Remedial after-school support classes offered in rural Gambia (The SCORE trial): study protocol for a cluster randomized controlled trial.
Low education levels are endemic in much of the developing world, particularly in rural areas where traditional government-provided public services often have difficulty reaching beneficiaries. Providing trained para-teachers to teach regular after-school remedial education classes has been shown to improve literacy and numeracy in children of primary school age residing in such areas in India. This trial investigates whether such an intervention can also be effective in a West African setting with similarly low learning levels and difficult geographic access. cluster-randomized controlled trial. Clusters: villages or groups of villages with 15-300 households and at least 15 eligible children in the Lower River and North Bank Regions of The Gambia. children born between 1 September 2007 and 31 August 2009 planning to enter the first grade, for the first time, in the 2015-2016 school year in eligible villages. We anticipate enrolling approximately 150 clusters of villages with approximately 6000 children as participants. a program providing remedial after-school lessons, focusing on literacy and numeracy, 5 to 6 days a week for 3 years to eligible children, based on the intervention evaluated in the Support To Rural India's Public Education System (STRIPES) trial (PLoS ONE 8(7):e65775). both the intervention and control groups will receive small bundles of useful materials during annual data collection as recompense for their time. If the education intervention is shown to be cost-effective at raising learning levels, it is expected that the control group villages will receive the intervention for several years after the trial results are available. the primary outcome of the trial is a composite mathematics and language test score. Secondary outcomes include school attendance, enrollment, performance on nationally administered exams, parents' spending on education, spillover learning to siblings and family members, and school-related time use of parents and children. Subgroup analyses of the primary outcome will also be carried out based on ethnic group, gender, distance from the main highway, parents' education level, and school type. The trial will run by independent research and implementation teams and supervised by a Trial Steering Committee. Along with the overall impact of the intervention, we will conduct a cost-effectiveness analysis. There are no major ethical issues for this study. Current controlled trials ISRCTN12500245 . 1 May 2015.


Circadian Forced Desynchrony of the Master Clock Leads to Phenotypic Manifestation of Depression in Rats.
In mammals, a master circadian clock within the suprachiasmatic nucleus (SCN) of the hypothalamus maintains the phase coherence among a wide array of behavioral and physiological circadian rhythms. Affective disorders are typically associated with disruption of this fine-tuned "internal synchronization," but whether this internal misalignment is part of the physiopathology of mood disorders is not clear. To date, depressive-like behavior in animal models has been induced by methods that fail to specifically target the SCN regulation of internal synchronization as the mode to generate depression. In the rat, exposure to a 22-h light-dark cycle (LD22) leads to the uncoupling of two distinct populations of neuronal oscillators within the SCN. This genetically, neurally, and pharmacologically intact animal model represents a unique opportunity to assess the effect of a systematic challenge to the central circadian pacemaker on phenotypic manifestations of mood disorders. We show that LD22 circadian forced desynchrony in rats induces depressive-like phenotypes including anhedonia, sexual dysfunction, and increased immobility in the forced swim test (FST), as well as changes in the levels and turnover rates of monoamines within the prefrontal cortex. Desynchronized rats show increased FST immobility during the dark (active) phase but decreased immobility during the light (rest) phase, suggesting a decrease in the amplitude of the normal daily oscillation in this behavioral manifestation of depression. Our results support the notion that the prolonged internal misalignment of circadian rhythms induced by environmental challenge to the central circadian pacemaker may constitute part of the etiology of depression.


Dehydroepiandrosterone sulfate levels and risk of atrial fibrillation: the Rotterdam Study.
High plasma dehydroepiandrosterone sulfate (DHEAS) levels have been associated with a reduced risk of cardiovascular disease and atherosclerosis. To our knowledge, no previous follow-up study has investigated the association between DHEAS and the development of atrial fibrillation. Our objective was to investigate the association between DHEAS levels and incident atrial fibrillation. The study was based on a random sample within the prospective population-based Rotterdam Study. The study population comprised 1180 participants without atrial fibrillation at baseline for whom baseline levels of DHEAS were measured in plasma. Atrial fibrillation was ascertained from centre visit electrocardiogram (ECG) assessments as well as medical records. During a mean follow-up period of 12.3 years, 129 participants developed atrial fibrillation. DHEAS levels were inversely associated with the risk of atrial fibrillation (hazard ratio (HR) per standard deviation (SD): 0.74, 95% confidence interval (CI): 0.58-0.94). Subjects in the highest DHEAS quartile had an almost three times lower risk of atrial fibrillation during follow-up, compared to those in the lowest DHEAS quartile (HR: 0.34, 95% CI: 0.18-0.64) adjusted for age, sex and cardiovascular risk factors. DHEAS can be regarded as an important indicator of future atrial fibrillation in both men and women, independent of known cardiovascular risk factors.


Efficacy and economics of topical calcineurin inhibitors for the treatment of atopic dermatitis.
Atopic dermatitis is a chronic, relapsing inflammatory skin disease that frequently affects infants and children. The worldwide prevalence of atopic dermatitis is estimated to be 5-20% of the pediatric population. Studies have shown that atopic dermatitis is associated with considerable economic costs and decreased quality of life. There is no proven curative therapy at present for atopic dermatitis; first-line therapy has generally consisted of dry skin care, avoidance of triggers, application of topical corticosteroids, and administration of histamine H1 receptor antagonists (antihistamines) and oral antibacterials as appropriate. Topical corticosteroids, while effective in many patients, carry the concern of local and systemic adverse effects. As a result, physicians and patients are reluctant to utilize stronger topical corticosteroids in certain areas of the body and for prolonged periods of time. The purpose of this article is to review the efficacy and economics of topical calcineurin inhibitors in the treatment of atopic dermatitis. This new class of agents (specifically tacrolimus ointment and pimecrolimus cream) represents an exciting advance in the treatment of atopic dermatitis. Clinical data show that topical calcineurin inhibitors are effective and do not cause the adverse effects associated with topical corticosteroids. Several studies have provided evidence that topical calcineurin inhibitors positively affect the quality of life of patients and their caregivers. Compared with branded topical corticosteroids and previous standards of care, topical calcineurin inhibitors appear to be a cost-effective treatment option. Drawing comparisons between tacrolimus and pimecrolimus is difficult because definitive head-to-head comparative studies involving these drugs have not been conducted.


Hardness, elasticity, and ultrastructure of bonded sound and caries-affected primary tooth dentin.
Biomechanical properties of bonded dentin are important factors for resin restoration. We evaluated the hardness and elastic modulus of bonded sound and caries-affected primary tooth dentin using a one-step adhesive system, and observed the microstructure of the bonded interface. Six sound and six carious primary teeth were used. For sound teeth, flat occlusal dentin surfaces were prepared with a water-cooled high-speed diamond bur. For carious teeth, infected dentin was stained with a caries detector and removed with a water-cooled low-speed round steel bur and hand instruments. The prepared dentin was bonded with One-Up Bond F Plus (Tokuyama Dental Co., Tokyo, Japan). The resin-dentin interface and dentin beneath the interface were measured with a nano-indentation tester and observed with SEM and TEM. For both the carious and sound teeth, there was no significant difference between the hardness of the interfacial dentin and dentin 10-80 microm beneath the interface. However, the Young's modulus of the interfacial dentin was significantly lower than the dentin 40-80 microm (carious teeth) or 50-80 microm (sound teeth) beneath the interface. Both the hardness and Young's modulus of the interfacial dentin were not significantly different between the carious and sound teeth. Compared to the sound dentin, the hybrid layer on the caries-affected dentin was thicker and exhibited more complicated morphologic features. The thickness of the hybrid layers was generally less than 1 microm.


Supraspinal Effects of Dorsal Root Ganglion Stimulation in Chronic Pain Patients.
Dorsal root ganglion stimulation (DRGS) has become a popular neuromodulatory treatment for neuropathic pain. We used magnetoencephalography (MEG) to investigate potential biomarkers of pain and pain relief, based on the differences in power spectral density (PSD) during varying degrees of pain and how these oscillations change during DRGS-mediated pain relief. Thirteen chronic pain patients with implanted dorsal root ganglion stimulators were included in the MEG analysis. MEG Recordings were performed at rest while the stimulator was turned ON or OFF. Numerical rating scale (NRS) scores were also recorded before and after DRGS was turned OFF and ON. Power spectral and source localization analyses were then performed on preprocessed MEG recordings. With DRGS-OFF, patients in severe pain had significantly increased cortical theta (4-7 Hz) power and decreased cortical alpha (7-13 Hz) power compared to patients reporting less pain. This shift in power toward lower frequencies was contrasted by a shift toward the higher frequency power spectrum (low beta 13-20 Hz activity) during DRGS-mediated pain relief. A significant correlation was found between the increase in low beta activity and the degree of reported pain relief. Our results demonstrate increased low-frequency power spectral activity in chronic pain patients in the absence of stimulation which shifts toward higher frequency power spectrum activity in response to therapeutic DRGS. These cortical changes in response to DRGS provide support for the use of neuroimaging in the search for potential biomarkers of pain.


