Specific refolding pathway of viscumin A chain in membrane-like medium reveals a possible mechanism of toxin entry into cell.
How is a water-soluble globular protein able to spontaneously cross a cellular membrane? It is commonly accepted that it undergoes significant structural rearrangements on the lipid-water interface, thus acquiring membrane binding and penetration ability. In this study molecular dynamics (MD) simulations have been used to explore large-scale conformational changes of the globular viscumin A chain in a complex environment - comprising urea and chloroform/methanol (CHCl3/MeOH) mixture. Being well-packed in aqueous solution, viscumin A undergoes global structural rearrangements in both organic media. In urea, the protein is "swelling" and gradually loses its long-distance contacts, thus resembling the "molten globule" state. In CHCl3/MeOH, viscumin A is in effect turned "inside out". This is accompanied with strengthening of the secondary structure and surface exposure of hydrophobic epitopes originally buried inside the globule. Resulting solvent-adapted models were further subjected to Monte Carlo simulations with an implicit hydrophobic slab membrane. In contrast to only a few point surface contacts in water and two short regions with weak protein-lipid interactions in urea, MD-derived structures in CHCl3/MeOH reveal multiple determinants of membrane interaction. Consequently it is now possible to propose a specific pathway for the structural adaptation of viscumin A with respect to the cell membrane - a probable first step of its translocation into cytoplasmic targets.


Costs of diagnostic and preoperative workup with and without breast MRI in older women with a breast cancer diagnosis.
Breast cancer in the U.S. - estimated at 232,670 incident cases in 2014 - has the highest aggregate economic burden of care relative to other female cancers. Yet, the amount of cost attributed to diagnostic/preoperative work up has not been characterized. We examined the costs of imaging and biopsy among women enrolled in Medicare who did and did not receive diagnostic/preoperative Magnetic Resonance Imaging (MRI). Using Surveillance, Epidemiology and End Results (SEER)- Medicare data, we compared the per capita costs (PCC) based on amount paid, between diagnosis date and primary surgical treatment for a breast cancer diagnosis (2005-2009) with and without diagnostic/preoperative MRI. We compared the groups with and without MRI using multivariable models, adjusting for woman and tumor characteristics. Of the 53,653 women in the cohort, within the diagnostic/preoperative window, 20 % (N = 10,776) received diagnostic/preoperative MRI. Total unadjusted median costs were almost double for women with MRI vs. without ($2,251 vs. $1,152). Adjusted costs were higher among women receiving MRI, with significant differences in total costs ($1,065), imaging costs ($928), and biopsies costs ($138). Costs of diagnostic/preoperative workups among women with MRI are higher than those without. Using these cost estimates in comparative effectiveness models should be considered when assessing the benefits and harms of diagnostic/preoperative MRI.


Dynamic imaging and function of partial supraspinatus tendon tears.
It was the purpose of this study to identify and document normal and abnormal supraspinatus tendon function in vivo using real-time ultrasound. We defined 4 groups of 20 individuals each: partial tear (group 1), full-thickness tear (group 2), successfully repaired tear (group 3), and healthy asymptomatic controls (group 4). Except for group 4, all patients underwent magnetic resonance arthrography to confirm the diagnosis. All underwent ultrasound imaging of the supraspinatus tendon with the adducted arm at rest and under maximal isometric abduction. Tendon deformation was dynamically assessed and measured with tendon thickness changes at 0.5, 1, 1.5, and 2 cm from the tendon insertion. The clinical assessment consisted of absolute and relative Constant score, subjective shoulder value, and strength measurements. Without muscle contraction, the tendons of the 4 groups were not of significantly different thickness, with the least variation at 1.5 cm from the insertion site. On contraction, the normal tendon thickness significantly increased at a distance of 2 cm, whereas it did not for the full-thickness and partial supraspinatus tears. Thus contraction of the muscle resulted in measurable deformation of the tendon. Partially torn supraspinatus tendons can be functionally incompetent, leading to a biomechanical deformation of the musculotendinous unit that is not different from that of a unit with a full-thickness tendon tear. The dynamic sonographic finding of a successful repair of a supraspinatus tendon is similar to that of a normal tendon, even though the previously injured muscle appears unable to generate the same strength as a normal muscle. Level III, case-control study.


Relationship between 8-year weight change, body size, and health in a large cohort of adults in Thailand.
Overweight and obesity have been shown to be risk factors for a range of non-communicable diseases, especially cardio-metabolic conditions, worldwide. But less is known about the effects of weight change on adults' overall health and wellbeing, particularly in transitional low- and middle-income countries. This study aimed to assess the relationship between 8-year weight change and measures of self-assessed health among Thai adults. Data were collected from Thai adults aged 25-40 years (n = 27,003) enrolled in the Thai cohort Study and surveyed in 2005, 2009, and 2013. We used self-reported weight and height measurements at baseline and 2013, as well as three standard health questions regarding overall health, energy, and emotion asked at the two time points, to investigate the effects of weight change on health. Between 2005 and 2013, 6.0% of participants lost more than 5% of their baseline weight; 38.5% were stable (<5% loss to 5% gain); 23.0% slightly gained weight (>5%-10%); 22.8% gained moderate weight (>10%-20%); and 9.4% had heavy weight gain (>20%). Moderate (>10%-20%) and heavy weight gain (>20%) were both associated with an increased risk of reporting 'poor or very poor' overall health in 2013 among participants who had a normal body mass index (BMI) (adjusted odds ratio [AOR] 1.39; 95% confidence interval [CI], 1.13-1.71 and AOR 1.44; 95% CI, 1.09-1.90, respectively), were overweight (AOR 1.53; 955 CI, 1.01-2.29 and AOR 1.82; 95% CI, 1.04-3.19, respectively) or had obesity (AOR 2.47; 95% CI, 1.74-3.51 and AOR 3.20; 95% CI, 2.00-5.16, respectively) in 2005. Weight gain of over 20% also had a negative impact on energy level among cohort members with a normal BMI in 2005 (AOR 1.36; 95% CI, 1.11-1.65) and among participants with obesity in 2005 (AOR 1.93; 95% CI, 1.38-2.71). For those who were underweight, had a normal BMI, or had obesity at baseline, weight loss of more than 5% was associated with reporting emotional problems. Excessive weight gain adversely impacted participants who were underweight or had obesity at baseline. Our study found that weight change, in particular weight gain, was associated with negative health outcomes, and this effect appeared to increase at higher levels of body size. The present findings may be useful to promote weight maintenance and healthy lifestyles.


Role of antiarrhythmic therapy in patients at risk for sudden cardiac death: an evidence-based review.
Sudden cardiac death (SCD) accounts for more than half of all cardiac deaths occurring each year in the United States. Although it has several causes, patients at greatest risk are those with coronary artery disease and impaired left ventricular function, heart failure secondary to ischemia or idiopathic dilated cardiomyopathy, hypertrophic cardiomyopathy, documented sustained ventricular tachycardia or ventricular fibrillation, and survivors of cardiac arrest. The presence of asymptomatic ventricular arrhythmias, positive signal-averaged electrocardiogram (ECG), low heart rate variability index, or inducible ventricular tachycardia or ventricular fibrillation increases the risk. In primary prevention trials in patients with ischemic heart disease, beta-blockers reduced both total mortality and SCD, whereas class I antiarrhythmic drugs, especially class IC, increased mortality. Among class III agents, d,l-sotalol and dofetilide have a neutral effect on mortality, whereas d-sotalol increases mortality. Amiodarone has a neutral effect on total and cardiac mortality but does reduce the risk of arrhythmic death and cardiac arrest. Three primary prevention trials in patients with ischemic heart disease were conducted with implantable cardioverter-defibrillators (ICDs). Patients with low ejection fractions (EFs), asymptomatic ventricular arrhythmias, and inducible ventricular tachycardia or ventricular fibrillation had significant reductions in total, cardiac, and arrhythmic death with ICDs compared with either no drug therapy or conventional antiarrhythmic agents. The ICDs did not reduce mortality in patients with low EFs and a positive signal-averaged ECG undergoing coronary bypass graft. In those with heart failure, beta-blockers reduced total and SCD mortality, but dofetilide and amiodarone had a neutral effect on mortality. In the secondary prevention of SCD, antiarrhythmic drugs alone generally are not thought to improve survival. In three trials in patients with documented sustained ventricular tachycardia or ventricular fibrillation, or survivors of SCD, ICDs reduced cardiac and arrhythmic mortality. Total mortality, however, was significantly reduced in only one of these trials. The role of antiarrhythmic drugs in secondary prevention of SCD is limited to patients in whom ICD is inappropriate or in combination with ICD. Antiarrhythmics can be given selectively with ICDs to decrease episodes of ventricular tachycardia or fibrillation to reduce ICD discharges, to suppress episodes of nonsustained ventricular tachycardia that trigger ICD discharges, to slow the rate of ventricular tachycardia to increase hemodynamic stability, to allow effective antitachycardia pacing, or to suppress supraventricular arrhythmias.


Methotrexate causes apoptosis in postmitotic endothelial cells.
Methotrexate (MTX) is a commonly used chemotherapy agent for a variety of cancers. However, therapeutic levels are associated with numerous untoward effects such as central nervous system damage in children with acute lymphoblastic leukemia. The purpose of this study was to determine if MTX caused injury to endothelial cells using cultured bovine pulmonary artery endothelial cells as a model. Light microscopy showed gaps between cells and reduced numbers of endothelial cells after exposure to MTX (10(-9) to 10(-5) M), a range consistent with therapeutic drug levels. Proliferation and viability of subconfluent and confluent MTX-treated endothelial cells were measured by colorimetric (MTS) assay. There was a significant decline in cell numbers in MTX-treated subconfluent (growing) cells cultured after 4 days of MTX exposure compared to controls, as expected. However, there was also an unexpected decline in cell numbers in MTX-treated postmitotic endothelial cells after 1, 3, and 4 days of drug exposure. This suggested that MTX induced endothelial cell death. Fluorescent ApoAlert Enhanced Annexin-V binding demonstrated apoptosis in endothelial cells after 1 day of MTX exposure. Apoptosis was confirmed by a DNA fragment assay. This is apparently the first report of MTX-induced apoptosis of postmitotic, cultured endothelial cells. The findings suggest that apoptosis may be one mechanism of MTX-induced injury to endothelial cells.


