Supplemental Nutrition Assistance Program Eligibility and HIV Incidence in the United States.
The connection between food insecurity and HIV outcomes is well established. The Supplemental Nutrition Assistance Program (SNAP), the primary food safety net program in the United States, may have collateral impacts on HIV incidence. "Broad-based categorical eligibility" for SNAP is a policy that provides a mechanism for states to increase the income or asset limits for SNAP eligibility. We estimated the association between the number of new HIV diagnoses in 2010-2014 for each state and (1) state income limits and (2) state asset limits for SNAP eligibility. We fitted multivariable negative binomial regression models with number of HIV diagnoses specified as the outcome; SNAP policies as the primary explanatory variable of interest; state and year fixed effects; and time-varying covariates related to the costs of food, health care, housing, employment, other SNAP policies, and Temporary Assistance for Needy Families spending. HIV diagnoses within states had a statistically significant association with state income limits for SNAP eligibility (incidence rate ratio [IRR], 0.94 per increase in the income limit by 35% of federal poverty level; 95% CI, 0.91-0.98), but no association with state asset limits (increased asset limit vs no change: IRR, 1.02; 95% CI, 0.94-1.10; eliminated asset limit vs no change: IRR, 1.04; 95% CI, 0.99-1.10). State income limits for SNAP eligibility were inversely associated with the number of new HIV diagnoses for states between 2010 and 2014. Proposals to eliminate the use of broad-based categorical eligibility to increase the income limit for SNAP may undercut efforts to end the HIV epidemic in the United States.


Ethnic differences in ATP-binding cassette transporter, sub-family G, member 2 (ABCG2/BCRP): genotype combinations and estimated functions.
ATP-binding cassette transporter, sub-family G, member 2 (ABCG2/BCRP) is a xenobiotic transporter and also regulates serum uric acid levels as a urate transporter. We have shown that the severity of ABCG2 dysfunction can be estimated by simple genotyping of two dysfunctional variants, Q126X (rs72552713) and Q141K (rs2231142). This genotyping method is widely accepted for the risk analysis of hyperuricemia/gout, but there is no report on ethnic differences in ABCG2 dysfunctions. Here, we estimated ABCG2 dysfunctions by its genotype combination (Q126X and Q141K) and compared them in three different ethnic groups (500 Japanese, 200 Caucasians and 100 African-Americans). The minor allele frequencies of Q126X and Q141K in Japanese (0.025 and 0.275, respectively) were significantly higher than those in Caucasians (0.005 and 0.085, respectively) and African-Americans (0 and 0.090, respectively). Additionally, the rates of mild, moderate and severe ABCG2 dysfunctions in Japanese (35.4%, 12.4% and 1.6%, respectively) were higher than those in Caucasians (14.0%, 2.5% and 0%, respectively) and African-Americans (14.0%, 2.0% and 0%, respectively). Because ABCG2 dysfunctional diplotypes were commonly observed in both Caucasians (16.5%) and African-Americans (16.0%), the genotyping of the two ABCG2 dysfunctional variants is useful for evaluating individual differences in the ABCG2 dysfunction which affect the pharmacokinetics of substrate drugs and hyperuricemia risk in all three ethnic groups.


Acute adverse reactions to gadopentetate dimeglumine and gadobenate dimeglumine: experience with 32,659 injections.
The purpose of this study was to retrospectively assess the frequency, manifestations, and severity of acute adverse reactions associated with administration of two gadolinium-based contrast agents to patients who underwent MRI at a single large academic institution. Data from continuous quality assurance records on the number of administrations of and acute adverse reactions to gadopentetate dimeglumine and gadobenate dimeglumine at our institution October 2007 to December 2008 were tabulated and analyzed. During the investigation period, 32,659 administrations of gadolinium-based contrast agents were performed for MRI examinations. Of these, 27,956 administrations were gadopentetate dimeglumine, and 4,703 administrations were gadobenate dimeglumine. Data were collected on the frequency and severity of acute adverse reactions. A total of 51 acute adverse reactions occurred in 50 patients (16 men, 34 women; mean age, 48 years), accounting for 0.16% of all administrations (51/32,659). Thirty-eight reactions (38/27,956, 0.14%) were associated with gadopentetate dimeglumine, and 13 (13/4,703, 0.28%) were associated with gadobenate dimeglumine. Forty-three reactions were mild, six were moderate, and two were severe. The severe reactions occurred with the use of gadobenate dimeglumine. The rates of acute adverse reactions to gadopentetate dimeglumine and gadobenate dimeglumine were 0.14% and 0.28%, respectively. The overall adverse reaction rate was 0.16% in our patient sample. Direct comparison of adverse reaction rates of the two agents was not possible because of the retrospective uncontrolled study design.


Identification of polyphenol from Ziziphi spinosae semen against human colon cancer cells and colitis-associated colorectal cancer in mice.
Homology of medicine and food-zizyphi spinosi semen (ZSS) exhibits abundant pharmacological activities, such as sedation, hypnosis and anti-depression. In the present study, the water soluble polyphenols extracted from ZSS via the acid digestion method were named ZSSP, and exhibited significant anti-colorectal cancer (CRC) activity, characterized by restraining cell proliferation, promoting cell apoptosis and increasing chemo-sensitivity of CRC cells. The potential of ZSSP in vivo was further evaluated in an AOM/DSS-induced colitis-associated carcinogenesis (CAC) mouse model. Intriguingly, ZSSP diminished the number and volume of CAC polyps in mice in a dose-dependent manner, and effectively limited the damage of mice organs induced by AOM/DSS. The immunohistochemistry result showed that the elevated CRC early markers in CAC mice, such as COX-II, EMR1, and Ki67, were potently prevented by the ZSSP treatment. Further, the component in ZSSP with the anti-CRC activity was identified as spinosin by the macroporous resin of SP207 and RP-HPLC-MS/MS. Interestingly, during the extraction process, sodium ions were introduced forming spinosin·Na+, which had better water solubility and more remarkable anti-CRC activity than the spinosin. This study provides a new pharmacological property of spinosin derived from ZSS, inhibiting the growth of human CRC cells and colitis-associated CRC in mice, which indicates its potential use as a natural agent against CRC.


[The enzymatic degradation of DDT. 5. Direct transformation of DDD (dichlorodiphenyldichloroethane) into an aldehyde].
The chemical-preparative preparation of the aldehyde (DDHO) is possible by using of saponification. Its enzymatic formation in the organism of warm-blooded animals has not been described up to now. The identification of the aldehyde after application of DDD to rats was successful, inspite of the inhibition of the HCl-cleaving consecutive reactions, whereby the enzymatic formation of the aldehyde was indicated. A possible reaction mechanism is presented.


Underlying Hippocampal Mechanism of Posttraumatic Stress Disorder Treatment Outcome: Evidence From Two Clinical Trials.
The hippocampus plays an important role in the pathophysiology of posttraumatic stress disorder (PTSD) and its prognosis. Accumulating findings suggest that individuals with larger pretreatment hippocampal volume are more likely to benefit from PTSD treatment, but the mechanism underlying this effect is unknown. We investigated whether further increase in hippocampal volume during treatment explains the better prognosis of individuals with greater pretreatment hippocampal volume. We collected structural magnetic resonance imagesfrom patients with PTSD before and after treatment. We examined whether larger hippocampal volume moderates the effect of increased hippocampal volume during treatment on symptom reduction. Given the relatively small sample sizes of treatment studies with pre- and posttreatment magnetic resonance imaging, we focused on effect sizes and sought to replicate findings in an external sample. We tested our hypothesis in study 1 (N = 38; prolonged exposure therapy) and then tested whether the results could be externally replicated in study 2 (N = 20; ketamine infusion followed by exposure therapy). Findings from study 1 revealed that increased right hippocampal volume during treatment was associated with greater PTSD symptom reduction only in patients with greater pretreatment right hippocampal volume (p = .03; η2 = 0.13, a large effect). Findings were partially replicated in study 2 for depressive symptoms (p = .034; η2 = 0.25, a very large effect) and for PTSD symptoms (p = .15; η2 = 0.15, a large effect). Elucidating increased hippocampal volume as one of the neural mechanisms predictive of therapeutic outcome for individuals with larger pretreatment hippocampal volume may help identify clinical targets for this subgroup.


Fermented black radish (Raphanus sativus L. var. niger) attenuates methionine and choline deficient diet-induced nonalcoholic fatty liver disease in mice.
As one of the wide-ranging form of chronic liver disease, there are only limited therapeutic options for nonalcoholic fatty liver disease (NAFLD). We evaluated whether fermented black radish (Raphanus sativus L. var. niger; FBR) ameliorates lipid accumulation, inflammation, and hepatic fibrosis, which are characteristics of the pathogenesis of NAFLD. Fermented black radish treatment reduced lipid accumulation in 3T3-L1 adipocytes, which appeared to be associated with the downregulation of adipogenic transcription factors, including sterol regulatory element-binding protein 1c, CCAAT/enhancer-binding protein α, peroxisome proliferator-activated receptor γ, and lipid accumulation-related genes including adipocyte protein-2 and fatty acid synthase. Administration of FBR to C57BL/6J mice challenged with methionine and choline deficient (MCD) diet significantly attenuated the increased serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and triglyceride. In addition, treatment with FBR interestingly repressed the hepatic inflammation induced with MCD diet, by lowering the expression of inducible nitric oxide synthase and suppressing the inactivation of macrophages and Kupffer cells in the liver. Fermented black radish was also shown to mitigate liver fibrosis through the inhibition of alpha-smooth muscle actin, transforming growth factor beta-1, and collagen type I alpha 1 chain. Our results indicate that FBR ameliorates NAFLD and its related metabolic disease by regulating multiple pathways, suggesting that FBR may be an effective dietary supplement for ameliorating NAFLD.