Evaluation of a commercial web-based weight loss and weight loss maintenance program in overweight and obese adults: a randomized controlled trial.
Obesity rates in adults continue to rise and effective treatment programs with a broad reach are urgently required. This paper describes the study protocol for a web-based randomized controlled trial (RCT) of a commercially available program for overweight and obese adult males and females. The aim of this RCT was to determine and compare the efficacy of two web-based interventions for weight loss and maintenance of lost weight. Overweight and obese adult males and females were stratified by gender and BMI and randomly assigned to one of three groups for 12-weeks: waitlist control, or basic or enhanced online weight-loss. Control participants were re-randomized to the two weight loss groups at the end of the 12-week period. The basic and enhanced group participants had an option to continue or repeat the 12-week program. If the weight loss goal was achieved at the end of 12, otherwise on completion of 24 weeks of weight loss, participants were re-randomized to one of two online maintenance programs (maintenance basic or maintenance enhanced), until 18 months from commencing the weight loss program. Assessments took place at baseline, three, six, and 18 months after commencing the initial weight loss intervention with control participants repeating the initial assessment after three month of waiting. The primary outcome is body mass index (BMI). Other outcomes include weight, waist circumference, blood pressure, plasma markers of cardiovascular disease risk, dietary intake, eating behaviours, physical activity and quality of life.Both the weight loss and maintenance of lost weight programs were based on social cognitive theory with participants advised to set goals, self-monitor weight, dietary intake and physical activity levels. The enhanced weight loss and maintenance programs provided additional personalized, system-generated feedback on progress and use of the program. Details of the methodological aspects of recruitment, inclusion criteria, randomization, intervention programs, assessments and statistical analyses are described. Importantly, this paper describes how an RCT of a currently available commercial online program in Australia addresses some of the short falls in the current literature pertaining to the efficacy of web-based weight loss programs.Australian New Zealand Clinical Trials Registry (ANZCTR) number: ACTRN12610000197033.


Mutagenesis of human acetylcholinesterase. Identification of residues involved in catalytic activity and in polypeptide folding.
Evidence for the involvement of Ser-203, His-447, and Glu-334 in the catalytic triad of human acetylcholinesterase was provided by substitution of these amino acids by alanine residues. Of 20 amino acid positions mutated so far in human acetylcholinesterase (AChE), these three were unique in abolishing detectable enzymatic activity (less than 0.0003 of wild type), yet allowing proper production, folding, and secretion. This is the first biochemical evidence for the involvement of a glutamate in a hydrolase triad (Schrag, J.D., Li, Y., Wu, M., and Cygler, M. (1991) Nature 351, 761-764), supporting the x-ray crystal structure data of the Torpedo californica acetylcholinesterase (Sussman, J.L., Harel, M., Frolow, F., Oefner, C., Goldman, A., Toker, L. and Silman, I. (1991) Science 253, 872-879). Attempts to convert the AChE triad into a Cys-His-Glu or Ser-His-Asp configuration by site-directed mutagenesis did not yield effective AChE activity. Another type of substitution, that of Asp-74 by Gly or Asn, generated an active enzyme with increased resistance to succinylcholine and dibucaine; thus mimicking in an AChE molecule the phenotype of the atypical butyrylcholinesterase natural variant (D70G mutation). Mutations of other carboxylic residues Glu-84, Asp-95, Asp-333, and Asp-349, all conserved among cholinesterases, did not result in detectable alteration in the recombinant AChE, although polypeptide productivity of the D95N mutant was considerably lower. In contrast, complete absence of secreted human AChE polypeptide was observed when Asp-175 or Asp-404 were substituted by Asn. These two aspartates are conserved in the entire cholinesterase/thyroglobulin family and appear to play a role in generating and/or maintaining the folded state of the polypeptide. The x-ray structure of the Torpedo acetylcholinesterase supports this assumption by revealing the participation of these residues in salt bridges between neighboring secondary structure elements.


Hyperresponsiveness of the Neural Fear Network During Fear Conditioning and Extinction Learning in Male Cocaine Users.
The authors investigated whether cocaine use disorder is associated with abnormalities in the neural underpinnings of aversive conditioning and extinction learning, as these processes may play an important role in the development and persistence of drug abuse. Forty male regular cocaine users and 51 male control subjects underwent a fear conditioning and extinction protocol during functional MRI. Skin conductance response was measured throughout the experiment as an index of conditioned responses. Cocaine users showed hyperresponsiveness of the amygdala and insula during fear conditioning, as well as hyporesponsiveness of the dorsomedial prefrontal cortex during extinction learning. In cocaine users, but not in control subjects, skin conductance responses were positively correlated with responsiveness of the insula, amygdala, and dorsomedial prefrontal cortex during fear conditioning but negatively correlated with responsiveness of the ventromedial prefrontal cortex during extinction learning. Increased sensitivity to aversive conditioned cues in cocaine users might be a risk factor for stress-relief craving in cocaine use disorder. These results support the postulated role of altered aversive conditioning in cocaine use disorder and may be an important step in understanding the role of aversive learning in the pathology of cocaine use disorder.


Psychological morbidity in Nepali cross-border migrants in India: a community based cross-sectional study.
Since Nepali cross-border migrants can freely enter, work and stay in India, they are largely undocumented. The majority is involved in semi-skilled or unskilled jobs with limited labour rights and social security, a fact which predisposes them to psychological distress. We aimed to assess the prevalence of and factors associated with psychological morbidity among Nepali migrants upon their return from India. A community based cross-sectional study was conducted in six districts of Nepal between September 2017 and February 2018. A total of 751 participants who had worked at least six months in India and returned to Nepal were interviewed from 24 randomly selected clusters. The General Health Questionnaire (GHQ)-12 was used to measure the psychological morbidity. Data were analysed using Poisson regression analysis. The majority was younger than 35 years (64.1%), male (96.7%), married (81.8%), had at least a primary education (66.6%), and belonged to Dalit, Janajati and religious minorities (53.7%). The prevalence of psychological morbidity was 13.5% (CI: 11.2-16.1%). Participants aged 45 years and above (adjusted prevalence ratio (aPR) = 2.74), from the Terai (aPR = 3.29), a religious minority (aPR = 3.64), who received no sick leave (aPR = 2.4), with existing health problems (aPR = 2.0) and having difficulty in accessing health care (aPR = 1.88) were more likely than others to exhibit a psychological morbidity. This study demonstrated that psychological morbidity was prevalent in the study participants and varied significantly with individual characteristics, work conditions and health. Multifaceted approaches including psychological counselling for returnees and protection of labour and health rights in the workplace are recommended to help reduce psychological morbidity.


Visualizing mechanosensory endings of TrkC-expressing neurons in HS3ST-2-hPLAP mice.
Somatosensory neurons are classified into three main types according to their modalities: nociceptive, thermal, and mechanosensory. Within each modality group, neurons can be further divided into morphologically and functionally distinct subclasses. Here we show that heparan sulfate D-glucosaminyl 3-O-sulfotransferase 2 (HS3ST-2) is a marker for specific subsets of TrkC-expressing cutaneous low-threshold mechanosensory and proprioceptive mechanosensory neurons. Two-color in situ analysis revealed that almost all HS3ST-2 signals colocalized with TrkC but not with TrkA or TrkB mRNA. To visualize the morphological subtypes of HS3ST-2/TrkC-expressing neurons, we generated a HS3ST-2-hPLAP knock-in mouse line, in which HS3ST-2-expressing neurons and their projections are labeled by human placental alkaline phosphatase (hPLAP). AP staining in these mice demonstrated that sensory endings of muscle spindles and Golgi tendon organs as well as the cutaneous mechanosensory Merkel and longitudinal lanceolate endings in the whiskers are strongly positive for hPLAP activity. In contrast, no nociceptive endings are labeled. In the glabrous and hairy skin, rare Merkel endings and transverse lanceolate endings are weakly stained. During development, each type of nerve endings forms at different time point. Muscle innervations differentiate first, followed by formation of cutaneous sensory endings. Our results revealed the subtype identities of TrkC-positive mechanosensory neurons and demonstrated the usefulness of HS3ST-2 as a genetic marker for these subclasses of neurons.