Screening for gestational diabetes: a summary of the evidence for the U.S. Preventive Services Task Force.
To systematically review the evidence for screening for gestational diabetes mellitus (GDM). We established eligibility criteria for relevant studies. We systematically searched MEDLINE and the Cochrane Collaboration Library for studies meeting eligibility criteria. We supplemented this search with further studies identified from reference lists of reviews. Two reviewers examined each article for eligibility. A single reviewer abstracted relevant data from the included articles; a second reviewer checked the abstractions. We graded the quality of the articles according to criteria developed by the U.S. Preventive Services Task Force. No well-conducted, randomized, controlled trial provides direct evidence for the health benefits of screening for GDM. The evidence is unclear regarding the optimal screening and reference diagnostic test for GDM. The impact of hyperglycemia on adverse maternal and neonatal health outcomes is probably continuous. Although insulin therapy decreases the incidence of fetal macrosomia for those women with more severe degrees of hyperglycemia, the magnitude of any effect on maternal and neonatal health outcomes is not clear. The evidence is insufficient to determine the magnitude of health benefit for any treatment among the large number of women with GDM at milder degrees of hyperglycemia. We found limited evidence regarding the potential adverse effects of screening for GDM. Because of the lack of high-quality evidence concerning critical issues, we are unable to determine the extent to which screening has an important impact on maternal and neonatal health outcomes. A randomized, controlled trial of screening is necessary to answer the many remaining questions.


Structure-function analysis of the C-terminal domain of CNM67, a core component of the Saccharomyces cerevisiae spindle pole body.
The spindle pole body of the budding yeast Saccharomyces cerevisiae has served as a model system for understanding microtubule organizing centers, yet very little is known about the molecular structure of its components. We report here the structure of the C-terminal domain of the core component Cnm67 at 2.3 Å resolution. The structure determination was aided by a novel approach to crystallization of proteins containing coiled-coils that utilizes globular domains to stabilize the coiled-coils. This enhances their solubility in Escherichia coli and improves their crystallization. The Cnm67 C-terminal domain (residues Asn-429-Lys-581) exhibits a previously unseen dimeric, interdigitated, all α-helical fold. In vivo studies demonstrate that this domain alone is able to localize to the spindle pole body. In addition, the structure reveals a large functionally indispensable positively charged surface patch that is implicated in spindle pole body localization. Finally, the C-terminal eight residues are disordered but are critical for protein folding and structural stability.


Home Help Service Staffs' Descriptions of Their Role in Promoting Everyday Activities Among Older People in Sweden Who Are Dependent on Formal Care.
The study aimed to explore how home help service staff described their role in improving the abilities of older people, in particular, older women with chronic pain who are dependent on formal care, to perform everyday activities. Three focus group interviews were conducted, and a qualitative inductive thematic content analysis was used. The analysis resulted in one theme: struggling to improve the care recipients' opportunities for independence but being inhibited by complex environmental factors. By encouraging the care recipients to perform everyday activities, the staff perceived themselves to both maintain and improve their care recipients' independence and quality of life. An important goal for society and health care professionals is to improve older people's abilities to "age in place" and to enable them to age independently while maintaining their quality of life. A key resource is home help service staff, and this resource should be utilized in the best possible way.


Recognition of HLA-Cw4 but not HLA-Cw6 by the NK cell receptor killer cell Ig-like receptor two-domain short tail number 4.
NK cells are cytotoxic to virus-infected and tumor cells that have lost surface expression of class I MHC proteins. Target cell expression of class I MHC proteins inhibits NK cytotoxicity through binding to inhibitory NK receptors. In contrast, a similar family of activating NK receptors, characterized by the presence of a charged residue in their transmembrane portion and a truncated cytoplasmic tail, augment lysis by NK cells when ligated by an appropriate class I MHC protein. However, the class I MHC specificity of many of these activating NK receptors is still unknown. Here, we show enhanced lysis of HLA-Cw4 but not HLA-Cw6-expressing cells, by a subset of NK clones. This subset may express killer cell Ig-like receptor two-domain short tail number 4 (KIR2DS4), as suggested by staining with various mAb. It is still possible, however, that these clones may express receptors other than KIR2DS4 that might recognize HLA-Cw4. Binding of KIR2DS4-Ig fusion protein to cells expressing HLA-Cw4 but not to those expressing HLA-Cw6 was also observed. The binding of KIR2DS4-Ig to HLA-Cw4 is weaker than that of killer cell Ig-like receptor two-domain long tail number 1 (KIR2DL1)-Ig fusion protein; however, such weak recognition is capable of inhibiting lysis by an NK transfectant expressing a chimeric molecule of KIR2DS4 fused to the transmembrane and cytoplasmic portion of KIR2DL1. Residue alpha14 is shown to be important in the KIR2DS4 binding to HLA-Cw4. Implications of the role of the activating NK receptors in immunosurveillance are discussed.


Clinically-Relevant Rapamycin Treatment Regimens Enhance CD8+ Effector Memory T Cell Function In The Skin and Allow their Infiltration into Cutaneous Squamous Cell Carcinoma.
Patients receiving immunosuppressive drugs to prevent organ transplant rejection exhibit a greatly increased risk of developing cutaneous squamous cell carcinoma (SCC). However, not all immunosuppressive drugs confer the same risk. Randomised, controlled trials demonstrate that switching renal transplant recipients receiving calcineurin inhibitor-based therapies to mammalian target of rapamycin (mTOR) inhibitors results in a reduced incidence of de novo SSC formation, and can even result in the regression of pre-existing premalignant lesions. However, the contribution played by residual immune function in this setting is unclear. We examined the hypotheses that mTOR inhibitors promote the enhanced differentiation and function of CD8+ memory T cells in the skin. Here, we demonstrate that the long-term oral administration of rapamycin to achieve clinically-relevant whole blood drug target thresholds, creates a "low rapamycin dose" environment in the skin. While both rapamycin and the calcineurin inhibitor tacrolimus elongated the survival of OVA-expressing skin grafts, and inhibited short-term antigen-specific CD8+ T cell responses, rapamycin but not tacrolimus permitted the statistically significant infiltration of CD8+ effector memory T cells into UV-induced SCC lesions. Furthermore, rapamycin uniquely enhanced the number and function of CD8+ effector and central memory T cells in a model of long-term contact hypersensitivity provided that rapamycin was present during the antigen sensitization phase. Thus, our findings suggest that patients switched to mTOR inhibitor regimens likely experience enhanced CD8+ memory T cell function to new antigen-challenges in their skin, which could contribute to their lower risk of de novo SSC formation and regression of pre-existing premalignant lesions.


Tracking the learning curve in microsurgical skill acquisition.
Despite advances in surgical training, microsurgery is still based on an apprenticeship model. To evaluate skill acquisition and apply targeted feedback to improve their training model, the authors applied the Structured Assessment of Microsurgery Skills to the training of microsurgical fellows. They hypothesized that subjects would demonstrate measurable improvement in performance throughout the study period and consistently across evaluators. Seven fellows were evaluated during 118 microsurgical cases by 16 evaluators over three 1-month evaluation periods in 1 year (2010 to 2011). Evaluators used the Structured Assessment of Microsurgery Skills questionnaire, which measures dexterity, visuospatial ability, operative flow, and judgment. To validate the data, microsurgical anastomoses in rodents performed by the fellows in a laboratory at the beginning and end of the study period were evaluated by five blinded plastic surgeons using the same questionnaire. Primary outcomes were change in scores between evaluation periods and interevaluator reliability. Between the first two evaluation periods, all skill areas and overall performance improved significantly. Between the second two periods, most skill areas improved, but only a few improved significantly. Operative errors decreased significantly between the first and subsequent periods (81 versus 36; p < 0.05). In the laboratory study, all skills were significantly (p < 0.05) or marginally (0.05 ≤ p < 0.10) improved between time points. The overall interevaluator reliability of the questionnaire was acceptable (α = 0.67). The Structured Assessment of Microsurgery Skills questionnaire is a valid instrument for assessing microsurgical skill, providing individualized feedback with acceptable interevaluator reliability. Use of the questionnaire is anticipated to enhance microsurgical training.


Oxidative stress induced mitochondrial protein kinase A mediates cytochrome c oxidase dysfunction.
Previously we showed that Protein kinase A (PKA) activated in hypoxia and myocardial ischemia/reperfusion mediates phosphorylation of subunits I, IVi1 and Vb of cytochrome c oxidase. However, the mechanism of activation of the kinase under hypoxia remains unclear. It is also unclear if hypoxic stress activated PKA is different from the cAMP dependent mitochondrial PKA activity reported under normal physiological conditions. In this study using RAW 264.7 macrophages and in vitro perfused mouse heart system we investigated the nature of PKA activated under hypoxia. Limited protease treatment and digitonin fractionation of intact mitochondria suggests that higher mitochondrial PKA activity under hypoxia is mainly due to increased sequestration of PKA Catalytic α (PKAα) subunit in the mitochondrial matrix compartment. The increase in PKA activity is independent of mitochondrial cAMP and is not inhibited by adenylate cyclase inhibitor, KH7. Instead, activation of hypoxia-induced PKA is dependent on reactive oxygen species (ROS). H89, an inhibitor of PKA activity and the antioxidant Mito-CP prevented loss of CcO activity in macrophages under hypoxia and in mouse heart under ischemia/reperfusion injury. Substitution of wild type subunit Vb of CcO with phosphorylation resistant S40A mutant subunit attenuated the loss of CcO activity and reduced ROS production. These results provide a compelling evidence for hypoxia induced phosphorylation as a signal for CcO dysfunction. The results also describe a novel mechanism of mitochondrial PKA activation which is independent of mitochondrial cAMP, but responsive to ROS.


