn from the normalization movement for people with developmental disabilities.


Building biases in infancy: the influence of race on face and voice emotion matching.
Early in the first year of life infants exhibit equivalent performance distinguishing among people within their own race and within other races. However, with development and experience, their face recognition skills become tuned to groups of people they interact with the most. This developmental tuning is hypothesized to be the origin of adult face processing biases including the other-race bias. In adults the other-race bias has also been associated with impairments in facial emotion processing for other-race faces. The present investigation aimed to show perceptual narrowing for other-race faces during infancy and to determine whether the race of a face influences infants' ability to match emotional sounds with emotional facial expressions. Behavioral (visual-paired comparison; VPC) and electrophysiological (event-related potentials; ERPs) measures were recorded in 5-month-old and 9-month-old infants. Behaviorally, 5-month-olds distinguished faces within their own race and within another race, whereas 9-month-olds only distinguish faces within their own race. ERPs were recorded while an emotion sound (laughing or crying) was presented prior to viewing an image of a static African American or Caucasian face expressing either a happy or a sad emotion. Consistent with behavioral findings, ERPs revealed race-specific perceptual processing of faces and emotion/sound face congruency at 9 months but not 5 months of age. In addition, from 5 to 9 months, the neural networks activated for sound/face congruency were found to shift from an anterior ERP component (Nc) related to attention to posterior ERP components (N290, P400) related to perception.


iTRAQ-based quantitative proteomic profiling of the immune response of the South African abalone, Haliotis midae.
The South African abalone Haliotis midae is a commercially important species farmed at high densities in land-based aquaculture systems. Disease outbreaks have had a severe financial impact on the abalone industry yet the molecular mechanisms underlying the immune response of H. midae remain obscure. In this study, a comparative shotgun proteomics approach using iTRAQ coupled with LC-MS/MS was employed to investigate H. midae proteome changes in response to Vibrio anguillarum challenge. A total of 118 non-redundant, unique haemocyte proteins were identified and quantified, with 16 proteins significantly regulated. Hierarchical clustering and pathway analysis uncovered a coordinated response dominated by calcium and cAMP signalling via activation of MAPK cascades. Early up-regulated biological processes involve phagocytosis, nitric oxide production and ATP-synthesis, whilst down-regulated responses were predominantly involved in the regulation of apoptosis. The late up-regulated response involved protein kinase activity and detoxification processes. Expression of selected proteins was validated by Western blot. A putative allograft inflammatory factor-1 protein was further selected to establish its functional molecular role in haemocytes. Confocal imaging revealed that allograft inflammatory factor-1 regulates phagocytosis via a functional interaction with filamentous actin. This is the first time a high-throughput proteomics approach has been used to investigate the immune response of H. midae.


Evidence of One-Dimensional Channels in Hydrogen-Bonded Organic Porous Thin Films Fabricated at the Air/Liquid Interface.
Visualization of periodically aligned pores in organic frameworks is a key to the understanding of their structural control. Comparing to monolayer-thick self-assembled molecular networks, real-space nanoscale characterization of thicker films, especially obtaining information on the stacking manner of molecules is challenging. Here, we report an atomic force microscopy study of hydrogen-bonded thin films fabricated at the air/liquid interface. The presence of one-dimensional channels is evidenced by resolving honeycomb structures over the films with the thickness variation of more than several nanometers. We also demonstrate that the film thickness can be controlled by the ratio of mixed solvent rather than the surface pressure during the fabrication at the air/liquid interface.


Neotropical mammal diversity and the Great American Biotic Interchange: spatial and temporal variation in South America's fossil record.
The vast mammal diversity of the Neotropics is the result of a long evolutionary history. During most of the Cenozoic, South America was an island continent with an endemic mammalian fauna. This isolation ceased during the late Neogene after the formation of the Isthmus of Panama, resulting in an event known as the Great American Biotic Interchange (GABI). In this study, we investigate biogeographic patterns in South America, just before or when the first immigrants are recorded and we review the temporal and geographical distribution of fossil mammals during the GABI. We performed a dissimilarity analysis which grouped the faunal assemblages according to their age and their geographic distribution. Our data support the differentiation between tropical and temperate assemblages in South America during the middle and late Miocene. The GABI begins during the late Miocene (~10-7 Ma) and the putative oldest migrations are recorded in the temperate region, where the number of GABI participants rapidly increases after ~5 Ma and this trend continues during the Pleistocene. A sampling bias toward higher latitudes and younger records challenges the study of the temporal and geographic patterns of the GABI.


Cycle dependent RCAS1 expression with respect to the immune cells presence and activity.
The number of cytotoxic immune cells grows in the endometrium during the secretory cycle phase. RCAS1 is a protein inhibiting the activated immune cytotoxic cells. The expression of RCAS1 has been confirmed in endometrium. The aim of the present study was to evaluate the RCAS1 expression alterations with respect to the menstrual cycle changes and the number and activity of cytotoxic immune cells. RCAS1, CD25, CD69, CD56, CD16, CD68 antigens expression was assessed by immunohistochemistry in endometrial tissue samples which were obtained from 33 patients. Tissue samples were classified according to the menstrual cycle phases, with division of the cycle into three phases: proliferative (8 cases), periovulatory (10 cases), and secretory (15 cases) ones. A significantly higher RCAS1 expression was observed in the periovulatory and the secretory menstrual cycle phases than in the proliferative phase. The changes in RCAS1 expression were combined with significant differences in the number of immune cells and their activity. The highest level of CD69 antigen expression was observed during the periovulatory cycle phase, while the highest level of CD25 antigen expression was observed during proliferative phase, the number of CD56 positive cells was at the highest level during the secretory cycle phase. No significant differences in the number of macrophages and CD16 antigen expression were observed with respect to the menstrual cycle phases. RCAS1 endometrial expression may favor the coexistence of active lymphocytes and endometrial cells.