Utilization of Advanced Cardiovascular Therapies in the United States and Canada: An Observational Study of New York and Ontario Administrative Data.
Endovascular aortic aneurysm repair (EVAR), left ventricular assist device (LVAD), and transcatheter aortic valve replacement (TAVR) are expensive cardiovascular technologies with potential to benefit large numbers of patients. There are few population-based studies comparing utilization between countries. Our objective was to compare patient characteristics and utilization patterns of EVAR, LVAD, and TAVR in Ontario, Canada, and New York State, United States. We performed a retrospective cohort study using administrative data to identify all adults who received EVAR, LVAD, or TAVR in Ontario and New York between 2012 and 2015. We compared socio-demographics of EVAR, LVAD, and TAVR recipients in Ontario and New York. We compared standardized utilization rates between jurisdictions for each procedure. We identified 3295 EVAR recipients from Ontario and 6236 from New York (mean age 74.6 versus 74.5 years; P=0.61): 136 LVAD recipients from Ontario and 686 from New York (age, 57.4 versus 57.7 years; P=0.80): 1708 TAVR recipients from Ontario and 4838 from New York (age, 83.1 versus 83.1; P=1.0). A significantly smaller percentage of EVAR and TAVR recipients in Ontario were female compared to New York (EVAR, 15.8% versus 22.1% female; P<0.001; TAVR, 45.9% versus 51.8%; P<0.001), but for LVAD the percentage female was similar (21.3% versus 20.8%; P=0.99). Utilization was significantly higher in New York for all procedures: EVAR (12.8 procedures per-100 000 adults per-year in Ontario, 20.2 in New York; P<0.001); LVAD (0.3 in Ontario versus 1.3 in New York; P<0.001); and TAVR (6.6 in Ontario, 14.3 in New York; P<0.001). Higher utilization of EVAR and TAVR in New York relative to Ontario increased substantially with increasing age. We observed significantly higher utilization of EVAR, LVAD, and TAVR in New York compared to Ontario. Our results highlight important differences in how 2 different countries are using advanced cardiovascular therapies.


Teaching elderly adults to use the Internet to access health care information: before-after study.
Much has been written about the Internet's potential to revolutionize health care delivery. As younger populations increasingly utilize Internet-based health care information, it will be essential to ensure that the elderly become adept at using this medium for health care purposes, especially those from minority, low income, and limited educational backgrounds. This paper presents the results of a program designed to teach elderly adults to use the Internet to access health care information. The objective was to examine whether the training led to changes in participant's perceptions of their health, perceptions of their interactions with health care providers, health information-seeking behaviors, and self-care activities. Participants attended a 5-week training course held in public libraries and senior community centers within the greater Pittsburgh and Allegheny County region. Classes within each seminar lasted 2 hours and consisted of lecture and hands-on training. Baseline surveys were administered prior to the course, 5-week follow-up surveys were administered immediately after the course, and final surveys were mailed 1 year later. Instruments included the Multidimensional Health Locus of Control (MHLC) Scale, which measures three domains of locus of control (internal, external, and chance); the Krantz Health Opinion Survey (HOS); and the Lau, Hartman, and Ware Health Value Survey. Two additional questionnaires included multiple choice and qualitative questions designed to measure participants' Internet utilization and levels of health care participation. The Health Participation Survey was administered with the baseline survey. The Internet Use Survey was administered at the 1-year mark and contained several items from the Health Participation Survey, which allowed comparison between baseline and 1-year responses. Of the60 elderly adults who began the training course, 42 (mean age 72) completed the entire 5-week training program and the 5-week follow-up questionnaire administered immediately after the program, and 27 completed the 1-year follow-up survey. Statistically significant differences were found between baseline and 5-week follow-up results for MHLC chance subscores in males (P = .02) and females (P = .05), as well as total HOS information seeking scores (P = .05). However, these statistically significant findings disappeared when all 60 original participants were included using a "last observation carried forward" imputation. No statistically significant changes were found between baseline and 5-week follow-up surveys for MHLC external (P = .44) and internal (P = .97) locus of control scores in both genders, or for the HOS behavioral involvement subscale (P = .65). We failed to show robust before-after effects for most of the outcomes measured. Elderly adults may be willing to use the Internet as a source for general health information; however, when making decisions about their health care, our participants seemed to adhere to a physician-centered model of care. Demographic and situational variables may play a large role in determining which seniors will use the Internet for making behavioral decisions about their health care and in which scenarios they will do so.


Evaluation of a Database for Tracking Cases of Child Sexual Abuse.
Administrative databases are used by criminal justice professionals to guide specialist responses to crimes of child sexual abuse. Assumptions might be made that the database will be accurate, contemporaneous, complete, and meaningful; however, this may not be the case. The main aim of the current study was to critically evaluate a database used by practitioners for tracking cases of child sexual abuse, in order to identify evidence that may justify investment in improved data gathering and centralised information management systems. Three data quality dimensions were examined: (1) completeness, measured as data that were not missing and were of adequate breadth and depth, (2) accuracy, namely that the data are correct, and (3) believability, where the data may be regarded as credible or plausible. Results indicated that data quality was of concern for all three dimensions, with missing and inaccurate data found across a range of variables, and issues with believability found on two variables. The implications of these results for development of new data documentation methods are discussed.


Performance of SAPS3, compared with APACHE II and SOFA, to predict hospital mortality in a general ICU in Southern Europe.
Simplified Acute Physiology Score (SAPS3) has not been validated in Southern European countries. The purpose of this study was to validate the ability of SAPS3 to predict hospital mortality in adult patients in an interdisciplinary intensive care unit in Southern Europe, compared with Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA). This is a cohort study of 864 patients with a prospective collection of SAPS3 and SOFA variables and retrospective analysis of APACHE II in a mixed intensive care unit at a teaching hospital in Spain throughout 2006. The performance of the systems was determined by examining their discrimination and calibration. The discrimination of SAPS3 was excellent, with an area under the receiver operating characteristic curve of 0.916, similar to APACHE II (area under the receiver operating characteristic curve = 0.893) or SOFA (area under the receiver operating characteristic curve = 0.846). The calibration was good for SAPS3 but insufficient for APACHE II. Hospital death rates were lower than those that were predicted by the models. Our data demonstrate a better calibration of SAPS3 than APACHE II. Calibration was sufficient only for SAPS3. Hospital mortality was lower than predicted by both models. The discrimination of SAPS3 is excellent, and, when it is customized for Southern Europe, SAPS3 accurately predicts mortality risk in our adult mixed-case ICU.


Professionalism lapses and hierarchies: A qualitative analysis of medical students' narrated acts of resistance.
Resistance is classified as a reaction against confining social structures. During their education, medical students encounter traditional medical and interprofessional hierarchies as they learn to become doctors. These create a power disparity that may prevent their empowerment and ability to resist. Despite their subordinate position, students are not always powerless when encountering situations that contradict their ethical, moral, and professional understandings of appropriate medical practice - so called 'professionalism dilemmas.' A qualitative analysis of over 1500 narratives from interviews, focus groups, and questionnaires with 808 medical students in the UK and Australia highlights how students draw on a number of direct and indirect, verbal and bodily, instantaneous and delayed forms of resistance to counter the professionalism lapses of their seniors, which they face in everyday clinical and educational interactions. Within students' narratives of resistance we come to see how they resist hegemonic practices and their reasons for doing so, such as to prevent patient and student abuse, promote hygienic practice, and uphold patient consent. Through these various acts of resistance (and their narration), medical students may promote the subtle transformation of the dominant medical structure either consciously or unconsciously. They may do this through reflecting on acts of resistance to professionalism lapses, making sense of their moral position and the development of their professional identities, by encouraging others to also resist through sharing resistance narratives, and finally, by altering the professional conduct of their seniors. We encourage all workplace learning stakeholders to better understand the social dynamics of hierarchies and resistance and to encourage the enactment of resistance in the face of professionalism lapses in order to protect the health and wellbeing of learners and patients.


Glucocorticoids inhibit E-selectin expression by targeting NF-kappaB and not ATF/c-Jun.
E-selectin, an adhesion molecule expressed on the surface of activated endothelial cells, is essential for leukocyte rolling on endothelium which leads to extravasation in the process of inflammation. Induction of E-selectin expression by proinflammatory stimuli such as TNF-alpha or LPS is reduced markedly in the presence of dexamethasone, a synthetic glucocorticoid and potent anti-inflammatory agent. We have investigated the molecular mechanism underlying dexamethasone-mediated E-selectin repression in porcine aortic endothelial cells. Reduced E-selectin protein expression is paralleled by a decrease in E-selectin mRNA and is based on changes in transcription rate. Analysis of the E-selectin promoter revealed that induction by proinflammatory stimuli as well as repression by dexamethasone are mediated by the same promoter region containing three closely spaced binding sites for nuclear factor (NF)-kappaB and an element, NF-ELAM-1 (endothelial leukocyte adhesion molecule-1), constitutively occupied by ATF and c-Jun. NF-ELAM-1 contributes to maximal promoter activity, but does not confer glucocorticoid inhibition, as demonstrated by site-directed mutagenesis. In contrast, transcription directed by the E-selectin NF-kappaB elements is reduced strongly in the presence of dexamethasone, thus identifying NF-kappaB as the primary target for glucocorticoid-mediated E-selectin repression.


