The etiologic role of genetic and environmental factors in criminal behavior as determined from full- and half-sibling pairs: an evaluation of the validity of the twin method.
Twin studies have shown that criminal behavior (CB) is influenced by both genetic and shared environmental factors. Could these results be replicated using full-siblings and half-siblings? In 911 009 full-siblings reared together (FSRT), 41 872 half-siblings reared together (HSRT) and 52 590 half-siblings reared apart (HSRA), CB was assessed from the Swedish Crime Register. Modeling, including testing for age differences and rearing status, was performed using the OpenMx package. Five sibling models were fitted examining FSRT and HSRT 0-2 years different in age, and both FSRT and HSRT, and FSRT, HSRT and HSRA 0-10 years different in age with and without a specified shared environment indexing age differences. Heritability estimates for CB ranged from 33 to 55% in females and 39 to 56% in males, similar to those found in our prior twin study on the same population. Estimates for the shared environment varied from 1 to 14% in females and 10 to 23% in males, lower than those estimated in the twin study. The specified shared environment indexed by sibling age differences was significant in all models tested. Heritability estimates for CB from full- and half-siblings closely approximated those found from twins in the same population, validating the twin method. Shared environmental estimates were lower, suggesting the presence of shared environmental factors for CB specific to twins. When rearing status can be assessed, full- and half-siblings offer an additional method for assessing the role of genetic and environmental factors in complex disorders. However, age differences in siblings may need to be included in the models.


HYVIA™: A novel, topical chia seed extract that improves skin hydration.
Chia seeds have gained importance as it is the highest known plant source of omega-3 (ω3) polyunsaturated fatty acids. Specifically, chia seeds possess ω3 α-linolenic acid (ALA) and ω6 linoleic acid (LA), together known as Vitamin F, which play an important role in maintaining skin function. Protein phosphatase 2A (PP2A) is a master regulatory protein that plays a critical role in skin barrier function and its activity is modulated by natural lipids. Obtain a chia seed extract (HYVIA™) with significant higher levels of Vitamin F, determine in vitro PP2A activity and skin hydration markers compared to other commercial chia seed extracts (CCSEs), and evaluate the potential skin hydration benefits clinically in human subjects. A PP2A demethylation assay was utilized to assess PP2A activity. In vitro studies utilizing normal human epidermal keratinocytes (NHEKs) were treated with HYVIA™ and gene expression of hydration markers (AQP3, HAS2) were measured by quantitative PCR (qPCR). A 16-subject clinical trial was performed with 0.1% HYVIA™ formulated in a cream and applied topically to assess its skin moisturizing potential. We demonstrate here that HYVIA™, ALA, and LA inhibit PP2A demethylation, boosting PP2A activity, while most other CCSEs do not. Unlike other CCSEs, HYVIA™ increases keratinocyte hydration factors aquaporin-3 and hyaluronic acid synthase-2 in vitro. Clinical assessment of 0.1% HYVIA™ cream shows that HYVIA™ improves skin hydration. HYVIA™ is a novel chia seed extract, enriched for Vitamin F, that modulates PP2A activity and clinically improves skin hydration and barrier function.


Prevention of late‑life dementia: what works and what does not.
Advances in the treatment and prevention of disease have contributed to an aging global population. Subsequently, there is an increasing prevalence of age‑related conditions, such as dementia. There are currently no disease‑modifying therapies commercially available, and there is a growing emphasis on strategies to prevent dementia. We have reviewed the relevant literature pertaining to dementia risk and putative prevention factors. We present our findings by summarizing the pertinent items that may play a role in prevention and conclude our recommendations at this time.


Post-transcriptional regulation of HSP70 expression following oxidative stress in SH-SY5Y cells: the potential involvement of the RNA-binding protein HuR.
Brain aging is associated with a progressive imbalance between intracellular concentration of Reactive Oxygen Species (ROS) and cells ability to activate defensive genes. Heat Shock Protein 70 (HSP70) has been shown to act as a fundamental defensive mechanism for neurons exposed to an oxidant challenge, and its expression decreases during senescence. In the present report we show that the RNA-binding protein ELAV/HuR can affect, post-transcriptionally, the fate of HSP70 mRNA following H(2)O(2)-mediated oxidative stress in SH-SY5Y human neuroblastoma cells. As a consequence of H(2)O(2) treatment (1mM for 30 minutes), HSP70 mRNA accumulates in the ribosomes associated to the cytoskeleton, where parallel Western blotting experiments reveal statistically significant increase for both HuR and HSP70 protein levels. We also confirm the capability of HuR to bind to HSP70 mRNA, and describe how the biological effect of this ELAV protein on the HSP70 mRNA could be due to a direct phosphorylation in serine/threonine residues of HuR itself by the early (10 minutes) H(2)O(2)-mediated activation of PKC alpha. Our findings shed light on the post-transcriptional regulation of HSP70 expression, suggesting the existence of a new molecular cascade -involving PKC/HuR/HSP70- that possibly represents an early event in the cellular response to H(2)O(2)-mediated oxidative stress in SH-SY5Y human neuroblastoma cells. The present results lead us to speculate that an impairment in this regulatory mechanism might directly contribute to the defective cellular response to oxidative stress, thus helping to dissect a potential tool useful to counteract some aspects associated to cerebral senescence.


Netrin-1 is a novel regulator of vascular endothelial function in diabetes.
Netrin-1, a secreted laminin-like protein identified as an axon guidance molecule, has been shown to be of critical importance in the cardiovascular system. Recent studies have revealed pro-angiogenic, anti-apoptotic and anti-inflammatory properties of netrin-1 as well as cardioprotective actions against myocardial injury in diabetic mice. To examine the role of netrin-1 in diabetes-and high glucose (HG)-induced vascular endothelial dysfunction (VED) using netrin-1 transgenic mice (Tg3) and cultured bovine aortic endothelial cells (BAEC). Overexpression of netrin-1 prevented diabetes-induced VED in aorta from diabetic mice and netrin-1 treatment attenuated HG-induced impairment of nitric oxide synthase (NOS) function in BAECs. Experiments were performed in Tg3 and littermate control (WT) mice rendered diabetic with streptozotocin (STZ) and in BAECs treated with HG (25 mmol/L). Levels of netrin-1 and its receptor DCC, markers of inflammation and apoptosis and vascular function were assessed in aortas from diabetic and non-diabetic Tg3 and WT mice. Vascular netrin-1 in WT mice was reduced under diabetic conditions. Aortas from non-diabetic Tg3 and WT mice showed similar maximum endothelium-dependent relaxation (MEDR) (83% and 87%, respectively). MEDR was markedly impaired in aorta from diabetic WT mice (51%). This effect was significantly blunted in Tg3 diabetic aortas (70%). Improved vascular relaxation in Tg3 diabetic mice was associated with increased levels of phospho-ERK1/2 and reduced levels of oxidant stress, NFκB, COX-2, p16INK4A, cleaved caspase-3 and p16 and p53 mRNA. Netrin-1 treatment prevented the HG-induced decrease in NO production and elevation of oxidative stress and apoptosis in BAECs. Diabetes decreases aortic levels of netrin-1. However, overexpression of netrin-1 attenuates diabetes-induced VED and limits the reduction of NO levels, while increasing expression of p-ERK1/2, and suppressing oxidative stress and inflammatory and apoptotic processes. Enhancement of netrin-1 function may be a useful therapeutic means for preventing vascular dysfunction in diabetes.


Evaluation of genotoxic effects of oral exposure to aluminum oxide nanomaterials in rat bone marrow.
Nanomaterials have novel properties and functions because of their small size. The unique nature of nanomaterials may be associated with potentially toxic effects. The aim of this study was to evaluate the in vivo genotoxicity of rats exposed with Aluminum oxide nanomaterials. Hence in the present study, the genotoxicity of Aluminum oxide nanomaterials (30 and 40 nm) and its bulk material was studied in bone marrow of female Wistar rats using chromosomal aberration and micronucleus assays. The rats were administered orally with the doses of 500, 1000 and 2000 mg/kg bw. Statistically significant genotoxicity was observed with Aluminum oxide 30 and 40 nm with micronucleus as well as chromosomal aberration assays. Significantly (p < 0.05 or p < 0.001) increased frequency of MN was observed with 1000 and 2000 mg/kg bw dose levels of Aluminum oxide 30 nm (9.4 +/- 1.87 and 15.2 +/- 2.3, respectively) and Aluminum oxide 40 nm (8.1 +/- 1.8 and 13.9 +/- 2.21, respectively) over control (2.5 +/- 0.7) at 30 h. Likewise, at 48 h sampling time a significant (p < 0.05 or p < 0.001) increase in frequency of MN was evident at 1000 and 2000 mg/kg bw dose levels of Aluminum oxide 30 nm (10.6 +/- 1.68 and 16.6 +/- 2.66, respectively) and Aluminum oxide 40 nm (9.0 +/- 1.38 and 14.7 +/- 1.68, respectively) compared to control (1.8 +/- 0.75). Significantly increased frequencies (p < 0.05 or p < 0.001) of chromosomal aberrations were observed with Aluminum oxide 30 nm (1000 and 2000 mg/kg bw) and Aluminum oxide 40 nm (2000 mg/kg bw) in comparison to control at 18 and 24 h. Further, since there is need for information on the toxicokinetics of nanomaterials, determination of these properties of the nanomaterials was carried out in different tissues, urine and feces using inductively coupled plasma mass spectrometry (ICP-MS). A significant size dependent accumulation of Aluminum oxide nanomaterials occurred in different tissues, urine and feces of rats as shown by ICP-MS data. The results of our study suggest that exposure to Aluminum oxide nanomaterials has the potential to cause genetic damage.