Silymarin protects dopaminergic neurons against lipopolysaccharide-induced neurotoxicity by inhibiting microglia activation.
An inflammatory response in the central nervous system mediated by activation of microglia is a key event in the early stages of the development of neurodegenerative diseases. Silymarin is a polyphenolic flavanoid derived from milk thistle that has anti-inflammatory, cytoprotective and anticarcinogenic effects. In this study, we first investigated the neuroprotective effect of silymarin against lipopolysaccharide (LPS)-induced neurotoxicity in mesencephalic mixed neuron-glia cultures. The results showed that silymarin significantly inhibited the LPS-induced activation of microglia and the production of inflammatory mediators, such as tumour necrosis factor-alpha and nitric oxide (NO), and reduced the damage to dopaminergic neurons. Therefore, the inhibitory mechanisms of silymarin on microglia activation were studied further. The production of inducible nitric oxide synthase (iNOS) was studied in LPS-stimulated BV-2 cells as a model of microglia activation. Silymarin significantly reduced the LPS-induced nitrite, iNOS mRNA and protein levels in a dose-dependent manner. Moreover, LPS could induce the activation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase but not extracellular signal-regulated kinase. The LPS-induced production of NO was inhibited by the selective p38 MAPK inhibitor SB203580. These results indicated that the p38 MAPK signalling pathway was involved in the LPS-induced NO production. However, the activation of p38 MAPK was not inhibited by silymarin. Nevertheless, silymarin could effectively reduce LPS-induced superoxide generation and nuclear factor kappaB (NF-kappaB) activation. It suggests that the inhibitory effect of silymarin on microglia activation is mediated through the inhibition of NF-kappaB activation.


Age, estrogen, and immune response in breast adenocarcinoma and adjacent normal tissue.
Chronic inflammation promotes breast tumor growth and invasion by accelerating angiogenesis and tissue remodeling in the tumor microenvironment. There is a complex relationship between inflammation and estrogen, which drives the growth of 70 percent of breast tumors. While low levels of estrogen exposure stimulate macrophages and other inflammatory cell populations, very high levels are immune suppressive. Breast tumor incidence is increased by obesity and age, which interact to influence inflammatory cell populations in normal breast tissue. To characterize the impact of these factors on tumors and the tumor microenvironment, we measured gene expression in 195 breast adenocarcinomas and matched adjacent normal breast tissue samples collected at Akershus University Hospital (AHUS). Age and Body Mass Index (BMI) were independently associated with inflammation in adjacent normal tissue but not tumors. Estrogen Receptor (ER)-negative tumors had elevated macrophage expression compared with matched normal tissue, but ER-positive tumors showed an unexpected decrease in macrophage expression. We found an inverse relationship between the increase in tumor estrogen pathway expression compared with adjacent normal tissue and tumor macrophage score. We validated this finding in 126 breast tumor-normal pairs from the previously published METABRIC cohort. We developed a novel statistic, the Rewiring Coefficient, to quantify the rewiring of gene co-expression networks at the level of individual genes. Differential correlation analysis demonstrated distinct pathways were rewired during tumorigenesis. Our data support an immune suppressive effect of high doses of estrogen signaling in breast tumor microenvironment, suggesting that this effect contributes to the greater presence of prognostic and therapeutically relevant immune cells in ER-negative tumors.


Many roads from mTOR to eIF4F.
The process of cell growth depends on a complex co-ordinated programme of macromolecular synthesis that can be tuned to environmental constraints. In eukaryotes, the mTOR [mammalian (or mechanistic) target of rapamycin] signalling pathway is a master regulator of this process, in part by regulating mRNA translation through control of the eIF4F (eukaryotic initiation factor 4F) initiation complex. The present review discusses the role of this relationship in mTOR-regulated gene expression, and its contribution to phenotypes associated with deregulated mTOR signalling, such as cancer.


Contribution of α7 nicotinic receptor to airway epithelium dysfunction under nicotine exposure.
Loss or dysfunction of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) leads to impairment of airway mucus transport and to chronic lung diseases resulting in progressive respiratory failure. Nicotinic acetylcholine receptors (nAChRs) bind nicotine and nicotine-derived nitrosamines and thus mediate many of the tobacco-related deleterious effects in the lung. Here we identify α7 nAChR as a key regulator of CFTR in the airways. The airway epithelium in α7 knockout mice is characterized by a higher transepithelial potential difference, an increase of amiloride-sensitive apical Na(+) absorption, a defective cAMP-dependent Cl(-) conductance, higher concentrations of Na(+), Cl(-), K(+), and Ca(2+) in secretions, and a decreased mucus transport, all relevant to a deficient CFTR activity. Moreover, prolonged nicotine exposure mimics the absence of α7 nAChR in mice or its inactivation in vitro in human airway epithelial cell cultures. The functional coupling of α7 nAChR to CFTR occurs through Ca(2+) entry and activation of adenylyl cyclases, protein kinase A, and PKC. α7 nAChR, CFTR, and adenylyl cyclase-1 are physically and functionally associated in a macromolecular complex within lipid rafts at the apical membrane of surface and glandular airway epithelium. This study establishes the potential role of α7 nAChR in the regulation of CFTR function and in the pathogenesis of smoking-related chronic lung diseases.


Biomimetic Ant-Nest Electrode Structures for High Sulfur Ratio Lithium-Sulfur Batteries.
The lithium-sulfur (Li-S) rechargeable battery has the benefit of high gravimetric energy density and low cost. Significant research currently focuses on increasing the sulfur loading and sulfur/inactive-materials ratio, to improve life and capacity. Inspired by nature's ant-nest structure, this research results in a novel Li-S electrode that is designed to meet both goals. With only three simple manufacturing-friendly steps, which include slurry ball-milling, doctor-blade-based laminate casting, and the use of the sacrificial method with water to dissolve away table salt, the ant-nest design has been successfully recreated in an Li-S electrode. The efficient capabilities of the ant-nest structure are adopted to facilitate fast ion transportation, sustain polysulfide dissolution, and assist efficient precipitation. High cycling stability in the Li-S batteries, for practical applications, has been achieved with up to 3 mg·cm(-2) sulfur loading. Li-S electrodes with up to a 85% sulfur ratio have also been achieved for the efficient design of this novel ant-nest structure.


Monitoring Commercial Ibuprofen Potency Changes Over 1 Year When Stored in a Household Setting.
Background: Most over-the-counter medications are labeled for storage in a dry, room temperature environment. Despite this, many households store medications in the bathroom, where temperature and humidity extremes may be experienced. Objective: In this project, we sought to investigate the effect that long-term storage in a household bathroom had on potency of over-the-counter ibuprofen (IBU) products as well as on the emergence of a known toxic degradation product, 4-isobutylacetophenone (4-IBP). Methods: A liquid chromatography-tandem mass spectrometry method was developed for the quantitative determination of IBU and 4-IBP in aqueous samples. Three brands each of IBU tablets (200 mg) and suspensions (100 mg/5 mL) were assayed for IBU concentration at the initiation of the study and once monthly thereafter. The samples were stored in a household bathroom, with continuous temperature and humidity monitoring. Each sample was assayed in triplicate and percent recovery was calculated against freshly prepared standards of IBU using bulk powder. Results: Tablets maintained >90% average strength through 3 months, with statistically significant deviation from initial concentration (2-way analysis of variance, P = .05) detected after 6 to 7 months. Suspensions maintained >90% average strength through 5 months, with statistically significant changes from initial concentration emerging after 7 months. After 12 months, the average strength was 73% and 83% for tablets and suspensions, respectively. 4-IBP was not detected in any of the samples during the duration of the study. Conclusions: These data indicate that, while 4-IBP was not detected following 12-month bathroom storage of commercial IBU products, significant changes in potency should negatively affect efficacy.


Regulation of chloride channels by protein kinase C in normal and cystic fibrosis airway epithelia.
Apical membrane chloride channels control chloride secretion by airway epithelial cells. Defective regulation of these channels is a prominent characteristic of cystic fibrosis. In normal intact cells, activation of protein kinase C (PKC) by phorbol ester either stimulated or inhibited chloride secretion, depending on the physiological status of the cell. In cell-free membrane patches, PKC also had a dual effect: at a high calcium concentration, PKC inactivated chloride channels; at a low calcium concentration, PKC activated chloride channels. In cystic fibrosis cells, PKC-dependent channel inactivation was normal, but activation was defective. Thus it appears that PKC phosphorylates and regulates two different sites on the channel or on an associated membrane protein, one of which is defective in cystic fibrosis.


Effects of elevated carbon dioxide on the hematological parameters of a temperate catshark.
Atmospheric CO2 levels have been rising due to an increase in anthropic activities and its implications over marine ecosystems are unprecedented. The present study focused on the effects of ocean acidification (OA) on key hematological parameters of the juvenile small-spotted catsharks (Scyliorhinus canicula). Eggs were reared throughout the entire embryogenesis (~4 months) plus 5 additional months, in two experimental treatments (control: pCO2 ~ 400 μatm; and high CO2 : pCO2 ~ 900 μatm, Δ -0.3 pH units). After blood collection, the following hematological parameters were evaluated: (a) normal blood cells count (erythrocytes, leukocytes, and thrombocytes), (b) presence of erythrocytes with nuclear abnormalities, and (c) erythrocyte nucleus to cytoplasmic ratio. Concomitantly, to determine the cardiac and hematopoietic conditions, the spleen and heart to body ratios were also assessed. The present findings indicate that the measured variables may not be affected by elevated pCO2 in this temperate species, as no significant differences were observed between treatments across all the endpoints tested. Nonetheless, it is worth mentioning a decreasing trend observed in a number of thrombocytes associated with OA, which should foster further investigation, regarding other aspects of their coagulation response. Along with OA, other stressors are expected to impact marine life, such as warming and hypoxia. Thus, future research should aim to investigate the cumulative effect of these stressors on hematological parameters in sharks.


Investigation of GluA1 and GluA2 AMPA receptor subtype distribution in the hippocampus and anterior cingulate cortex of Long Evans rats during development.
Preadolescent development is characterized by a reorganization of connectivity within and between brain regions that coincides with the emergence of complex behaviors. During the preadolescent period, the rodent hippocampus and regions of the frontal cortex are remodelled as the brain strengthens active connections and eliminates others. In the developing and mature brain, changes in the properties of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAr)-mediated synaptic responses contribute to experience-dependent changes in neural organization and function. AMPAr are made up of 4 subunits, of which GluA1 and GluA2 have been shown to play the most prominent role in functional plasticity. In this study, we sought to determine whether levels of these two subunits changed during the course of pre-adolescent development in the hippocampus and anterior cingulate cortex (ACC). To investigate the developmental changes in GluA1 and GluA2 AMPAr subunits, Western blotting and immunohistochemistry were performed on the ACC and hippocampus from P18 - P30 and compared to adult (P50) levels and distribution. Within the hippocampus, protein levels of GluA1 and GluA2 peaked around P26-30 whereby localized staining in the dentate gyrus reflected this pattern. GluA1 and GluA2 levels within the ACC showed little variation during this developmental period. These results indicate that changes in AMPAr subunits within the hippocampus coincide with developmental modifications that underlie the shift from juvenile- to adult-like capabilities. However, changes in AMPAr distribution in the ACC might not mediate changes that reflect preadolescent developmental shifts.