Current practice in analysing and reporting binary outcome data-a review of randomised controlled trial reports.
Randomised controlled trials (RCTs) need to be reported so that their results can be unambiguously and robustly interpreted. Binary outcomes yield unique challenges, as different analytical approaches may produce relative, absolute, or no treatment effects, and results may be particularly sensitive to the assumptions made about missing data. This review of recently published RCTs aimed to identify the methods used to analyse binary primary outcomes, how missing data were handled, and how the results were reported. Systematic review of reports of RCTs published in January 2019 that included a binary primary outcome measure. We identified potentially eligible English language papers on PubMed, without restricting by journal or medical research area. Papers reporting the results from individually randomised, parallel-group RCTs were included. Two hundred reports of RCTs were included in this review. We found that 64% of the 200 reports used a chi-squared-style test as their primary analytical method. Fifty-five per cent (95% confidence interval 48% to 62%) reported at least one treatment effect measure, and 38% presented only a p value without any treatment effect measure. Missing data were not always adequately described and were most commonly handled using available case analysis (69%) in the 140 studies that reported missing data. Imputation and best/worst-case scenarios were used in 21% of studies. Twelve per cent of articles reported an appropriate sensitivity analysis for missing data. The statistical analysis and reporting of treatment effects in reports of randomised trials with a binary primary endpoint requires substantial improvement. Only around half of the studied reports presented a treatment effect measure, hindering the understanding and dissemination of the findings. We also found that published trials often did not clearly describe missing data or sensitivity analyses for these missing data. Practice for secondary endpoints or observational studies may differ.


SARs for pocket-mounted mobile telephones at 835 and 1900 MHz.
Increasingly, mobile telephones are becoming pocket-sized and are being left in the shirt pocket with a connection to the ear for hands-free operation. We have considered an anatomic model of the chest and a planar phantom recommended by US FCC to compare the peak 1 and 10 g SARs for four typical cellular telephones, two each at 835 and 1900 MHz. An agreement within +/- 10% is obtained between calculated and experimental 1 and 10 g SARs for various separations (2-8 mm) from the planar phantom used to represent different thicknesses of the clothing both for the antenna away from or turned back towards the body. Because of the closer placement of the antennas relative to the body, the peak 1 and 10 g SARs are considerably higher (by a factor of 2-7) for pocket-mounted telephones as compared to the SARs obtained using a 6 mm thick plastic ear head model--a procedure presently accepted both in the US and Europe. This implies that a telephone tested for SAR compliance against the model of the head may be severely out of compliance if it were placed in the shirt pocket.


The prevalence of osteoarthritis of the atlanto-odontoid joint in adults using multidetector computed tomography.
The prevalence of osteoarthritis of the atlanto-odontoid joint has been reported by radiology, autopsy, and conventional computed tomography (CT), but the prevalence has not yet been assessed by multidetector computed tomography (MDCT). To reveal the prevalence of osteoarthritis of the atlanto-odontoid joint and to analyze the inter-relationships among gender, age, and osteoarthritis with MDCT in adults. First, a series of 700 selected domestic patients aged >18 years undergoing an upper cervical MDCT scan were divided equally into seven age groups. Second, using the postprocessing technique of multiplanar reconstruction, osteoarthritis of the atlanto-odontoid joint was viewed from any direction and classified into four grades, which were normal, mild, moderate, and severe. Lastly, the incidence of the different grades of osteoarthritis was assessed, and the reproducibility was tested. There was no significant difference between gender and osteoarthritis of atlanto-odontoid joint (P > 0.05). The rate of osteoarthritis was 16% in the age group 18-25 years, 23% in the age group 25-30 years, 33% in the age group 30-40 years, 54% in the age group 40-50 years, 70% in the age group 50-60 years, 87% in the age group 60-70 years, and 93% in the age group >70 years. Mild osteoarthritis appeared at the earliest at age 19.6 years, moderate osteoarthritis in at earliest at age 24.2 years, and severe osteoarthritis at the earliest at age 48.5 years. The inter-observer reliability was excellent (k = 0.86). Osteoarthritis of the atlanto-odontoid joint could be detected by MDCT in a young adult. It increased rapidly with increasing age on MDCT.


Spanish human proteome project: dissection of chromosome 16.
The Chromosome 16 Consortium forms part of the Human Proteome Project that aims to develop an entire map of the proteins encoded by the human genome following a chromosome-centric strategy (C-HPP) to make progress in the understanding of human biology in health and disease (B/D-HPP). A Spanish consortium of 16 laboratories was organized into five working groups: Protein/Antibody microarrays, protein expression and Peptide Standard, S/MRM, Protein Sequencing, Bioinformatics and Clinical healthcare, and Biobanking. The project is conceived on a multicenter configuration, assuming the standards and integration procedures already available in ProteoRed-ISCIII, which is encompassed within HUPO initiatives. The products of the 870 protein coding genes in chromosome 16 were analyzed in Jurkat T lymphocyte cells, MCF-7 epithelial cells, and the CCD18 fibroblast cell line as it is theoretically expected that most chromosome 16 protein coding genes are expressed in at least one of these. The transcriptome and proteome of these cell lines was studied using gene expression microarray and shotgun proteomics approaches, indicating an ample coverage of chromosome 16. With regard to the B/D section, the main research areas have been adopted and a biobanking initiative has been designed to optimize methods for sample collection, management, and storage under normalized conditions and to define QC standards. The general strategy of the Chr-16 HPP and the current state of the different initiatives are discussed.