Sample size requirements to detect a two- or three-way interaction in longitudinal cluster randomized clinical trials with second-level randomization.
When randomizations are assigned at the cluster level for longitudinal cluster randomized trials (longitudinal-CRTs) with a continuous outcome, formulae for determining the required sample size to detect a two-way interaction effect between time and intervention are available. To show that (1) those same formulae can also be applied to longitudinal trials when randomizations are assigned at the subject level within clusters and (2) this property can be extended to 2-by-2 factorial longitudinal-CRTs with two treatments and different levels of randomization for which testing a three-way interaction between time and the two interventions is of primary interest. We show that slope estimates from different treatment arms are uncorrelated, regardless of whether randomization occurs at the third or second level and also regardless of whether slopes are considered fixed or random in the mixed-effects model for testing two-way or three-way interactions. Sample size formulae are extended to unbalanced designs. Simulation studies were applied to verify the findings. Sample size formulae for testing two-way and three-way interactions in longitudinal-CRTs with second-level randomization are identical to those for trials with third-level randomization. In addition, the total number of observations required for testing a three-way interaction is demonstrated to be four times as large as that required for testing a two-way interaction, regardless of the level of randomization for both fixed- and random-slope models. The findings may be only applicable to longitudinal-CRTs with normally distributed continuous outcome. All of the findings are validated by simulation studies and enable the design of longitudinal clinical trials to be more flexible in regard to the level of randomization and allocation of clusters and subjects.


Use of Zinc Carbonate Spiking to Obtain Phytotoxicity Thresholds Comparable to Those in Field-Collected Soils.
Several studies have reported the presence of smithsonite (ZnCO3 ) in soils polluted by zinc mining. The present study aimed to determine upper critical threshold values of Zn phytotoxicity in a substrate spiked with ZnCO3 and to compare them with those obtained in field-collected soils. We studied Zn toxicity to perennial ryegrass (Lolium perenne L.) grown in pots with unpolluted peat treated with increasing concentrations of ZnCO3 that produced nominal total Zn concentrations of 0, 0.7, 1.3, 2.0, 2.6, and 3.3%. To keep constant near-neutral pH value in all the treatments, we used decreasing concentrations of dolomitic lime. In the treatment with total soil Zn of 3.3% (pH 6.8), the foliar Zn concentration of L. perenne was 1914 ± 211 mg kg-1 , falling into the range of 2400 ± 300 mg kg-1 reported for Lolium species grown under similar laboratory conditions in a polluted soil (total soil Zn 5.4%, pH 7.3) collected near a Zn smelter. The value of 92 ± 98 mg kg-1 was obtained for the median effective concentration (EC50) values of 0.01 M KNO3 -extractable Zn using the responses of shoot dry biomass, shoot length, and total pigments. This value falls within the range of 95 ± 46 mg kg-1 reported in other studies for the EC50 values of salt-extractable Zn using field-collected soils. The application of ZnCO3 for spiking was able to mimic foliar Zn concentrations of Lolium species observed in field-collected soils. The effective concentrations of soil Zn obtained in the present study are comparable to those obtained in field-collected soils. Future research should determine effective concentrations of metals using soils spiked with metal-containing compounds that mimic a real source of contamination. Environ Toxicol Chem 2020;39:1790-1796. © 2020 SETAC.


Correlating clinical indicators of lower-limb ischaemia with quality of life.
The objectives of the study were to analyse the impact of increasing lower-limb ischaemia upon quality of life and to assess the correlation between clinical indicators of lower-limb ischaemia and such quality. A prospective observational study of a consecutive series of 235 patients (144 men and 91 women; median age 68 (range 41-87) years presenting with varying degrees of lower-limb ischaemia graded according to ISCVS criteria was performed. Data was collected at interview before any intervention. Clinical indicators of lower-limb perfusion included: intermittent claudication and maximum walking distance on standardized treadmill testing; ankle:brachial pressure indices and isotope limb blood flow. Quality of life analysis was performed using the EuroQol (EQ) questionnaire. This is a standardized generic instrument for describing health-related quality of life and consists of a descriptive system of five dimensions, each measured on three levels. Thus, a profile and two single indices of quality of life were derived using different methods. Increasing lower-limb ischaemia results in a statistically significant deterioration in both global quality of life and in all EQ-measured quality of life dimensions (P < 0.01 Kruskal-Wallis, ANOVA). The correlation between clinical indicators and quality of life is statistically significant but not sufficiently close (correlation coefficients < 0.6) to assume that variations in clinical indicators result in reciprocal variations in quality of life. In conclusion, as might be expected, a significant correlation exists between clinical indicators of lower-limb ischaemia and health-related quality of life. However, the low correlation coefficients emphasize how tenuous the association is. Thus, a significant improvement in the clinical indicators of lower-limb ischaemia cannot be assumed to impart a similar benefit on quality of life. The latter concept must therefore be analysed independently.


GGA1 interacts with the adaptor protein AP-1 through a WNSF sequence in its hinge region.
The Golgi-associated gamma-adaptin-related ADP-ribosylation factor-binding proteins (GGAs) are critical components of the transport machinery that mediates the trafficking of the mannose 6-phosphate receptors and associated cargo from the trans-Golgi network to the endosomes. The GGAs colocalize in vivo with the clathrin adaptor protein AP-1 and bind to AP-1 in vitro, suggesting that the two proteins may cooperate in packaging the mannose 6-phosphate receptors into clathrin-coated vesicles at the trans-Golgi network. Here, we demonstrate that the sequence, (382)WNSF(385), in the hinge region of GGA1 mediates its interaction with the AP-1 gamma-ear. The Trp and Phe constitute critical amino acids in this interaction. The binding of Rabaptin5 to the AP-1 gamma-ear, which occurs through a FXXPhi motif, is inhibited by a peptide encoding the GGA1 (382)WNSF(385) sequence. Moreover, mutations in the AP-1 gamma-ear that abolish its interaction with Rabaptin5 also preclude its association with GGA1. These results suggest that the GGA1 WXXF-type and Rabaptin5 FXXPhi-type motifs bind to the same or highly overlapping sites in the AP-1 gamma-ear. This binding is modulated by residues adjacent to the core motifs.


Heme oxygenase-1-mediated autophagy protects against hepatocyte cell death and hepatic injury from infection/sepsis in mice.
Adaptive responses to sepsis are necessary to prevent organ failure and death. Cellular signaling responses that limit cell death and structural damage allow a cell to withstand insult from sepsis to prevent irreversible organ dysfunction. One such protective pathway to reduce hepatocellular injury is the up-regulation of heme oxygenase-1 (HO-1) signaling. HO-1 is up-regulated in the liver in response to multiple stressors, including sepsis and lipopolysaccharide (LPS), and has been shown to limit cell death. Another recently recognized rudimentary cellular response to injury is autophagy. The aim of these investigations was to test the hypothesis that HO-1 protects against hepatocyte cell death in experimental sepsis in vivo or LPS in vitro via induction of autophagy. These data demonstrate that both HO-1 and autophagy are up-regulated in the liver after cecal ligation and puncture (CLP) in C57BL/6 mice or in primary mouse hepatocytes after treatment with LPS (100 ng/mL). CLP or LPS results in minimal hepatocyte cell death. Pharmacological inhibition of HO-1 activity using tin protoporphyrin or knockdown of HO-1 prevents the induction of autophagic signaling in these models and results in increased hepatocellular injury, apoptosis, and death. Furthermore, inhibition of autophagy using 3-methyladenine or small interfering RNA specific to VPS34, a class III phosphoinositide 3-kinase that is an upstream regulator of autophagy, resulted in hepatocyte apoptosis in vivo or in vitro. LPS induced phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), in part, via HO-dependent signaling. Moreover, inhibition of p38 MAPK prevented CLP- or LPS-induced autophagy. Sepsis or LPS-induced autophagy protects against hepatocellular death, in part via an HO-1 p38 MAPK-dependent signaling. Further investigations are needed to elucidate how autophagic signaling prevents apoptosis and cell death.


Street connectivity and walking for transport: role of neighborhood destinations.
Built environment attributes may be important determinants of physical activity. Greater street connectivity has been shown in several studies to be associated with adults' walking for transport (WFT). We examined the extent to which this association can be explained by the availability of utilitarian destinations. Adults (n=2544) participating in the Physical Activity in Localities and Community Environments (PLACE) study in Adelaide, Australia during 2003-2004, reported their WFT and perceived distances to 16 utilitarian destinations. Connectivity was calculated as the ratio of the number of intersections to Census Collection District land area. Marginal models via generalized estimating equations were used and the product-of-coefficients test was used to test mediation effects. Connectivity was significantly associated with destination availability and with WFT frequency. The connectivity-WFT relationship was attenuated after taking availability of destinations into account, but remained significant. Availability of destinations accounted for 16% of the total effect of connectivity on WFT. Higher connectivity can be associated with more frequent WFT, partly because more utilitarian destinations are available in areas with well-connected street networks. Further clarification of these relationships and other pathways through which connectivity influences residents' walking can inform urban design initiatives to promote physical activity.


Social context and depression after a disaster: the role of income inequality.
To examine the association between neighbourhood income inequality and depression, both overall and among those with different levels of income, in the post-disaster context. A representative cross sectional random digit dial telephone survey was conducted. New York City (NYC) six months after September 11, 2001. 1570 respondents were interviewed, of whom 1355 provided residence information permitting their inclusion in this analysis. Past six month depression was assessed using a lay administered instrument consistent with DSM-IV criteria. Income inequality was measured with the Gini coefficient. The sample was demographically representative of NYC (56.2% female, 35.7% white, 6.3% Asian 24.2% African American, 29.7% Hispanic, and 4.2% other race or ethnicity) and the prevalence of past six month depression was 12.4%. In a final adjusted model, neighbourhood level income inequality was positively associated with depression but this association was not significant (beta = 7.58, p = 0.1). However, among those with low individual income (< 20,000 US dollars) there was a strong significant association between income inequality and depression (beta = 35.02, p<0.01), while there was no association among those with higher income. In the post-disaster context, neighbourhood level income inequality was associated with depression among persons with lower income; this group may be more socially or economically marginalized and dependent on local resources. Future research should examine potential mechanisms through which income inequality and other features of the social context may affect mental health in the post-disaster context.


Multiphoton autofluorescence and second-harmonic generation imaging of the ex vivo porcine eye.
The purpose of this work was to demonstrate the use of the combined imaging modality of multiphoton autofluorescence and second-harmonic generation (SHG) microscopy in obtaining spectrally resolved morphologic features of the cornea, limbus, conjunctiva, and sclera in whole, ex vivo porcine eyes. The 780-nm output of a femtosecond, titanium-sapphire laser was used to induce broadband autofluorescence (435-700 nm) and SHG (390 nm) from various regions of the surface of ex vivo porcine eyes. A water-immersion objective was used for convenient imaging of the curved surface of the eye. Multiphoton autofluorescence was useful in identifying cellular structures of the different domains of the ocular surface, and the SHG signal can be used to resolve collagen organization within the cornea stroma and sclera of ex vivo porcine eyes. Multiphoton autofluorescence and SHG microscopy have been demonstrated to be an effective technique for resolving, respectively, the cellular and collagen structures within the ocular surface of ex vivo porcine eyes. SHG imaging resolved the difference in structural orientations between corneal and sclera collagen fibers. Specifically, the corneal collagen is organized in a depth-dependent fashion, whereas the scleral collagen is randomly packed. Because this technique does not require histologic preparation procedures, it has the potential to be applied for in vivo studies with minimal disturbance to the eye.