Anatomical characterization of a novel reticulospinal vasodepressor area in the rat medulla oblongata.
Microinjection of L-glutamate into a subregion of the gigantocellular nucleus of the rat medulla oblongata significantly lowers arterial pressure. This vasodepressor area, the gigantocellular depressor area, is topographically distinct from other vasoactive areas of the medulla. We sought to determine the efferent projections of the gigantocellular depressor area and compare these to the efferent projections of sympathoexcitatory neurons within the rostral ventrolateral medulla. The anterograde tracer Phaseolus vulgaris-leucoagglutinin was deposited into sites in the gigantocellular depressor area or rostral ventrolateral medulla (pressor area) functionally defined as vasodepressor or vasopressor by microinjections of L-glutamate. Following Phaseolus vulgaris-leucoagglutinin injections into the gigantocellular depressor area, labeled punctuate fibers were seen bilaterally within distinct areas of a number of autonomic regions including the nuclei of the solitary tract, subcoeruleus area, parabrachial complex, the medial medullary reticular formation of the medulla and pons, and laminae 7 and 10 of the thoracic spinal cord. Following deposits into the rostral ventrolateral medulla (pressor area), labeled fibers were seen in many of these same autonomic nuclei; however, efferents from the gigantocellular depressor area to the nucleus of the solitary tract, the parabrachial complex and the reticular formation were medial to rostral ventrolateral medulla (pressor area) efferents to these same areas. These data indicate that neurons within the gigantocellular depressor area and the rostral ventrolateral medulla (pressor area) project to autonomic nuclei throughout the central nervous system and further suggest a heterogeneity of function with regard to autonomic control both within the reticular formation and its efferent targets. In addition, these data support the view that the gigantocellular depressor area may be a novel reticulospinal sympathoinhibitory area.


Development of a gene-activated scaffold platform for tissue engineering applications using chitosan-pDNA nanoparticles on collagen-based scaffolds.
Biomaterial scaffolds that support cell infiltration and tissue formation can also function as platforms for the delivery of therapeutics such as drugs, proteins, and genes. As burst release of supraphysiological quantities of recombinant proteins can result in adverse side effects, the objective of this study was to explore the potential of a series of collagen-based scaffolds, developed in our laboratory, as gene-activated scaffold platforms with potential in a range of tissue engineering applications. The potential of chitosan, a biocompatible material derived from the shells of crustaceans, as a gene delivery vector was assessed using mesenchymal stem cells (MSCs). A transfection efficiency of >45% is reported which is similar to what is achieved with polyethyleneimine (PEI), a non-viral gold standard vector, without causing cytotoxic side effects. When the optimised chitosan nanoparticles were incorporated into a series of collagen-based scaffolds, sustained transgene expression from MSCs seeded on the scaffolds was maintained for up to 28days and interestingly the composition of the scaffold had an effect on transfection efficiency. These results demonstrate that by simply varying the scaffold composition and the gene (or combinations thereof) chosen; the system has potential for a myriad of therapeutic applications.


Effectiveness of physiotherapy for seniors with recurrent headaches associated with neck pain and dysfunction: a randomized controlled trial.
A previous study demonstrated that in seniors, the presence of cervical musculoskeletal impairment was not specific to cervicogenic headache but was present in various recurrent headache types. Physiotherapy treatment is indicated in those seniors diagnosed with cervicogenic headache but could also be adjunct treatment for those with cervical musculoskeletal signs who are suspected of having transitional headaches. This study aimed to determine the effectiveness of a physiotherapy program for seniors with recurrent headaches associated with neck pain and cervical musculoskeletal dysfunction, irrespective of the headache classification. This is a prospective, stratified, randomized controlled trial with blinded outcome assessment. Sixty-five participants with recurrent headache, aged 50-75 years, were randomly assigned to either a physiotherapy (n=33) or a usual care group (n=32). The primary outcome was headache frequency. Secondary outcomes were headache intensity and duration, neck pain and disability, cervical range of motion, quality of life, participant satisfaction, and medication intake. Participants in the physiotherapy group received 14 treatment sessions. Participants in the usual care group continued with their usual care. Outcome measures were recorded at baseline, 11 weeks, 6 months, and 9 months. This study was funded by a government research fund of $6,850. No conflict of interest is declared. There was no loss to follow-up for the primary outcome measure. Compared with usual care, participants receiving physiotherapy reported significant reductions in headache frequency immediately after treatment (mean difference -1.6 days, 95% confidence interval [CI] -2.5 to -0.6), at 6-month follow-up (-1.7 days, 95% CI -2.6 to -0.8), and at 9-month follow-up (-2.4 days, 95% CI -3.2 to -1.5), and significant improvements in all secondary outcomes immediately posttreatment and at 6- and 9-month follow-ups, (p<.05 for all). No adverse events were reported. Physiotherapy treatment provided benefits over usual care for seniors with recurrent headache associated with neck pain and dysfunction.


Plant behaviour from human imprints and the cultivation of wild cereals in Holocene Sahara.
The human selection of food plants cannot always have been aimed exclusively at isolating the traits typical of domesticated species today. Each phase of global change must have obliged plants and humans to cope with and develop innovative adaptive strategies. Hundreds of thousands of wild cereal seeds from the Holocene 'green Sahara' tell a story of cultural trajectories and environmental instability revealing that a complex suite of weediness traits were preferred by both hunter-gatherers and pastoralists. The archaeobotanical record of the Takarkori rockshelter in southwest Libya covering four millennia of human occupation in the central Sahara gives us a unique insight into long-term plant manipulation and cultivation without domestication. The success of a number of millets was rooted in their invasive-opportunistic behaviour, rewarded during their coexistence with people in Africa. These wild plants were selected for features that were precious in the past but pernicious for agriculture today. Reconnecting past practices with modern farming strategies can help us to seek out the best resources for the future.


The DSM-IV criteria for adolescent alcohol and cannabis use disorders.
The aims of this study are to compare DSM-IV criteria for alcohol and cannabis use disorders with its predecessor, DSM-III-R, and to examine the validity of the new criteria in an adolescent drug clinic sample. During evaluation, a sample of 772 adolescents (63% boys, 77% white) were administered a structured interview of diagnostic symptoms and additional problem severity measures. Independent staff ratings of problem severity and treatment referral were collected as well. Compared to its predecessor, DSM-III-R, application of the DSM-IV criteria for alcohol and cannabis users resulted in more abuse assignments and fewer dependence assignments. The shift in assignments appeared to be largely due to a lowering of the abuse threshold, rather than to a tightening of the dependence criteria. The external validity data generally supported the DSM-IV abuse and dependence distinction in adolescents, and the newer criteria were as valid as the older criteria. In contrast to DSM-III-R, the DSM-IV system yields more abuse cases and fewer dependence cases among adolescent alcohol and cannabis abusers. Validity evidence for the new criteria are defensible, yet the findings are seen as a starting point for discussing the need for tailoring substance use disorder criteria for adolescents.


Association of peripheral inflammatory markers with chronic fatigue in a population-based sample.
Alterations in the innate immune response may contribute to the pathogenesis of chronic fatigue syndrome (CFS). However, studies have been limited by small sample sizes, use of patients from tertiary care settings, inappropriate selection of controls, and failure to control for confounding demographic, medical and behavioral factors independently associated with immune activity. It is also not known whether specific symptoms account for observed associations between CFS and the innate immune response. To address these limitations, the current study examined plasma concentrations of high-sensitivity c-reactive protein (hs-CRP), white blood cell count (WBC) and a combined inflammation factor in a large population-based sample. Log-transformed mean plasma concentrations of hs-CRP were increased in subjects with CFS (n=102) and in subjects with unwellness symptoms that did not meet diagnostic criteria for CFS (defined as "insufficient fatigue" [ISF]) (n=240) when compared to subjects who were well (n=115). Log transformed WBC was increased in ISF and was increased at a trend level in CFS. The combined inflammation factor was increased in both CFS and ISF. Subjects with CFS and ISF did not differ on any of the inflammation measures. In the entire subject population, the physical component summary score (PCS), but not the mental component summary score (MCS), from the Medical Outcomes Study Short Form-36 (SF-36) was negatively associated with each of the inflammation measures. Depressive symptoms were also associated with increased log hs-CRP. After adjustment for age, sex, race, location of residence, BMI, depressive status and immune-modulating medications, subjects classified as ISF continued to demonstrate increased log hs-CRP, WBC and elevations on the inflammation factor when compared to well controls; however, associations between CFS and log hs-CRP and the inflammation factor were no longer statistically significant. After adjustment, PCS score also remained independently associated with each of the inflammation measures. These findings support a role for innate immune activation in unexplained fatigue and unwellness, but do not suggest that immune activation is specific to CFS.


A Compact Surface Plasmon Resonance Biosensor for Sensitive Detection of Exosomal Proteins for Cancer Diagnosis.
Exosomes are nanosized (50-150 nm) extracellular vesicles released by all types of cells in the body. They transport various biological molecules, such as DNAs, RNAs, proteins, and lipids from parent cells to recipient cells for intercellular communication. Exosomes, especially those from tumor cells, are actively involved in caner development, metastasis, and drug resistance. Recently, many studies have shown that exosomal proteins are promising biomarkers for cancer screening, early detection and prognosis. Among many detection techniques, surface plasmon resonance (SPR) is a highly sensitive, label-free, and real-time optical detection method. Commercial prism-based wavelength/angular-modulated SPR sensors afford high sensitivity and resolution, but their large footprint and high cost limit their adaptability for clinical settings. We have developed an intensity-modulated, compact SPR biosensor (25 cm × 10 cm × 25 cm) for the detection of exosomal proteins. We have demonstrated the potential application of the compact SPR biosensor in lung cancer diagnosis using exosomal epidermal growth factor receptor (EGFR) and programmed death-ligand 1 (PD-L1) as biomarkers. The compact SPR biosensor offers sensitive, simple, fast, user-friendly, and cost-effective detection of exosomal proteins, which may serve as an in vitro diagnostic test for cancer.