Bloodless medicine: what to do when you can't transfuse.
A better understanding of risks associated with allogeneic blood transfusions (ABTs), along with a growing population of patients who do not accept transfusions, have led to the emergence of new treatment paradigms with "bloodless medicine." In this chapter, we review prior studies describing management and outcomes in patients who refuse transfusion (referred to as "bloodless patients" herein) and summarize the approaches used at our institution. Bloodless management for surgical patients includes treatment of preoperative anemia, use of autologous blood salvage, and minimizing blood loss with procedures. Other adjuncts for both medical and surgical patients include minimizing blood loss from laboratory testing using pediatric phlebotomy tubes and conservative testing. Anemia can be treated with erythropoiesis-stimulating agents, as well as iron, folate, and B12 when indicated. Although there are limited retrospective studies and no prospective studies to guide management, prior reports suggest that outcomes for surgical patients managed without ABTs are comparable to historic controls. A recent risk-adjusted, propensity-matched, case-control study of outcomes of all hospitalized patients who refused ABT at a large academic health center showed that bloodless management was not an independent predictor of adverse outcomes. Surprisingly, there was a lower overall mortality in the bloodless group and discharge hemoglobin levels were similar for both bloodless and control groups. Further research is now needed to optimize therapy and identify novel interventions to manage bloodless patients. Lessons learned from bloodless patients are likely to benefit all patients given recent evidence suggesting that patients who avoid ABTs do as well, if not better, than those who accept transfusions.


High-resolution MRI: in vivo histology?
For centuries scientists have been fascinated with the question of how the brain works. Investigators have looked at both where different functions are localized and how the anatomical microstructure varies across the brain surface. Here we discuss how advances in magnetic resonance imaging (MRI) have allowed in vivo visualization of the fine structure of the brain that was previously only visible in post-mortem brains. We present data showing the correspondence between definitions of the primary visual cortex defined anatomically using very high-resolution MRI and functionally using functional MRI. We consider how this technology can be applied to allow the investigation of brains that differ from normal, and what this ever-evolving technology may be able to reveal about in vivo brain structure in the next few years.


Introduction to cardiac imaging in infants and children: techniques, potential, and role in the imaging work-up of various cardiac malformations and other pediatric heart conditions.
The increasing prevalence of congenital heart disease (CHD) can be attributed to major improvements in diagnosis and treatment. Although echocardiography is the most commonly used imaging modality for diagnosis and follow-up of subjects with CHD, the evolution of cardiovascular magnetic resonance (MR) imaging and increasingly computed tomography (CT) does offer new ways to visualize the heart and the great vessels. The development of cardiovascular MR techniques allows for a comprehensive assessment of cardiac anatomy and function. This provides information about the long-term sequlae of the underlying complex anatomy, hemodynamic assessment of residual post-operative lesions and complications of surgery. As much of the functional data in CHD patients is usually acquired with invasive X-ray angiography, non-invasive alternatives such as cardiovascular MR (and CT) are desirable. This review evaluates the role of MR imaging in the management of subjects with CHD, particularly detailing recent developments in imaging techniques as they relate to the various CHD diagnoses we commonly encounter in our practice.


Effect of dimethyl sulfoxide on human carcinoma cells, inhibition of plasminogen activator synthesis, change in cell morphology, and alteration of response to cholera toxin.
Human carcinoma HEp-3 lost its tumorigenic and metastatic potential upon prolonged culture in vitro. This change was accompanied by a reduced production of plasminogen activator (PA) of the urokinase type (uPA), which is secreted by HEp-3 cells, a change in response to effectors that modulate uPA production, and an alteration of cell morphology. Similar but more rapid changes occurred when malignant HEp-3 cells were exposed to dimethyl sulfoxide (DMSO). uPA activity in the culture medium dropped below 50% of the control level within 6 h after the addition of DMSO and became undetectable after 24 h of treatment. This drop in uPA activity was not caused by an increased production of PA inhibitors. The cell-associated uPA decreased to 25 to 30% of the control level within 6 h of DMSO treatment and remained at this level for at least 96 h; the reduced uPA production was partially accounted for by a rapid decrease in the functional and chemical concentration of uPA mRNA. In contrast, the concentrations of most of the abundant mRNA species did not appear to be significantly affected, and cell growth was only slightly inhibited in the presence of DMSO. Malignant HEp-3 cells treated with DMSO responded to cholera toxin with an enhanced production of uPA, and their morphology became indistinguishable from that of nonmalignant HEp-3 cells grown in vitro for prolonged periods of time. All of the above changes were fully and rapidly reversible. The inhibitory effect of DMSO on PA production appears to be specific for uPA of human cell lines.


A novel approach to the characterization of substrate specificity in short/branched chain Acyl-CoA dehydrogenase.
Rat and human short/branched chain acyl-CoA dehydrogenases exhibit key differences in substrate specificity despite an overall amino acid identity of 85% between them. Rat short/branched chain acyl-CoA dehydrogenases (SBCAD) are more active toward substrates with longer carbon side chains than human SBCAD, whereas the human enzyme utilizes substrates with longer primary carbon chains. The mechanism underlying this difference in substrate specificity was investigated with a novel surface plasmon resonance assay combined with absorbance and circular dichroism spectroscopy, and kinetics analysis of wild type SBCADs and mutants with altered amino acid residues in the substrate binding pocket. Results show that a relatively few amino acid residues are critical for determining the difference in substrate specificity seen between the human and rat enzymes and that alteration of these residues influences different portions of the enzyme mechanism. Molecular modeling of the SBCAD structure suggests that position 104 at the bottom of the substrate binding pocket is important in determining the length of the primary carbon chain that can be accommodated. Conformational changes caused by alteration of residues at positions 105 and 177 directly affect the rate of electron transfer in the dehydrogenation reactions, and are likely transmitted from the bottom of the substrate binding pocket to beta-sheet 3. Differences between the rat and human enzyme at positions 383, 222, and 220 alter substrate specificity without affecting substrate binding. Modeling predicts that these residues combine to determine the distance between the flavin ring of FAD and the catalytic base, without changing the opening of the substrate binding pocket.


Surface plasmon resonance sensor based on magnetic molecularly imprinted polymers amplification for pesticide recognition.
We reported here a method to enhance detection sensitivity in surface plasmon resonance (SPR) spectroscopy integrated with a surface molecular imprinting recognition system and employing magnetic molecular imprinting polymer nanoparticles for amplifying SPR response. The proposed magnetic molecular imprinting polymer was designed by self-polymerization of dopamine on the Fe3O4 NPs surface in weak base aqueous solution in the presence of template chlorpyrifos (CPF). The imprinted Fe3O4@polydopamine nanoparticles (Fe3O4@PDA NPs) were characterized by Fourier transform infrared spectroscopy, UV-vis absorption spectroscopy, and transmission electron microscopy. The biosensor showed a good linear relationship between the SPR angle shift and the chlorpyrifos concentration over a range from 0.001 to 10 μM with a detection limit of 0.76 nM. A significant increase in sensitivity was therefore afforded through the use of imprinted Fe3O4@PDA NPs as an amplifier, and meanwhile, the imprinted Fe3O4@PDA NPs had an excellent recognition capacity to chlorpyrifos over other pesticides. The excellent sensitivity and selectivity and high stability of the designed biosensor make this magnetic imprinted Fe3O4@PDA NP an attractive recognition element for various SPR sensors for detecting pesticide residuals and other environmentally deleterious chemicals.


Targets for the Treatment of Insomnia in Veterans With Serious Mental Illness.
Insomnia is pervasive among people with serious mental illnesses (SMI) and has a profound negative impact on their psychiatric symptom management and recovery. However, little is known about the factors that affect severity of insomnia in those with SMI. In addition, very few studies have explored whether evidence-based interventions developed for those without SMI are appropriate for or applicable to individuals with SMI. The purpose of this study was to test the role of arousal, dysfunctional cognitions about sleep, and sleep-related behaviors in predicting severity of insomnia in a sample of 60 Veterans who were receiving care in Veterans Health Administration mental health and psychosocial rehabilitation programs and who reported subjective insomnia. In addition, information was collected regarding the types of insomnia treatments provided to these Veterans. Participants completed assessments of insomnia severity and sleep-related arousal, behaviors, and cognitions. Medical records were reviewed to determine whether participants had been screened/assessed for insomnia and whether treatments for insomnia were provided before the date of referral to the study. Multiple regression was used to predict insomnia severity on the basis of these factors. Most participants (81.7%) reported moderate to severe insomnia, although only 3.3% had a diagnosis of insomnia in their medical records. Worry and helplessness about sleep were predictive of insomnia severity; better self-reported sleep hygiene and higher levels of arousal were also associated with greater severity of insomnia. Education about sleep hygiene and medication were the only types of insomnia treatment received. Similar to insomnia among individuals without SMI, insomnia in Veterans with SMI is associated with dysfunctional sleep-related behaviors and cognitions. Many of the Veterans also lacked access to settings and resources conducive to healthy sleep. Veterans with SMI should be regularly assessed for insomnia. Research is needed concerning optimal evidence-based insomnia interventions for addressing behaviors and cognitions in this population in the context of these challenges.


Electropositive seizures and non-convulsive status epilepticus in a critically ill patient with prior skull defect.
Epileptiform discharges captured on routine scalp EEG typically carry a surface negative dipole. We present a patient whose continuous EEG recording in the intensive care setting captured frequent electropositive non-convulsive seizures. Epileptiform discharges with positive polarity are common in the pediatric population but have rarely been reported in adult patients. When reported in adults, such patients usually have skull defects. As surface positive discharges are scarce, adult electroencephalographers should be prudent to differentiate such discharges from artifact, particularly in an intensive care setting where EEG artifact is common.


Regionalization of rainfall--runoff processes in rice agriculture dominated watersheds.
An approach for computing the instantaneous unit hydrograph of rice agriculture dominated watesheds is proposed using the topology and hydraulic charcterstics of its stream network and the hydrologic behaviour of the rice agriculture area. The effect of rice agriculture on the watershed response is considered as partial sink areas. The sink factor, a time-variant weight factor for a particular storm event, is computed from the daily water balanace equation of the rice field. The critcal features of the simulated instantaneous unit hydrographs in three gauged watersheds located in the river Mahanadi, India were then compared with that of the observed 24-hr unit hydrograph. The comparison shows a significant correlation between the two results.


Determination and phylogenetic analysis of partial sequences from TT virus isolates.
Sera from French in-patients were tested for the presence of the TT virus (TTV) genome using PCR and degenerate primers located in ORF1. Thirty-six sequences were determined and compared with those deposited in databases, revealing a high degree of genetic variability between TTV isolates (up to 47% for amino acid sequences). Phylogenetic analysis demonstrated the existence of three main groups corresponding to the previously described genotypes 1 and 2 and to a new genotype 3. Isolates could be assigned to distinct genotypes if their genetic distance was > 27%. No comparable genetic criteria were found for the definition of sub-types in the region studied. A 15-31 month follow-up of three haemodialysis patients proved the existence of chronic infection by TTV. In one patient, two strains belonging to different genotypes were detected at the same time. Sequences of both ORF1 and ORF2 remained unchanged for a given strain during the follow-up.