Helical flows and asymmetry of blood jet in dilated ascending aorta with normally functioning bicuspid valve.
Bicuspid aortic valve (BAV) is associated with aortic dilatation and aneurysm. Several studies evidenced an eccentric systolic flow in ascending aorta associated with increased wall shear stresses (WSS) and the occurrence of an helical systolic flow. This study seeks to elucidate the connections between jet asymmetry and helical flow in patients with normally functioning BAV and dilated ascending aorta. We performed a computational parametric study by varying, for a patient-specific geometry, the valve area and the flow rate entering the aorta and drawing also a tricuspid valve (TAV). We considered also phase-contrast magnetic resonance imaging of four BAV and TAV patients. Measurement of normalized flow asymmetry index, systolic WSS and of a new index (positive helix fraction, PHF) quantifying the presence of a single a single helical flow were performed. In our computation, BAV cases featured higher values of all indices with respect to TAV in both numerical and imaged-based results. Moreover, all indices increased with decreasing valve area and/or with increasing flow rate. This allowed to separate the BAV and TAV cases with respect to the jet asymmetry, WSS localization and helical flow. Interestingly, these results were obtained without modeling the leaflets.


Fast rebinding increases dwell time of Src homology 2 (SH2)-containing proteins near the plasma membrane.
Receptor tyrosine kinases (RTKs) control a host of biological functions by phosphorylating tyrosine residues of intracellular proteins upon extracellular ligand binding. The phosphotyrosines (p-Tyr) then recruit a subset of ∼100 Src homology 2 (SH2) domain-containing proteins to the cell membrane. The in vivo kinetics of this process are not well understood. Here we use total internal reflection (TIR) microscopy and single-molecule imaging to monitor interactions between SH2 modules and p-Tyr sites near the cell membrane. We found that the dwell time of SH2 modules within the TIR illumination field is significantly longer than predictions based on chemical dissociation rate constants, suggesting that SH2 modules quickly rebind to nearby p-Tyr sites after dissociation. We also found that, consistent with the rebinding model, the effective diffusion constant is negatively correlated with the respective dwell time for different SH2 domains and the dwell time is positively correlated with the local density of RTK phosphorylation. These results suggest a mechanism whereby signal output can be regulated through the spatial organization of multiple binding sites, which will prompt reevaluation of many aspects of RTK signaling, such as signaling specificity, mechanisms of spatial control, and noise suppression.


Effect of strong acid functional groups on electrode rise potential in capacitive mixing by double layer expansion.
The amount of salinity-gradient energy that can be obtained through capacitive mixing based on double layer expansion depends on the extent the electric double layer (EDL) is altered in a low salt concentration (LC) electrolyte (e.g., river water). We show that the electrode-rise potential, which is a measure of the EDL perturbation process, was significantly (P = 10(–5)) correlated to the concentration of strong acid surface functional groups using five types of activated carbon. Electrodes with the lowest concentration of strong acids (0.05 mmol g(–1)) had a positive rise potential of 59 ± 4 mV in the LC solution, whereas the carbon with the highest concentration (0.36 mmol g(–1)) had a negative rise potential (−31 ± 5 mV). Chemical oxidation of a carbon (YP50) using nitric acid decreased the electrode rise potential from 46 ± 2 mV (unaltered) to −6 ± 0.5 mV (oxidized), producing a whole cell potential (53 ± 1.7 mV) that was 4.4 times larger than that obtained with identical electrode materials (from 12 ± 1 mV). Changes in the EDL were linked to the behavior of specific ions in a LC solution using molecular dynamics and metadynamics simulations. The EDL expanded in the LC solution when a carbon surface (pristine graphene) lacked strong acid functional groups, producing a positive-rise potential at the electrode. In contrast, the EDL was compressed for an oxidized surface (graphene oxide), producing a negative-rise electrode potential. These results established the linkage between rise potentials and specific surface functional groups (strong acids) and demonstrated on a molecular scale changes in the EDL using oxidized or pristine carbons.


Genetic instability and transitional cell carcinoma of the bladder.
The development of cancer occurs in a stepwise fashion, with each step representing the mutation in one of several key genes. However, the mutation rate of somatic cells is too low to account for the number of mutations required for a cell to undergo carcinogenesis. Thus, the development of genetic instability is a vital early step towards carcinogenesis. We review the evidence for genetic instability, with particular reference to transitional cell carcinoma of the bladder. Both microsatellite instability and chromosomal instability are present in this tumour, and we discuss their incidence and clinical implications.


Akhirin regulates the proliferation and differentiation of neural stem cells in intact and injured mouse spinal cord.
Although the central nervous system is considered a comparatively static tissue with limited cell turnover, cells with stem cell properties have been isolated from most neural tissues. The spinal cord ependymal cells show neural stem cell potential in vitro and in vivo in injured spinal cord. However, very little is known regarding the ependymal niche in the mouse spinal cord. We previously reported that a secreted factor, chick Akhirin, is expressed in the ciliary marginal zone of the eye, where it works as a heterophilic cell-adhesion molecule. Here, we describe a new crucial function for mouse Akhirin (M-AKH) in regulating the proliferation and differentiation of progenitors in the mouse spinal cord. During embryonic spinal cord development, M-AKH is transiently expressed in the central canal ependymal cells, which possess latent neural stem cell properties. Targeted inactivation of the AKH gene in mice causes a reduction in the size of the spinal cord and decreases BrdU incorporation in the spinal cord. Remarkably, the expression patterns of ependymal niche molecules in AKH knockout (AKH-/-) mice are different from those of AKH+/+, both in vitro and in vivo. Furthermore, we provide evidence that AKH expression in the central canal is rapidly upregulated in the injured spinal cord. Taken together, these results indicate that M-AKH plays a crucial role in mouse spinal cord formation by regulating the ependymal niche in the central canal.


Metabolomics and human nutrition.
The present report summarises a workshop convened by the UK Food Standards Agency (Agency) on 25 March 2010 to discuss the current Agency's funded research on the use of metabolomics technologies in human nutrition research. The objectives of this workshop were to review progress to date, to identify technical challenges and ways of overcoming them, and to discuss future research priorities and the application of metabolomics in public health nutrition research and surveys. Results from studies nearing completion showed that by using carefully designed dietary and sampling regimens, it is possible to identify novel biomarkers of food intake that could not have been predicted from current knowledge of food composition. These findings provide proof-of-principle that the metabolomics approach can be used to develop new putative biomarkers of dietary intake. The next steps will be to validate these putative biomarkers, to develop rapid and inexpensive assays for biomarkers of food intake of high public health relevance, and to test their utility in population cohort studies and dietary surveys.


Leaderless secreted peptide signaling molecule alters global gene expression and increases virulence of a human bacterial pathogen.
Successful pathogens use complex signaling mechanisms to monitor their environment and reprogram global gene expression during specific stages of infection. Group A Streptococcus (GAS) is a major human pathogen that causes significant disease burden worldwide. A secreted cysteine protease known as streptococcal pyrogenic exotoxin B (SpeB) is a key virulence factor that is produced abundantly during infection and is critical for GAS pathogenesis. Although identified nearly a century ago, the molecular basis for growth phase control of speB gene expression remains unknown. We have discovered that GAS uses a previously unknown peptide-mediated intercellular signaling system to control SpeB production, alter global gene expression, and enhance virulence. GAS produces an eight-amino acid leaderless peptide [SpeB-inducing peptide (SIP)] during high cell density and uses the secreted peptide for cell-to-cell signaling to induce population-wide speB expression. The SIP signaling pathway includes peptide secretion, reimportation into the cytosol, and interaction with the intracellular global gene regulator Regulator of Protease B (RopB), resulting in SIP-dependent modulation of DNA binding and regulatory activity of RopB. Notably, SIP signaling causes differential expression of ∼14% of GAS core genes. Several genes that encode toxins and other virulence genes that enhance pathogen dissemination and infection are significantly up-regulated. Using three mouse infection models, we show that the SIP signaling pathway is active during infection and contributes significantly to GAS pathogenesis at multiple host anatomic sites. Together, our results delineate the molecular mechanisms involved in a previously undescribed virulence regulatory pathway of an important human pathogen and suggest new therapeutic strategies.


Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site.
The sigma-2 receptor, whose gene remains to be cloned, has been validated as a biomarker for tumour cell proliferation. Here we report the use of a novel photoaffinity probe, WC-21, to identify the sigma-2 receptor-binding site. WC-21, a sigma-2 ligand containing both a photoactive azide moiety and a fluorescein isothiocyanate group, irreversibly labels sigma-2 receptors in rat liver; the membrane-bound protein was identified as PGRMC1 (progesterone receptor membrane component 1). Immunocytochemistry reveals that both PGRMC1 and SW120, a fluorescent sigma-2 receptor ligand, colocalize with molecular markers of the endoplasmic reticulum and mitochondria in HeLa cells. Overexpression and knockdown of the PGRMC1 protein results in an increase and a decrease in binding of a sigma-2 selective radioligand, respectively. The identification of the putative sigma-2 receptor-binding site as PGRMC1 should stimulate the development of unique imaging agents and cancer therapeutics that target the sigma-2 receptor/PGRMC1 complex.