Essential oil of Artemisia capillaris induces apoptosis in KB cells via mitochondrial stress and caspase activation mediated by MAPK-stimulated signaling pathway.
Artemisia capillaris has been used in traditional Korean medicine for its variety of pharmacological activities. Previous studies have suggested that the essential oil of A. capillaris has chemopreventive potential, even though the mechanism of its action is unclear. This study examined whether or not the essential oil isolated from A. capillaris induces apoptosis in the human oral epidermoid carcinoma cells along with the possible mechanism(s) of the essential oil-mediated cytotoxicity. The essential oil induced cell death of KB cells through apoptosis, as evidenced by the increased cell population in the sub-G1 phase, the appearance of condensed and/or fragmented nuclei, and the generation of a cleaved PARP product. Treating the cells with the oil also caused changes in the mitochondrial level of the Bcl-2 family proteins such as Bcl-2 and Bax, thereby inducing the release of cytochrome c into the cytosol. Additional experiments using caspase or mitogen-activated protein kinase inhibitors suggested the involvement of the p38/NF-kappaB and JNK/Bcl-2-mediated pathways as well as caspase activation in the oil-mediated apoptosis. Collectively, we believe that the essential oil of A. capillaris induces apoptosis in human oral cancer cells and that it might be a good resource for searching new drugs, especially anticancer drugs.


The relationship between cognitive function and physical performance in older women: results from the women's health initiative memory study.
Cognitive function and physical performance are associated, but the common sequence of cognitive and physical decline remains unclear. In the Women's Health Initiative Memory Study (WHIMS) clinical trial, we examined associations at baseline and over a 6-year follow-up period between the Modified Mini-Mental State (3MS) Examination and three physical performance measures (PPMs): gait speed (meters/second), chair stands (number of stands in 15 seconds), and grip strength (kilograms). Using mixed models, we examined the baseline 3MS as predictor of change in PPM, change in the 3MS as predictor of change in PPM, and baseline PPM as predictors of 3MS change. Among 1,793 women (mean age = 70.3 years, 89% white, and mean 3MS score = 95.1), PPM were weakly correlated with 3MS-gait speed: r = .06, p = .02; chair stands: r = .09, p < .001; and grip strength: r = .10, p < .001. Baseline 3MS score was associated with subsequent PPM decline after adjustment for demographics, comorbid conditions, medications, and lifestyle factors. For every SD (4.2 points) higher 3MS score, 0.04 SD (0.04 m/s) less gait speed and 0.05 SD (0.29 kg) less grip strength decline is expected over 6 years (p </= .01 both). Changes in 3MS and PPM were associated, particularly with chair stands and grip strength (p < .003 both). Baseline PPMs were not associated with subsequent 3MS change. Baseline global cognitive function and change in global cognitive function were associated with physical performance change, but baseline physical performance was not associated with cognitive change in this cohort. These analyses support the hypothesis that cognitive decline on average precedes or co-occurs with physical performance decline.


Models of breast cancer show that risk is set by events of early life: prevention efforts must shift focus.
We have recently published a mathematical model of the etiology of breast cancer based on the data from the Nurses Health Study that extends the Pike model of breast cancer (see Appendix). The most salient feature of the model is that it identifies the years before the first birth of a child as the most crucial in establishing future risk of breast cancer. The extended model includes several additional details of reproductive risk factors, allowing us to quantify the relative importance of each of the reproductive risk factors and to estimate the effect of changes in key determinants of breast cancer. In this review, we present the evidence from both animal studies and epidemiological research that corroborate the critical importance of the exposures that occur before first birth. We argue that research and preventive interventions should now focus on youth. Population-wide prevention strategies are necessary because the inherited genetic risk for breast cancer accounts for no more than 10-15% of all breast cancer cases, leaving 85% of cases diagnosed among women who are not in this high-risk subgroup of the population. An example of a population-based intervention would be the promotion of increased physical activity among young girls that could result in the delay of menarche. An example of additional research that focuses on the importance of early life exposures would be an analysis of the relation between diet and other lifestyle factors during adolescence and the subsequent risk of breast cancer and studies of precursor lesions (atypical hyperplasia). Shifting the focus of breast cancer prevention to this age group is urgently needed.


22 Cases of Breast Implant-Associated ALCL: Awareness and Outcome Tracking from the Italian Ministry of Health.
To date, 359 cases of anaplastic large cell lymphoma (ALCL) in women with breast implants (breast implant-associated ALCL [BIA-ALCL]) worldwide have been reported among more than 10 million patients who have received implants, but health care authorities suspect this is a possible underestimation, and the limited number of cases makes it difficult to clarify its cause. The General Directorate of Medical Devices and Pharmaceutical Services of the Italian Ministry of Health has examined and studied the Italian BIA-ALCL cases. An official document has been diffused to all medical associations, aiming at encouraging all physicians to notify each BIA-ALCL case. A retrospective study has been performed on the notified BIA-ALCL cases collected in the database named Dispovigilance. Research on Dispovigilance returns a list of 22 BIA-ALCL cases. The mean patient age was 49.6 years (range, 30 to 71 years). The average time to the onset of the symptoms was 6.8 years (range, 1 to 22 years). The average time to diagnosis was 7.8 years (range, 4 to 22 years). The estimated incidence of the Italian BIA-ALCL cases related to 2015 is 2.8 per 100,000 patients. The pathogenesis of BIA-ALCL remains unknown. The establishment of a national breast implant registry is needed to better understand some aspects of this disease. Future genetic studies on the population affected could clarify why only some patients with implants develop this disease.