Genetic markers and quantitative genetic variation in Medicago truncatula (Leguminosae): a comparative analysis of population structure.
Two populations of the selfing annual Medicago truncatula Gaertn. (Leguminoseae), each subdivided into three subpopulations, were studied for both metric traits (quantitative characters) and genetic markers (random amplified polymorphic DNA and one morphological, single-locus marker). Hierarchical analyses of variance components show that (1) populations are more differentiated for quantitative characters than for marker loci, (2) the contribution of both within and among subpopulations components of variance to overall genetic variance of these characters is reduced as compared to markers, and (3) at the population level, within population structure is slightly but not significantly larger for markers than for quantitative traits. Under the hypothesis that most markers are neutral, such comparisons may be used to make hypotheses about the strength and heterogeneity of natural selection in the face of genetic drift and gene flow. We thus suggest that in these populations, quantitative characters are under strong divergent selection among populations, and that gene flow is restricted among populations and subpopulations.


Use of declarative statements in creating and maintaining computer-interpretable knowledge bases for guideline-based care.
Developing computer-interpretable clinical practice guidelines (CPGs) to provide decision support for guideline-based care is an extremely labor-intensive task. In the EON/ATHENA and SAGE projects, we formulated substantial portions of CPGs as computable statements that express declarative relationships between patient conditions and possible interventions. We developed query and expression languages that allow a decision-support system (DSS) to evaluate these statements in specific patient situations. A DSS can use these guideline statements in multiple ways, including: (1) as inputs for determining preferred alternatives in decision-making, and (2) as a way to provide targeted commentaries in the clinical information system. The use of these declarative statements significantly reduces the modeling expertise and effort required to create and maintain computer-interpretable knowledge bases for decision-support purpose. We discuss possible implications for sharing of such knowledge bases.


Glyph-based SPECT visualization for the diagnosis of coronary artery disease.
Myocardial perfusion imaging with single photon emission computed tomography (SPECT) is an established method for the detection and evaluation of coronary artery disease (CAD). State-of-the-art SPECT scanners yield a large number of regional parameters of the left-ventricular myocardium (e.g., blood supply at rest and during stress, wall thickness, and wall thickening during heart contraction) that all need to be assessed by the physician. Today, the individual parameters of this multivariate data set are displayed as stacks of 2D slices, bull's eye plots, or, more recently, surfaces in 3D, which depict the left-ventricular wall. In all these visualizations, the data sets are displayed side-by-side rather than in an integrated manner, such that the multivariate data have to be examined sequentially and need to be fused mentally. This is time consuming and error-prone. In this paper we present an interactive 3D glyph visualization, which enables an effective integrated visualization of the multivariate data. Results from semiotic theory are used to optimize the mapping of different variables to glyph properties. This facilitates an improved perception of important information and thus an accelerated diagnosis. The 3D glyphs are linked to the established 2D views, which permit a more detailed inspection, and to relevant meta-information such as known stenoses of coronary vessels supplying the myocardial region. Our method has demonstrated its potential for clinical routine use in real application scenarios assessed by nuclear physicians.


Comparison of efficacy and safety of atorvastatin (10mg) with simvastatin (10mg) at six weeks. ASSET Investigators.
The 6-week efficacy and safety of atorvastatin versus simvastatin was determined during a 54-week, open-label, multicenter, parallel-arm, treat-to-target study. In all, 1,424 patients with mixed dyslipidemia (triglyceride 200 to 600 mg/dl [2.26 to 6.77 mmol/L]) were stratified to 1 of 2 groups (diabetes or no diabetes). Patients were then randomized to receive either atorvastatin 10 mg/ day (n = 730) or simvastatin 10 mg/day (n = 694). Efficacy was determined by measuring changes from baseline in lipid parameters including low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, and apolipoprotein B. Compared with simvastatin, atorvastatin produced significantly greater (p < 0.0001) reductions from baseline in LDL cholesterol (37.2% vs 29.6%), total cholesterol (27.6% vs 21.5%), triglycerides (22.1% vs 16.0%), the ratio of LDL cholesterol to high-density lipoprotein (HDL) cholesterol (41.1% vs 33.7%), and apolipoprotein B (28.3% vs 21.2%), and a comparable increase from baseline in HDL cholesterol (7.4% vs 6.9%). Atorvastatin was also significantly (p < 0.0001) more effective than simvastatin at treating the overall patient population to LDL cholesterol goals (55.6% vs 38.4%). Fewer than 6% of patients in either treatment group experienced drug-attributable adverse events, which were mostly mild to moderate in nature. Diabetic patients treated with either statin had safety characteristics similar to nondiabetics, with atorvastatin exhibiting superior efficacy to simvastatin. In conclusion, atorvastatin, at a dose of 10 mg/day, is more effective than simvastatin 10 mg/day at lowering lipids and reaching LDL cholesterol goals in patients with mixed dyslipidemia. Both statins are well tolerated with safety profiles similar to other members of the statin class.


[Eating disorders; 25 years of research and treatment].
As a result of the publication of DSM-III(-R) bulimia nervosa was recognised as a separate eating disorder, distinct from anorexia nervosa. Eating disorders occur mainly in young females. The incidence of anorexia nervosa in Dutch females aged 15 to 19 doubled between the 1980s and the 1990s. Over the past 25 years there have been many improvements in the treatment of patients with eating disorders, but only a very few of them utilise the health care facilities that are now available.


Aberrant production of leukotriene C4 by macrophages from autoimmune-prone mice.
Eicosanoids have been implicated in the pathogenesis of autoimmune diseases. In this study, peritoneal macrophages from autoimmune-prone mice were examined for their capacity to produce proinflammatory 5-lipoxygenase metabolites. The results indicate that enhanced production of leukotriene C4 is a common feature of murine autoimmunity and suggest further that aberrations in 5-lipoxygenase activity may play a role in the development of lupus.


A cardiac microRNA governs systemic energy homeostasis by regulation of MED13.
Obesity, type 2 diabetes, and heart failure are associated with aberrant cardiac metabolism. We show that the heart regulates systemic energy homeostasis via MED13, a subunit of the Mediator complex, which controls transcription by thyroid hormone and other nuclear hormone receptors. MED13, in turn, is negatively regulated by a heart-specific microRNA, miR-208a. Cardiac-specific overexpression of MED13 or pharmacologic inhibition of miR-208a in mice confers resistance to high-fat diet-induced obesity and improves systemic insulin sensitivity and glucose tolerance. Conversely, genetic deletion of MED13 specifically in cardiomyocytes enhances obesity in response to high-fat diet and exacerbates metabolic syndrome. The metabolic actions of MED13 result from increased energy expenditure and regulation of numerous genes involved in energy balance in the heart. These findings reveal a role of the heart in systemic metabolic control and point to MED13 and miR-208a as potential therapeutic targets for metabolic disorders.


A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest oncology group study (9031).
Older age is a poor prognosis factor in acute myeloid leukemia (AML). This double-blind trial was designed to test the hypothesis that granulocyte colony-stimulating factor (G-CSF) used as supportive care could improve the treatment of elderly AML patients. Two hundred thirty-four patients 55 or more years of age with a morphologic diagnosis of de novo or secondary AML, French-American-British (FAB) M0-M7, excluding M3, were randomly assigned to a standard induction regimen (daunorubicin at 45 mg/m2 intravenously [IV] on days 1 through 3 and Ara-C at 200 mg/m2 IV continuous infusion on days 1 through 7) plus either placebo or G-CSF (400 microg/m2 IV over 30 minutes once daily). Results are reported here for 211 centrally confirmed cases of non-M3 AML. The two groups were well balanced in demographic, clinical, and hematological parameters, with median ages of 68 years in the G-CSF and 67 years in the placebo groups. The complete response (CR) rate was not significantly better in the G-CSF group: 50% in the placebo and 41% in the G-CSF group (one-tailed P = .89). Median overall survival was also similar, 9 months (95% confidence interval [CI], 7 to 10 months) in the placebo and 6 months (95% CI, 3 to 8 months) in the G-CSF arms (P = .71). We found a significant 15% reduction in the time to neutrophil recovery in the G-CSF group (P = .014). G-CSF had no impact on recovery from thrombocytopenia (P = .80) or duration of first hospitalization (P = .27). When infection complications were evaluated, G-CSF had a beneficial effect on the duration but not on incidence of infection. G-CSF patients had fewer days with fever and shorter duration of antibiotic use. However, there was no difference in the frequency of total documented infections or in the number of fatal infections (19% placebo v 20% G-CSF). In this study of elderly AML patients, G-CSF improved clinical parameters of duration of neutropenia and antibiotic use, but did not change CR rate or survival or shorten hospitalization.


"Negative" results in cohort studies--how to recognize fallacies.
Negative studies are important in occupational medicine because knowledge on noneffect levels for harmful exposures is pertinent. A truly negative study must (i) be large, (ii) be sensitive, and (iii) have well-documented exposure data. Small and/or insensitive so-called negative studies are uninformative, and negative results can only be related to the actual or lower exposure levels. Some of the causes for falsely negative results are inappropriate design (eg, cross-sectional instead of longitudinal), crude measuring methods, inappropriate type of examination, wrong categories of exposed workers, inclusion of workers with too short an exposure time and too low an exposure intensity in the exposed series, too short a follow-up for diseases with long latency times (eg, cancer), incomplete follow-up, wrong reference category (eg, the general population), poor precision of measuring methods, and insensitive or wrong statistical methods. Finally, the same data may be interpreted in different ways. Correct interpretation requires both knowledge of the subject and apprehension of the fact that errors in design and measurement often tend to mask existing differences. At the most, a small insensitive study may rule out very strong effects.