[Evaluation of urinary antigen detection methods for rapid diagnosis of Legionella pneumonia].
We have evaluated urine specimens of presumptive cases of legionnaires' disease (110 cases, 173 sample), collected in the past eight years (April, 1990-August, 1998) with the Binax EIA kit which detects the soluble antigen of Legionella pneumophila serogroup (SG) 1, and the Biotest EIA kit which detects Legionella species. Seven cases (19 specimens) were positive for the Binax EIA kit, and nine cases (22 specimens) were positive for the Biotest EIA kit. The sensitivity for culture, PCR, IFA method were 100%, 100%, and 50%, the specificity for these method were 93%, 97.1%, and 90% respectively. Overall agreements for these method were 93.5%, 97.4%, 86.8%, these results suggested that the urinary antigen detection test had high sensitivity and specificity. Our study indicated that concentrated urine samples increase sensitivity. We also evaluated the capabilities of both EIAs to detect soluble antigens were extracted from bacterial suspension of 18 strains of 5 Legionella species by heating. Both assays detected L. pneumophila serogroups 1 to 14, L. bozemanii. The Binax EIA proved to be useful as the Biotest EIA for diagnosis of legionellosis caused by Legionella species and serogroups other than L. pneumophila serogroup 1. Some cases have been shown to excrete antigen for prolonged period of times despite recovery from infection, so that the patient's history should be sought. The urine antigen detection EIA methods proved to be rapid and easy to use, detect antigen in the early stage of the disease with high sensitivity and specificity. Its use for the definition of legionellosis should be considered in Japan.


Removal and Recovery of Methyl Tertiary Butyl Ether (MTBE) from Water Using Carbon Nanotube and Graphene Oxide Immobilized Membranes.
Methyl tert-butyl ether (MTBE) is a widely used gasoline additive that has high water solubility, and is difficult to separate from contaminated ground and surface waters. We present the development in functionalized carbon nanotube-immobilized membranes (CNIM-f) and graphene oxide-immobilized membranes (GOIM) for enhanced separation of MTBE via sweep gas membrane distillation (SGMD). Both types of modified membranes demonstrated high performance in MTBE removal from its aqueous mixture. Among the membranes studied, CNIM-f provided the best performance in terms of flux, removal efficiency, mass transfer coefficients and overall selectivity. The immobilization f-CNTs and GO altered the surface characteristics of the membrane and enhanced partition coefficients, and thus assisted MTBE transport across the membrane. The MTBE flux reached as high as 1.4 kg/m2 h with f-CNTs, which was 22% higher than that of the unmodified PTFE membrane. The maximum MTBE removal using CNIM-f reached 56% at 0.5 wt % of the MTBE in water, and at a temperature of 30 °C. With selectivity as high as 60, MTBE recovery from contaminated water is very viable using these nanocarbon-immobilized membranes.


An Examination of the Relationship Between Motivation, Physical Activity, and Wearable Activity Monitor Use.
Wearable physical activity (PA) monitors are widely promoted as a means to motivate people to be more active, but the motivational profile of users has never been assessed. This study's purpose was to classify adult users by their motivational regulation scores and examine how these profiles were associated with moderate to vigorous PA (MVPA). Current users (N = 320) recruited across the United States completed a Web-based survey. Motivational regulations were measured using the Behavioral Regulation in Exercise Questionnaire, and associations with MVPA were explored using bivariate correlations. MVPA was more highly correlated with autonomous rather than controlling regulations. A cluster analysis was conducted using the respondents' motivational regulation scores. Five motivational profiles emerged from this analysis, and they differed significantly across motivation and MVPA scores. PA monitor users characterized by more autonomous motives presented with higher MVPA. As technology use increases, assessing the multidimensionality of PA monitor users' motivation may add value when researching PA behaviors.


Efficient fluoride-catalyzed conversion of CO2 to CO at room temperature.
A protocol for the efficient and selective reduction of carbon dioxide to carbon monoxide has been developed. Remarkably, this oxygen abstraction step can be performed with only the presence of catalytic cesium fluoride and a stoichiometric amount of a disilane in DMSO at room temperature. Rapid reduction of CO2 to CO could be achieved in only 2 h, which was observed by pressure measurements. To quantify the amount of CO produced, the reduction was coupled to an aminocarbonylation reaction using the two-chamber system, COware. The reduction was not limited to a specific disilane, since (Ph2MeSi)2 as well as (PhMe2Si)2 and (Me3Si)3SiH exhibited similar reactivity. Moreover, at a slightly elevated temperature, other fluoride salts were able to efficiently catalyze the CO2 to CO reduction. Employing a nonhygroscopic fluoride source, KHF2, omitted the need for an inert atmosphere. Substituting the disilane with silylborane, (pinacolato)BSiMe2Ph, maintained the high activity of the system, whereas the structurally related bis(pinacolato)diboron could not be activated with this fluoride methodology. Furthermore, this chemistry could be adapted to (13)C-isotope labeling of six pharmaceutically relevant compounds starting from Ba(13)CO3 in a newly developed three-chamber system.


Heterodyne frequency-domain multispectral diffuse optical tomography of breast cancer in the parallel-plane transmission geometry.
The authors introduce a state-of-the-art all-optical clinical diffuse optical tomography (DOT) imaging instrument which collects spatially dense, multispectral, frequency-domain breast data in the parallel-plate geometry. The instrument utilizes a CCD-based heterodyne detection scheme that permits massively parallel detection of diffuse photon density wave amplitude and phase for a large number of source-detector pairs (10(6)). The stand-alone clinical DOT instrument thus offers high spatial resolution with reduced crosstalk between absorption and scattering. Other novel features include a fringe profilometry system for breast boundary segmentation, real-time data normalization, and a patient bed design which permits both axial and sagittal breast measurements. The authors validated the instrument using tissue simulating phantoms with two different chromophore-containing targets and one scattering target. The authors also demonstrated the instrument in a case study breast cancer patient; the reconstructed 3D image of endogenous chromophores and scattering gave tumor localization in agreement with MRI. Imaging with a novel parallel-plate DOT breast imager that employs highly parallel, high-resolution CCD detection in the frequency-domain was demonstrated.


Targeted deletion of PD-1 in myeloid cells induces antitumor immunity.
PD-1, a T cell checkpoint receptor and target of cancer immunotherapy, is also expressed on myeloid cells. The role of myeloid-specific versus T cell-specific PD-1 ablation on antitumor immunity has remained unclear because most studies have used either PD-1-blocking antibodies or complete PD-1 KO mice. We generated a conditional allele, which allowed myeloid-specific (PD-1f/fLysMcre) or T cell-specific (PD-1f/fCD4cre) targeting of Pdcd1 gene. Compared with T cell-specific PD-1 ablation, myeloid cell-specific PD-1 ablation more effectively decreased tumor growth. We found that granulocyte/macrophage progenitors (GMPs), which accumulate during cancer-driven emergency myelopoiesis and give rise to myeloid-derived suppressor cells (MDSCs), express PD-1. In tumor-bearing PD-1f/fLysMcre but not PD-1f/fCD4cre mice, accumulation of GMP and MDSC was prevented, whereas systemic output of effector myeloid cells was increased. Myeloid cell-specific PD-1 ablation induced an increase of T effector memory cells with improved functionality and mediated antitumor protection despite preserved PD-1 expression in T cells. In PD-1-deficient myeloid progenitors, growth factors driving emergency myelopoiesis induced increased metabolic intermediates of glycolysis, pentose phosphate pathway, and TCA cycle but, most prominently, elevated cholesterol. Because cholesterol is required for differentiation of inflammatory macrophages and DC and promotes antigen-presenting function, our findings indicate that metabolic reprogramming of emergency myelopoiesis and differentiation of effector myeloid cells might be a key mechanism of antitumor immunity mediated by PD-1 blockade.