Malaria.
This review addresses recent developments that relate to the pathogenesis of severe malaria and its treatment, and also highlights the increase in the global burden of malaria and provides a summary of clinical trials of malaria vaccines. Malaria, one of the world's most important parasitic infections, is on the increase globally. This has resulted in an increase in the morbidity and mortality from malaria in endemic areas, a resurgence in areas where it was previous eradicated, and an increase in imported malaria in Europe and North America. Mortality from severe malaria continues to be high, even when effective drugs are available, because most deaths occur within hours of admission to hospital. In severe malaria, the presence of acidosis is the most important prognostic factor in children and adults. A number of therapies have resulted in clinical improvements and the correction of acidosis in phase I and II studies, but larger trials are required to examine the effect on mortality. More malaria vaccines are now in phase I or II trials; however, available data do not yet promise an imminent impact on malaria control. Recent developments include a better understanding of the pathogenesis of severe malaria, and have given rise to a number of novel therapeutic strategies that should be examined in larger phase III trials. Similarly, there has been considerable progress in the field of vaccine development.


C2-symmetric chiral disulfoxide ligands in rhodium-catalyzed 1,4-addition: from ligand synthesis to the enantioselection pathway.
A family of chiral C(2)-symmetric disulfoxide ligands possessing biaryl atropisomeric backbones has been synthesized by using the Andersen methodology. Complete characterization includes X-ray crystallographic studies of all ligands and some of their rhodium complexes. Their synthesis, optical purity, electronic properties, and catalytic behavior in the prototypical rhodium-catalyzed 1,4-addition of phenylboronic acid to 2-cyclohexen-1-one are presented through an in depth study of this ligand class. Density functional theory calculations on the step of the catalytic cycle that determines the enantioselectivity are presented and reinforce the first hypothetical explanations for the high levels of asymmetric induction observed.


Imputation of low-frequency variants using the HapMap3 benefits from large, diverse reference sets.
Imputation allows the inference of unobserved genotypes in low-density data sets, and is often used to test for disease association at variants that are poorly captured by standard genotyping chips (such as low-frequency variants). Although much effort has gone into developing the best imputation algorithms, less is known about the effects of reference set choice on imputation accuracy. We assess the improvements afforded by increases in reference size and diversity, specifically comparing the HapMap2 data set, which has been used to date for imputation, and the new HapMap3 data set, which contains more samples from a more diverse range of populations. We find that, for imputation into Western European samples, the HapMap3 reference provides more accurate imputation with better-calibrated quality scores than HapMap2, and that increasing the number of HapMap3 populations included in the reference set grant further improvements. Improvements are most pronounced for low-frequency variants (frequency <5%), with the largest and most diverse reference sets bringing the accuracy of imputation of low-frequency variants close to that of common ones. For low-frequency variants, reference set diversity can improve the accuracy of imputation, independent of reference sample size. HapMap3 reference sets provide significant increases in imputation accuracy relative to HapMap2, and are of particular use if highly accurate imputation of low-frequency variants is required. Our results suggest that, although the sample sizes from the 1000 Genomes Pilot Project will not allow reliable imputation of low-frequency variants, the larger sample sizes of the main project will allow.


Differential incorporation of halogenated deoxyuridines during UV-induced DNA repair synthesis in human cells.
Double labeling of interphase and metaphase chromosomes by 5-chlorodeoxyuridine (CldU) and 5-iododeoxyuridine (IdU) has been used in studies of the dynamics of DNA replication. Here, we have used this approach and confocal microscopy to analyze sites of DNA repair synthesis during nucleotide excision repair (NER) in quiescent human fibroblasts. Surprisingly, we have found that when both precursors are added at the same time to UV-irradiated cells they label different sites in the nucleus. In contrast, even very short periods of simultaneous IdU+CldU labeling of S-phase cells produced mostly overlapped IdU and CldU replication foci. The differential labeling of repair sites might be due to compartmentalization of I-dUTP and Cl-dUTP pools, or to differential utilization of these thymidine analogs by DNA polymerases delta and epsilon (Poldelta and Polepsilon). To explore the latter possibility we used purified mammalian polymerases to find that I-dUTP is efficiently utilized by both Poldelta and Polepsilon. However, we found that the UV-induced incorporation of IdU was more strongly stimulated by treatment of cells with hydroxyurea than was incorporation of CldU. This indicates that there may be distinct IdU and CldU-derived nucleotide pools differentially affected by inhibition of the ribonucleotide reductase pathway of dNTP synthesis and that is consistent with the view that differential incorporation of IdU and CldU during NER may be caused by compartmentalization of IdU- and CldU-derived nucleotide pools.


Instantaneous frequency measurement system using optical mixing in highly nonlinear fiber.
A broadband photonic instantaneous frequency measurement system utilizing four-wave mixing in highly nonlinear fiber is demonstrated. This new approach is highly stable and does not require any high-speed electronics or photodetectors. A first principles model accurately predicts the system response. Frequency measurement responses from 1 to 40 GHz are demonstrated and simple reconfiguration allows the system to operate over multiple bands.