Production and characterization of human monoclonal antibody recognizing the N-terminal residues of Pseudomonas aeruginosa exotoxin A.
Human cell lines producing monoclonal antibodies (MAbs) against Pseudomonas aeruginosa exotoxin A were established by EBV transformation followed by cell fusion. Monoclonal antibody FK-001, IgM (mu, kappa), was demonstrated to be specifically reactive with exotoxin A in ELISA and immunoblotting, by recognizing N-terminal 16 amino acid residues of exotoxin A as an epitope. This epitope region belongs to domain I which is required for the binding of exotoxin A to the receptor on target cells. FK-001 showed a partial neutralizing activity for cell toxicity caused by exotoxin A and appeared to be effective against exotoxin A-producing P. aeruginosa infection in mice. A line of evidence suggests that monoclonal antibody FK-001 neutralizes exotoxin A-induced cell toxicity by the interference of accessibility and/or binding of exotoxin A to animal cell receptors.


G Protein and β-arrestin signaling bias at the ghrelin receptor.
The G protein-coupled ghrelin receptor GHSR1a is a potential pharmacological target for treating obesity and addiction because of the critical role ghrelin plays in energy homeostasis and dopamine-dependent reward. GHSR1a enhances growth hormone release, appetite, and dopamine signaling through G(q/11), G(i/o), and G(12/13) as well as β-arrestin-based scaffolds. However, the contribution of individual G protein and β-arrestin pathways to the diverse physiological responses mediated by ghrelin remains unknown. To characterize whether a signaling bias occurs for GHSR1a, we investigated ghrelin signaling in a number of cell-based assays, including Ca(2+) mobilization, serum response factor response element, stress fiber formation, ERK1/2 phosphorylation, and β-arrestin translocation, utilizing intracellular second loop and C-tail mutants of GHSR1a. We observed that GHSR1a and β-arrestin rapidly form metastable plasma membrane complexes following exposure to an agonist, but replacement of the GHSR1a C-tail by the tail of the vasopressin 2 receptor greatly stabilizes them, producing complexes observable on the plasma membrane and also in endocytic vesicles. Mutations of the contiguous conserved amino acids Pro-148 and Leu-149 in the GHSR1a intracellular second loop generate receptors with a strong bias to G protein and β-arrestin, respectively, supporting a role for conformation-dependent signaling bias in the wild-type receptor. Our results demonstrate more balance in GHSR1a-mediated ERK signaling from G proteins and β-arrestin but uncover an important role for β-arrestin in RhoA activation and stress fiber formation. These findings suggest an avenue for modulating drug abuse-associated changes in synaptic plasticity via GHSR1a and indicate the development of GHSR1a-biased ligands as a promising strategy for selectively targeting downstream signaling events.


Molecular improvement of alfalfa for enhanced productivity and adaptability in a changing environment.
Due to an expanding world population and increased buying power, the demand for ruminant products such as meat and milk is expected to grow substantially in coming years, and high levels of forage crop production will therefore be a necessity. Unfortunately, urbanization of agricultural land, intensive agricultural practices, and climate change are all predicted to limit crop production in the future, which means that the development of forage cultivars with improved productivity and adaptability will be essential. Because alfalfa (Medicago sativa L.) is one of the most widely cultivated perennial forage crops, it has been the target of much research in this field. In this review, we discuss progress that has been made towards the improvement of productivity, abiotic stress tolerance, and nutrient-use efficiency, as well as disease and pest resistance, in alfalfa using biotechnological techniques. Furthermore, we consider possible future priorities and avenues for attaining further enhancements in this crop as a means of contributing to the realization of food security in a changing environment.


The development and psychometric evaluation of a safety climate measure for primary care.
Building a safety culture is an important part of improving patient care. Measuring perceptions of safety climate among healthcare teams and organisations is a key element of this process. Existing measurement instruments are largely developed for secondary care settings in North America and many lack adequate psychometric testing. Our aim was to develop and test an instrument to measure perceptions of safety climate among primary care teams in National Health Service for Scotland. Questionnaire development was facilitated through a steering group, literature review, semistructured interviews with primary care team members, a modified Delphi and completion of a content validity index by experts. A cross-sectional postal survey utilising the questionnaire was undertaken in a random sample of west of Scotland general practices to facilitate psychometric evaluation. Statistical methods, including exploratory and confirmatory factor analysis, and Cronbach and Raykov reliability coefficients were conducted. Of the 667 primary care team members based in 49 general practices surveyed, 563 returned completed questionnaires (84.4%). Psychometric evaluation resulted in the development of a 30-item questionnaire with five safety climate factors: leadership, teamwork, communication, workload and safety systems. Retained items have strong factor loadings to only one factor. Reliability coefficients was satisfactory (α = 0.94 and ρ = 0.93). This study is the first stage in the development of an appropriately valid and reliable safety climate measure for primary care. Measuring safety climate perceptions has the potential to help primary care organisations and teams focus attention on safety-related issues and target improvement through educational interventions. Further research is required to explore acceptability and feasibility issues for primary care teams and the potential for organisational benchmarking.


Biphasic in vitro maturation with C-type natriuretic peptide enhances the developmental competence of juvenile-goat oocytes.
In vitro embryo production success in juvenile animals is compromised due to their intrinsic lower oocyte quality. Conventional in vitro maturation (IVM) impairs oocyte competence by inducing spontaneous meiotic resumption. A series of experiments were performed to determine if maintaining meiotic arrest during a pre-maturation culture phase (pre-IVM) prior to conventional IVM improves oocyte competence of juvenile-goat (2 months old) cumulus-oocyte complexes (COCs). In experiment 1, COCs were cultured with C-type natriuretic peptide (CNP; 0, 50, 100, 200 nM) for 6 and 8 h. Nuclear stage was assessed, revealing no differences in the incidence of germinal vesicle (GV) breakdown. In experiment 2, the same CNP concentrations were assessed plus 10 nM estradiol, the known upstream agonist activating expression of NPR2, the exclusive receptor of CNP. CNP (200 nM) plus estradiol increased the rate of oocytes at GV stage at 6 h compared to control group (74.7% vs 28.3%; P<0.05) with predominantly condensed chromatin configuration. In experiment 3, relative mRNA quantification revealed NPR2 expression was down-regulated after pre-IVM (6 h). In experiment 4, analysis of transzonal projections indicated that pre-IVM maintained cumulus-oocyte communication after oocyte recovery. For experiments 5 and 6, biphasic IVM (6 h pre-IVM with CNP and estradiol, plus 24 h IVM) and control IVM (24 h) were compared. Biphasic IVM increased intra-oocyte glutathione and decreased ROS, up-regulated DNA-methyltransferase 1 and pentraxin 3 expression and led to an increase in rate of blastocyst development compared to control group (30.2% vs 17.2%; P<0.05). In conclusion, a biphasic IVM, including a pre-IVM with CNP, maintains oocyte meiotic arrest for 6 h and enhances the embryo developmental competence of oocytes from juvenile goats.


Correct Me if I'm Wrong: Groups Outperform Individuals in the Climate Stabilization Task.
Avoiding dangerous climate change requires ambitious emissions reduction. Scientists agree on this, but policy-makers and citizens do not. This discrepancy can be partly attributed to faulty mental models, which cause individuals to misunderstand the carbon dioxide (CO2) system. For example, in the Climate Stabilization Task (hereafter, "CST") (Sterman and Booth-Sweeney, 2007), individuals systematically underestimate the emissions reduction required to stabilize atmospheric CO2 levels, which may lead them to endorse ineffective "wait-and-see" climate policies. Thus far, interventions to correct faulty mental models in the CST have failed to produce robust improvements in decision-making. Here, in the first study to test a group-based intervention, we found that success rates on the CST markedly increased after participants deliberated with peers in a group discussion. The group discussion served to invalidate the faulty reasoning strategies used by some individual group members, thus increasing the proportion of group members who possessed the correct mental model of the CO2 system. Our findings suggest that policy-making and public education would benefit from group-based practices.


Income inequality and 'hospitalisations of despair' in Canada: a study on longitudinal, population-based data.
Rates of drug overdoses, alcohol-related liver disease and suicide attempts represent a major public health burden in Canada. While the existing literature does highlight some evidence of association between income inequality and mental health and deaths of despair, no existing research has investigated more intermediate events. As such, the objective of the current study is to investigate the association between income inequality and hospitalisations of despair over time. Data from the 2006 Canadian Census, the 2007/2008 Canadian Community Health Survey and the 2007-2018 Discharge Abstract Database were linked. Data were analysed using Cox proportional hazards modelling accounting for robust standard errors at the area level to investigate associations between income inequality at baseline and hazards for hospitalisations of despair, hospitalisations attributable to drug overdose, alcohol-related liver disease and suicide attempts, and all-cause hospitalisations, while controlling for sociodemographics characteristics (including income) and relevant area-level variables. The results highlighted statistically significant associations between income inequality and hazard of hospitalisations of despair (HR 1.38, 95% CI 1.06 to 1.80), hospitalisations related to drug overdose (HR 1.51, 95% CI 1.07 to 2.13) and all-cause hospitalisations (HR 1.17, 95% CI 1.05 to 1.30). The association between income inequality and hospitalisations related to alcohol-related liver disease and suicide attempts/self-harm were not statistically significant. Overall, the results showed evidence of associations between income inequality and hospitalisations of despair, drug overdose-related hospitalisations and all-cause hospitalisations. These findings are applicable to upstream policy discussion regarding reducing income inequality and identify potential points of intervention for prevention of drug overdose, alcohol-related liver disease and suicide attempts/self-harm.