Results of Late Gadolinium Enhancement in Children Affected by Dilated Cardiomyopathy.
Little is known about the clinical value of late gadolinium enhancement (LGE), in children affected by dilated cardiomyopathy (DCM). We retrospectively evaluated 15 patients (8 ± 6 years, 6 males) with diagnosis of DCM who underwent cardiac magnetic resonance since 2014. All scans were performed with a 1.5 T system (Aera, Siemens). Study protocol included cine steady-state free precession sequences, followed by administration of 0.2 mmol/kg of gadolinium-based contrast agent. Inversion recovery Turbo Flash sequences, in the same position of cine images, were acquired 10-15 min after the injection of contrast agent, in order to assess the presence of LGE. The latter was considered positive with a signal intensity >6 SD from normal myocardial tissue. Indexed end-diastolic volume (EDVi) and end-systolic volume (ESVi), and left ventricle (LV) ejection fraction (EF) were calculated by using dedicated software on off-line workstation. Global longitudinal strain and diastolic function were evaluated by echocardiography. Clinical follow-up, including death, transplant, and listing for heart transplant [major adverse cardiac events (MACE)], were evaluated. Patients were divided into two different subgroups: negative (Group A) and positive (Group B) for presence of LGE. Statistical analysis was performed by using Mann-Whitney U test (p < 0.05 considered as statistically significant). Seven patients (47%) showed LGE. A global diffuse subendocardial pattern was evident in all patients presenting LGE (7/7, 100%). The following main LV indexes were observed in the two subgroups. Group A: EDVi = 96 ± 33 ml, ESVi = 56 ± 29 ml, LV EF = 45 ± 10%, global longitudinal strain = -16 ± 5%, E/e' ratio = 10 ± 3, MACE = 1. Group B: EDVi = 130 ± 60 ml, ESVi = 89 ± 43 ml, LV EF = 31 ± 6%, global longitudinal strain = -13 ± 4%, E/e' ratio = 9 ± 3, MACE = 3. There was no statistically significant difference between the two groups, in terms of EDVi (p: 0.2), ESVi (p: 0.2), and E/e' ratio (0.9), whereas a significant difference of LV EF, presence of significative mitral regurgitation, and global longitudinal strain were observed (respectively, p: 0.03, p: 0.009, and p: 0.03). In our population of children with DCM, LGE shows a global diffuse subendocardial pattern. Presence of LGE seems to play a role in these patients determining a worst global systolic function.


OK, Doc . . . What Do I Really Have? Posttraumatic Stress Disorder Versus Traumatic Brain Injury.
The authors review the diagnostic overlap that exists between posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI). Achieving the correct diagnosis is much more difficult and the potential to inappropriately treat patients is greater than most physicians realize. The need to properly diagnose and select appropriate treatment strategies is essential, especially with TBI cases. A number of new and experimental therapies are being used to treat PTSD effectively and reverse the neurological sequelae of TBI, potentially returning to active duty Servicemembers who are undergoing a medical review board.


Schizoaffective Disorder in the DSM-5.
Characterization of patients with both psychotic and mood symptoms, either concurrently or at different points during their illness, has always posed a nosological challenge and this is reflected in the poor reliability, low diagnostic stability, and questionable validity of DSM-IV Schizoaffective Disorder. The clinical reality of the frequent co-occurrence of psychosis and Mood Episodes has also resulted in over-utilization of a diagnostic category that was originally intended to only rarely be needed. In the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, an effort is made to improve reliability of this condition by providing more specific criteria and the concept of Schizoaffective Disorder shifts from an episode diagnosis in DSM-IV to a life-course of the illness in DSM-5. When psychotic symptoms occur exclusively during a Mood Episode, DSM-5 indicates that the diagnosis is the appropriate Mood Disorder with Psychotic Features, but when such a psychotic condition includes at least a two-week period of psychosis without prominent mood symptoms, the diagnosis may be either Schizoaffective Disorder or Schizophrenia. In the DSM-5, the diagnosis of Schizoaffective Disorder can be made only if full Mood Disorder episodes have been present for the majority of the total active and residual course of illness, from the onset of psychotic symptoms up until the current diagnosis. In earlier DSM versions the boundary between Schizophrenia and Schizoaffective Disorder was only qualitatively defined, leading to poor reliability. This change will provide a clearer separation between Schizophrenia with mood symptoms from Schizoaffective Disorder and will also likely reduce rates of diagnosis of Schizoaffective Disorder while increasing the stability of this diagnosis once made.


An Integrated Approach for Preventing Oral Cavity and Oropharyngeal Cancers: Two Etiologies with Distinct and Shared Mechanisms of Carcinogenesis.
Head and neck squamous cell carcinoma (HNSCC) was the 7th most common malignancy worldwide in 2018 and despite therapeutic advances, the overall survival rate for oral squamous cell carcinoma (OSCC; ∼50%) has remained unchanged for decades. The most common types are OSCC and oropharyngeal squamous cell carcinoma (OPSCC, survival rate ∼85%). Tobacco smoking is a major risk factor of HNSCC. In the developed world, the incidence of OSCC is declining as a result of tobacco cessation programs. However, OPSCC, which is also linked to human papillomavirus (HPV) infection, is on the rise and now ranks as the most common HPV-related cancer. The current state of knowledge indicates that HPV-associated disease differs substantially from other types of HNSCC and distinct biological differences between HPV-positive and HPV-negative HNSCC have been identified. Although risk factors have been extensively discussed in the literature, there are multiple clinically relevant questions that remain unanswered and even unexplored. Moreover, existing approaches (e.g., tobacco cessation, vaccination, and chemoprevention) to manage and control this disease remain a challenge. Thus, in this review, we discuss potential future basic research that can assist in a better understanding of disease pathogenesis which may lead to novel and more effective preventive strategies for OSCC and OPSCC.


A watershed-scale assessment of cost-effectiveness of sediment abatement with flow diversion terraces.
Soil conservation beneficial management practices (BMPs) are effective at controlling soil loss from farmlands and minimizing water pollution in agricultural watersheds. However, costs associated with implementing and maintaining these practices are high and often deter farmers from using them. Consequently, it is necessary to conduct cost-benefit analysis of BMP implementation to assist decision-makers with planning to provide the greatest level of environmental protection with limited resources and funding. The Soil and Water Assessment Tool (SWAT) was used to evaluate the efficacy of flow diversion terraces (FDT) in abating sediment yield at the outlet of Black Brook Watershed (BBW), northwestern New Brunswick. Different FDT-implementation scenarios were expressed as the ratio of land area protected by FDT to the total cultivated area. From this analysis, we found that average annual sediment yield decreased exponentially with increased FDT protection. When the proportion of FDT-protected areas was low, sediment reductions caused by FDT increased sharply with increasing use of FDT. Similarly, marginal sediment yield abatement costs (dollar per tonne of sediment reduction) increased exponentially with increasing proportion of FDT-protected area. The results indicated that increasing land protection with FDT from 6 to 50% would result in a reduction of about 2.1 tonne ha(-1) yr(-1) and costs of sediment reduction increased from $7 to $12 per tonne. Increasing FDT-protected cropland from 50 to 100%, a reduction of about 0.9 tonne of sediment ha(-1) yr(-1) would occur and the costs would increase from $12 to $53 per tonne of sediment yield reduction.


Reproductive biology of the Rasptail skate Rostroraja velezi (Rajiformes: Rajidae).
The Rasptail skate Rostroraja velezi is commercially exploited in artisanal elasmobranch fisheries along the west coast of Baja California Sur, Mexico, but information on its life history is limited. This study aimed to investigate the reproductive biology of R. velezi. A total of 105 specimens were caught from April 2008 to May 2012, including the largest reported specimen with 121 cm total length, 96 cm disc width (DW ). Females attained larger sizes than males. Males and females presented functional gonads. There was an asymmetry in the testes of males, with the left testis being larger. Histological analysis of the reproductive biology of R. velezi was performed here for the first time. The presence of sperm storage in females and spermatogenic development beginning at the first stages of maturity in males was recorded. It was possible to identify the development of secretions in the club, baffle and terminal zone of the oviducal gland. DW at maturity, defined as the DW at which 50% of the population is mature, was estimated at 68-72 cm for females and 65.1 cm for males. Egg-bearing females caught in April and May presented one egg capsule per uterus. Furthermore, a description of the egg capsule of R. velezi is provided. Elucidating the reproductive cycle, the type of reproductive strategies, and the fecundity of R. velezi will allow us to understand the impact of fisheries on this species.


Does a Nintendo Wii exercise program provide similar exercise demands as a traditional pulmonary rehabilitation program in adults with COPD?
The chronic obstructive pulmonary disease (COPD) population can experience lower activity and fitness levels than the non-COPD population. The Nintendo Wii may be an appropriate at-home training device for the COPD population, which could be used as a supplement for a pulmonary rehabilitation program. This study was a randomized, within-subject, cross-over study involving 10 adults with COPD previously enrolled in St Paul's Hospital's pulmonary rehabilitation program. This study attempted to determine if specific Wii activities resulted in similar energy expenditures to that of a more traditional pulmonary rehabilitation activity. Participants completed two 15-min exercise interventions in a single session, with a washout period of 30 min in-between. The interventions were an experimental Wii intervention and a traditional treadmill intervention. There was no significant difference in total energy expenditure between the two 15-min exercise interventions [mean difference 36.3 joules; 95% confidence interval (CI): 31.4, 104]. There was no significant difference in heart rate (mean difference -0.167 beats per minute; 95% CI: -4.83, 4.50), rating of perceived exertion (mean difference 0.100; 95% CI: -0.416, 0.616) and Borg dyspnea scale (mean difference 0.267; 95% CI: -0.004, 0.537) between the two 15-min exercise interventions. There was a significant difference in SpO2 between the two 15-min exercise interventions (Wii intervention mean difference 2.33% > treadmill intervention; 95% CI: 1.52, 3.15). Gaming technology can provide an exercise program that has similar cardiovascular demands to traditional pulmonary rehabilitation programs for patients with COPD. Further research is necessary to address feasibility and long-term adherence.