Density functional theory calculations for the band gap and formation energy of Pr4-xCaxSi12O3+xN18-x; a highly disordered compound with low symmetry and a large cell size.
A novel oxynitride compound, Pr4-xCaxSi12O3+xN18-x, synthesized using a solid-state route has been characterized as a monoclinic structure in the C2 space group using Rietveld refinement on synchrotron powder X-ray diffraction data. The crystal structure of this compound was disordered due to the random distribution of Ca/Pr and N/O ions at various Wyckoff sites. A pragmatic approach for an ab initio calculation based on density function theory (DFT) for this disordered compound has been implemented to calculate an acceptable value of the band gap and formation energy. In general, for the DFT calculation of a disordered compound, a sufficiently large super cell and infinite variety of ensemble configurations is adopted to simulate the random distribution of ions; however, such an approach is time consuming and cost ineffective. Even a single unit cell model gave rise to 43 008 independent configurations as an input model for the DFT calculations. Since it was nearly impossible to calculate the formation energy and the band gap energy for all 43 008 configurations, an elitist non-dominated sorting genetic algorithm (NSGA-II) was employed to find the plausible configurations. In the NSGA-II, all 43 008 configurations were mathematically treated as genomes and the calculated band gap and the formation energy as the objective (fitness) function. Generalized gradient approximation (GGA) was first employed in the preliminary screening using NSGA-II, and thereafter a hybrid functional calculation (HSE06) was executed only for the most plausible GGA-relaxed configurations with lower formation and higher band gap energies. The final band gap energy (3.62 eV) obtained after averaging over the selected configurations, resembles closely the experimental band gap value (4.11 eV).


PRL gene expression in individual living mammotropes displays distinct functional pulses that oscillate in a noncircadian temporal pattern.
PRL gene expression in the anterior pituitary has been the focus of intensive investigation for many years, but very little information is available on the actual dynamics by which this process occurs in individual mammotrope cells. Here, we used single cell bioluminescent imaging microscopy and a recently refined reporter gene strategy to measure PRL promoter-driven gene expression (PRL-GE) in individual living primary mammotropes. Using this approach we report a new phenomenon involving repetitive on/off gene expression bursts that occurred in a distinctly noncircadian oscillatory pattern. Furthermore, we demonstrate a functional basis for these gene expression oscillations, inasmuch as PRL-GE pulses were sensitive to calcium-dependent modulation, which we show arose exclusively as changes in the shape of individual pulse episodes. Our results provide the first clear evidence that PRL-GE, in its homologous cell environment, displays oscillatory bursts of activity. Moreover, they strongly support the idea that these discrete on/off bursts of activity serve as an important determinant of the timing and level of PRL-GE under both basal and stimulated conditions.


A randomised controlled trial of three psychological treatments for anorexia nervosa.
There is a lack of evidence pointing to the efficacy of any specific psychotherapy for adults with anorexia nervosa (AN). The aim of this study was to compare three psychological treatments for AN: Specialist Supportive Clinical Management, Maudsley Model Anorexia Nervosa Treatment for Adults and Enhanced Cognitive Behavioural Therapy. A multi-centre randomised controlled trial was conducted with outcomes assessed at pre-, mid- and post-treatment, and 6- and 12-month follow-up by researchers blind to treatment allocation. All analyses were intention-to-treat. One hundred and twenty individuals meeting diagnostic criteria for AN were recruited from outpatient treatment settings in three Australian cities and offered 25-40 sessions over a 10-month period. Primary outcomes were body mass index (BMI) and eating disorder psychopathology. Secondary outcomes included depression, anxiety, stress and psychosocial impairment. Treatment was completed by 60% of participants and 52.5% of the total sample completed 12-month follow-up. Completion rates did not differ between treatments. There were no significant differences between treatments on continuous outcomes; all resulted in clinically significant improvements in BMI, eating disorder psychopathology, general psychopathology and psychosocial impairment that were maintained over follow-up. There were no significant differences between treatments with regard to the achievement of a healthy weight (mean = 50%) or remission (mean = 28.3%) at 12-month follow-up. The findings add to the evidence base for these three psychological treatments for adults with AN, but the results underscore the need for continued efforts to improve outpatient treatments for this disorder. Trial Registration Australian New Zealand Clinical Trials Registry (ACTRN 12611000725965) http://www.anzctr.org.au/.


Frequency-frequency correlation functions and apodization in two-dimensional infrared vibrational echo spectroscopy: a new approach.
Ultrafast two-dimensional infrared (2D-IR) vibrational echo spectroscopy can probe structural dynamics under thermal equilibrium conditions on time scales ranging from femtoseconds to approximately 100 ps and longer. One of the important uses of 2D-IR spectroscopy is to monitor the dynamical evolution of a molecular system by reporting the time dependent frequency fluctuations of an ensemble of vibrational probes. The vibrational frequency-frequency correlation function (FFCF) is the connection between the experimental observables and the microscopic molecular dynamics and is thus the central object of interest in studying dynamics with 2D-IR vibrational echo spectroscopy. A new observable is presented that greatly simplifies the extraction of the FFCF from experimental data. The observable is the inverse of the center line slope (CLS) of the 2D spectrum. The CLS is the inverse of the slope of the line that connects the maxima of the peaks of a series of cuts through the 2D spectrum that are parallel to the frequency axis associated with the first electric field-matter interaction. The CLS varies from a maximum of 1 to 0 as spectral diffusion proceeds. It is shown analytically to second order in time that the CLS is the T(w) (time between pulses 2 and 3) dependent part of the FFCF. The procedure to extract the FFCF from the CLS is described, and it is shown that the T(w) independent homogeneous contribution to the FFCF can also be recovered to yield the full FFCF. The method is demonstrated by extracting FFCFs from families of calculated 2D-IR spectra and the linear absorption spectra produced from known FFCFs. Sources and magnitudes of errors in the procedure are quantified, and it is shown that in most circumstances, they are negligible. It is also demonstrated that the CLS is essentially unaffected by Fourier filtering methods (apodization), which can significantly increase the efficiency of data acquisition and spectral resolution, when the apodization is applied along the axis used for obtaining the CLS and is symmetrical about tau=0. The CLS is also unchanged by finite pulse durations that broaden 2D spectra.


Social differences in oral health: Dental status of individuals buried in and around Trakai Church in Lithuania (16th-17th c.c.).
The evaluation of social differences in dental health is based on the assumption that individuals belonging to a higher social class consumed a different diet than a common people. The aim of our study was to analyse and compare dental health of 16(th) - 17(th) c. individuals, buried inside and around the Roman Catholic Church in Trakai (Lithuania). All material (189 adult individuals) was divided in two samples of a presumably different social status: the Churchyard (ordinary townsmen) and the Presbytery (elite). Dental status analysis included that of tooth loss, tooth wear, caries, abscesses and calculus. Results revealed higher prevalence of dental disease in the Churchyard sample compared to the Presbytery. Individuals buried around the church had statistically higher prevalence of caries, antemortem tooth loss and abscesses compared to those who were buried inside the church. The Churchyard sample was also characterised by a higher increase in severity of caries with age, and a more rapid tooth wear. Differences in dental health between the samples the most probably reflect different dietary habits of people from different social groups: poor quality carbohydrate based diet of laymen buried in the churchyard and more varied diet with proteins and of a better quality of local elite, buried inside the church. Substantial sex differences in dental health were found only in the Churchyard sample: males had statistically higher prevalence of abscesses and calculus, while females had higher prevalence of caries and AMTL (antemortem tooth loss). Females were also characterised by a higher increase in the number of dental decay and tooth loss with age and had higher prevalence of gross caries, which indicates a more rapid progression of the disease. Worse dental health of females could be a result of culturally based dietary differences between females (more carbohydrates) and males (more proteins) and different physiological demands (hormonal fluctuations and suppression of immune system during pregnancy).


The 21-aminosteroid tirilazad mesylate can ameliorate inflammatory bowel disease in rats.
The 21-aminosteroid tirilazad mesylate (U74006F) is a lipophilic antioxidant and free radical scavenger that has been reported to attenuate brain or spinal cord injury caused by trauma, stroke, ischemia and reperfusion injury. In this study, we have examined the effect of U74006F in reducing the inflammatory parameters of trinitrobenzene sulfonic acid (TNBS)-induced inflammatory bowel disease (IBD) in rats. To induce IBD, rats were given ethanolic TNBS intracolonically. Rats received either 1) TNBS and U74006F 2) TNBS and vehicle or 3) saline and vehicle. Rats were sacrificed 1, 2 and 3 weeks after IBD induction. Colon to body weight ratio (an index of tissue edema) was markedly increased in the vehicle-treated IBD rats after 1 week of administration of TNBS. The ratio was significantly lower after U74006F treatment and the trend remained even after 3 weeks of chronic inflammation. Myeloperoxidase (MPO) activity in vehicle-treated IBD rats was substantially increased compared with controls during the entire 3 weeks of the experiment. U74006F-treated animals had significantly reduced MPO activity (60% lower) when compared with vehicle-treated animals at the end of the second and third weeks. These observations were confirmed by histopathology studies showing reduced granulocyte infiltration after drug treatment. U74006F treatment decreased basal (by 70%) and fMLP stimulated (by 75%) superoxide generation from colonic tissue from IBD rats compared with vehicle treatment after 2 weeks, but there was no apparent difference in superoxide generation among all three groups after 3 weeks. The results of this study suggested that administration of U74006F effectively reduces the inflammatory parameters in this chronic rat model of IBD. As such, U74006F may be therapeutically beneficial for the treatment of IBD in humans.


Is drinking water a risk factor for endemic cryptosporidiosis? A case-control study in the immunocompetent general population of the San Francisco Bay Area.
Cryptosporidiosis, caused by Cryptosporidium, is an enteric illness that has received much attention as an infection of immunocompromised persons as well as in community outbreaks (frequently waterborne). There are, however, no studies of the risk factors for sporadic community-acquired cryptosporidiosis in the immunocompetent US population. We undertook a case-control study in the San Francisco Bay Area as part of a national study sponsored by the Centers for Disease Control and Prevention to ascertain the major routes of transmission for endemic cryptosporidiosis, with an emphasis on evaluating risk from drinking water. Cases were recruited from a population-based, active surveillance system and age-matched controls were recruited using sequential random-digit dialing. Cases (n = 26) and controls (n = 62) were interviewed by telephone using a standardized questionnaire that included information about the following exposures: drinking water, recreational water, food items, travel, animal contact, and person-to-person fecal contact, and (for adults) sexual practices. In multivariate conditional logistic regression analyses no significant association with drinking water was detected. The major risk factor for cryptosporidiosis in the San Francisco Bay Area was travel to another country (matched odds ratio [95% confidence interval]: 24.1 [2.6, 220]). The results of this study do not support the hypothesis that drinking water is an independent risk factor for cryptosporidiosis among the immunocompetent population. These findings should be used to design larger studies of endemic cryptosporidiosis to elucidate the precise mechanisms of transmission, whether waterborne or other.