Effectiveness of an herbal preparation containing echinacea, propolis, and vitamin C in preventing respiratory tract infections in children: a randomized, double-blind, placebo-controlled, multicenter study.
To evaluate the effectiveness and safety of a preparation containing echinacea, propolis, and vitamin C in the prevention of respiratory tract infections in children during a 12-week winter period. Randomized, double-blind, placebo-controlled study. Four hundred thirty children, aged 1 to 5 years, were randomized to an herbal extract preparation (n = 215) or a placebo elixir (n = 215). Administration of an herbal preparation (Chizukit) containing 50 mg/mL of echinacea, 50 mg/mL of propolis, and 10 mg/mL of vitamin C, or placebo (5.0 mL and 7.5 mL twice daily for ages 1 to 3 years and 4 to 5 years, respectively) for 12 weeks. Significant mean +/- SD reductions of illnesses were seen in the Chizukit group in the number of illness episodes, 138 vs 308 (55% reduction); number of episodes per child, 0.9 +/- 1.1 vs 1.8 +/- 1.3 (50% reduction, P<.001); and number of days with fever per child, 2.1 +/- 2.9 vs 5.4 +/- 4.4) (62% reduction, P<.001). The total number of illness days and duration of individual episodes were also significantly lower in the Chizukit group. Adverse drug reactions were rare, mild, and transient. A preventive effect of a product containing echinacea, propolis, and vitamin C on the incidence of respiratory tract infections was observed.


Identification of epidermal growth factor receptor-positive glioblastoma using lipid-encapsulated targeted superparamagnetic iron oxide nanoparticles in vitro.
Targeted superparamagnetic iron oxide (SPIO) nanoparticles have emerged as a promising biomarker detection tool for molecular magnetic resonance (MR) image diagnosis. To identify patients who could benefit from Epidermal growth factor receptor (EGFR)-targeted therapies, we introduce lipid-encapsulated SPIO nanoparticles and hypothesized that anti-EGFR antibody cetuximab conjugated of such nanoparticles can be used to identify EGFR-positive glioblastomas in non-invasive T2 MR image assays. The newly introduced lipid-coated SPIOs, which imitate biological cell surface and thus inherited innate nonfouling property, were utilized to reduce nonspecific binding to off-targeted cells and prevent agglomeration that commonly occurs in nanoparticles. The synthesized targeted EGFR-antibody-conjugated SPIO (EGFR-SPIO) nanoparticles were characterized using dynamic light scattering, zeta potential assays, gel electrophoresis mobility shift assays, transmission electron microscopy (TEM) images, and cell line affinity assays, and the results showed that the conjugation was successful. The targeting efficiency of the synthesized EGFR-SPIO nanoparticles was confirmed through Prussian blue staining and TEM images by using glioblastoma cell lines with high or low EGFR expression levels. The EGFR-SPIO nanoparticles preferentially targeted U-251 cells, which have high EGFR expression, and were internalized by cells in a prolonged incubation condition. Moreover, the T2 MR relaxation time of EGFR-SPIO nanoparticles could be used for successfully identifying glioblastoma cells with elevated EGFR expression in vitro and distinguishing U-251 cells from U-87MG cells, which have low EFGR expression. These findings reveal that the lipid-encapsulated EGFR-SPIO nanoparticles can specifically target cells with elevated EGFR expression in the three tested human glioblastoma cell lines. The results of this study can be used for noninvasive molecular MR image diagnosis in the future.


Overexpression of SPARC in human trabecular meshwork increases intraocular pressure and alters extracellular matrix.
Intraocular pressure (IOP) regulation is largely unknown. SPARC-null mice demonstrate a lower IOP resulting from increased outflow. SPARC is a matricellular protein often associated with fibrosis. We hypothesized that SPARC overexpression would alter IOP by affecting extracellular matrix (ECM) synthesis and/or turnover in the trabecular meshwork (TM). An adenoviral vector containing human SPARC was used to increase SPARC expression in human TM endothelial cells and perfused human anterior segments using multiplicities of infection (MOIs) 25 or 50. Total RNA from TM was used for quantitative PCR, while protein from cell lysates and conditioned media were used for immunoblot analyses and zymography. After completion of perfusion, the anterior segments were fixed, sectioned, and examined by light and confocal microscopy. SPARC overexpression increased the IOP of perfused human anterior segments. Fibronectin and collagens IV and I protein levels were elevated in both TM cell cultures and within the juxtacanalicular (JCT) region of perfused anterior segments. Collagen VI and laminin protein levels were increased in TM cell cultures but not in perfused anterior segments. The protein levels of pro-MMP-9 decreased while the kinetic inhibitors of metalloproteinases, TIMP-1 and PAI-1 protein levels, increased at MOI 25. At MOI 50, the protein levels of pro-MMP-1, -3, and -9 also decreased while PAI-1 and TIMP-1 and -3 increased. Only MMP-9 activity was decreased on zymography. mRNA levels of the collagens, fibronectin, and laminin were not affected by SPARC overexpression. SPARC overexpression increases IOP in perfused cadaveric human anterior segments resulting from a qualitative change the JCT ECM. Selective decrease of MMP-9 activity is likely part of the mechanism. SPARC is a regulatory node for IOP.


Delayed Primary Reposition in a Patient with Traumatic Globe Avulsion: A Case Report.
Globe avulsion is an extremely rare and difficult to manage emergency after trauma. Especially in cases of post-traumatic globe avulsion, management and treatment depend on the condition of the globe and the surgeon's judgment. It can be done in primary reposition as well as enucleation in treatment. Recently published cases show that surgeons prefer primary reposition to reduce the psychological stress that may occur in these patients and to achieve better cosmetic results. We report the treatment and follow-up results of a patient whose globe avulsion was repositioned on the 5th post-traumatic day.


Efficacy and safety of fresh fibroblast allografts in the treatment of diabetic foot ulcers.
Various types of allogenic skin substitutes composed of cryopreserved keratinocytes, fibroblasts, or both have been used for treatments of diabetic foot ulcers, but the effects have generally not been dramatic because cryopreservation impairs cell activities. The purpose of the study was to evaluate the use of non-cryopreserved fresh human fibroblast allografts in treating diabetic foot ulcers. Human dermal fibroblasts from healthy teenagers were cultured and applied over the foot ulcers of 37 patients with diabetes. Control treatment was performed in 18 patients. Eight weeks after treatment, the percentages of complete healing, mean healing times, and patient satisfaction were compared, with follow-up ranging from 6 to 40 months. Our study showed that 83.8% of the treated group and 50.0% of the control group experienced complete healing. The times required for complete healing were 30.9+/-10.1 and 47.2+/-7.8 days in the treated and control groups, respectively. Patient satisfaction with fresh fibroblast treatment was also superior to satisfaction with the conventional method (mean scores: 8.0+/-1.0 and 4.9+/-1.4, respectively). No adverse events related to the study treatment occurred. The use of fresh human fibroblast allografts was found to be a safe and effective treatment for diabetic foot ulcers. The authors have indicated no significant interest with commercial supporters.


Diagnostic accuracy of different imaging modalities following computed tomography (CT) scanning for assessing the resectability with curative intent in pancreatic and periampullary cancer.
Periampullary cancer includes cancer of the head and neck of the pancreas, cancer of the distal end of the bile duct, cancer of the ampulla of Vater, and cancer of the second part of the duodenum. Surgical resection is the only established potentially curative treatment for pancreatic and periampullary cancer. A considerable proportion of patients undergo unnecessary laparotomy because of underestimation of the extent of the cancer on computed tomography (CT) scanning. Other imaging methods such as magnetic resonance imaging (MRI), positron emission tomography (PET), PET-CT, and endoscopic ultrasound (EUS) have been used to detect local invasion or distant metastases not visualised on CT scanning which could prevent unnecessary laparotomy. No systematic review or meta-analysis has examined the role of different imaging modalities in assessing the resectability with curative intent in patients with pancreatic and periampullary cancer. To determine the diagnostic accuracy of MRI, PET scan, and EUS performed as an add-on test or PET-CT as a replacement test to CT scanning in detecting curative resectability in pancreatic and periampullary cancer. We searched MEDLINE, Embase, Science Citation Index Expanded, and Health Technology Assessment (HTA) databases up to 5 November 2015. Two review authors independently screened the references and selected the studies for inclusion. We also searched for articles related to the included studies by performing the "related search" function in MEDLINE (OvidSP) and Embase (OvidSP) and a "citing reference" search (by searching the articles that cite the included articles). We included diagnostic accuracy studies of MRI, PET scan, PET-CT, and EUS in patients with potentially resectable pancreatic and periampullary cancer on CT scan. We accepted any criteria of resectability used in the studies. We included studies irrespective of language, publication status, or study design (prospective or retrospective). We excluded case-control studies. Two review authors independently performed data extraction and quality assessment using the QUADAS-2 (quality assessment of diagnostic accuracy studies - 2) tool. Although we planned to use bivariate methods for analysis of sensitivities and specificities, we were able to fit only the univariate fixed-effect models for both sensitivity and specificity because of the paucity of data. We calculated the probability of unresectability in patients who had a positive index test (post-test probability of unresectability in people with a positive test result) and in those with negative index test (post-test probability of unresectability in people with a positive test result) using the mean probability of unresectability (pre-test probability) from the included studies and the positive and negative likelihood ratios derived from the model. The difference between the pre-test and post-test probabilities gave the overall added value of the index test compared to the standard practice of CT scan staging alone. Only two studies (34 participants) met the inclusion criteria of this systematic review. Both studies evaluated the diagnostic test accuracy of EUS in assessing the resectability with curative intent in pancreatic cancers. There was low concerns about applicability for most domains in both studies. The overall risk of bias was low in one study and unclear or high in the second study. The mean probability of unresectable disease after CT scan across studies was 60.5% (that is 61 out of 100 patients who had resectable cancer after CT scan had unresectable disease on laparotomy). The summary estimate of sensitivity of EUS for unresectability was 0.87 (95% confidence interval (CI) 0.54 to 0.97) and the summary estimate of specificity for unresectability was 0.80 (95% CI 0.40 to 0.96). The positive likelihood ratio and negative likelihood ratio were 4.3 (95% CI 1.0 to 18.6) and 0.2 (95% CI 0.0 to 0.8) respectively. At the mean pre-test probability of 60.5%, the post-test probability of unresectable disease for people with a positive EUS (EUS indicating unresectability) was 86.9% (95% CI 60.9% to 96.6%) and the post-test probability of unresectable disease for people with a negative EUS (EUS indicating resectability) was 20.0% (5.1% to 53.7%). This means that 13% of people (95% CI 3% to 39%) with positive EUS have potentially resectable cancer and 20% (5% to 53%) of people with negative EUS have unresectable cancer. Based on two small studies, there is significant uncertainty in the utility of EUS in people with pancreatic cancer found to have resectable disease on CT scan. No studies have assessed the utility of EUS in people with periampullary cancer.There is no evidence to suggest that it should be performed routinely in people with pancreatic cancer or periampullary cancer found to have resectable disease on CT scan.