The palindromic series I repeats in the simian cytomegalovirus major immediate-early promoter behave as both strong basal enhancers and cyclic AMP response elements.
A 600-base-pair (bp) enhancer region upstream from the major IE94 gene of simian cytomegalovirus (SCMV) produces very strong basal expression of associated gene products. This domain consists of multiple sets of interspersed repetitive elements, including 11 copies of a conserved 16-bp palindromic sequence with the consensus CCATTGACGTCAATGG. These series I repeats contain an 8-bp core TGACGTCA that resembles the cyclic AMP (cAMP) response element (CRE) of cellular genes. In transient chloramphenicol acetyltransferase assays in K562 human erythroleukemia cells, a set of deleted variants of the IE94 promoter all responded up to 15-fold to induction by cAMP. However, successive removal of most of the SCMV 16-bp motifs reduced basal expression over 20-fold. The cAMP stimulation was also manifested at the steady-state RNA level after SCMV infection of K562 cells and was detectable within 1.5 h after treatment of DNA-transfected cells. Addition of a single 30-bp oligonucleotide encompassing the 16-bp palindrome conveyed up to 10-fold cAMP responsiveness onto a heterologous weak promoter but had no effect on basal expression. In contrast, two or more adjacent copies produced 20- to 40-fold increases in basal expression and provided greater than 200-fold activation in the presence of cAMP. Similar effects were obtained when the oligonucleotides were placed in a downstream location relative to the reporter gene. Studies with mutant oligonucleotides revealed that both the core CRE and the flanking sequence portions of the 16-bp elements were essential for enhancer function. Both components were also important for maximum cAMP responsiveness. Band shift assays with fractionated nuclear extracts from Raji lymphocytes revealed multiple competable complexes with cellular DNA-binding factors that recognized the series I elements. Three distinct CREB-like factors were detected that required only the core 8-bp elements for binding. We conclude that the 16-bp series I repeats provide a major contribution to the constitutive enhancer properties of the IE94 promoter and also act as functional CREs. The cAMP response properties appear likely to play a key role in reactivation of the virus from a latent state in appropriately differentiating cell types.


Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia.
Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) [inv(3)/t(3;3)] is recognized as a distinctive entity in the WHO classification. Risk assignment and clinical and genetic characterization of AML with chromosome 3q abnormalities other than inv(3)/t(3;3) remain largely unresolved. Cytogenetics, molecular genetics, therapy response, and outcome analysis were performed in 6,515 newly diagnosed adult AML patients. Patients were treated on Dutch-Belgian Hemato-Oncology Cooperative Group/Swiss Group for Clinical Cancer Research (HOVON/SAKK; n = 3,501) and German-Austrian Acute Myeloid Leukemia Study Group (AMLSG; n = 3,014) protocols. EVI1 and MDS1/EVI1 expression was determined by real-time quantitative polymerase chain reaction. 3q abnormalities were detected in 4.4% of AML patients (288 of 6,515). Four distinct groups were defined: A: inv(3)/t(3;3), 32%; B: balanced t(3q26), 18%; C: balanced t(3q21), 7%; and D: other 3q abnormalities, 43%. Monosomy 7 was the most common additional aberration in groups (A), 66%; (B), 31%; and (D), 37%. N-RAS mutations and dissociate EVI1 versus MDS1/EVI1 overexpression were associated with inv(3)/t(3;3). Patients with inv(3)/t(3;3) and balanced t(3q21) at diagnosis presented with higher WBC and platelet counts. In multivariable analysis, only inv(3)/t(3;3), but not t(3q26) and t(3q21), predicted reduced relapse-free survival (hazard ratio [HR], 1.99; P < .001) and overall survival (HR, 1.4; P = .006). This adverse prognostic impact of inv(3)/t(3;3) was enhanced by additional monosomy 7. Group D 3q aberrant AML also had a poor outcome related to the coexistence of complex and/or monosomal karyotypes and cryptic inv(3)/t(3;3). Various categories of 3q abnormalities in AML can be distinguished according to their clinical, hematologic, and genetic features. AML with inv(3)/t(3;3) represents a distinctive subgroup with unfavorable prognosis.


Hemodynamic effects of S-nitrosocysteine, an intravenous regional vasodilator.
S-nitrosocysteine is a carrier form of nitric oxide that can be delivered intravenously. S-nitrosocysteine is rapidly metabolized by plasma (half-life = 2-3 seconds), forming nitric oxide and cysteine. With its short half-life and potent vasodilatory properties, S-nitrosocysteine may be useful as a pulmonary vasodilating agent in cases of postoperative and chronic pulmonary hypertension. Our objective was to determine the hemodynamic properties of S-nitrosocysteine on the pulmonary and systemic circulations to assess its potential utility as a pulmonary vasodilatory agent. Eleven adult swine were anesthetized. Thermodilution (Swan-Ganz; Baxter International, Inc, Deerfield, Ill) and arterial catheters were inserted. Flow probes were placed around the coronary, renal, superior mesenteric, and iliac arteries. Incremental infusion doses of S-nitrosocysteine (5-80 nmol. kg(-1). min(-1)) were delivered into the right atrium. Cardiac output, right and left heart pressures, heart rate, Pao(2), and iliac, renal, coronary, and mesenteric blood flow rates were recorded at baseline and at each infusion dose of S-nitrosocysteine. Low-dose S-nitrosocysteine infusion decreased mean pulmonary artery pressure (15%, P =.013) without a significant reduction in mean systemic artery pressure. Higher dose infusions produced further dose-dependent declines in pulmonary vascular resistance and measurable reductions in systemic vascular resistance (P =.01). At an S-nitrosocysteine dosage of 40 nmol. kg(-1). min(-1), there was a significant reduction in renal (P <.001) and mesenteric (P =.003) blood flow but no change in iliac (P >.2) or coronary (P >.2) blood flow. Cardiac output remained constant up to infusion rates of 40 nmol. kg(-1). min(-1) (P >.2). Doses higher than 5 nmol. kg(-1). min(-1) resulted in a substantial dose-dependent reduction in Pao(2) (P <.001), suggesting dilation of atelectatic areas of the lung. S-nitrosocysteine is a potent vasodilatory agent capable of overcoming the hypoxic vasoconstrictive response of the lung. Our results suggest it may prove useful as a pulmonary vasodilatory agent at low doses. Higher dose infusions reduce mean systemic pressure and lead to compensatory reductions in renal and mesenteric blood flow without a decrease in cardiac output.


RANKL/RANK/MMP-1 molecular triad contributes to the metastatic phenotype of breast and prostate cancer cells in vitro.
The osteolytic nature of bone metastasis results from a tumor-driven increased bone resorption. Bone remodeling is orchestrated by the molecular triad RANK-RANKL-OPG. This process is dysregulated in bone metastases, mostly via induction of RANKL by tumor-derived factors. These factors increase expression of RANKL, which induce osteoclast formation, function, and survival, thereby increasing bone resorption. RANK is unexpectedly expressed by cancer cells, and the activation of RANKL-RANK pathway correlates with an increased invasive phenotype. To investigate the interaction between RANK expression in human breast and prostate cancer cells and their pro-metastatic phenotype we analyzed the activation of RANKL-RANK pathway and its effects on cell migration, invasion, gene expression in vitro, and osteolysis-inducing ability in vivo. RANKL activates kinase signaling pathways, stimulates cell migration, increases cell invasion, and up-regulates MMP-1 expression. In vivo, MMP-1 knockdown resulted in smaller x-ray osteolytic lesions and osteoclastogenesis, and decreased tumor burden. Therefore, RANKL inhibition in bone metastatic disease may decrease the levels of the osteoclastogenesis inducer MMP-1, contributing to a better clinical outcome.