The Burden of Unavailable Drugs Cost to Patients Admitted to Internal Medicine Ward of Tikur Anbessa Specialized Hospital.
To assess the burden of unavailable drugs cost to patients admitted to TikurAnbessa Specialized Hospital's internal medicine ward. Costs of medications obtained inside and outside the pharmacy and other burdens associated with drugs' unavailability are also estimated and explored. A facility-based cross-sectional study design was conducted from November 9 to November 23, 2020. Quantitative data on medication costs were collected from patients admitted to TikurAnbessa Specialized Hospital internal medicine ward B8. Qualitative information was collected from patients, caregivers, and health care professionals through interviews to assess the burdens of unavailability of pharmaceuticals on patients and the health care system. A total of 32 patients were enrolled in the study. Participants' age ranged from 14 to 92. Eighteen (56.25%) paid in cash for medications bought within the hospital pharmacy, while the remaining 14 (43.75%) were treated for free. A total of 68 medicines were prescribed during the study period. Of this, 33 (48.53%) medicines were not available in the hospital pharmacy. The total costs of patients were 78.07$ and 1530.84$ when purchased from inside and outside the hospital pharmacy, respectively. The average price of medications per patient ranged from 0.025 to 8.41$ inside the hospital pharmacy, where the average cost per patient outside the hospital pharmacy ran from 0.128 to 54.67$. For the qualitative part, four patients and/or caregivers and five health care professionals were interviewed, and three key themes emerged from the thematic analysis: (i) awareness of the availability of medication, (ii) management of the burden of stock out, and (iii) impact of the stock out. The study came up with a result that the hospital pharmacy has high unavailability of medication. Patients complain about unwanted and unreasonably expenditure to purchase pharmaceuticals from outside pharmacies and associated delayed treatment.


Fusion-dependent formation of lipid nanoparticles containing macromolecular payloads.
The success of Onpattro™ (patisiran) clearly demonstrates the utility of lipid nanoparticle (LNP) systems for enabling gene therapies. These systems are composed of ionizable cationic lipids, phospholipid, cholesterol, and polyethylene glycol (PEG)-lipids, and are produced through rapid-mixing of an ethanolic-lipid solution with an acidic aqueous solution followed by dialysis into neutralizing buffer. A detailed understanding of the mechanism of LNP formation is crucial to improving LNP design. Here we use cryogenic transmission electron microscopy and fluorescence techniques to further demonstrate that LNP are formed through the fusion of precursor, pH-sensitive liposomes into large electron-dense core structures as the pH is neutralized. Next, we show that the fusion process is limited by the accumulation of PEG-lipid on the emerging particle. Finally, we show that the fusion-dependent mechanism of formation also applies to LNP containing macromolecular payloads including mRNA, DNA vectors, and gold nanoparticles.


Strain-specific Plasmodium falciparum multifunctional CD4(+) T cell cytokine expression in Malian children immunized with the FMP2.1/AS02A vaccine candidate.
Based on Plasmodium falciparum (Pf) apical membrane antigen 1 (AMA1) from strain 3D7, the malaria vaccine candidate FMP2.1/AS02A showed strain-specific efficacy in a Phase 2 clinical trial in 400 Malian children randomized to 3 doses of the AMA1 vaccine candidate or control rabies vaccine on days 0, 30 and 60. A subset of 10 Pf(-) (i.e., no clinical malaria episodes) AMA1 recipients, 11 Pf(+) (clinical malaria episodes with parasites with 3D7 or Fab9-type AMA1 cluster 1 loop [c1L]) AMA1 recipients, and 10 controls were randomly chosen for analysis. Peripheral blood mononuclear cells (PBMCs) isolated on days 0, 90 and 150 were stimulated with full-length 3D7 AMA1 and c1L from strains 3D7 (c3D7) and Fab9 (cFab9). Production of IFN-γ, TNF-α, IL-2, and/or IL-17A was analyzed by flow cytometry. Among AMA1 recipients, 18/21 evaluable samples stimulated with AMA1 demonstrated increased IFN-γ, TNF-α, and IL-2 derived from CD4(+) T cells by day 150 compared to 0/10 in the control group (p<0.0001). Among AMA1 vaccines, CD4(+) cells expressing both TNF-α and IL-2 were increased in Pf(-) children compared to Pf(+) children. When PBMCs were stimulated with c3D7 and cFab9 separately, 4/18 AMA1 recipients with an AMA1-specific CD4(+) response had a significant response to one or both c1L. This suggests that recognition of the AMA1 antigen is not dependent upon c1L alone. In summary, AMA1-specific T cell responses were notably increased in children immunized with an AMA1-based vaccine candidate. The role of CD4(+)TNF-α(+)IL-2(+)-expressing T cells in vaccine-induced strain-specific protection against clinical malaria requires further exploration. Clinicaltrials.gov Identifier: NCT00460525.


Hair and nail nicotine levels of mothers and their infants as valid biomarkers of exposure to intrauterine tobacco smoke.
Tobacco use remains the single most modifiable cause of adverse pregnancy outcomes. It is crucial to be able to accurately quantify the burden of tobacco exposure on both the mother and fetus to have better measures of efficacy with interventions being studied. This is a descriptive and exploratory study conducted within a randomized controlled trial. Pregnant smoking and non-smoking women were followed from ≤22 weeks' gestation through delivery with monthly maternal smoking questionnaires, urine cotinine levels, and collection of maternal and infant hair and nail samples, at delivery. Nicotine was extracted and measured (ng/mg) using high-performance liquid chromatography with electrochemical detection. Forty-six mother-infant dyads (34 pregnant smokers and 12 pregnant non-smokers) had successful completion of maternal and infant hair and nails samples. The median hair nicotine levels of the smoking mothers and their infants was significantly higher than those of the non-smokers (1.015 vs 0.037 ng/ mg, p<0.05 for the mothers; 0.445 vs 0.080 ng/mg, p<0.01 for the infants). Similarly, the median nail nicotine levels for smoking mothers and their infants were significantly higher than the non-smokers (2.130 vs 0.056 ng/mg, p<0.01 for the mothers; 0.594 vs 0.132 ng/mg, p<0.05 for the infants). We found a moderate but significant correlation between maternal hair and nail nicotine (r=0.64, p<0.001), infant hair and nail nicotine (r=0.64; p<0.001), maternal and infant hair nicotine (r=0.61, p<0.001), and maternal and infant nail nicotine levels (r=0.58, p<0.001). Our study shows that both infant hair and nail nicotine levels are valid biomarkers of intrauterine tobacco smoke exposure, and can be used to identify prenatal smoke exposure, correlating well with the level of maternal nicotine exposure.


Simple closure of perforated duodenal ulcer.
A study was undertaken to evaluate the efficacy of simple closure followed by drug therapy in cases of perforated duodenal ulcer and to identify the risk factors in relation to the mortality. The male to female ratio was 5:1. Of the patients 59.2% were up to 50 years of age, while 40.8% were above the age of 50 years. Of the patients 47% were admitted 24 hours after the onset of peritonitis. All these patients were surgically treated with simple closure of the perforation with omental patch. Nine patients expired leading to 7.5% mortality. The risk factors identified for mortality were age 60 years and above, presence of shock on admission and delayed presentation. The mortality is directly related to the number of risk factors present in a given patient. At the time of discharge the patients were advised to take orally famotidine 40 mg at bed time for a period of 8 weeks. Eighty-one patients could be followed up and Visick grading was done. Sixty-two patients were in grade I, 11 in grade II, 3 in grade III and 5 in grade IV. The results indicate that simple closure followed by drug therapy is acceptable treatment for perforated duodenal ulcer.


Enzyme Therapy: Current Perspectives.
Enzymes control all metabolic processes in human system from simple digestion of food to highly complex immune response. Physiological reactions occuring in healthy individuals are disturbed when enzymes are deficient or absent. Enzymes are administered for normalizing biological function in certain pathologies. Initially, crude proteolytic enzymes were used for the treatment of gastrointestinal disorders. Recent advances have enabled enzyme therapy as a promising tool in the treatment of cardiovascular, oncological and hereditary diseases. Now, a spectrum of other diseases are also covered under enzyme therapy. But, the available information on the use of enzymes as therapeutic agents for different diseases is scanty. This review details the enzymes which have been used to treat various diseases/disorders.


Cytologic Analysis of Pancreatic Juice Increases Specificity of Detection of Malignant IPMN-A Systematic Review.
Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas can progress to cancer. Biomarkers have been identified that were reported to increase the accuracy of identification of malignant lesions; we performed a systematic review of the accuracy of these markers. We performed a systematic review of published studies on biomarkers of malignant IPMNs by searching MEDLINE and Web of Science databases from January 2005 through December 2017. Our methods were developed based on the Meta-analysis Of Observational Studies in Epidemiology guidelines. Pooled sensitivity, specificity, receiver operating characteristic curves, and their respective areas under the curve (AUC) were calculated from groups of markers (cell-, protein-, or DNA-based) measured in samples collected before and after surgery. A hypothetical test model was developed to determine how to meaningfully amend the revised Fukuoka guidelines, focusing on increasing test specificity for patients with IPMNs that have worrisome features. We collected data from 193 published studies, comprising 12,297 patients, that analyzed 7 preoperative and 21 postoperative markers of IPMNs. The 3 biomarkers that identified malignant IPMNs with the largest AUC values were pancreatic juice cytology (AUC, 0.84; sensitivity, 0.54; specificity, 0.91), serum protein carbohydrate antigen 19-9 (AUC, 0.81; sensitivity, 0.45; specificity, 0.90), and cyst fluid cytology (AUC, 0.82; sensitivity, 0.57; specificity, 0.84). A combination of cytologic and immunohistochemical analysis of MUC1 and MUC2 in pancreatic juice samples identified malignant IPMNs with the largest AUC and sensitivity values (AUC, 0.85; sensitivity, 0.85; specificity, 0.65). In a test model, inclusion of cytologic analysis of pancreatic juice in the guideline algorithm significantly increased the specificity of detection of malignant IPMNs. In a systematic review, we found cytologic analysis of pancreatic juice to have the greatest effect in increasing the specificity of detection of malignant IPMNs. We propose addition of this test to the Fukuoka guidelines for assessment of patients with IPMNs with worrisome features.


The effect of surface passivation on the structure of sulphur-rich PbS colloidal quantum dots for photovoltaic application.
The use of PbS colloidal quantum dots in photovoltaic devices is very promising because of their simple and low cost production processes and their unique properties, such as bandgap tunability and potential multiple exciton generation. Here we report the synthesis of PbS nanocrystals used for application in solar cells. The sulphur-rich nature of their surface appears to be caused by the exposure to ambient conditions. The use of methanol as medium during the ligand exchange process has a crucial role in the removal of native oleate ligands. Without proper ligand exchange, the unpassivated surface is subject to ambient hydroxylation leading to the depletion of Pb atoms and the formation of a polysulfide phase. Devices assembled with this material showed good performance with an efficiency of 3.2%.