Scope and Social Determinants of Food Insecurity Among Adults With Atherosclerotic Cardiovascular Disease in the United States.
Background Atherosclerotic cardiovascular disease (ASCVD) results in high out-of-pocket healthcare expenditures predisposing to food insecurity. However, the burden and determinants of food insecurity in this population are unknown. Methods and Results Using 2013 to 2018 National Health Interview Survey data, we evaluated the prevalence and sociodemographic determinants of food insecurity among adults with ASCVD in the United States. ASCVD was defined as self-reported diagnosis of coronary heart disease or stroke. Food security was measured using the 10-item US Adult Food Security Survey Module. Of the 190 113 study participants aged 18 years or older, 18 442 (adjusted prevalence 8.2%) had ASCVD, representing ≈20 million US adults annually. Among adults with ASCVD, 2968 or 14.6% (weighted ≈2.9 million US adults annually) reported food insecurity compared with 9.1% among those without ASCVD (P<0.001). Individuals with ASCVD who were younger (odds ratio [OR], 4.0 [95% CI, 2.8-5.8]), women (OR, 1.2 [1.0-1.3]), non-Hispanic Black (OR, 2.3 [1.9-2.8]), or Hispanic (OR, 1.6 [1.2-2.0]), had private (OR, 1.8 [1.4-2.3]) or no insurance (OR, 2.3 [1.7-3.1]), were divorced/widowed/separated (OR, 1.2 [1.0-1.4]), and had low family income (OR, 4.7 [4.0-5.6]) were more likely to be food insecure. Among those with ASCVD and 6 of these high-risk characteristics, 53.7% reported food insecurity and they had 36-times (OR, 36.2 [22.6-57.9]) higher odds of being food insecure compared with those with ≤1 high-risk characteristic. Conclusion About 1 in 7 US adults with ASCVD experience food insecurity, with more than 1 in 2 adults reporting food insecurity among the most vulnerable sociodemographic subgroups. There is an urgent need to address the barriers related to food security in this population.


The androgen receptor transactivation domain: the interplay between protein conformation and protein-protein interactions.
The AR (androgen receptor) belongs to the nuclear receptor superfamily and directly regulates patterns of gene expression in response to the steroids testosterone and dihydrotestosterone. Sequences within the large N-terminal domain of the receptor have been shown to be important for transactivation and protein-protein interactions; however, little is known about the structure and folding of this region. Folding of the AR transactivation domain was observed in the presence of the helix-stabilizing solvent trifluorethanol and the natural osmolyte TMAO (trimethylamine N-oxide). TMAO resulted in the movement of two tryptophan residues to a less solvent-exposed environment and the formation of a protease-resistant conformation. Critically, binding to a target protein, the RAP74 subunit of the general transcription factor TFIIF, resulted in a similar resistance to protease digestion, consistent with induced folding of the receptor transactivation domain. Our current hypothesis is that the folding of the transactivation domain in response to specific protein-protein interactions creates a platform for subsequent interactions, resulting in the formation of a competent transcriptional activation complex.


Blood-brain barrier dysfunction in hemorrhagic transformation: a therapeutic opportunity for nanoparticles and melatonin.
Stroke is the second leading cause of death worldwide, estimated that one-sixth of the world population will suffer it once in their life. The most common type of this medical condition is the ischemic stroke (IS), produced by a thrombotic or embolic occlusion of a major cerebral artery or its branches, leading to the formation of a complex infarct region caused by oxidative stress, excitotoxicity, and endothelial dysfunction. Nowadays, the immediate treatment for IS involves thrombolytic agents or mechanical thrombectomy, depending on the integrity of the blood-brain barrier (BBB). A common stroke complication is the hemorrhagic transformation (HT), which consists of bleeding into the ischemic brain area. Currently, better treatments for IS are urgently needed. As such, the neurohormone melatonin has been proposed as a good candidate due to its antioxidant, anti-inflammatory, and neuroprotective effects, particularly against lipid peroxidation and oxidative stress during brain ischemia. Here, we proposed to develop intravenous or intranasal melatonin nanoformulation to specifically target the brain in patients with stroke. Nowadays, the challenge is to find a formulation able to cross the barriers and reach the target organ in an effective dose to generate the pharmacological effect. In this review, we discuss the current literature about stroke pathophysiology, melatonin properties, and its potential use in nanoformulations as a novel therapeutic approach for ischemic stroke.


Surface-confined assemblies and polymers for molecular logic.
Stimuli responsive materials are capable of mimicking the operation characteristics of logic gates such as AND, OR, NOR, and even flip-flops. Since the development of molecular sensors and the introduction of the first AND gate in solution by de Silva in 1993, Molecular (Boolean) Logic and Computing (MBLC) has become increasingly popular. In this Account, we present recent research activities that focus on MBLC with electrochromic polymers and metal polypyridyl complexes on a solid support. Metal polypyridyl complexes act as useful sensors to a variety of analytes in solution (i.e., H(2)O, Fe(2+/3+), Cr(6+), NO(+)) and in the gas phase (NO(x) in air). This information transfer, whether the analyte is present, is based on the reversible redox chemistry of the metal complexes, which are stable up to 200 °C in air. The concurrent changes in the optical properties are nondestructive and fast. In such a setup, the input is directly related to the output and, therefore, can be represented by one-input logic gates. These input-output relationships are extendable for mimicking the diverse functions of essential molecular logic gates and circuits within a set of Boolean algebraic operations. Such a molecular approach towards Boolean logic has yielded a series of proof-of-concept devices: logic gates, multiplexers, half-adders, and flip-flop logic circuits. MBLC is a versatile and, potentially, a parallel approach to silicon circuits: assemblies of these molecular gates can perform a wide variety of logic tasks through reconfiguration of their inputs. Although these developments do not require a semiconductor blueprint, similar guidelines such as signal propagation, gate-to-gate communication, propagation delay, and combinatorial and sequential logic will play a critical role in allowing this field to mature. For instance, gate-to-gate communication by chemical wiring of the gates with metal ions as electron carriers results in the integration of stand-alone systems: the output of one gate is used as the input for another gate. Using the same setup, we were able to display both combinatorial and sequential logic. We have demonstrated MBLC by coupling electrochemical inputs with optical readout, which resulted in various logic architectures built on a redox-active, functionalized surface. Electrochemically operated sequential logic systems such as flip-flops, multivalued logic, and multistate memory could enhance computational power without increasing spatial requirements. Applying multivalued digits in data storage could exponentially increase memory capacity. Furthermore, we evaluate the pros and cons of MBLC and identify targets for future research in this Account.