Improving birth dose coverage of hepatitis B vaccine.
Administration of a birth dose of hepatitis B vaccine (HepB vaccine) to neonates is recommended to prevent mother-to-infant transmission and chronic infection with the hepatitis B virus (HBV). Although manufacturers recommend HepB vaccine distribution and storage at 2-8 degrees C, recognition of the heat stability of hepatitis B surface antigen stimulated research into its use after storage at, or exposure to, ambient or high temperatures. Storage of HepB vaccine at ambient temperatures would enable birth dosing for neonates delivered at home in remote areas or at health posts lacking refrigeration. This article reviews the current evidence on the thermostability of HepB vaccine when stored outside the cold chain (OCC). The reports reviewed show that the vaccines studied were safe and effective whether stored cold or OCC. Field and laboratory data also verifies the retained potency of the vaccine after exposure to heat. The attachment of a highly stable variety of a vaccine vial monitor (measuring cumulative exposure to heat) on many HepB vaccines strongly supports policies allowing their storage OCC, when this will benefit birth dose coverage. We recommend that this strategy be introduced to improve birth dose coverage, especially in rural and remote areas. Concurrent monitoring and evaluation should be undertaken to affirm the safe implementation of this strategy, and assess its cost, feasibility and effect on reducing HBV infection rates. Meanwhile, release of manufacturer data verifying the potency of currently available HepB vaccines after exposure to heat will increase confidence in the use of vaccine vial monitors as a managerial tool during storage of HepB vaccine OCC.


Chicken blood provides a suitable meal for the sand fly Lutzomyia longipalpis and does not inhibit Leishmania development in the gut.
The aim of this study was to address the role of chickens as bloodmeal sources for female Lutzomyia longipalpis and to test whether chicken blood is harmful to Leishmania parasite development within the sand flies. Bloodmeal ingestion, excretion of urate, reproduction, fecundity, as well as Leishmania infection and development were compared in sand flies fed on blood from chickens and different mammalian sources. Large differences in haemoglobin and protein concentrations in whole blood (dog>human>rabbit> chicken) did not correlate with differences in bloodmeal protein concentrations (dog = chicken>human>rabbit). This indicated that Lu. longipalpis were able to concentrate bloodmeals taken from different hosts using prediuresis and this was confirmed by direct observation. Sand flies fed on chickens or dogs produced significantly more eggs than those fed on human blood. Female Lu. longipalpis retained significantly more urate inside their bodies when fed on chicken blood compared to those fed on rabbit blood. However, when the amounts of urate excreted after feeding were measured, sand flies fed on rabbit blood excreted significantly more than those fed on chicken blood. There was no difference in female longevity after feeding on avian or mammalian blood.Sand flies infected via chicken blood produced Leishmania mexicana infections with a similar developmental pattern but higher overall parasite populations than sand flies infected via rabbit blood. The results of this study help to define the role that chickens play in the epidemiology of leishmaniasis. The present study using a Lu. longipalpis/L. mexicana model indicates that chickens are suitable hosts to support a Lu. longipalpis population and that chicken blood is likely to support the development of transmissible Leishmania infections in Lu. longipalpis.


Can cognitive processes help explain the success of instructional techniques recommended by behavior analysts?
The fields of cognitive psychology and behavior analysis have undertaken separate investigations into effective learning strategies. These studies have led to several recommendations from both fields regarding teaching techniques that have been shown to enhance student performance. While cognitive psychology and behavior analysis have studied student performance independently from their different perspectives, the recommendations they make are remarkably similar. The lack of discussion between the two fields, despite these similarities, is surprising. The current paper seeks to remedy this oversight in two ways: first, by reviewing two techniques recommended by behavior analysts-guided notes and response cards-and comparing them to their counterparts in cognitive psychology that are potentially responsible for their effectiveness; and second, by outlining some other areas of overlap that could benefit from collaboration. By starting the discussion with the comparison of two specific recommendations for teaching techniques, we hope to galvanize a more extensive collaboration that will not only further the progression of both fields, but also extend the practical applications of the ensuing research.


Visual search for orientation of faces by a chimpanzee (Pan troglodytes): face-specific upright superiority and the role of facial configural properties.
A previous experiment showed that a chimpanzee performed better in searching for a target human face that differed in orientation from distractors when the target had an upright orientation than when targets had inverted or horizontal orientation [Tomonaga (1999a) Primate Res 15:215-229]. This upright superiority effect was also seen when using chimpanzee faces as targets but not when using photographs of a house. The present study sought to extend these results and explore factors affecting the face-specific upright superiority effect. Upright superiority was shown in a visual search for orientation when caricaturized human faces and dog faces were used as stimuli for the chimpanzee but not when shapes of a hand and chairs were presented. Thus, the configural properties of facial features, which cause an inversion effect in face recognition in humans and chimpanzees, were thought to be a source of the upright superiority effect in the visual search process. To examine this possibility, various stimuli manipulations were introduced in subsequent experiments. The results clearly show that the configuration of facial features plays a critical role in the upright superiority effect, and strongly suggest similarity in face processing in humans and chimpanzees.


Tuneable Magnetic Phase Transitions in Layered CeMn2Ge(2-x)Six Compounds.
The structural and magnetic properties of seven CeMn2Ge(2-x)Six compounds with x = 0.0-2.0 have been investigated in detail. Substitution of Ge with Si leads to a monotonic decrease of both a and c along with concomitant contraction of the unit cell volume and significant modifications of the magnetic states - a crossover from ferromagnetism at room temperature for Ge-rich compounds to antiferromagnetism for Si-rich compounds. The magnetic phase diagram has been constructed over the full range of CeMn2Ge(2-x)Six compositions and co-existence of ferromagnetism and antiferromagnetism has been observed in CeMn2Ge1.2Si0.8, CeMn2Ge1.0Si1.0 and CeMn2Ge0.8Si1.2 with novel insight provided by high resolution neutron and X-ray synchrotron radiation studies. CeMn2Ge(2-x)Six compounds (x = 0, 0.4 and 0.8) exhibit moderate isothermal magnetic entropy accompanied with a second-order phase transition around room temperature. Analysis of critical behaviour in the vicinity of TC(inter) for CeMn2Ge2 compound indicates behaviour consistent with three-dimensional Heisenberg model predictions.


Genome-wide profiling of pluripotent cells reveals a unique molecular signature of human embryonic germ cells.
Human embryonic germ cells (EGCs) provide a powerful model for identifying molecules involved in the pluripotent state when compared to their progenitors, primordial germ cells (PGCs), and other pluripotent stem cells. Microarray and Principal Component Analysis (PCA) reveals for the first time that human EGCs possess a transcription profile distinct from PGCs and other pluripotent stem cells. Validation with qRT-PCR confirms that human EGCs and PGCs express many pluripotency-associated genes but with quantifiable differences compared to pluripotent embryonic stem cells (ESCs), induced pluripotent stem cells (IPSCs), and embryonal carcinoma cells (ECCs). Analyses also identified a number of target genes that may be potentially associated with their unique pluripotent states. These include IPO7, MED7, RBM26, HSPD1, and KRAS which were upregulated in EGCs along with other pluripotent stem cells when compared to PGCs. Other potential target genes were also found which may contribute toward a primed ESC-like state. These genes were exclusively up-regulated in ESCs, IPSCs and ECCs including PARP1, CCNE1, CDK6, AURKA, MAD2L1, CCNG1, and CCNB1 which are involved in cell cycle regulation, cellular metabolism and DNA repair and replication. Gene classification analysis also confirmed that the distinguishing feature of EGCs compared to ESCs, ECCs, and IPSCs lies primarily in their genetic contribution to cellular metabolism, cell cycle, and cell adhesion. In contrast, several genes were found upregulated in PGCs which may help distinguish their unipotent state including HBA1, DMRT1, SPANXA1, and EHD2. Together, these findings provide the first glimpse into a unique genomic signature of human germ cells and pluripotent stem cells and provide genes potentially involved in defining different states of germ-line pluripotency.


The RCAF complex mediates chromatin assembly during DNA replication and repair.
Chromatin assembly is a fundamental biological process that is essential for the replication and maintenance of the eukaryotic genome. In dividing cells, newly synthesized DNA is rapidly assembled into chromatin by the deposition of a tetramer of the histone proteins H3 and H4, followed by the deposition of two dimers of histones H2A and H2B to complete the nucleosome-the fundamental repeating unit of chromatin. Here we describe the identification, purification, cloning, and characterization of replication-coupling assembly factor (RCAF), a novel protein complex that facilitates the assembly of nucleosomes onto newly replicated DNA in vitro. RCAF comprises the Drosophila homologue of anti-silencing function 1 protein ASF1 and histones H3 and H4. The specific acetylation pattern of H3 and H4 in RCAF is identical to that of newly synthesized histones. Genetic analyses in Saccharomyces cerevisiae demonstrate that ASF1 is essential for normal cell cycle progression, and suggest that RCAF mediates chromatin assembly after DNA replication and the repair of double-strand DNA damage in vivo.


Population genomics of parallel adaptation in threespine stickleback using sequenced RAD tags.
Next-generation sequencing technology provides novel opportunities for gathering genome-scale sequence data in natural populations, laying the empirical foundation for the evolving field of population genomics. Here we conducted a genome scan of nucleotide diversity and differentiation in natural populations of threespine stickleback (Gasterosteus aculeatus). We used Illumina-sequenced RAD tags to identify and type over 45,000 single nucleotide polymorphisms (SNPs) in each of 100 individuals from two oceanic and three freshwater populations. Overall estimates of genetic diversity and differentiation among populations confirm the biogeographic hypothesis that large panmictic oceanic populations have repeatedly given rise to phenotypically divergent freshwater populations. Genomic regions exhibiting signatures of both balancing and divergent selection were remarkably consistent across multiple, independently derived populations, indicating that replicate parallel phenotypic evolution in stickleback may be occurring through extensive, parallel genetic evolution at a genome-wide scale. Some of these genomic regions co-localize with previously identified QTL for stickleback phenotypic variation identified using laboratory mapping crosses. In addition, we have identified several novel regions showing parallel differentiation across independent populations. Annotation of these regions revealed numerous genes that are candidates for stickleback phenotypic evolution and will form the basis of future genetic analyses in this and other organisms. This study represents the first high-density SNP-based genome scan of genetic diversity and differentiation for populations of threespine stickleback in the wild. These data illustrate the complementary nature of laboratory crosses and population genomic scans by confirming the adaptive significance of previously identified genomic regions, elucidating the particular evolutionary and demographic history of such regions in natural populations, and identifying new genomic regions and candidate genes of evolutionary significance.