Special considerations for endoscopists on PEG indications in older patients.
Undernutrition in frail elderly people is a pathological condition that needs to be recognized and addressed early. Neurological dysphagia is among the most frequent causes of this condition in the elderly but should be considered a terminal event in Alzheimer-type dementias. Tube feeding is an important resource for facilitating metabolic recovery in cachectic patients and is particularly successful in "bridging" and stabilizing therapies prior to major treatment able to cure the patient. Clinical management of tube feeding in "incurable" conditions is complex and becomes part of the palliative care and comfort provided in the terminal stages of illness. Non-specialized physicians are often unfamiliar with the theory and practice of end-of-life interventions, and the resulting decisions are in many cases actually contrary to patient comfort. These problems deserve to be more carefully addressed when the patient is unable to cooperate or express his/her preferences and needs. The success of percutaneous endoscopic gastrostomy has led to increasingly frequent referrals for placement in critically ill elderly patients. Endoscopists therefore become a key figure in stimulating rational, correct treatment of these patients.


Uterine rupture and scar dehiscence. A five-year survey.
A review of the medical records from two public hospitals in Sydney was undertaken to determine the incidence of this uncommon complication. Twenty-seven cases of uterine rupture were reported out of 31,115 deliveries with an incidence of 0.086% (versus 0.05% in the current literature). The incidence associated with previous caesarean section was 0.038% (versus 0.8% in the current literature). Predisposing and associated factors in this review were similar to those reported by others. There was no maternal mortality in our series but the fetal mortality rate was 5 out of 27 cases. Uterine ruptures in the midtrimester were associated with high rates of maternal morbidity and fetal loss. Forty-eight per cent of patients with uterine rupture received epidural analgesia. The associated factors and outcomes are discussed. The current literature is reviewed in relation to this high-risk group of patients.


Temperature-Dependent Spin-Driven Dimerization Determines the Ultrafast Dynamics of a Copper(II)-Bound Tripyrrindione Radical.
Radicals and other open-shell molecules play a central role in chemical transformations and redox chemistry. While radicals are often highly reactive, stable radical systems are desirable for a range of potential applications, ranging from materials chemistry and catalysis to spintronics and quantum information. Here we investigate the ultrafast properties of a stable radical system with temperature-dependent spin-tunable properties. This radical complex, Cu(II) hexaethyl tripyrrin-1,14-dione, accommodates unpaired electrons localized on both the copper metal center and the tripyrrolic ligand. The unusual combination of two unpaired electrons and high stability in this radical molecule enable switchable temperature-dependent spin coupling. Two-dimensional electronic spectroscopy measurements of Cu(II) hexaethyl tripyrrin-1,14-dione were collected at room temperature and at 77 K. At room temperature, the molecules are present as monomers and have short picosecond lifetimes. At 77 K, the molecules are present in a dimer form mediated by ferromagnetic and antiferromagnetic coupling. This reversible spin-driven dimerization changes the optical properties of the system, generating long-lived excitonic states.


Long-term pharmacotherapy in the management of obesity. National Task Force on the Prevention and Treatment of Obesity.
To examine the rationale for long-term use of medications in the management of obesity, to provide an overview of published scientific information on their safety and efficacy, and to provide guidance to patients and practitioners regarding risks and benefits of treatment. Original reports and reviews obtained through electronic database searches on anorexiant drugs supplemented by a manual search of bibliographies. English-language articles that discussed the role of medications in the treatment of human obesity, and studies that evaluated their safety and efficacy for a minimum of 24 weeks. Studies were reviewed by experts in the fields of nutrition, obesity, and eating disorders to evaluate study design and the validity of authors' conclusions. The long-term use of medications in the management of obesity is consistent with the current consensus that obesity responds poorly to short-term interventions. Net weight loss attributable to medication is modest, ranging from 2 to 10 kg, but patients taking active drug are more likely to lose 10% or more of initial body weight. Weight loss tends to reach a plateau by 6 months. Weight remains below baseline throughout treatment, although some studies show partial weight regain despite continued drug therapy. Most adverse effects are mild and self-limited, but rare serious outcomes have been reported. Pharmacotherapy for obesity, when combined with appropriate behavioral approaches to change diet and physical activity, helps some obese patients lose weight and maintain weight loss for at least 1 year. There is little justification for the short-term use of anorexiant medications, but few studies have evaluated their safety and efficacy for more than 1 year. Until more data are available, pharmacotherapy cannot be recommended for routine use in obese individuals, although it may be helpful in carefully selected patients.


Homotypic and heterotypic antibodies for prevention of experimental rotavirus gastroenteritis.
We investigated the abilities of homologous and heterologous antibody preparations to neutralize murine rotavirus in a mouse model of rotavirus infection. We found that incubation of virus with murine sera obtained from animals experimentally infected with the homologous epizootic diarrhea of infant mice strain of rotavirus resulted in inability of the virus to cause symptomatic disease in infant mice. Sera from nonimmune mice and mice infected or immunized with a heterotypic strain of rotavirus did not effectively neutralize virus in this system. On the other hand, neutralization was noted after incubation of virus with a number of immunoglobulins from other animal and human sources. The neutralizing activity of the preparations in the murine model correlated partially, but not completely, with the level of in vitro neutralizing antibody to the murine strain of rotavirus measured in a tissue culture system. In most cases, asymptomatic infection after feeding of the virus and the antibody preparation resulted in subsequent generation of an active immune response in infected animals.


Remodeling Translation Primes CD8+ T-cell Antitumor Immunity.
The requisites for protein translation in T cells are poorly understood and how translation shapes the antitumor efficacy of T cells is unknown. Here we demonstrated that IL15-conditioned T cells were primed by the metabolic energy sensor AMP-activated protein kinase to undergo diminished translation relative to effector T cells. However, we showed that IL15-conditioned T cells exhibited a remarkable capacity to enhance their protein translation in tumors, which effector T cells were unable to duplicate. Studying the modulation of translation for applications in cancer immunotherapy revealed that direct ex vivo pharmacologic inhibition of translation elongation primed robust T-cell antitumor immunity. Our work elucidates that altering protein translation in CD8+ T cells can shape their antitumor capability.


An analysis of invasive airway management in a suburban emergency medical services system.
Airway management is the most critical and potentially life-saving intervention performed by emergency medical service (EMS) providers. Invasive airway management often is required in non-cardiac-arrest patients who are combative or otherwise uncooperative. The success of prehospital invasive airway management in this patient population was evaluated. A retrospective review was undertaken of the records of all such patients requiring endotracheal intubation over a three-year period (1987-1989). The study population included 278 patients enrolled by five advanced life support (ALS) units serving a suburban population of 425,000. Field trip sheets were reviewed for diagnosis, intubation method and success, number of intubation attempts, provider experience, reasons for unsuccessful intubations, and complications. A total of 394 invasive airway management attempts were performed on 278 patients. The overall successful intubation rate was 75% (41% orotracheal, 52% nasotracheal, 7% other or unknown). The most common diagnoses were COPD and pulmonary edema (30%) and trauma (24%). Experienced providers were successful on the first attempt in 57% of cases compared to 50% by inexperienced providers (p=.24). Multiple intubation attempts were required in 33% of the patients. There was no statistically significant difference in success rates between the orotracheal and nasotracheal methods (p=.51). The most common reason for unsuccessful intubation was altered level of consciousness. Complications occurred with 7% of successful attempts and in 18% of unsuccessful attempts (p less than .001). Forty-six percent of the patients who were not intubated successfully in the field and required intubation in the emergency department (ED) received a neuromuscular blocking agent prior to successful intubation. Prehospital providers can intubate a high but improvable proportion of non-cardiac-arrested patients by both the orotracheal and nasotracheal routes. The use of pharmacologic adjuncts to facilitate the prehospital intubation of selected, non-cardiac-arrested patients is a promising adjunct that needs further evaluation.


Color schemes to represent the orientation of anisotropic tissues from diffusion tensor data: application to white matter fiber tract mapping in the human brain.
This paper investigates the use of color to represent the directional information contained in the diffusion tensor. Ideally, one wants to take into account both the properties of human color vision and of the given display hardware to produce a representation in which differences in the orientation of anisotropic structures are proportional to the perceived differences in color. It is argued here that such a goal cannot be achieved in general and therefore, empirical or heuristic schemes, which avoid some of the common artifacts of previously proposed approaches, are implemented. Directionally encoded color (DEC) maps of the human brain obtained using these schemes clearly show the main association, projection, and commissural white matter pathways. In the brainstem, motor and sensory pathways are easily identified and can be differentiated from the transverse pontine fibers and the cerebellar peduncles. DEC maps obtained from diffusion tensor imaging data provide a simple and effective way to visualize fiber direction, useful for investigating the structural anatomy of different organs. Magn Reson Med 42:526-540, 1999.


Coffee grounds as filler for pectin: Green composites with competitive performances dependent on the UV irradiation.
Novel composite bioplastics were successfully prepared by filling pectin matrix with treated coffee grounds. The amount of coffee dispersed into the pectin was changed within a wide filler range. The morphology of the pectin/coffee hybrid films was studied by microscopic techniques in order to investigate their mesoscopic structure as well as the sizes distribution of the particles dispersed into the matrix. The micrographs showed that the coffee grounds are uniformly dispersed within the polymeric matrix. The morphological characteristics of the biocomposite films were correlated to their properties, such as wettability, water uptake, thermal behavior and mechanical performances. Dynamic mechanical test were conducted as a function of the humidity conditions. As a general result, a worsening of the mechanical performances was induced by the addition of the coffee grounds into the pectin. An additional UV curing treatment was conducted on the pectin/coffee films with the aim to improve their tensile and viscoelastic features. The cured films showed promising and tunable properties that are dependent on both the filler content and the UV irradiation. In particular, the presence of single coffee particles into the pectin matrix renders the UV curing treatment effective in the enhancement of the elasticity as well as the traction resistance, whereas the cured composite films containing coffee clusters showed only more elastic characteristics. With this study, we fabricated pectin/coffee bioplastics with controlled behavior appealing for specific application within the food packaging.