APPLICATION OF A NOVEL QUANTITATIVE TRACTOGRAPHY-BASED ANALYSIS OF DIFFUSION TENSOR IMAGING TO EXAMINE FIBER BUNDLE LENGTH IN HUMAN CEREBRAL WHITE MATTER.
This paper reviews basic methods and recent applications of length-based fiber bundle analysis of cerebral white matter using diffusion magnetic resonance imaging (dMRI). Diffusion weighted imaging (DWI) is a dMRI technique that uses the random motion of water to probe tissue microstructure in the brain. Diffusion tensor imaging (DTI) is an extension of DWI that measures the magnitude and direction of water diffusion in cerebral white matter, using either voxel-based scalar metrics or tractography-based analyses. More recently, quantitative tractography based on diffusion tensor imaging (qtDTI) technology has been developed to help quantify aggregate structural anatomical properties of white matter fiber bundles, including both scalar metrics of bundle diffusion and more complex morphometric properties, such as fiber bundle length (FBL). Unlike traditional scalar diffusion metrics, FBL reflects the direction and curvature of white matter pathways coursing through the brain and is sensitive to changes within the entire tractography model. In this paper, we discuss applications of this approach to date that have provided new insights into brain organization and function. We also discuss opportunities for improving the methodology through more complex anatomical models and potential areas of new application for qtDTI.


Hydroxocobalamin as a cyanide antidote: safety, efficacy and pharmacokinetics in heavily smoking normal volunteers.
The safety, efficacy and pharmacokinetic parameters of 5 g of hydroxocobalamin given intravenously, alone or in combination with 12.5 g of sodium thiosulfate, were evaluated in healthy adult men who were heavy smokers. Sodium thiosulfate caused nausea, vomiting, and localized burning, muscle cramping, or twitching at the infusion site. Hydroxocobalamin was associated with a transient reddish discoloration of the skin, mucous membranes, and urine, and when administered alone produced mean elevations of 13.6% in systolic and 25.9% in diastolic blood pressure, with a concomitant 16.3% decrease in heart rate. No other clinically significant adverse effects were noted. Hydroxocobalamin alone decreased whole blood cyanide levels by 59% and increased urinary cyanide excretion. Pharmacokinetic parameters of hydroxocobalamin were best defined in the group who received both antidotes: t1/2 (alpha), 0.52 h; t1/2 (beta), 2.83 h; Vd (beta), 0.24 L/kg; and mean peak serum concentration 753 mcg/mL (560 mumol/L) at 0-50 minutes after completion of infusion. Hydroxocobalamin is safe when administered in a 5 gram intravenous dose, and effectively decreases the low whole blood cyanide levels found in heavy smokers.


Identification and characterization of monoclonal antibodies specific for polymorphic antigenic determinants within the V2 region of the human immunodeficiency virus type 1 envelope glycoprotein.
We have identified six monoclonal antibodies (MAbs) mapping to both linear and conformation-dependent epitopes within the V2 region of the human immunodeficiency virus type 1 clone HXB10. Three of the MAbs (12b, 66c, and 66a) were able to neutralize the molecular clones HXB10 and HXB2, with titers in the range of 9.5 to 20.0 micrograms/ml. MAbs mapping to the crown of the V2 loop (12b, 60b, and 74) bound poorly to cell surface-expressed oligomeric gp120, suggesting an explanation for the poor or negligible neutralizing activity of MAbs to this region. In contrast, MAbs 12b and 60b demonstrated good reactivity with recombinant gp120 in an enzyme-linked immunosorbent assay format, suggesting differential epitope exposure between the recombinant and native forms of gp120. Cross-competition analysis of these MAbs and additional V1V2 MAbs for gp120 binding enabled us to assign the MAbs to six groups (A to F). Selection of neutralization escape mutants with MAbs 10/76b and 11/68b, belonging to nonoverlapping competition groups, identified amino acid changes at residues 165 (I to T) and 185 (D to N), respectively. Interestingly, these escape variants remained sensitive to neutralization by the nonselecting V2 MAbs. All MAbs demonstrated good recognition of IIIB viral gp120 yet failed to neutralize nonclonal stocks of IIIB. In addition, MAbs 12b and 62c bound MN and RF viral gp120, respectively, yet failed to neutralize the respective isolates. Cloning and expression of a library of gp120 and V1V2 fragments from IIIB-, MN-, and RF-infected H9 cultures identified a number of polymorphic sites, resulting in antigenic variation and subsequent loss of V2 MAb recognition. In contrast, the V3 region from the clones of the same isolates showed no amino acid changes, suggesting that the V2 region is polymorphic in long-term-passaged laboratory isolates and may account for the reduced antibody recognition observed.


New antiherpesvirus agents. Their targets and therapeutic potential.
Of the large number of agents under development for the treatment of herpes virus infections [herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV)], only ten have apparently reached clinical development. Aciclovir was approved for the treatment of HSV infections over 10 years ago, and it remains an important and reliable antiviral agent. Recent approvals in some countries of valaciclovir for VZV infection and famciclovir for both HSV and VZV infections demonstrate the rapidity of change in this field. Intravenous ganciclovir and foscarnet are approved for the treatment of CMV infection in the immunocompromised patient. Five of the antiherpetic drugs under current clinical development are nucleoside analogues or their prodrugs; another is a phosphorylated nucleoside (nucleotide). Four of the nucleoside agents-penciclovir, famciclovir, valaciclovir and lobucavir-are being developed for the management of HSV and VZV infections. Valaciclovir is also being developed for the prevention of CMV infections and famciclovir and lobucavir for the treatment of hepatitis B virus infection. Oral ganciclovir, lobucavir, ISIS 2922 and cidofovir are being developed for the suppression of CMV infections in immunocompromised patients. Sorivudine has been studied in VZV infections. n-Docosanol is under development for HSV infections, and cidofovir is being developed for both HSV and CMV infections, as well as for treatment of other viral diseases. Traditionally, the adverse effects associated with anti-CMV compounds have been more difficult to manage and are acceptable clinically only because of the severity of the underlying infection and lack of safer therapeutic alternatives. In general, toxicity issues continue to be problematic in the anti-CMV arena, although newer agents have improved the situation to some extent. In contrast, the safety of anti-HSV compounds has traditionally been excellent, establishing a safety standard that must be met by newer agents entering the field.