Psychological problems in chronic prostatitis patients with pain.
Men with chronic prostatitis are frequently seen in urological practice and are difficult to treat with standard antimicrobial medications. This pilot study was designed to take a different perspective in assessing chronic prostatitis patients with pain by evaluating them using a standard chronic pain clinic psychological approach. Twenty men, 27% of the referred group of patients with chronic prostatitis and pain, completed the MMPI and a structured psychological interview. Their findings were compared to age- and education-matched men seeking treatment for chronic low back pain. Data were collected at the Pain Clinic within the Department of Anesthesiology at the University of Washington Medical Center. Patients were 20 men referred from a urology-based Prostatitis Clinic and 20 men referred to the Pain Clinic for chronic low back pain. The two groups differed in the impact of their pain problem on their lives. Prostatitis patients were employed but reported that their symptoms greatly interfered with their sexual/romantic relationships. Back pain patients reported that their pain interfered primarily with work; most of these patients had long-term marital relationships, whereas few prostatitis patients did. Half of the prostatitis patients met criteria for major depression, but back pain patients were more somatically focused, depressed, and anxious. The constellation of relationship problems, disruptions in sexual functioning, levels of depression, along with failure of multiple previous medical treatments in men with chronic prostatitis indicates that continued antimicrobial therapy is unlikely to provide the "cure" these patients seek. Psychological evaluation, couples' counseling, individual counseling, and medications for depression all may play a role in a comprehensive approach to these patients. These results must be considered as preliminary and as representative of a possibly skewed sample of prostatitis patients since only those men who accepted the referral to a pain clinic psychologist for an evaluation were assessed. Clearly, they are likely to be among the patients who are most psychologically and sexually impaired by the chronic prostatitis and associated pain. A further study with less self-selection is indicated.


Asymmetry of limbic structure (hippocampal formation and amygdaloidal complex) at ptsd.
Defining exact position of weak anatomic function which is find in a base of neurological and psychiatric disorder is just became the subject of intensive research interest. For this purposes it is important to implement structural and functional MRI techniques, also for further lightening and seeing subject of this work, more concretely connected to PTSD. Therefore, exactly MRI gives most sensitive volumetric measuring of hippocampal formation and amygdaloidal complex. The goal of this work was to research asymmetry of hippocampal formation and amygdaloidal complex to the PTSD patients. Results showed that at the axial slice length of hippocampal formation on the left and right side of all patients are significantly asymmetric. At the sagittal slice from the left side of hippocampal formation is in many cases longer than right about 50 %. At the coronal slice, there are no significant differences toward patient proportion according to symm./asymm. of the hippocampal formation width at the right and left side. Difference in volume average of hippocampal formation between right and left side for axial and coronal slice is not statistically significant, but it is significant for sagittal slice. In about amygdaloidal complex patients with PTSD toward symm./asymm. Amygdaloidal complex at the right and left side of axial and sagittal slice in all three measurement shows asymmetry, what is especially shown at sagittal slice. Difference in average length of amygdaloidal complex at the right and left side is not statistically significant for no one slice. Therefore, results of a new research that are used MRI, showed smaller hippocampal level at PTSD (researched by Van der Kolka 1996, Pitman 1996, Bremner et al., 1995.). Application of MRI technique in research of asymmetry of hippocampal formation and amygdaloidal complex, which we used in our research, we recommend as a template for future researches in a sense of lightening anatomic function that is a base of neuropsychiatric disorders.


Rehearsal strategies can enlarge or diminish the spacing effect: pure versus mixed lists and encoding strategy.
Using 5 experiments, the authors explored the dependency of spacing effects on rehearsal patterns. Encouraging rehearsal borrowing produced opposing effects on mixed lists (containing both spaced and massed repetitions) and pure lists (containing only one or the other), magnifying spacing effects on mixed lists but diminishing spacing effects on pure lists. Rehearsing with borrowing produced large spacing effects on mixed lists but not on pure lists for both free recall (Experiment 1) and recognition (Experiment 2). In contrast, rehearsing only the currently visible item produced spacing effects on both mixed lists and pure lists in free recall (Experiment 3) and recognition (Experiment 4). Experiment 5 demonstrated these effects using a fully within-subjects design. Rehearse-aloud protocols showed that rehearsal borrowing redistributed study from massed to spaced items on mixed lists, especially during massed presentations.


An Alternative Strategy of Preventive Control of Tick-Borne Relapsing Fever in Rural Areas of Sine-Saloum, Senegal.
In Senegal, tick-borne relapsing fever (TBRF) is a major cause of morbidity and a neglected public health problem. Borreliosis cases commonly detected in two villages led us to implement a borreliosis preventive control including cementing of floors in bedrooms and outbuildings attended by inhabitants to avoid human contacts with tick vectors. Epidemiological and medical monitoring of the TBRF incidence was carried out at Dielmo and Ndiop by testing the blood of febrile patients since 1990 and 1993, respectively. Intra-domiciliary habitat conditions were improved by cementing, coupled with accompanying measures, from March 2013 to September 2015. Application of this strategy was associated with a significant reduction of borreliosis incidence. This was more evident in Dielmo, dropping from 10.55 to 2.63 cases per 100 person-years (P < 0.001), than in Ndiop where it changed from 3.79 to 1.39 cases per 100 person-years (P < 0.001). Thirty-six cases of TBRF were estimated to be prevented at a cost of €526 per infection. The preventive control strategy was successful in Dielmo and Ndiop, being associated with decreased incidence by 89.8% and 81.5%, respectively, suggesting that TBRF may be widely decreased when the population is involved. Public health authorities or any development stakeholders should adopt this effective tool for promoting rural health through national prevention programs.


Elucidation of structural and functional properties of albumin bound to gold nanoparticles.
Nanoparticle-albumin complexes are being designed for targeted drug delivery and imaging. However, the changes in the functional properties of albumin due to adsorption on nanoparticles remain elusive. Thus, the objective of this work was to elucidate the structural and functional properties of human and bovine serum albumin bound to negatively charged gold nanoparticles (GNPs). Fluorescence data demonstrated static quenching of albumin by GNP with the quenching of buried as well as surface tryptophan in BSA. The binding process was enthalpy and entropy-driven in HSA and BSA, respectively. At lower concentrations of GNP there was a higher affinity for tryptophan, whereas at higher concentrations both tryptophan and tyrosine participated in the interaction. Synchronous fluorescence spectra revealed that the microenvironment of tryptophan in HSA turned more hydrophilic upon exposure to GNP. The α-helical content of albumin was unaltered by GNP. Approximately 37 and 23% reduction in specific activity of HSA and BSA was observed due to GNP binding. In presence of warfarin and ibuprofen the binding constants of albumin-GNP complexes were altered. A very interesting observation not reported so far is the retained antioxidant activity of albumin in presence of GNP i.e. we believe that GNPs did not bind to the free sulfhydryl groups of albumin. However enhanced levels of copper binding were observed. We have also highlighted the differential response in albumin due to gold and silver nanoparticles which could be attributed to differences in the charge of the nanoparticle.


The water supercooled regime as described by four common water models.
The temperature scale of simple water models in general does not coincide with the natural one. Therefore, in order to make a meaningful evaluation of different water models, a temperature rescaling is necessary. In this paper, we introduce a rescaling using the melting temperature and the temperature corresponding to the maximum of the heat capacity to evaluate four common water models (TIP4P-Ew, TIP4P-2005, TIP5P-Ew and Six-Sites) in the supercooled regime. Although all the models show the same general qualitative behavior, the TIP5P-Ew appears as the best representation of the supercooled regime when the rescaled temperature is used. We also analyze, using thermodynamic arguments, the critical nucleus size for ice growth. Finally, we speculate on the possible reasons why atomistic models do not usually crystalize while the coarse grained mW model do crystallize.


Methodological issues of patient utility measurement. Experience from two clinical trials.
This article explores various methodological issues of patient utility measurement in two randomized controlled clinical trials involving 85 patients with fibromyalgia and 144 with ankylosing spondylitis. In both trials one baseline and two follow-up measurements of the patients' preferences for their own health state and several hypothetical states were performed using the rating scale and the standard gamble methods. It was confirmed that standard gamble scores are consistently higher than rating scale scores for both the experienced and the hypothetical states. The 3-month test-retest reliability for hypothetical states measured by intraclass correlation coefficients ranged from 0.24 to 0.33 for the rating scale and from 0.43 to 0.70 for the standard gamble. Although the reproducibility is not high, the group mean scores are fairly stable over time. Mean standard gamble scores tend to differ depending on the way the measurements are undertaken. Utilities elicited with chained gambles were significantly higher than utilities elicited with basic reference gambles. At the individual level some inconsistent responses occurred. However, more than 70% of these fell within the bounds of the measurement error, which ranged from 0.11 to 0.13 on the standard gamble (0-1 scale) and from 8 to 10 on the rating scale (0-100 scale). The large number of negative utilities for the severe hypothetical state, which was used as an anchor point in the chained gambles, and the magnitude of these negative utilities (down to -19) calls for intensified research efforts to handle these responses in utility calculations.


Target Recognition in Tandem WW Domains: Complex Structures for Parallel and Antiparallel Ligand Orientation in h-FBP21 Tandem WW.
Protein-protein interactions often rely on specialized recognition domains, such as WW domains, which bind to specific proline-rich sequences. The specificity of these protein-protein interactions can be increased by tandem repeats, i.e., two WW domains connected by a linker. With a flexible linker, the WW domains can move freely with respect to each other. Additionally, the tandem WW domains can bind in two different orientations to their target sequences. This makes the elucidation of complex structures of tandem WW domains extremely challenging. Here, we identify and characterize two complex structures of the tandem WW domain of human formin-binding protein 21 and a peptide sequence from its natural binding partner, the core-splicing protein SmB/B'. The two structures differ in the ligand orientation and, consequently, also in the relative orientation of the two WW domains. We analyze and probe the interactions in the complexes by molecular simulations and NMR experiments. The workflow to identify the complex structures uses molecular simulations, density-based clustering, and peptide docking. It is designed to systematically generate possible complex structures for repeats of recognition domains. These structures will help us to understand the synergistic and multivalency effects that generate the astonishing versatility and specificity of protein-protein interactions.