IMiD immunomodulatory compounds block C/EBP{beta} translation through eIF4E down-regulation resulting in inhibition of MM.
Immunomodulatory derivatives of thalidomide (IMiD compounds), such as pomalidomide and lenalidomide, are highly active in multiple myeloma (MM) treatment. However, the precise mechanisms of action and resistance in MM are unresolved. Here we show that IMiD compounds down-regulate CCAAT/enhancer-binding protein-β (C/EBPβ) resulting in abrogation of cell proliferation. Overexpression of C/EBPβ rescued MM cells from IMiD-induced inhibition of proliferation, indicating that C/EBPβ is critical in mediating antiproliferative effects. IMiD-induced decrease of C/EBPβ protein led to impaired transcription of interferon regulatory factor 4 (IRF4). Down-regulation of IRF4 by lenalidomide was confirmed by longitudinal studies of bone marrow samples from 23 patients obtained before and during lenalidomide treatment using CD138⁺/IRF4⁺ double labeling. In contrast to down-regulation of C/EBPβ protein, IMiD compounds did not alter C/EBPβ mRNA levels or protein stability, suggesting translational regulation of C/EBPβ. We could demonstrate that C/EBPβ protein expression is under eIF4E-translational control in MM. Furthermore, inhibition of the eIF4E-C/EBPβ axis by IMiD compounds was not observed in IMiD-resistant MM cells. However, targeting translation at a different level by inhibiting eukaryotic translation initiation factor 4E-binding protein 1 phosphorylation overcame resistance, suggesting that this pathway is critical and might be a target to overcome drug resistance.


[Neuroendocrine control of human reproduction. The role of dopaminergic neurotransmitter systems].
By affecting central hypothalamic processes, the dopaminergic neuronal system governs episodic gonadotropin secretion. Serum gonadotropin profiles as an indirect reflection of central activity can consecutively indicate dopaminergic neurotransmitter activity and its changes by pharmacologic manipulation. Despite vigorous efforts, the role of dopamine in the neuroendocrine control of human reproduction remained contentious. Controversial effects of dopamine on gonadotropin discharge have been observed, presumably a result of different experimental conditions. As yet, numerous investigations have not convincingly evidenced a critical role of dopamine in the regulation of the human menstrual cycle. Since central neuroendocrine mechanisms may not be reduced to action of the dopaminergic system, a complexity of hypothalamic dopaminergic interactions with various neurotransmitters and reproductive hormones should be considered to operate in the biochemical control of the central pulse generator activity.


Machine learning classification of ADHD and HC by multimodal serotonergic data.
Serotonin neurotransmission may impact the etiology and pathology of attention-deficit and hyperactivity disorder (ADHD), partly mediated through single nucleotide polymorphisms (SNPs). We propose a multivariate, genetic and positron emission tomography (PET) imaging classification model for ADHD and healthy controls (HC). Sixteen patients with ADHD and 22 HC were scanned by PET to measure serotonin transporter (SERT') binding potential with [11C]DASB. All subjects were genotyped for thirty SNPs within the HTR1A, HTR1B, HTR2A and TPH2 genes. Cortical and subcortical regions of interest (ROI) were defined and random forest (RF) machine learning was used for feature selection and classification in a five-fold cross-validation model with ten repeats. Variable selection highlighted the ROI posterior cingulate gyrus, cuneus, precuneus, pre-, para- and postcentral gyri as well as the SNPs HTR2A rs1328684 and rs6311 and HTR1B rs130058 as most discriminative between ADHD and HC status. The mean accuracy for the validation sets across repeats was 0.82 (±0.09) with balanced sensitivity and specificity of 0.75 and 0.86, respectively. With a prediction accuracy above 0.8, the findings underlying the proposed model advocate the relevance of the SERT as well as the HTR1B and HTR2A genes in ADHD and hint towards disease-specific effects. Regarding the high rates of comorbidities and difficult differential diagnosis especially for ADHD, a reliable computer-aided diagnostic tool for disorders anchored in the serotonergic system will support clinical decisions.


Responsive deep brain stimulation guided by ventral striatal electrophysiology of obsession durably ameliorates compulsion.
Treatment-resistant obsessive-compulsive disorder (OCD) occurs in approximately one-third of OCD patients. Obsessions may fluctuate over time but often occur or worsen in the presence of internal (emotional state and thoughts) and external (visual and tactile) triggering stimuli. Obsessive thoughts and related compulsive urges fluctuate (are episodic) and so may respond well to a time-locked brain stimulation strategy sensitive and responsive to these symptom fluctuations. Early evidence suggests that neural activity can be captured from ventral striatal regions implicated in OCD to guide such a closed-loop approach. Here, we report on a first-in-human application of responsive deep brain stimulation (rDBS) of the ventral striatum for a treatment-refractory OCD individual who also had comorbid epilepsy. Self-reported obsessive symptoms and provoked OCD-related distress correlated with ventral striatal electrophysiology. rDBS detected the time-domain area-based feature from invasive electroencephalography low-frequency oscillatory power fluctuations that triggered bursts of stimulation to ameliorate OCD symptoms in a closed-loop fashion. rDBS provided rapid, robust, and durable improvement in obsessions and compulsions. These results provide proof of concept for a personalized, physiologically guided DBS strategy for OCD.


Pattern of growth and plasma growth hormone secretion in turkeys selected for increased egg production.
Male and female turkeys of a slow-growing line selected for increased 180-day egg production (Line E) and its faster growing randombred control (RBC1) were sampled weekly for BW and plasma growth hormone (GH) content. Hatching weights were higher for RBC1 than Line E poults, but no difference was observed between sexes. The pattern of growth of the two lines, as described by the Gompertz equation, was different in magnitude of growth [BW at point of inflection (POI) and asymptote] but not in form (slope and age at POI and age at asymptote). Males achieved higher weights at POI and asymptote but took longer to reach these weights. Slope at POI was greater for females than for males. Plasma GH was higher in Line E than in RBC1 at hatching but higher in RBC1 than in Line E from Weeks 7 to 28. Males had higher concentrations of circulating plasma GH than females at all ages. The GH pool size was maximal at 5 wk for females and 10 wk for males. Maximal concentrations of circulating GH preceded maximal GH pool size by several weeks.


Regulation of neutrophil function by adenosine.
Adenosine is an endogenously released purine nucleoside that signals via 4 widely expressed G protein-coupled receptors: A(1), A(2A), A(2B), and A(3). In the setting of inflammation, the generation and release of adenosine is greatly enhanced. Neutrophils play an important role in host defense against invading pathogens and are the cellular hallmark of acute inflammation. Neutrophils both release adenosine and can respond to it via expression of all 4 adenosine receptor subtypes. At low concentrations, adenosine can act via the A(1) and A(3) adenosine receptor subtypes to promote neutrophil chemotaxis and phagocytosis. At higher concentrations, adenosine acts at the lower-affinity A(2A) and A(2B) receptors to inhibit neutrophil trafficking and effector functions such as oxidative burst, inflammatory mediator production, and granule release. Modulation of neutrophil function by adenosine is relevant in a broad array of disease models, including ischemia reperfusion injury, sepsis, and noninfectious acute lung injury. This review will summarize relevant research in order to provide a framework for understanding how adenosine directly regulates various elements of neutrophil function.


Addition Of D-Sorbitol Improves The Usability Of Ophthalmic Viscosurgical Devices.
To evaluate the effects of D-sorbitol addition on changes in the extrusion force of ophthalmic viscosurgical devices (OVDs). OVD formulations; the mixtures of 3% hyaluronic acid (HA) and 4% chondroitin sulfate (CS) containing 0%, 0.5%, or 1.0% D-sorbitol were prepared. Each prefilled syringe of OVD was stored at room temperature for 0, 15, 30, 60, or 120 mins after a small amount of viscoelastic agent was discharged from the needle. The extrusion force values (kgf) of these OVDs when reused after storage were measured with a texture analyzer. Moreover, 10 healthy adults (5 men and 5 women) used a pinch sensor to measure the extrusion force values for the HA/CS combination without D-sorbitol which was stored in the above manner, and used a 4-step scale to score the usability of OVD. For the HA/CS combination without D-sorbitol, the extrusion force value was increased from its initial value (storage duration, 0 min) as storage duration increased. However, for the HA/CS combination containing 0.5% or 1.0% D-sorbitol, this value remained almost unchanged over time. Likewise, the pinch sensor-determined extrusion force values of HA/CS combination without D-sorbitol increased, depending on storage duration. The addition of D-sorbitol to viscoelastic agent may suppress the needle clogging that occurs with OVD storage, and may improve the usability of OVDs during surgery.


Comparison of the EDSS, Timed 25-Foot Walk, and the 9-Hole Peg Test as Clinical Trial Outcomes in Relapsing-Remitting Multiple Sclerosis.
Clinical trials in relapsing-remitting multiple sclerosis (RRMS) usually use the Expanded Disability Status Scale (EDSS) as their primary disability outcome measure, while the more recently developed outcomes timed 25-ft walk (T25FW) and 9-hole peg test (NHPT) may be more useful and patient relevant. The objective of this work was to compare the EDSS to the T25FW and NHPT in a large RRMS randomized controlled trial (RCT) dataset. We used the dataset from Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis (CombiRx) (clinicaltrials.gov identifier NCT00211887), a large phase 3 RCT, to compare the EDSS to the alternative outcomes T25FW and NHPT. We investigated disability worsening vs similarly defined improvement, unconfirmed vs confirmed and sustained disability change, and the presentation methods cumulative Kaplan-Meier survival curves vs cross-sectional disability worsening. CombiRx included 1,008 participants. A comparison of confirmed and sustained worsening events showed that, throughout the trial, there were substantially fewer sustained than confirmed events, with a positive predictive value of confirmed for sustained worsening at 24 months of 0.73 for the EDSS, 0.73 for the T25FW, and 0.8 for the NHPT. More concerning were the findings that worsening on the EDSS occurred as frequently as similarly defined improvement throughout the 3 years of follow-up and that improvement rates increased in parallel with worsening rates. The T25FW showed low improvement rates of <10% throughout the trial. We also found that Kaplan-Meier survival analysis, the standard presentation and analysis method in modern RRMS trials, yields exaggerated estimates of disability worsening. With the Kaplan-Meier method, the proportion of patients with worsening events steadily increases until it reaches several-fold the number of events seen with more conservative analysis methods. For 3-month confirmed disability worsening up to 36 months, the Kaplan-Meier method yields 2.6-fold higher estimates for the EDSS, 2.9-fold higher estimates for the T25FW, and 5.1-fold higher estimates for the NHPT compared to a more conservative presentation of the same data. Our analyses raise concerns about using the EDSS as the standard disability outcome in RRMS trials and suggest that the T25FW may be a more useful measure. These findings are relevant for the design and critical appraisal of RCTs.