Nocturnal enuresis and psychosocial problems in pediatric sickle cell disease and sibling controls.
To evaluate current and lifetime prevalence rates of nocturnal enuresis and psychosocial problems among children with sickle cell disease (SCD) in comparison with sibling controls, a structured interview and the Pediatric Symptom Checklist were administered to primary caretakers regarding 126 of their children aged 5 to 17 with SCD and 47 sibling controls. Lifetime rates of enuresis among children with SCD were comparable to similar studies, and exceeded population prevalence and sibling control rates. In addition, enuretic children had higher levels of total psychosocial problems on the Pediatric Symptom Checklist regardless of group status, although patterns of subscale differences varied by group and enuresis history after controlling for child age. These findings replicate and extend previous findings and provide further evidence to support a need for monitoring of hydration levels and screening for psychosocial problems among children with SCD and enuresis, as well as evaluation of the psychometric properties of psychosocial screening measures and identification of efficacious treatments for enuresis in children with SCD.


TREM-1, HMGB1 and RAGE in the Shoulder Tendon: Dual Mechanisms for Inflammation Based on the Coincidence of Glenohumeral Arthritis.
Rotator cuff injury (RCI) is a major musculoskeletal disorder in the adult population where inflammation and pain are major contributing factors. Coincidence of other clinical conditions like glenohumeral arthritis aggravates inflammation and delays the healing response. The mechanism and signaling factors underlying the sustenance of inflammation in the rotator cuff joint are largely unknown. The present article aims to elucidate the involvement of inflammatory molecule, TREM-1 (Triggering Receptors Expressed on Myeloid cells-1), and danger-associated molecular patterns (DAMPs), including high mobility group protein 1 (HMGB-1) and RAGE (receptor for advanced glycation end products), in the setting of RCI with respect to the severity of glenohumeral arthritis. Biceps tendons (15 specimens) from the shoulder and blood (11 samples) from patients with glenohumeral arthritis (Group-1, n = 4) and without glenohumeral arthritis (Group-2, n = 11) after RCI surgery were obtained for the study. Molecular and morphological alterations between the groups were compared using histology, immunofluorescence, RT-PCR and flow cytometry. MRI and histomorphology assessment revealed severe inflammation in Group-1 patients while in Group-2 ECM disorganization was prominent without any hallmarks of inflammation. A significant increase in TREM-1 expression in circulating neutrophils and monocytes was observed. Elevated levels of TREM-1, HMGB-1 and RAGE in Group-1 patients along with CD68+ and CD16+ cells confirmed DAMP-mediated inflammation. Expression of TREM-1 in the tendon of Group-2 patients even in the absence of immune cells presented a new population of TREM-expressing cells that were confirmed by real-time PCR analysis and immunofluorescence. Expression of HMGB-1 and RAGE in the biceps tendon from the shoulder of patients without glenohumeral arthritis implied TREM-1-mediated inflammation without involving immune cells, whereas in patients with glenohumeral arthritis, infiltration and the activation of the immune cells, primarily macrophages, release mediators to induce inflammation. This could be the reason for ECM disorganization without the classical signs of inflammation in patients without glenohumeral arthritis.


Informal care: choice or constraint?
'Choice' is increasingly pursued as a goal of social policy. However, the degree to which choice is exercised when entering an informal caring role is open to debate. In this study, we examined the degree of choice and constraint in entering a caring role, and the relationship between choice and carers' well-being. Data were derived from 1100 responses to a postal survey conducted in a British city. Statistical tests of association and multivariable regression modelling were applied to study the factors associated with choice in entering a caring role and the association that choice in entering a caring role had with carers' well-being. We found that informal care was generally perceived to be a free choice, albeit in most cases, a choice was also constrained by duty, financial or social resources. Having a sense of free choice in entering care was strongly and positively associated with the carer's well-being. The study findings are consistent with a view that enabling individuals to have more choice in their caring roles may be beneficial.


Do thrombolysis outcomes differ between anterior circulation stroke and posterior circulation stroke? A systematic review and meta-analysis.
It remains unclear whether thrombolysis outcomes can be influenced by the affected vascular territory (i.e. anterior circulation stroke vs. posterior circulation stroke) in stroke patients owing to the lack of randomized controlled trials. Using multiple comprehensive databases, we searched for observational studies of the safety and efficacy of intravenous thrombolytics and intra-arterial treatment with or without intravenous thrombolytics in accordance with the affected vascular territory. We performed a systematic review and meta-analysis. We evaluated symptomatic intracerebral hemorrhage, all-type intracerebral hemorrhage, mortality, and functional outcomes at three months. The recanalization rate was assessed in the intra-arterial treatment group. Twenty-one studies including a report from our own stroke registry were included through quantitative synthesis. Compared with the anterior circulation stroke group, the posterior circulation stroke group had a lower risk of ICH, including symptomatic intracerebral hemorrhage and all-type intracerebral hemorrhage, after intravenous thrombolytics and tended to have favorable functional outcomes at three months. Mortality was similar between the two groups. Regarding intra-arterial treatment, the symptomatic intracerebral hemorrhage and post-procedural recanalization rates were comparable between the two groups, although the posterior circulation stroke group had a higher mortality risk and lower tendency for a favorable functional outcome. Safety and efficacy of thrombolysis in posterior circulation stroke depends on involvement of large vessel occlusion and reperfusion modality such that intravenous thrombolytics is more effective and safer than in anterior circulation stroke; the safety and efficacy of intra-arterial treatment is comparable or lower than anterior circulation stroke. Considering the limitations of our meta-analysis, further studies are needed to provide high level evidence of a beneficial effect of intra-arterial treatment, and to identify patients' profiles associated with benefit of treatment.


Short exposure to endotoxin increases the constriction induced by angiotensin II in rat aorta.
The contraction elicited by angiotensin II (ANG II) was studied by using standard isometric tension techniques in aortic rings exposed for 1 h to 1 or 10 micrograms/ml Escherichia coli lipopolysaccharide endotoxin (LPS). This contraction was 18 and 71% greater for the two doses of LPS, respectively, than in unexposed control rings. In endothelium-denuded rings, the LPS-induced increase in contraction in response to ANG II was completely abolished. Because the contraction induced by ANG II is modulated by the simultaneous release of prostaglandins, we tested the hypothesis that LPS interferes with this modulation. We found that the LPS-induced increase in contraction to ANG II was inhibited in the presence of the cyclooxygenase inhibitor indomethacin (10(-5) M) or the prostaglandin H2/thromboxane A2-receptor antagonist SQ-29548 (2 x 10(-7) M). Conversely, the LPS-induced increase in contraction in response to ANG II was not inhibited by the presence of dexamethasone (10(-6) M), which inhibits new protein synthesis. In addition, there was no loss of vasodilator response to the endothelium-dependent receptor agonist acetylcholine (10(-8)-10(-4) M) or in the constrictor responses to norepinephrine (10(-9)-10(-5) M) and KCl (20-100 mM). We conclude that short exposure to LPS produces a specific increase in the constrictor response to ANG II via mechanisms mediated by prostaglandin H2/thromboxane A2. This effect could be a LPS-induced shift in favor of constrictor prostanoids in the balance of dilator/constrictor prostanoids, the release of which is associated with stimulation by ANG II.


Combinatorial control of prion protein biogenesis by the signal sequence and transmembrane domain.
The prion protein (PrP) is synthesized in three topologic forms at the endoplasmic reticulum. (sec)PrP is fully translocated into the endoplasmic reticulum lumen, whereas (Ntm)PrP and (Ctm)PrP are single-spanning membrane proteins of opposite orientation. Increased generation of (Ctm)PrP in either transgenic mice or humans is associated with the development of neurodegenerative disease. To study the mechanisms by which PrP can achieve three topologic outcomes, we analyzed the translocation of proteins containing mutations introduced into either the N-terminal signal sequence or potential transmembrane domain (TMD) of PrP. Although mutations in either domain were found to affect PrP topogenesis, they did so in qualitatively different ways. In addition to its traditional role in mediating protein targeting, the signal was found to play a surprising role in determining orientation of the PrP N terminus. By contrast, the TMD was found to influence membrane integration. Analysis of various signal and TMD double mutants demonstrated that the topologic consequence of TMD action was directly dependent on the previous, signal-mediated step. Together, these results reveal that PrP topogenesis is controlled at two discrete steps during its translocation and provide a framework for understanding how these steps act coordinately to determine the final topology achieved by PrP.


Improved Performance of Transgenic Fructan-Accumulating Tobacco under Drought Stress.
Fructans are polyfructose molecules produced by approximately 15% of the flowering plant species. It is possible that, in addition to being a storage carbohydrate, fructans have other physiological roles. Owing to their solubility they may help plants survive periods of osmotic stress induced by drought or cold. To investigate the possible functional significance of fructans, use was made of transgenic tobacco (Nicotiana tabacum) plants that accumulate bacterial fructans and hence possess an extra sink for carbohydrate. Biomass production was analyzed during drought stress with the use of lines differing only in the presence of fructans. Fructan-producing tobacco plants performed significantly better under polyethylene-glycol-mediated drought stress than wild-type tobacco. The growth rate of the transgenic plants was significantly higher (+55%), as were fresh weight (+33%) and dry weight (+59%) yields. The difference in weight was observed in all organs and was particularly pronounced in roots. Under unstressed control conditions the presence of fructans had no significant effect on growth rate and yield. Under all conditions the total nonstructural carbohydrate content was higher in the transgenic plants. We conclude that the introduction of fructans in this non-fructan-producing species mediates enhanced resistance to drought stress.