Implementation of a new policy results in a decrease of pressure ulcer frequency.
To determine the effects of a new policy on the efficiency of pressure ulcer care. Series of 1-day pressure ulcer surveys before and after the implementation. A 900-bed University Medical Centre in The Netherlands. On the days of the surveys, 657 patients were included before the implementation, 735 patients at 4 months after the implementation, and 755 patients at 11 months after the implementation. Implementation of a hospital guideline for pressure ulcer care combined with the introduction of viscoelastic foam mattresses on the efficiency of the prevention and treatment of pressure ulcers. Comparisons before versus after the implementation were made regarding the care behaviour of nurses and the frequency of patients with pressure ulcer. Inadequate prevention decreased from 19 to 4% after 4 months and to 6% after 11 months (P < 0.001), and inadequate treatment decreased from 60 to 31% (P = 0.005). Excluding the use of mattresses as a positive indicator for care behaviour, we found no significant increase in adequate care to prevent pressure ulcers. Also, in adequate treatment activities, we found no significant difference. Overall, we found a significant decrease in hospital-acquired pressure ulcer frequency from 18 to 13% (P = 0.003) after 4 months and 11% (P < 0.001) after 11 months. The number of pressure ulcer patients in hospital can successfully be reduced. General measures such as the introduction of adequate mattresses and guidelines for prevention and treatment are promising tools in this respect.


Lung cancer risk in never-smokers: a population-based case-control study of epidemiologic risk factors.
We conducted a case-control study in the greater Toronto area to evaluate potential lung cancer risk factors including environmental tobacco smoke (ETS) exposure, family history of cancer, indoor air pollution, workplace exposures and history of previous respiratory diseases with special consideration given to never smokers. 445 cases (35% of which were never smokers oversampled by design) between the ages of 20-84 were identified through four major tertiary care hospitals in metropolitan Toronto between 1997 and 2002 and were frequency matched on sex and ethnicity with 425 population controls and 523 hospital controls. Unconditional logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for the associations between exposures and lung cancer risk. Any previous exposure to occupational exposures (OR total population 1.6, 95% CI 1.4-2.1, OR never smokers 2.1, 95% CI 1.3-3.3), a previous diagnosis of emphysema in the total population (OR 4.8, 95% CI 2.0-11.1) or a first degree family member with a previous cancer diagnosis before age 50 among never smokers (OR 1.8, 95% CI 1.0-3.2) were associated with increased lung cancer risk. Occupational exposures and family history of cancer with young onset were important risk factors among never smokers.


Exercise proves effective in a systematic review of work-related complaints of the arm, neck, or shoulder.
Interventions such as physiotherapy and ergonomic adjustments play a major role in the treatment of most work-related complaints of the arm, neck, and/or shoulder (CANS). We evaluated whether conservative interventions have a significant impact on outcomes for work-related CANS. A systematic review was conducted. Only (randomized) trials studying interventions for patients suffering from work-related CANS were included. Interventions may include exercises, relaxation, physical applications, and workplace adjustments. Two authors independently selected the trials, assessed methodological quality, and extracted data. We included 26 studies (in total 2,376 patients); 23 studies included patients with chronic nonspecific complaints. Over 30 interventions were evaluated and 7 main subgroups of interventions could be determined, of which the subgroup "exercises" was the largest one. Overall, the quality of the studies appeared to be poor. There is limited evidence for the effectiveness of exercises when compared to massage, adding breaks during computer work, massage as add-on treatment to manual therapy, manual therapy as add-on treatment to exercises, and some keyboards in people with carpal tunnel syndrome when compared to other keyboards or placebo. For other interventions no clear effectiveness could be demonstrated.


Disulfiram overcomes bortezomib and cytarabine resistance in Down-syndrome-associated acute myeloid leukemia cells.
Children with Down syndrome (DS) have increased risk for developing AML (DS-AMKL), and they usually experience severe therapy-related toxicities compared to non DS-AMKL. Refractory/relapsed disease has very poor outcome, and patients would benefit from novel, less toxic, therapeutic strategies that overcome resistance. Relapse/resistance are linked to cancer stem cells with high aldehyde dehydrogenase (ALDH) activity. The purpose of the present work was to study less toxic alternative therapeutic agents for relapsed/refractory DS-AMKL. Fourteen AML cell lines including the DS-AMKL CMY and CMK from relapsed/refractory AML were used. Cytarabine (Ara-C), bortezomib (BTZ), disulfiram/copper (DSF/Cu2+) were evaluated for cytotoxicity, depletion of ALDH-positive cells, and resistance. BTZ-resistant CMY and CMK variants were generated by continuous BTZ treatment. Cell viability was assessed using CellTiter-Glo®, ALDH activity by ALDELUORTM, and proteasome inhibition by western blot of ubiquitinated proteins and the Proteasome-Glo™ Chymotrypsin-Like (CT-like) assay, apoptosis by Annexin V Fluos/Propidium iodide staining, and mutations were detected using PCR, cloning and sequencing. Ara-C-resistant AML cell lines were sensitive to BTZ and DSF/Cu2+. The Ara-C-resistant DS-AMKL CMY cells had a high percentage of ALDHbright "stem-like" populations that may underlie Ara-C resistance. One percent of these cells were still resistant to BTZ but sensitive to DSF/Cu2+. To understand the mechanism of BTZ resistance, BTZ resistant (CMY-BR) and (CMK-BR) were generated. A novel mutation PSMB5 Q62P underlied BTZ resistance, and was associated with an overexpression of the β5 proteasome subunit. BTZ-resistance conferred increased resistance to Ara-C due to G1 arrest in the CMY-BR cells, which protected the cells from S-phase damage by Ara-C. CMY-BR and CMK-BR cells were cross-resistant to CFZ and MG-132 but sensitive to DSF/Cu2+. In this setting, DSF/Cu2+ induced apoptosis and proteasome inhibition independent of CT-like activity inhibition. We provide evidence that DSF/Cu2+ overcomes Ara-C and BTZ resistance in cell lines from DS-AMKL patients. A novel mutation underlying BTZ resistance was detected that may identify BTZ-resistant patients, who may not benefit from treatment with CFZ or Ara-C, but may be responsive to DSF/Cu2+. Our findings support the clinical development of DSF/Cu2+ as a less toxic efficacious treatment approach in patients with relapsed/refractory DS-AMKL.