Effects of liquiritigenin treatment on the learning and memory deficits induced by amyloid beta-peptide (25-35) in rats.
Considerable evidence has emerged supporting the neuroprotective and cognition-preserving effects of estrogen, but these benefits are complicated by the evidence that estrogen increases the risk of certain cancers. Selective estrogen receptor modulators (SERMs) that specifically target the brain while avoiding peripheral organs offer a way to allow the application of estrogen treatment to neurodegenerative diseases with fewer undesirable effects. In an attempt to find such estrogen substitutes, liquiritigenin was discovered as a relatively selective estrogen receptor beta (ERbeta) agonist. In the present study, we extend our previous findings to investigate the effects of liquiritigenin on the learning and memory deficits and related neuropathology in Abeta(25-35) hippocampal-injected rats. Our results show that liquiritigenin treatment improves the behavioral performance of the model rats and attenuates neuronal loss in the brain. More importantly, liquiritigenin treatment decreases mRNA levels and protein expression of Notch-2, an effect that could promote the generation of new neurons. These findings provide evidence for the beneficial activity of liquiritigenin in a brain-injured rat model and support the continued investigation of SERMs such as liquiritigenin as an alternative to estrogen-based hormone therapy in reducing the risk of neurodegenerative diseases such as Alzheimer's disease.


Members of the BMP, Shh, and FGF morphogen families promote chicken statoacoustic ganglion neurite outgrowth and neuron survival in vitro.
Mechanosensory hair cells of the chicken inner ear are innervated by the peripheral processes of statoacoustic ganglion (SAG) neurons. Members of several morphogen families are expressed within and surrounding the chick inner ear during stages of SAG axon outgrowth and pathfinding. On the basis of their localized expression patterns, we hypothesized that bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), and sonic hedgehog (Shh) may function as guidance cues for growing axons and/or may function as trophic factors once axons have reached their targets. To test this hypothesis, three-dimensional collagen cultures were used to grow Embryonic Day 4 (E4) chick SAG explants for 24 h in the presence of purified proteins or beads soaked in proteins. The density of neurite outgrowth was quantified to determine effects on neurite outgrowth. Explants displayed enhanced neurite outgrowth when cultured in the presence of purified BMP4, BMP7, a low concentration of Shh, FGF8, FGF10, or FGF19. In contrast, SAG neurons appeared unresponsive to FGF2. Collagen gel cultures were labeled with terminal dUTP nick-end labeling and immunostained with anti-phosphohistone H3 to determine effects on neuron survival and proliferation, respectively. Treatments that increased neurite outgrowth also yielded significantly fewer apoptotic cells, with no effect on cell proliferation. When presented as focal sources, BMP4, Shh, and FGFs -8, -10, and -19 promoted asymmetric outgrowth from the ganglion in the direction of the beads. BMP7-soaked beads did not induce this response. These results suggest that a subset of morphogens enhance both survival and axon outgrowth of otic neurons.


In vitro and in vivo antioxidant potential of milks, yoghurts, fermented milks and cheeses: a narrative review of evidence.
The antioxidant potential (AP) is an important nutritional property of foods, as increased oxidative stress is involved in most diet-related chronic diseases. In dairy products, the protein fraction contains antioxidant activity, especially casein. Other antioxidants include: antioxidant enzymes; lactoferrin; conjugated linoleic acid; coenzyme Q10; vitamins C, E, A and D3; equol; uric acid; carotenoids; and mineral activators of antioxidant enzymes. The AP of dairy products has been extensively studied in vitro, with few studies in animals and human subjects. Available in vivo studies greatly differ in their design and objectives. Overall, on a 100 g fresh weight-basis, AP of dairy products is close to that of grain-based foods and vegetable or fruit juices. Among dairy products, cheeses present the highest AP due to their higher protein content. AP of milk increases during digestion by up to 2·5 times because of released antioxidant peptides. AP of casein is linked to specific amino acids, whereas β-lactoglobulin thiol groups play a major role in the AP of whey. Thermal treatments such as ultra-high temperature processing have no clear effect on the AP of milk. Raw fat-rich milks have higher AP than less fat-rich milk, because of lipophilic antioxidants. Probiotic yoghurts and fermented milks have higher AP than conventional yoghurt and milk because proteolysis by probiotics releases antioxidant peptides. Among the probiotics, Lactobacillus casei/acidophilus leads to the highest AP. The data are insufficient for cheese, but fermentation-based changes appear to make a positive impact on AP. In conclusion, AP might participate in the reported dairy product-protective effects against some chronic diseases.


The centrality of affective instability and identity in Borderline Personality Disorder: Evidence from network analysis.
We argue that the series of traits characterizing Borderline Personality Disorder samples do not weigh equally. In this regard, we believe that network approaches employed recently in Personality and Psychopathology research to provide information about the differential relationships among symptoms would be useful to test our claim. To our knowledge, this approach has never been applied to personality disorders. We applied network analysis to the nine Borderline Personality Disorder traits to explore their relationships in two samples drawn from university students and clinical populations (N = 1317 and N = 96, respectively). We used the Fused Graphical Lasso, a technique that allows estimating networks from different populations separately while considering their similarities and differences. Moreover, we examined centrality indices to determine the relative importance of each symptom in each network. The general structure of the two networks was very similar in the two samples, although some differences were detected. Results indicate the centrality of mainly affective instability, identity, and effort to avoid abandonment aspects in Borderline Personality Disorder. Results are consistent with the new DSM Alternative Model for Personality Disorders. We discuss them in terms of implications for therapy.


TREK2 expressed selectively in IB4-binding C-fiber nociceptors hyperpolarizes their membrane potentials and limits spontaneous pain.
Ongoing/spontaneous pain behavior is associated with ongoing/spontaneous firing (SF) in adult DRG C-fiber nociceptors (Djouhri et al., 2006). Causes of this SF are not understood. We show here that conducting (sometimes called uninjured) C-nociceptors in neuropathic pain models with more hyperpolarized resting membrane potentials (Ems) have lower SF rates. Understanding the control of their Ems may therefore be important for limiting pathological pain. We report that TREK2, a leak K(+) channel, is selectively expressed in IB4 binding rat C-nociceptors. These IB4(+) C-neurons are ∼10 mV more hyperpolarized than IB4(-) C-neurons in vivo (Fang et al., 2006). TREK2 knockdown by siRNA in these neurons in culture depolarized them by ∼10 mV, suggesting that TREK2 is responsible for this ∼10 mV difference. In vivo, more hyperpolarized C-nociceptor Ems were associated with higher cytoplasmic edge-TREK2 expression (edge-TREK2). Edge-TREK2 decreased in C-neurons 7 d after axotomy, and their Ems depolarized by ∼10 mV. This again supports a contribution of TREK2 to their Ems. These relationships between (1) Em and TREK2, (2) SF rate and Em, and (3) spontaneous pain behavior and C-nociceptor SF rate suggested that TREK2 knockdown might increase spontaneous pain. After CFA-induced inflammation, spontaneous foot lifting (a measure of spontaneous pain) was (1) greater in rats with naturally lower TREK2 in ipsilateral small DRG neurons and (2) increased by siRNA-induced TREK2 knockdown in vivo. We conclude that TREK2 hyperpolarizes IB4 binding C-nociceptors and limits pathological spontaneous pain. Similar TREK2 distributions in small DRG neurons of several species suggest that these role(s) of TREK2 may be widespread.


Long-term individual foraging site fidelity--why some gannets don't change their spots.
Many established models of animal foraging assume that individuals are ecologically equivalent. However, it is increasingly recognized that populations may comprise individuals who differ consistently in their diets and foraging behaviors. For example, recent studies have shown that individual foraging site fidelity (IFSF, when individuals consistently forage in only a small part of their population's home range) occurs in some colonial breeders. Short-term IFSF could result from animals using a win-stay, lose-shift foraging strategy. Alternatively, it may be a consequence of individual specialization. Pelagic seabirds are colonial central-place foragers, classically assumed to use flexible foraging strategies to target widely dispersed, spatiotemporally patchy prey. However, tracking has shown that IFSF occurs in many seabirds, although it is not known whether this persists across years. To test for long-term IFSF and to examine alternative hypotheses concerning its cause, we repeatedly tracked 55 Northern Gannets (Morus bassanus) from a large colony in the North Sea within and across three successive breeding seasons. Gannets foraged in neritic waters, predictably structured by tidal mixing and thermal stratification, but subject to stochastic, wind-induced overturning. Both within and across years, coarse to mesoscale (tens of kilometers) IFSF was significant but not absolute, and foraging birds departed the colony in individually consistent directions. Carbon stable isotope ratios in gannet blood tissues were repeatable within years and nitrogen ratios were also repeatable across years, suggesting long-term individual dietary specialization. Individuals were also consistent across years in habitat use with respect to relative sea surface temperature and in some dive metrics, yet none of these factors accounted for IFSF. Moreover, at the scale of weeks, IFSF did not decay over time and the magnitude of IFSF across years was similar to that within years, suggesting that IFSF is not primarily the result of win-stay, lose-shift foraging. Rather, we hypothesize that site familiarity, accrued early in-life, causes IFSF by canalizing subsequent foraging decisions. Evidence from this and other studies suggests that IFSF may be common in colonial central-place foragers, with far-reaching consequences for our attempts to understand and conserve these animals in a rapidly changing environment.


Childhood maltreatment and psychiatric disorders among detained youths.
This study examined the prevalence of childhood maltreatment and its relationship with current psychiatric disorders among detained youths. Clinical research interviewers assessed history of childhood maltreatment with the Child Maltreatment Assessment Profile and psychiatric diagnosis with the Diagnostic Interview Schedule for Children, version 2.3, in a stratified, random sample of 1,829 youths detained at the Cook Country Juvenile Temporary Detention Center (final sample, N=1,735). History of maltreatment was also ascertained from Cook County Court Child Protection Division records. More than three-quarters of females and more than two-thirds of males had a history of physical abuse (moderate or severe). More than 40% of females and 10% of males had a history of sexual abuse. Females and non-Hispanic whites had the highest prevalence rates of childhood maltreatment. Among females, sexual abuse was associated with every type of psychiatric disorder. Females who experienced various types of abuse were 2.6 to 10.7 times as likely as females with no maltreatment to have any disorder. Among males, maltreatment was associated with every disorder except anxiety disorders (range of odds ratios, 1.9-7.9). Among youths who were sexually abused, abuse with force was associated with anxiety and affective disorders among females and attention-deficit hyperactivity or disruptive behavior disorders and substance use disorders among males. Childhood maltreatment is common among detained youths and is also highly associated with psychiatric disorders. The mental health, child welfare, and juvenile justice systems must collaborate to ensure that youths receive protection and care when they return to their communities.