Oviductal Transcriptome Is Modified after Insemination during Spontaneous Ovulation in the Sow.
Gene Expression Microarray technology was used to compare oviduct transcriptome between inseminated and non-inseminated pigs during spontaneous oestrus. We used an in vivo model approaching the study from a physiological point of view in which no hormonal treatment (animals were in natural oestrus) and no artificial sperm selection (selection was performed within the female genital) were imposed. It is therefore emphasised that no surgical introduction of spermatozoa and no insemination at a site other than the physiological one were used. This approach revealed 17 genes that were two-fold or more up-regulated in oviducts exposed to spermatozoa and/or developing embryos and 9 genes that were two-fold or more down-regulated. Functional analysis of the genes revealed that the top canonical pathways affected by insemination were related to the inflammatory response and immune system (Network 1) to molecular transport, protein trafficking and developmental disorder (Network 2) and to cell-to-cell signalling and interaction (Network 3). Some of the genes in network 1 had been previously detected in the oviduct of human and animals, where they were over-expressed in the presence of spermatozoa or pre-implantation embryos (C3, IGHG1, ITIH4, TNF and SERPINE1) whereas others were not previously reported (SAA2, ALOX12, CD1D and SPP1). Genes in Network 2 included RAB1B and TOR3A, the latter being described for the first time in the oviduct and clearly expressed in the epithelial cells of the mucosa layer. Network 3 integrated the genes with the highest down-regulation level (CYP51, PTH1R and TMOD3). Data in the present study indicate a change in gene expression during gamete encounter at the site of fertilization after a natural sperm selection within the female genital tract. These changes would indicate a modification of the environment preparing the oviduct for a successful fertilization and for an adequate embryo early development.


Fusiform gyrus volume reduction and facial recognition in chronic schizophrenia.
The fusiform gyrus (FG), or occipitotemporal gyrus, is thought to subserve the processing and encoding of faces. Of note, several studies have reported that patients with schizophrenia show deficits in facial processing. It is thus hypothesized that the FG might be one brain region underlying abnormal facial recognition in schizophrenia. The objectives of this study were to determine whether there are abnormalities in gray matter volumes for the anterior and the posterior FG in patients with chronic schizophrenia and to investigate relationships between FG subregions and immediate and delayed memory for faces. Patients were recruited from the Boston VA Healthcare System, Brockton Division, and control subjects were recruited through newspaper advertisement. Study participants included 21 male patients diagnosed as having chronic schizophrenia and 28 male controls. Participants underwent high-spatial-resolution magnetic resonance imaging, and facial recognition memory was evaluated. Main outcome measures included anterior and posterior FG gray matter volumes based on high-spatial-resolution magnetic resonance imaging, a detailed and reliable manual delineation using 3-dimensional information, and correlation coefficients between FG subregions and raw scores on immediate and delayed facial memory derived from the Wechsler Memory Scale III. Patients with chronic schizophrenia had overall smaller FG gray matter volumes (10%) than normal controls. Additionally, patients with schizophrenia performed more poorly than normal controls in both immediate and delayed facial memory tests. Moreover, the degree of poor performance on delayed memory for faces was significantly correlated with the degree of bilateral anterior FG reduction in patients with schizophrenia. These results suggest that neuroanatomic FG abnormalities underlie at least some of the deficits associated with facial recognition in schizophrenia.


Kinetics of ozone decomposition in porous In2O3 monoliths.
The performance of many chemical gas-phase reactions is strongly influenced by the interaction of reactants with interfaces. Nanoporous materials, which exhibit pore diameters up to 100 nm and high specific surface areas, can be utilized to reduce the amount of cost-intensive materials (e.g. noble metals). However, due to limitations in material transport and reaction kinetics detailed knowledge of the diffusion and the kinetics of a chemical reaction is necessary to improve the performance of chemical processes in industry and research. To experimentally study the diffusion and reaction kinetics of gaseous species inside such pores, the chemoresistive behavior of certain metal oxides such as In2O3 can be utilized. In this work, we present a model system based on hierarchically porous monolithic indium oxide (In2O3) which allows the determination of kinetic effects by utilizing its gas transducing properties. The experimental data obtained by electrical measurements are compared to two diffusion and diffusion-reaction models. Using these methods, the rate constant of ozone decomposition in porous In2O3 is estimated. The results are the basis for a suitable material design for semiconducting gas sensors, on the nano-, meso- and macroscale, which helps in understanding the underlying mechanisms of diffusion and reaction.


An Introduction to the Processionary Caterpillar, An Underrecognized Threat to US Military Personnel in Australia.
Processionary caterpillars are well-described threats to human and animal health. They are found throughout Central Asia, Northern Africa, and Southern Europe. However, US military personnel may not be familiar with the threat that these organisms pose in Australia. The larval form of the bag-shelter moth (Ochrogaster lunifer) is a processionary caterpillar that has been found throughout inland and coastal Australia. These organisms are habitually associated with Acacia and Eucalyptus trees and they tend to form long chains known as "processions" as they travel between nesting and pupating sites. They are covered with numerous hairs that can detach, become airborne, and cause potentially life-threatening inflammatory reactions and ocular trauma in susceptible personnel. They can also cause severe inflammatory reactions in military working animals. It is important that military and preventive medical personnel become aware of the presence of processionary caterpillars in Australia, and that they can identify aerial or ground-based nests so that these dangerous organisms can be avoided by both humans and animals. Early identification is important so that prompt medical treatment can be rendered in the event of an accidental exposure.


Adult intestinal intussusception: can abdominal MDCT distinguish an intussusception caused by a lead point?
Aim of our study was to assess the ability of computed tomography to distinguish between an intussusception with a lead-point from one without it. Approval was granted by the Institutional Review Board. Ninety-three consecutive patients diagnosed with an intussusception on abdominal CT were classified with or without lead-point by surgery, clinical or radiological follow-up. Two radiologists blinded to the classification independently reviewed the CT images for predefined predictive variables. Non-lead-point intussusception was shorter in length (mean 4.9 vs. 11.1 cm for Reader 1 (R1); mean 4.0 vs. 8.9 cm for Reader 2 (R2), respectively, P < 0.001), smaller in axial diameter (mean 3.0 vs. 4.8 cm for R1; mean 2.8 vs. 4.4 cm for R2, P < 0.001, respectively), less likely associated with obstruction (P = 0.002 R1; P = 0.039 R2) and infiltration (P < 0.001 for R1, P = 0.003 R2) than lead-point intussusception. Abdominal CT is helpful in distinguishing between an intussusception with a lead-point from one without a lead-point. Length, axial diameter, and their product, as well as obstruction and infiltration, all suggest the presence of a lead-point. Analysis of CT findings can reduce unnecessary imaging follow-up or operation.


Functional and evolutionary insight from the crystal structure of rubella virus protein E1.
Little is known about the three-dimensional organization of rubella virus, which causes a relatively mild measles-like disease in children but leads to serious congenital health problems when contracted in utero. Although rubella virus belongs to the same family as the mosquito-borne alphaviruses, in many respects it is more similar to other aerosol-transmitted human viruses such as the agents of measles and mumps. Although the use of the triple MMR (measles, mumps and rubella) live vaccine has limited its incidence in western countries, congenital rubella syndrome remains an important health problem in the developing world. Here we report the 1.8 Å resolution crystal structure of envelope glycoprotein E1, the main antigen and sole target of neutralizing antibodies against rubella virus. E1 is the main player during entry into target cells owing to its receptor-binding and membrane-fusion functions. The structure reveals the epitope and the neutralization mechanism of an important category of protecting antibodies against rubella infection. It also shows that rubella virus E1 is a class II fusion protein, which had hitherto only been structurally characterized for the arthropod-borne alphaviruses and flaviviruses. In addition, rubella virus E1 has an extensive membrane-fusion surface that includes a metal site, reminiscent of the T-cell immunoglobulin and mucin family of cellular proteins that bind phosphatidylserine lipids at the plasma membrane of cells undergoing apoptosis. Such features have not been seen in any fusion protein crystallized so far. Structural comparisons show that the class II fusion proteins from alphaviruses and flaviviruses, despite belonging to different virus families, are closer to each other than they are to rubella virus E1. This suggests that the constraints on arboviruses imposed by alternating cycles between vertebrates and arthropods resulted in more conservative evolution. By contrast, in the absence of this constraint, the strictly human rubella virus seems to have drifted considerably into a unique niche as sole member of the Rubivirus genus.


Substrate influence on the interlayer electron-phonon couplings in fullerene films probed with doubly-resonant SFG spectroscopy.
We present doubly-resonant sum frequency generation (DR-SFG) spectra of fullerene thin films on metallic and dielectric substrates as a way to investigate the interplay between nuclear and electronic coupling at buried interfaces. Modal and substrate selectivity in the electronic enhancement of the C60 vibrational signatures is demonstrated for excitation wavelengths spanning the visible range. While the SFG response of the totally symmetric Ag(2) mode of fullerene is distinctly coupled to the optically allowed electronic transition corresponding to the HOMO-LUMO+1 of C60 (ca. 2.6 eV), the T1u(4) vibrational mode appears to be coupled to a symmetry-forbidden HOMO-LUMO transition at lower energies (ca. 2.0 eV). For dielectric substrates, the DR-SFG intensity of the T1u(4) mode shows lack of enhancement for upconversion wavelengths off-resonance with the optically-dark LUMO. However, the T1u(4) mode shows a unique coupling to an intermediate state (∼2.4 eV) only for the fullerene films on the gold substrate. We attribute this coupling to unique interactions at the buried C60/gold interface. These results demonstrate the occurrence of clear electron-phonon couplings at the C60/substrate interfaces and shed light on the impact of these couplings on the optical response of electronically excited fullerene. This coupling may influence charge and energy transport in organic electronic devices mediated by vibrational motions. We also demonstrate a potential use of this added selectivity in chemical imaging.