Is iron and zinc nutrition a concern for vegetarian infants and young children in industrialized countries?
Well-planned vegetarian diets are considered adequate for all stages of the life cycle, despite limited data on the zinc status of vegetarians during early childhood. The bioavailability of iron and zinc in vegetarian diets is poor because of their higher content of absorption inhibitors such as phytate and polyphenols and the absence of flesh foods. Consequently, children as well as adult vegetarians often have lower serum ferritin concentrations than omnivores, which is indicative of reduced iron stores, despite comparable intakes of total iron; hemoglobin differences are small and rarely associated with anemia. However, data on serum zinc concentrations, the recommended biomarker for identifying population groups at elevated risk of zinc deficiency, are sparse and difficult to interpret because recommended collection and analytic procedures have not always been followed. Existing data indicate no differences in serum zinc or growth between young vegetarian and omnivorous children, although there is some evidence of low serum zinc concentrations in vegetarian adolescents. Some vegetarian immigrants from underprivileged households may be predisposed to iron and zinc deficiency because of nondietary factors such as chronic inflammation, parasitic infections, overweight, and genetic hemoglobin disorders. To reduce the risk of deficiency, the content and bioavailability of iron and zinc should be enhanced in vegetarian diets by consumption of fortified cereals and milk, by consumption of leavened whole grains, by soaking dried legumes before cooking and discarding the soaking water, and by replacing tea and coffee at meals with vitamin C-rich drinks, fruit, or vegetables. Additional recommended practices include using fermented soy foods and sprouting at least some of the legumes consumed. Fortified foods can reduce iron deficiency, but whether they can also reduce zinc deficiency is less certain. Supplements may be necessary for vegetarian children following very restricted vegan diets.


Lysophosphatidic acid triggers mast cell-driven atherosclerotic plaque destabilization by increasing vascular inflammation.
Lysophosphatidic acid (LPA), a bioactive lysophospholipid, accumulates in the atherosclerotic plaque. It has the capacity to activate mast cells, which potentially exacerbates plaque progression. In this study, we thus aimed to investigate whether LPA contributes to plaque destabilization by modulating mast cell function. We here show by an imaging mass spectrometry approach that several LPA species are present in atherosclerotic plaques. Subsequently, we demonstrate that LPA is a potent mast cell activator which, unlike other triggers, favors release of tryptase. Local perivascular administration of LPA to an atherosclerotic carotid artery segment increases the activation status of perivascular mast cells and promotes intraplaque hemorrhage and macrophage recruitment without impacting plaque cell apoptosis. The mast cell stabilizer cromolyn could prevent intraplaque hemorrhage elicited by LPA-mediated mast cell activation. Finally, the involvement of mast cells in these events was further emphasized by the lack of effect of perivascular LPA administration in mast cell deficient animals. We demonstrate that increased accumulation of LPA in plaques induces perivascular mast cell activation and in this way contributes to plaque destabilization in vivo. This study points to local LPA availability as an important factor in atherosclerotic plaque stability.


Population-based trends in osteoporosis management after new initiations of long-term systemic glucocorticoids (1998-2008).
Our objective was to describe changes in glucocorticoid-induced osteoporosis (GIOP) preventive care from 1998-2008 including rates and correlates of bone mineral density (BMD) testing and osteoporosis treatment in new long-term glucocorticoid initiations. A population-based study of adults aged 20 yr or older in Manitoba, Canada, was conducted using linked healthcare databases. Subjects with new long-term (≥90 d) systemic glucocorticoid initiations were identified within each fiscal year. High-quality GIOP preventive care was defined by the composite of BMD testing or osteoporosis treatment within 6 months of starting glucocorticoids. For each initiation, we identified sociodemographic and clinical characteristics, prednisone dose equivalents, and prescriber specialty. Multivariable Poisson regression models were used to calculate adjusted incidence rate ratios (aIRR). We studied 17,736 new long-term glucocorticoid initiations; one third were at least 10 mg prednisone daily, and most (64%) were prescribed by general practitioners. Overall, 6-month rates of BMD testing were 6%, osteoporosis treatment 22%, and the composite of testing or treatment 25%. From 1998-2008, there were modest increases in BMD testing (from 4 to 6%), osteoporosis treatment (from 15 to 24%), and testing or treatment [from 17 to 27%; aIRR = 1.51; 95% confidence interval (CI) = 1.40-1.63]. High-quality GIOP preventive care varied significantly by age (16% for those <50 yr vs. 27% for those ≥70 yr; aIRR = 0.57; 95% CI = 0.52-0.63), sex (13% for men vs. 34% for women; aIRR = 0.40; 95% CI = 0.37-0.43), and prescriber (23% general practice vs. 44% rheumatology; aIRR = 0.56; 95% CI = 0.52-0.60). Quality of GIOP preventive care has improved but remains suboptimal with only one quarter of those starting long-term glucocorticoids receiving BMD testing or osteoporosis treatment. Interventions to improve GIOP prevention, especially targeting younger patients, men, and nonspecialists, are needed.


Deciphering the antimicrobial activity of phenanthroline chelators.
The opportunistic fungal pathogen, Candida albicans, causes a range of diseases in susceptible individuals. The adverse side effects of many of the current anti-fungal prescription drugs and the emergence of C. albicans isolates and other Candida species which are resistant to these compounds have accelerated the search for new drug candidates which have different modes of action. A family of metal chelators, which are based on the 1,10-phenanthroline core, exhibit excellent growth inhibitory effects in vitro against a number of Candida species, including clinical isolates. The compounds sequester transition metal ions, damage mitochondrial function and uncouple cell respiration. Additionally, fungal cell morphology undergoes dramatic changes and there is evidence of apoptotic cell death. Importantly, in vivo studies have confirmed that the compounds have an acceptably low toxicity profile.


Immunochemical studies on heterogeneity of IgD myeloma proteins.
An antigenic heterogeneity among IgD myeloma proteins was tested by immunoelectrophoresis and double immunodiffusion in agar with four kinds of anti-delta(Fc) antisera produced by immunization with isolated Fc fragments of IgD myeloma proteins. According to antigenicity of the Fc fragment, IgD myeloma proteins were divided into two different groups. Anti-delta(Fc)-T1 (S.T.) antiserum, absorbed with te Y.S. myeloma protein or serum, either gave a faint precipitin line or failed to react against the isolated IgD myeloma proteins or sera. With the papain-digested IgD myeloma proteins and sera, anti-delta(Fc)-T1 antiserum either gave heavy precipitin lines or failed to react. Of twelve papain-digested sera containing IgD myeloma proteins tested, nine (75%) showed positive precipitin lines using anti-delta(Fc)-T1 antiserum. No relationship was found between the two groups of myeloma proteins with respect to IgD levels. SDS polyacrylamide gel electrophoresis of the IgD myeloma proteins (S.T. and Y.S.) showed no difference in the molecular weights of the whole myeloma proteins, and their light and heavy chains. Polyacrylamide gel electrophoresis of the IgD myeloma proteins (S.T. and Y.S.), after treatment with papain, revealed almost the same patterns.


Differential Impact of Malnutrition on Health Outcomes Among Indigenous and Non-Indigenous Adults Admitted to Hospital in Regional Australia-A Prospective Cohort Study.
The burden of malnutrition in Indigenous people is a major health priority and this study's aims are to understand health outcomes among Indigenous and non-Indigenous patients. This cohort study includes 608 medical inpatients in three regional hospitals. Participants were screened for malnutrition using the Subjective Global Assessment tool. Hospital length of stay, discharge destination, 30-day and six-month hospital readmission and survival were measured. Although no significant difference was observed between Indigenous participants who were malnourished or nourished (p = 0.120), malnourished Indigenous participants were more likely to be readmitted back into hospital within 30 days (Relative Risk (RR) 1.53, 95% CI 1.19⁻1.97, p = 0.002) and six months (RR 1.40, 95% Confidence Interval (CI) 1.05⁻1.88, p = 0.018), and less likely to be alive at six months (RR 1.63, 95% CI 1.20⁻2.21, p = 0.015) than non-Indigenous participants. Malnutrition was associated with higher mortality (Hazards Ratio (HR) 3.32, 95% CI 1.87⁻5.89, p < 0.001) for all participants, and independent predictors for six-month mortality included being malnourished (HR 2.10, 95% CI 1.16⁻3.79, p = 0.014), advanced age (HR 1.04, 95% CI 1.02⁻1.06, p = 0.001), increased acute disease severity (Acute Physiology and Chronic Health Evaluation score, HR 1.03, 95% CI 1.01⁻1.05, p = 0.002) and higher chronic disease index (Charlson Comorbidity Index, HR 1.36, 95% CI 1.16⁻3.79, p = 0.014). Malnutrition in regional Australia is associated with increased healthcare utilization and decreased survival. New approaches to malnutrition-risk screening, increased dietetic resourcing and nutrition programs to proactively identify and address malnutrition in this context are urgently required.


Permeability of the landscape matrix between amphibian breeding sites.
For organisms that reproduce in discrete habitat patches, land cover between patches (known as the matrix) is important for dispersal among breeding sites. Models of patchy populations often incorporate information on the permeability of the matrix to dispersal, sometimes based on expert opinion. I estimated the relative resistance to gene flow of land cover types and barriers using F(ST) calculated from microsatellite markers in two amphibians, within an 800-km(2) area in northern Switzerland. The species included a frog (Rana temporaria: 996 individuals, 48 populations, seven markers) and a newt (Triturus alpestris: 816 individuals, 41 populations, seven markers). Open fields and urban areas were more resistant to gene flow than forested land; roads and highways also reduced permeability. Results were similar for the two species. However, differences in resistance among matrix elements were relatively low: gene flow through urban areas was reduced by only 24-42% relative to forest; a divided highway reduced gene flow by 11-40% and was 7-8 times more resistant than a secondary road. These data offer an empirically based alternative to expert opinion for setting relative resistance values in landscape models.