The risk of Alzheimer's disease associated with benzodiazepines and related drugs: a nested case-control study.
To assess the association between benzodiazepine and related drug (BZDR) use and risk of Alzheimer's disease (AD) with cumulative consumption and duration of use based models. A nationwide nested case-control study of all Finnish community-dwelling persons who received clinically verified AD diagnosis in 2005-2011 (N = 70 719) and their matched controls (N = 282 862). AD diagnosis was based on DSM-IV and NINCDS-ADRDA criteria. BZDR purchases were extracted from the Prescription Register since 1995. The association between BZDR use and AD was assessed using conditional logistic regression with 5-year lag time between exposure and outcome. Benzodiazepine and related drug use was associated with modestly increased risk of AD (adjusted OR 1.06, 95% CI 1.04-1.08). A dose-response relationship was observed with both cumulative consumption and duration. Adjustment for other psychotropics removed the cumulative dose-response relationship by attenuating the ORs in the highest dose category. Benzodiazepine and related drug use in general was associated with modestly increased risk of AD. No major differences were observed between different subcategories of BZDRs (i.e. benzodiazepines, Z drugs, short-/medium-acting or long-acting BZDRs). As dose-response relationship abolished after adjustment for other psychotropics, it is possible that the association may partially be due to antidepressants and/or antipsychotics, or concomitant use of these medications.


Trace metal behavior during in-situ iron removal tests in Leuven, Belgium.
Subsurface iron removal (SIR) is an in-situ technique to lower the iron content of extracted groundwater. Through cyclic injection of oxygenated water ferrous iron oxidises and precipitates as iron hydroxide in a zone surrounding the extraction well, enhancing the sorptive capacity of the aquifer. During subsequent pumping phases, groundwater traverses the oxidation zone and ferrous iron sorbs to available and newly formed exchange and sorption sites, thereby retarding the breakthrough of dissolved iron. The process is well-understood in regards to the retardation of iron. Less well understood, however, is the behavior of a number of trace metals and metalloids during SIR operations, foremost arsenic (As). In this study, we analyse major and minor ion and trace metal concentrations from a number of SIR tests in a sand aquifer near Leuven, Belgium. We use reactive transport modelling to evaluate conceptual models of trace metal release and arrest. The test data, underpinned by model results, show that metal release, namely arsenic and barium (Ba), occurs through the oxidation of trace amounts of sulphide minerals during the injection phase. Sorption through cation exchange retards Ba while complexation lowers dissolved As concentrations. Arsenic is mobilized again during the pumping phase through varying phosphate concentrations in the native groundwater, despite available sorption surfaces, while Ba remains adsorbed. Concentrations, however, remain below WHO guideline values for As and Ba (10 μg/l and 0.7 mg/l), respectively. The developed conceptual model of As fate reveals a high propensity for As mobility during SIR due to desorption reactions and delivers an explanation as to why many SIR operations fail to show substantial As removal, despite efficient iron removal. Other monitored trace elements showed no mobilisation, including Zn, Al, Cd, Cr, Cu, F, Hg, Ni, Pb, Sb and Se.


Clinical and experimental evidence for targeting CD6 in immune-based disorders.
CD6 is a cell surface glycoprotein expressed by most T cells and a subset of B cells that has incompletely-defined roles in regulation of lymphocyte development, selection, activation and differentiation. The two main known mammalian CD6 ligands, CD166/ALCAM and the very recently reported CD318, are widely expressed by both immune cells and a wide range of other cell types, including various epithelial and mesenchymal cell types, as well as many neoplasms. Moreover, CD6 is also a receptor for several pathogen- and damage-associated molecular patterns. Further layers of complexity of CD6 function are implied by the existence of multiple CD6 isoforms generated by alternative splicing of CD6 transcripts and soluble forms of CD6 released by proteases from the lymphocyte surface. Multiple lines of evidence are now emerging to implicate CD6 and its ligands in the pathogenesis and potentially the treatment of human autoimmune diseases, such as multiple sclerosis and psoriasis. CD6 is an important multiple sclerosis risk gene, and mice genetically deficient in CD6 or CD318, or treated with antibodies or chimerical proteins that interfere with CD6-ligand interactions, are protected from experimental allergic encephalomyelitis, a mouse model of multiple sclerosis. CD6 deficient mice also show reduced TH17 differentiation and protection from disease in a moue model of psoriasis, providing a foundation for successful clinical trials of an anti-CD6 monoclonal antibody (Itolizumab) in psoriasis. Here we review current knowledge about CD6 and its ligands, and consider its potential value as a therapeutic target in a range of immune-mediated disorders.


Clinical utility of FDG uptake within reticuloendothelial system on F-18 FDG PET/CT for prediction of tumor recurrence in breast cancer.
The aim of this study was to investigate the metabolism of the spleen, bone marrow (BM), and liver from preoperative F-18 FDG PET/CT scans for the prediction of recurrence in breast cancer. We retrospectively included 153 patients diagnosed with invasive ductal carcinoma (IDC) of the breast who underwent preoperative F-18 FDG PET/CT scan and a curative operation. The mean standardized uptake value (SUVmean) of the spleen, liver, and BM and maximum SUV (SUVmax) of primary tumors were measured. The relationships between spleen, BM, and liver metabolism and clinicopathologic parameters were evaluated, and possible prognostic parameters predicting recurrence were assessed using disease-free survival (DFS). Spleen SUVmean was significantly correlated with primary tumor SUVmax, pathologic T (pT) stage, and histologic grade of primary tumor. BM SUVmean also showed a positive correlation with primary tumor SUVmax. Spleen SUVmean were significantly associated with recurrence from binary logistic regression analysis (P = 0.004). Spleen, BM, liver, and primary tumor SUVs were all significant prognostic factors for DFS in univariate Cox regression analysis (all P<0.024). Among all PET parameters analyzed, spleen SUVmean ≥ 2.21 (P = 0.032) was in the multivariable analysis the powerful poor prognostic factor predicting DFS that was independent of other clinicopathological features like T stage (pT >2; P = 0.009) and estrogen receptor (ER) status (ER negativity; P = 0.001). Splenic metabolism together with pT stage and ER status was an independent prognostic factor for predicting recurrence in breast cancer. Metabolic activity of reticuloendothelial system such as spleen, liver or BM on preoperative F-18 FDG PET/CT can be a meritorious imaging factor for discriminating patients with IDC that require adjunctive therapy to prevent recurrence.


Damage to ovarian development and function.
Ovarian function in women can be compromised by exposure to toxic environmental factors. Chemicals that affect ovarian function can act through direct effects on hormone action (ovary) or by interference with steroid hormone action (hypothalamus and/or pituitary). These effects can cause problems in the form of infertility. Alternatively, ovarian toxicants can directly cause ovarian failure by extensive follicular destruction. This targeting can result in loss of ovarian steroid hormones, eventual ovarian failure (menopause), and ultimate disruption of neuroendocrine feedback causing increased levels of FSH and LH. This article provides an overview of chemicals that in animal studies have been identified to cause disrupted ovarian function with a focus on the sites of targeting by which these disruptions occur. In predicting the impact of environmental factors on reproductive function in women, it is critical to gain a better appreciation of the physiological consequences resulting from the potential variety of mechanisms by which toxicants can disrupt ovarian function. This article attempts to provide such a perspective within the context of specific chemicals for which ovarian sites of toxicity have been identified.


Transcriptional repression of the IMD2 gene mediated by the transcriptional co-activator Sub1.
Sub1 was originally identified as a transcriptional co-activator and later demonstrated to have pleiotropic functions during multiple transcription steps, including initiation, elongation and termination. The present study reveals a novel function of Sub1 as a transcription repressor in budding yeast. Sub1 does not activate IMP dehydrogenase 2 (IMD2) gene expression but rather represses its expression. First, we examined the genetic interaction of Sub1 with the transcription elongation factor S-II/TFIIS, which is encoded by the DST1 gene. Disruption of the SUB1 gene partially suppressed sensitivity to the transcription elongation inhibitor mycophenolate (MPA) in a dst1 gene deletion mutant. SUB1 gene deletion increased the expression level of the IMD2 gene, which confers resistance to MPA, indicating that Sub1 functions to repress IMD2 gene expression. Sub1 located around the promoter region of the IMD2 gene. The upstream region of the transcription start sites was required for Sub1 to repress the IMD2 gene expression. These results suggest that the transcriptional co-activator Sub1 also has a role in transcriptional repression during transcription initiation in vivo.


Effects of Minimal-Equipment Resistance Training and Blood Flow Restriction on Military-Relevant Performance Outcomes.
Cintineo, HP, Chandler, AJ, Mastrofini, GF, Lints, BS, McFadden, BA, and Arent, SM. Effects of minimal-equipment resistance training and blood flow restriction on military-relevant performance outcomes. J Strength Cond Res 38(1): 55-65, 2024-This study compared minimal-equipment resistance training (RT) with and without blood flow restriction (BFR) to traditional-equipment RT on performance and body composition changes over 6 weeks. Reserve officers' training corps cadets and midshipmen (N = 54, 40.7% female) were randomized into traditional-equipment RT (TRAD), minimal-equipment RT (MIN), or minimal-equipment RT with BFR (MIN + BFR). Performance and body composition were assessed pretraining and post-training, and measures of intensity and workload were evaluated throughout. Performance assessments included the army combat fitness test (ACFT), countermovement vertical jump, 3RM bench press, and V̇O2max; body composition measures included body fat percentage, fat-free mass, and muscle and tendon thickness. All groups trained 4 days per week after a full-body routine. Data were analyzed by mixed-effects models (α = 0.05). Group-by-time interactions for 3RM deadlift and 3RM bench press (p < 0.004) showed larger improvements for TRAD compared with MIN and MIN + BFR. Time main effects for all other performance variables, body fat percentage, fat-free mass, and muscle thickness (p ≤ 0.035) indicated improvements in all groups. A group-by-time interaction for blood lactate (p < 0.001) and group main effects for heart rate (p < 0.001) and workload variables (p < 0.008) indicated higher intensity and workload for MIN and MIN + BFR compared with TRAD. A sex-by-time interaction for 3RM deadlift (p = 0.008) and sex-by-group-by-time interaction for 3RM bench press (p = 0.018) were also found. Minimal-equipment RT improved performance and body composition, although strength improvements were greater with traditional equipment. Minimal-equipment RT and minimal-equipment RT with BFR exhibited higher exertion levels than TRAD, although adaptations were similar. Overall, individuals can improve performance and body composition using portable, field-expedient RT equipment.