A global research agenda for family planning: results of an exercise for setting research priorities.
To develop a global research agenda that will guide investment in effective interventions to satisfy the large unmet need for modern methods of family planning. In a global survey, experts on contraception were invited to identify and rank the types of research that would be needed--and the knowledge gaps that would have to be filled--to reduce the unmet need for family planning in the next decade. The experts were then asked to score the research on a given topic in terms of the likelihood of its leading to an intervention that would: (i) be deliverable, affordable and sustainable; (ii) substantially reduce the unmet need for contraceptives; (iii) be effective and efficient in improving health systems; (iv) be ethically implemented; and (v) improve equity in the target population. The overall scores were then ranked. Most of the topics that received the 15 highest scores fell into three categories: implementation of policies in family planning; the integration of services to address barriers to contraceptive use; and interventions targeted at underserved groups, such as adolescents. Experts on contraception gave top priority ranking to research on improving the implementation and integration of health services and on strengthening the health systems supporting family planning services. The results of the exercise may help decision-makers, researchers and funding agencies to develop a clear and focused approach to satisfying the global need for family planning and reach the target set by the Family Planning 2020 initiative.


Obesogenic behaviours and depressive symptoms in children: a narrative literature review.
This review examines peer-reviewed, published articles exploring the role of obesogenic behaviours, including physical activity, screen time, and diet, and depressive symptoms, in 6- to 12-year-old children. Searches were conducted March-May 2014 and in August 2015 using PubMed, PsychInfo, and Embase. Eligible studies published between January 1990-August 2015 included 8- to 12-year-old children, any of the three previously identified obesogenic behaviours, and a measure of depressive symptoms. The search yielded 415 articles that were screened and assessed for eligibility; 21 were retained. Some studies included depression and a single obesogenic behaviour, while others included multiple obesogenic behaviours. Fifteen studies assessed physical activity, twelve assessed screen time, and five assessed dietary intake. Lower physical activity was associated with higher depression in 80% of studies. Higher screen time was associated with higher depression in all studies. Poor dietary intake was associated with higher depression in 60% of studies. Significant associations were found between depression and all three obesogenic behaviours. Stronger associations were found between depression and physical activity and screen time than between depression and dietary intake. This review broadens the understanding of the relationship between obesogenic behaviours and depression, and shows outcome consistency despite the lack of a consistent measurement technique. © 2016 World Obesity.


Attitudes of Jordanian Adolescent Students Toward Overweight and Obesity.
Obesity is a serious public health problem especially among adolescents. Understanding adolescents' attitudes toward obesity and healthy lifestyle is a crucial step to develop effective health programs to treat and prevent obesity. To examine the attitudes toward overweight and obesity among Jordanian adolescent students and to identify the components of obesity prevention program that the students perceive as important. A sample of 1000 students in 8th to 10th grades was randomly selected from 16 schools in Irbid, Jordan. A self-reported questionnaire including attitude related questions was used in a descriptive, cross-sectional study. Generally, the students expressed positive attitudes toward obesity; which means that their attitudes were consistent with societal norms in terms of health and social functioning (mean= 3.5, SD=0.39). Furthermore, the students expressed positive attitudes toward lifestyle; which means that their attitudes were consistent with healthy behaviors (mean=3.7, SD=0.58). However, boys had significantly more positive attitudes than girls (p=0.04). The prevalence of overweight and obesity was 23.8%, while obese and non-obese students had similar attitudes toward lifestyle and obesity. Finally, around 20% to 30% of students desired a prevention program out of school time shared with their families and friends and involves eating healthy food and getting more exercise. More efforts are needed to build effective obesity prevention programs that focus on eating healthy diet and getting more exercise considering gender differences.


Caregiver placebo effect in analgesic clinical trials for cats with naturally occurring degenerative joint disease-associated pain.
A literature review identified six placebo-controlled studies of analgesics in client-owned cats with degenerative joint disease-associated pain. Five studies with 96 cats had available data. Caregiver responses on a clinical metrology instrument, Client-Specific Outcome Measure (CSOM), were compared to measured activity. Cats were categorised as 'successes' or 'failures' based on change in CSOM score and activity counts from baseline. Effect sizes based on CSOM score were calculated; factors that were associated with success/failure were analysed using logistic regression. Effect sizes ranged from 0.97 to 1.93. The caregiver placebo effect was high, with 54-74 per cent of placebo-treated cats classified as CSOM successes compared with 10-63 per cent of cats classified as successes based on objectively measured activity. 36 per cent of CSOM successes were also activity successes, while 19 per cent of CSOM failures were activity successes. No significant effects of cat age, weight, baseline activity, radiographic score, orthopaedic pain score or study type on CSOM success in the placebo groups were found. The caregiver placebo effect across these clinical trials was remarkably high, making demonstration of efficacy for an analgesic above a placebo difficult. Further work is needed to determine whether a potential placebo-by-proxy effect could benefit cats in clinical settings.


Neurotoxicity of sub-anesthetic doses of sevoflurane and dexmedetomidine co-administration in neonatal rats.
Preclinical studies suggest that exposures of infant animals to general anesthetics cause acute neurotoxicity and affect their neurobehavioral development representing a potential risk to human infants undergoing anesthesia. Alternative or mitigating strategies to counteract such adverse effects are desirable. Dexmedetomidine (DEX) is a clinically established sedative with potential neuroprotective properties. DEX ameliorates experimental brain injury as well as neurotoxicity caused by anesthetic doses of sevoflurane (SEVO) or other general anesthetics in infant animals. However, it is unknown whether DEX also is beneficial when given together with lower doses of these drugs. Here we tested the hypothesis that DEX co-administration with a sub-anesthetic dose of SEVO reduces responsiveness to external stimuli while also protecting against SEVO-induced brain cell apoptosis. Rats were exposed on postnatal day 7 for 6 h to SEVO 1.1, 1.8, or 2.5% and were given intraperitoneal injections of saline or DEX at different doses (1-25 μg/kg) three times during the exposure. Responsiveness to external stimuli, respiratory rates, and blood gases were assessed. Apoptosis was determined in cortical and subcortical brain areas by activated caspase-3 immunohistochemistry. Rats exposed to SEVO 1.1% alone were sedated but still responsive to external stimuli whereas those exposed to SEVO 1.8% reached complete unresponsiveness. SEVO-induced brain cell apoptosis increased dose-dependently, with SEVO 1.1% causing a small increase in apoptosis above that in controls. Co-administration of DEX at 1 μg/kg did not alter the responsiveness to stimuli nor the apoptosis induced by SEVO 1.1%. In contrast, co-administration of DEX at 5 μg/kg or higher with SEVO 1.1% reduced responsiveness but potentiated apoptosis. In the neonatal rat model, co-administration of a clinically relevant dose of DEX (1 μg/kg) with a sub-anesthetic dose of SEVO (1.1%) does not affect the neurotoxicity of the anesthetic while co-administration of higher doses of DEX with SEVO 1.1% potentiates it.


Posterolateral corner of the knee: an expert consensus statement on diagnosis, classification, treatment, and rehabilitation.
To develop a statement on the diagnosis, classification, treatment, and rehabilitation concepts of posterolateral corner (PLC) injuries of the knee using a modified Delphi technique. A working group of three individuals generated a list of statements relating to the diagnosis, classification, treatment, and rehabilitation of PLC injuries to form the basis of an initial survey for rating by an international group of experts. The PLC expert group (composed of 27 experts throughout the world) was surveyed on three occasions to establish consensus on the inclusion/exclusion of each item. In addition to rating agreement, experts were invited to propose further items for inclusion or to suggest modifications of existing items at each round. Pre-defined criteria were used to refine item lists after each survey. Statements reaching consensus in round three were included within the final consensus document. Twenty-seven experts (100% response rate) completed three rounds of surveys. After three rounds, 29 items achieved consensus with over 75% agreement and less than 5% disagreement. Consensus was reached in 92% of the statements relating to diagnosis of PLC injuries, 100% relating to classification, 70% relating to treatment and in 88% of items relating to rehabilitation statements, with an overall consensus of 81%. This study has established a consensus statement relating to the diagnosis, classification, treatment, and rehabilitation of PLC injuries. Further research is needed to develop updated classification systems, and better understand the role of non-invasive and minimally invasive approaches along with standardized rehabilitation protocols. Consensus of expert opinion, Level V.


Variability in the Use of Protective Mechanical Ventilation During General Anesthesia.
The purpose of this study was to determine whether significant variation exists in the use of protective ventilation across individual anesthesia providers and whether this difference can be explained by patient, procedure, and provider-related characteristics. The cohort consisted of 262 anesthesia providers treating 57,372 patients at a tertiary care hospital between 2007 and 2014. Protective ventilation was defined as a median positive end-expiratory pressure of 5 cm H2O or more, tidal volume of <10 mL/kg of predicted body weight and plateau pressure of <30 cm H2O. Analysis was performed using mixed-effects logistic regression models with propensity scores to adjust for covariates. The definition of protective ventilation was modified in sensitivity analyses. In unadjusted analysis, the mean probability of administering protective ventilation was 53.8% (2.5th percentile of provider 19.9%, 97.5th percentile 80.8%). After adjustment for a large number of covariates, there was little change in the results with a mean probability of 51.1% (2.5th percentile 24.7%, 97.5th percentile 77.2%). The variations persisted when the thresholds for protective ventilation were changed. There was significant variability across individual anesthesia providers in the use of intraoperative protective mechanical ventilation. Our data suggest that this variability is highly driven by individual preference, rather than patient, procedure, or provider-related characteristics.


Novel 3-nitro-1H-1,2,4-triazole-based aliphatic and aromatic amines as anti-chagasic agents.
A series of novel 2-nitro-1H-imidazole- and 3-nitro-1H-1,2,4-triazole-based aromatic and aliphatic amines were screened for antitrypanosomal activity and mammalian cytotoxicity by the Drugs for Neglected Diseases initiative (DNDi). Out of 42 compounds tested, 18 3-nitro-1,2,4-triazoles and one 2-nitroimidazole displayed significant growth inhibitory properties against T. cruzi amastigotes (IC(50) ranging from 40 nM to 1.97 μM), without concomitant toxicity toward the host cells (L6 cells), having selectivity indices (SI) 44-1320. Most (16) of these active compounds were up to 33.8-fold more potent than the reference drug benznidazole, tested in parallel. Five novel 3-nitro-1,2,4-triazoles were active against bloodstream-form (BSF) T. b. rhodesiense trypomastigotes (IC(50) at nM levels and SI 220-993). An NADH-dependent nitroreductase (TbNTR) plays a role in the antiparasitic activity because BSF T. b. brucei trypomastigotes with elevated TbNTR levels were hypersensitive to tested compounds. Therefore, a novel class of affordable 3-nitro-1,2,4-triazole-based compounds with antitrypanosomal activity has been identified.