Effect of insulin on the inflammatory and acute phase response after burn injury.
After a severe burn, the liver plays a pivotal role by modulating inflammatory processes, metabolic pathways, immune functions, and the acute phase response. Therefore, liver integrity and function are important for recovery. A thermal injury, however, causes hepatic damage by inducing hepatic edema, fatty infiltration, hepatocyte apoptosis, and metabolic derangements associated with insulin resistance and impaired insulin signaling. In preliminary studies, we found that these pathophysiological processes are related to hepatic inflammation, altered intracellular signaling, and mitochondrial dysfunction. We hypothesize that modulation of these processes with insulin could improve hepatic structure and function and, therefore, outcome of burned and critically ill patients. Insulin administration improves survival and decreases the rate of infections in severely burned and critically ill patients. Here, we show that insulin administration decreases the synthesis of proinflammatory cytokines and signal transcription factors and improves hepatic structure and function after a severe burn injury; insulin also restores hepatic homeostasis and improves hepatic dysfunction postburn via alterations in the signaling cascade.


Standardization of extracellular vesicle measurements by flow cytometry through vesicle diameter approximation.
Essentials Platelet extracellular vesicles (EVs) concentrations measured by flow cytometers are incomparable. A model is applied to convert ambiguous scatter units to EV diameter in nanometer. Most included flow cytometers lack the sensitivity to detect EVs of 600 nm and smaller. The model outperforms polystyrene beads for comparability of platelet EV concentrations. Background Detection of extracellular vesicles (EVs) by flow cytometry has poor interlaboratory comparability, owing to differences in flow cytometer (FCM) sensitivity. Previous workshops distributed polystyrene beads to set a scatter-based diameter gate in order to improve the comparability of EV concentration measurements. However, polystyrene beads provide limited insights into the diameter of detected EVs. Objectives To evaluate gates based on the estimated diameter of EVs instead of beads. Methods A calibration bead mixture and platelet EV samples were distributed to 33 participants. Beads and a light scattering model were used to set EV diameter gates in order to measure the concentration of CD61-phycoerythrin-positive platelet EVs. Results Of the 46 evaluated FCMs, 21 FCMs detected the 600-1200-nm EV diameter gate. The 1200-3000-nm EV diameter gate was detected by 31 FCMs, with a measured EV concentration interlaboratory variability of 81% as compared with 139% with the bead diameter gate. Part of the variation in both approaches is caused by precipitation in some of the provided platelet EV samples. Flow rate calibration proved essential because systems configured to 60 μL min-1 differed six-fold in measured flow rates between instruments. Conclusions EV diameter gates improve the interlaboratory variability as compared with previous approaches. Of the evaluated FCMs, 24% could not detect 400-nm polystyrene beads, and such instruments have limited utility for EV research. Finally, considerable differences were observed in sensitivity between optically similar instruments, indicating that maintenance and training affect the sensitivity.


Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: Rationale and design of the STRENGTH trial.
It is uncertain whether omega-3 fatty acids are beneficial in statin-treated patients. Epanova is a mix of omega-3 free fatty acids, not requiring co-ingestion with food, which can lower triglycerides by up to 31%. STRENGTH will examine whether Epanova 4 g daily reduces the rate of cardiovascular events in statin-treated patients with hypertriglyceridemia and low levels of HDL-C at high risk for developing cardiovascular events. STRENGTH is a randomized, double-blind, placebo-controlled trial. Patients had a triglyceride level ≥ 180 to <500 mg/dL and HDL-C < 42 mg/dL (men) or < 47 mg/dL (women) in the presence of either (1) established atherosclerotic cardiovascular disease, (2) diabetes with one additional risk factor, or (3) were other high-risk primary prevention patients, based on age and risk factor assessment. Patients should be treated with a statin, for >4 weeks, and have LDL-C < 100 mg/dL, but were also eligible if LDL-C was ≥100 mg/dL while on maximum tolerated statin therapy. The study will extend from October 30, 2014 to October 30, 2019. 13 086 patients were randomized to Epanova 4 g or placebo daily in addition to standard medical therapy. The primary efficacy outcome is time to first event of cardiovascular death, myocardial infarction, stroke, coronary revascularization or hospitalization for unstable angina. The trial will continue until 1600 patients reach the primary endpoint, with a median duration of therapy of 3 years. STRENGTH will determine whether Epanova 4 g daily will reduce cardiovascular events in statin-treated high-risk patients with hypertriglyceridemia and low HDL-C levels.