Genotoxicity of the neurotransmitter dopamine in vitro.
Alterations in dopamine levels play a role in several human pathological conditions and their pharmacological treatment. Here we describe an induction of genomic damage detected as micronucleus formation by concentrations in the low micromolar range (6.25-25 microM) in three cell lines in vitro. Rat neuronal PC12 cells exhibited a more pronounced induction (about 10-fold over control at 100 microM) than human lymphoblastoid TK6 cells and rat kidney NRK cells (about 2-fold over control at 100 microM). The role of transporters and receptors in the formation of genomic damage was investigated in PC12 cells, in which the effect of dopamine was reduced by addition of the antioxidants TEMPOL and dimethylthiourea, by inhibitors of the dopamine transporter (GBR 12909 and nomifensine) and by a D2 antagonist (sulpiride). Antioxidative effects of nomifensine and sulpiride, but not of GBR 12909, were excluded, since they did not protect oxidative stress sensitive HL-60 cells from hydrogen peroxide-induced damage in the comet assay. Thus, the transport of dopamine into the cell and the signalling upon binding to D2 receptors was required for the genotoxic effect of dopamine in PC12 cells, which was mediated by intracellular dopamine oxidation products and/or reactive oxygen species.


SQualTrack: a tool for robust fault detection.
One of the techniques used to detect faults in dynamic systems is analytical redundancy. An important difficulty in applying this technique to real systems is dealing with the uncertainties associated with the system itself and with the measurements. In this paper, this uncertainty is taken into account by the use of intervals for the parameters of the model and for the measurements. The method that is proposed in this paper checks the consistency between the system's behavior, obtained from the measurements, and the model's behavior; if they are inconsistent, then there is a fault. The problem of detecting faults is stated as a quantified real constraint satisfaction problem, which can be solved using the modal interval analysis (MIA). MIA is used because it provides powerful tools to extend the calculations over real functions to intervals. To improve the results of the detection of the faults, the simultaneous use of several sliding time windows is proposed. The result of implementing this method is SemiQUALitative TRACKing (SQualTrack), a fault-detection tool that is robust in the sense that it does not generate false alarms, i.e., if there are false alarms, they indicate either that the interval model does not represent the system adequately or that the interval measurements do not represent the true values of the variables adequately. SQualTrack is currently being used to detect faults in real processes. Some of these applications using real data have been developed within the European project Advanced Decision Support System for Chemical/Petrochemical Manufacturing Processes and are also described in this paper.


The Port Arthur massacre and the National Firearms Agreement: 20 years on, what are the lessons?
The 20th anniversary of the National Firearms Agreement (NFA) offers lessons for mental health and public health. Along with similar international legislation, the NFA exemplifies how firearms regulation can prevent firearm mortality and injuries. The gun lobby claims that mental illness underpins gun violence and should be a key site for intervention. A modest but significant link exists between mental disorders and community violence. However, the vast majority of mentally ill individuals are not violent. Despite media portrayals of their dangerousness, they are more likely to be victims of violence and of suicide. Most violent individuals do not have mental illness, and most mass murderers do not have identifiable severe mental illness. Many have maladaptive personality configurations. Gun availability and gun ownership, not severe mental illness, determines most gun homicides. Following recent gun massacres in the United States, there have been calls for better resourcing of mental health services to help identify and respond to those at risk and to regulate firearms access. Screening mentally ill populations for violence risk is misguided. However, clinicians can play a key role in working with legal authorities to monitor and assist regulation of firearm access, especially among high risk populations. Clinician involvement must be complemented by wider gun control measures. The gun lobby's turning the firearms availability debate into a question about whether people with mental illness histories should access such weapons is a calculated appeal to prejudice.


Knowledge, attitude, perception of Muslim parents towards vaccination in Malaysia.
Malaysia is a predominant Muslim country and the recent surge in vaccine-preventable disease enticed us to conduct a survey to measure the Knowledge, Attitude and Perception of Muslim parents toward vaccination process. The data were collected under four segments such as demography, Knowledge, Attitude and Perception. The questionnaire had high internal consistency (0.823) for Cronbach's alpha. The sociodemographic determinants such as marital status (OR = 1.12; 0.91-1.38;p < .05), education level (college OR = 1.35; 1.12-1.64;p < .05, secondary OR = 1.22; 1.01-1.47;p < .05) and the occupation of parents (OR = 1.25; 1.07-1.45;p < .05) were observed affecting the Knowledge score significantly. Majority of Malaysian Muslim parents believed that "vaccine is not prohibited in Islam" and most of them also rejected the belief that "all vaccines are non halal and hence should be avoided". None of the sociodemographic determinants significantly affected the Attitude and Perception score of the Muslim parents. It was observed that the Attitude and Perception score did not establish any association with any of the socio-demographic determinants and hence the null hypothesis that Malaysian Muslim parents had positive Attitude and good Perception toward vaccination process was accepted.


Dental care utilization among caregivers who care for older adults.
The goal of this study was to investigate individual and contextual factors associated with dental care utilization by U.S. informal caregivers. The sample included all 2010 Behavioral Risk Factor Surveillance System respondents who completed the caregiver module and reported providing care for 1 year or more to an individual aged ≥ 50 years or older (n = 1,196). Multiple logistic regressions were used to examine associations of caregiver and care characteristics and county-level contextual characteristics (from Area Resource File data) with two outcomes: dental visits and dental cleaning during previous year. Caregivers with health insurance coverage and higher education were more likely to use dental care; those who had lost more teeth and who were spouse caregivers were less likely to do so. Community characteristics were not correlated with caregivers' use of dental care. Our findings suggest that better access to dental care could improve dental care utilization by caregivers.


Simulation of chemical metabolism for fate and hazard assessment. II CATALOGIC simulation of abiotic and microbial degradation.
The unprecedented pollution of the environment by xenobiotic compounds has provoked the need to understand the biodegradation potential of chemicals. Mechanistic understanding of microbial degradation is a premise for adequate modelling of the environmental fate of chemicals. The aim of the present paper is to describe abiotic and biotic models implemented in CATALOGIC software. A brief overview of the specificities of abiotic and microbial degradation is provided followed by detailed descriptions of models built in our laboratory during the last decade. These are principally new models based on unique mathematical formalism already described in the first paper of this series, which accounts more adequately than currently available approaches the multipathway metabolic logic in prokaryotes. Based on simulated pathways of degradation, the models are able to predict quantities of transformation products, biological oxygen demand (BOD), carbon dioxide (CO(2)) production, and primary and ultimate half-lives. Interpretation of the applicability domain of models is also discussed.


Immunomodulatory Drugs Exert Anti-Leukemia Effects in Acute Myeloid Leukemia by Direct and Immunostimulatory Activities.
Immunomodulatory drugs (IMiDs) are anticancer drugs with immunomodulatory, anti-angiogenesis, anti-proliferative, and pro-apoptotic properties. IMiDs are currently used for the treatment of multiple myeloma, myelodysplastic syndrome, and B-cell lymphoma; however, little is known about efficacy in acute myeloid leukemia (AML). We proposed in this study to investigate the relevance of IMiDs therapy for AML treatment. We evaluated the effect of IMiDs on primary AML blasts (n = 24), and the impact in natural killer (NK) cell-mediated immunosurveillance of AML. Using primary AML cells and an immunodeficient mouse leukemia xenograft model, we showed that IMiDs induce AML cell death in vitro and impair leukemia progression in vivo. In addition, treatment of AML blasts with IMiDs resulted in enhanced allogeneic NK cell anti-leukemia reactivity. Treatment by pomalidomide of AML blasts enhanced lysis, degranulation, and cytokine production by primary allogeneic NK cells. Furthermore, the treatment with lenalidomide of patients with myeloid malignancies resulted in NK cell phenotypic changes similar to those observed in vitro. IMiDs increased CD56 and decreased NKp30, NKp46, and KIR2D expression on NK cells. Finally, AML blasts treatment with IMiDs induced phenotypic alterations including downregulation of HLA-class I. The effect of pomalidomide was not correlated with cereblon expression and A/G polymorphism in AML cells. Our data revealed, a yet unobserved, dual effects on AML affecting both AML survival and their sensitivity to NK immunotherapy using IMiDs. Our study encourages continuing investigation for the use of IMiDs in AML, especially in combination with conventional therapy or immunotherapy strategies.


Characterizing dynamic amplitude of low-frequency fluctuation and its relationship with dynamic functional connectivity: An application to schizophrenia.
The human brain is a highly dynamic system with non-stationary neural activity and rapidly-changing neural interaction. Resting-state dynamic functional connectivity (dFC) has been widely studied during recent years, and the emerging aberrant dFC patterns have been identified as important features of many mental disorders such as schizophrenia (SZ). However, only focusing on the time-varying patterns in FC is not enough, since the local neural activity itself (in contrast to the inter-connectivity) is also found to be highly fluctuating from research using high-temporal-resolution imaging techniques. Exploring the time-varying patterns in brain activity and their relationships with time-varying brain connectivity is important for advancing our understanding of the co-evolutionary property of brain network and the underlying mechanism of brain dynamics. In this study, we introduced a framework for characterizing time-varying brain activity and exploring its associations with time-varying brain connectivity, and applied this framework to a resting-state fMRI dataset including 151 SZ patients and 163 age- and gender matched healthy controls (HCs). In this framework, 48 brain regions were first identified as intrinsic connectivity networks (ICNs) using group independent component analysis (GICA). A sliding window approach was then adopted for the estimation of dynamic amplitude of low-frequency fluctuation (dALFF) and dFC, which were used to measure time-varying brain activity and time-varying brain connectivity respectively. The dALFF was further clustered into six reoccurring states by the k-means clustering method and the group difference in occurrences of dALFF states was explored. Lastly, correlation coefficients between dALFF and dFC were calculated and the group difference in these dALFF-dFC correlations was explored. Our results suggested that 1) ALFF of brain regions was highly fluctuating during the resting-state and such dynamic patterns are altered in SZ, 2) dALFF and dFC were correlated in time and their correlations are altered in SZ. The overall results support and expand prior work on abnormalities of brain activity, static FC (sFC) and dFC in SZ, and provide new evidence on aberrant time-varying brain activity and its associations with brain connectivity in SZ, which might underscore the disrupted brain cognitive functions in this mental disorder.