Exogenous Administration of Recombinant MIF at Physiological Concentrations Failed to Attenuate Infarct Size in a Langendorff Perfused Isolated Mouse Heart Model.
Evidence suggests a two-pronged role of endogenous macrophage migration inhibitory factor (MIF) release in ischemia/reperfusion injury. We aimed to assess whether its exogenous administration confers cardioprotection. Male C57/BL6 mice were randomly allocated to receive recombinant mouse MIF (rMIF) at physiological (ng/mL) concentrations in a dose-response fashion before or after a protocol of 35 min of ischemia and 2 h of reperfusion in an isolated Langendorff-perfused model with infarct size as endpoint. Isolated primary cardiomyocytes were also used for cell survival studies using rMIF at a supra-physiological concentration of 1 μg/mL. Pro-survival kinase activation was also studied using Western blot analyses. Exogenous MIF did not elicit a cardioprotective effect either when administered before the ischemic insult or when applied at reperfusion. rMIF did not confer protection when it was applied immediately before or after a hypoxia/reoxygenation insult in primary isolated cardiomyocytes. Consistently, hearts treated with MIF did not show a significant increase in phosphorylated Akt and ERK1/2. The exogenous administration of rMIF in a physiological concentration range both before ischemia and at reperfusion did not show cardioprotective effects. Although these results do not address the role of endogenous MIF after an ischemic insult followed by reperfusion, they may limit the potential translational value of rMIF.


Seasonal patterns of dengue fever and associated climate factors in 4 provinces in Vietnam from 1994 to 2013.
In Vietnam, dengue fever (DF) is still a leading cause of hospitalization. The main objective of this study was to evaluate the seasonality and association with climate factors (temperature and precipitation) on the incidences of DF in four provinces where the highest incidence rates were observed from 1994 to 2013 in Vietnam. Incidence rates (per 100,000) were calculated on a monthly basis from during the study period. The seasonal-decomposition procedure based on loess (STL) was used in order to assess the trend and seasonality of DF. In addition, a seasonal cycle subseries (SCS) plot and univariate negative binomial regression (NBR) model were used to evaluate the monthly variability with statistical analysis. Lastly, a generalized estimating equation (GEE) was used to assess the relationship between monthly incidence rates and weather factors (temperature and precipitation). We found that increased incidence rates were observed in the second half of each year (from May through December) which is the rainy season in each province. In Hanoi, the final model showed that 1 °C rise of temperature corresponded to an increase of 13% in the monthly incidence rate of DF. In Khanh Hoa, the final model displayed that 1 °C increase in temperature corresponded to an increase of 17% while 100 mm increase in precipitation corresponded to an increase of 11% of DF incidence rate. For Ho Chi Minh City, none of variables were significant in the model. In An Giang, the final model showed that 100 mm increase of precipitation in the preceding and same months corresponded to an increase of 30% and 22% of DF incidence rate. Our findings provide insight into understanding the seasonal pattern and associated climate risk factors.


Pharmacokinetics and tissue distribution of 14C-labeled grape polyphenols in the periphery and the central nervous system following oral administration.
Grape polyphenols confer potential health benefits, including prevention of neurodegenerative diseases. To determine the absorption and tissue distribution of the complex grape polyphenol mixture, (14)C-labeled polyphenols were biosynthesized by grape cell suspension cultures, during co-incubation with radioisotopically labeled sucrose, and fractionated into polyphenolic subfractions. The pharmacokinetics and distribution of grape polyphenols into blood, brain, and peripheral interstitial fluid were determined by tracking the (14)C label. The blood peak (14)C concentration of the fractions ranged from 15 minutes to 4 hours. Absorption and tissue distribution varied greatly between fractions. Concentrations in interstitial fluid were lower than in blood. The amount of residual label in the brain at 24 hours ranged from 0.1% to 1.7% of the dose, depending on the fraction. (14)C label found in the brain tissue and brain microdialysate indicated that grape polyphenols or their metabolites are able to cross the blood-brain barrier. Using (14)C-labeled plant polyphenols it is possible to track the compounds or their metabolic products into any tissue and determine distribution patterns in spite of low concentrations. A central question regarding the potential role of dietary polyphenolics in neurodegenerative research is whether they are bioavailable in the brain. Our observations indicate that some grape-derived polyphenolics do reach the brain, which suggests their potential value for applications in neurodegenerative disorders.


Cancer stem cell markers CD133 and CD24 correlate with invasiveness and differentiation in colorectal adenocarcinoma.
To verify that CD markers are available for detecting cancer stem cell populations and to evaluate their clinical significance in colon cancer. Immunohistochemistry for CD133, CD24 and CD44 was performed on the tissue microarray of 523 colorectal adenocarcinomas. Medical records were reviewed and clinicopathological analysis was performed. In colorectal adenocarcinoma, 128 of 523 cases (24.5%) were positive and 395 cases (75.5%) were negative for CD133 expression. Two hundred and sixty-four of 523 cases (50.5%) were positive and 259 cases (49.5%) were negative for CD24 expression. Five hundred and two of 523 cases (96%) were negative and 21 cases (4%) were positive for CD44 expression. Upon clinicopathological analysis, CD133 expression was present more in male patients (P = 0.002) and in advanced T stage cancer (P = 0.024). Correlation between CD24 expression and clinicopathological factors was seen in the degree of differentiation (P = 0.006). Correlation between CD44 expression and clinicopathological factors was seen in the tumor size (P = 0.001). Survival was not significantly related to CD133, CD24 and CD44 expression. CD markers were related to invasiveness and differentiation of colorectal adenocarcinoma. However, CD expression was not closely related to survival.


Redox instability induced by 4-hydroxy-2-nonenal in porcine and bovine myoglobins at pH 5.6 and 4 degrees C.
Myoglobin (Mb) redox stability affects meat color and is compromised by lipid oxidation products such as 4-hydroxy-2-nonenal (HNE). Pork lipids are generally more unsaturated and would be expected to oxidize readily and produce more oxidation products than beef. Supranutritional supplementation of vitamin E improves Mb redox stability of beef but not pork. The present study investigated HNE-induced redox instability in porcine and bovine myoglobins at 4 degrees C and pH 5.6. Oxymyoglobin (OxyMb) was incubated with HNE (0.075 mM porcine OxyMb + 0.5 mM HNE; 0.15 mM bovine OxyMb + 1.0 mM HNE). In porcine Mb, only monoadducts formed via Michael addition were detected after 72 h, whereas in bovine Mb both mono- and diadducts were identified. LC-MS-MS identified four histidine residues (His 36, 81, 88, and 152) of bovine Mb that were readily adducted by HNE, whereas in porcine Mb only two histidine residues (His 24 and 36) were adducted. These results suggested that the primary structure of bovine Mb predisposes it to greater nucleophilic attack by HNE and subsequent adduction than is suffered by porcine Mb.


Differences in Host Innate Responses among Coccidioides Isolates in a Murine Model of Pulmonary Coccidioidomycosis.
Coccidioides immitis and Coccidioides posadasii are soil-dwelling fungi and the causative agents of coccidioidomycosis, a mycosis endemic to certain semiarid regions in the Americas. The most common route of infection is by inhalation of airborne Coccidioides arthroconidia. Once a susceptible host inhales the conidia, a transition to mature endosporulated spherules can occur within the first 5 days of infection. For this study, we examined the host response in a murine model of coccidioidomycosis during a time period of infection that has not been well characterized. We collected lung tissue and bronchoalveolar lavage fluid (BALF) from BALB/c mice that were infected with a C. immitis pure strain, a C. immitis hybrid strain, or a C. posadasii strain as well as uninfected mice. We compared the host responses to the Coccidioides strains used in this study by assessing the level of transcription of selected cytokine genes in lung tissues and characterized host and fungal proteins present in BALF. Host response varied depending on the Coccidioides strain that was used and did not appear to be overly robust. This study provides a foundation to begin to dissect the host immune response early in infection, to detect abundant Coccidioides proteins, and to develop diagnostics that target these early time points of infection.


Metabolic Model of the Phytophthora infestans-Tomato Interaction Reveals Metabolic Switches during Host Colonization.
The oomycete pathogen Phytophthora infestans causes potato and tomato late blight, a disease that is a serious threat to agriculture. P. infestans is a hemibiotrophic pathogen, and during infection, it scavenges nutrients from living host cells for its own proliferation. To date, the nutrient flux from host to pathogen during infection has hardly been studied, and the interlinked metabolisms of the pathogen and host remain poorly understood. Here, we reconstructed an integrated metabolic model of P. infestans and tomato (Solanum lycopersicum) by integrating two previously published models for both species. We used this integrated model to simulate metabolic fluxes from host to pathogen and explored the topology of the model to study the dependencies of the metabolism of P. infestans on that of tomato. This showed, for example, that P. infestans, a thiamine auxotroph, depends on certain metabolic reactions of the tomato thiamine biosynthesis. We also exploited dual-transcriptome data of a time course of a full late blight infection cycle on tomato leaves and integrated the expression of metabolic enzymes in the model. This revealed profound changes in pathogen-host metabolism during infection. As infection progresses, P. infestans performs less de novo synthesis of metabolites and scavenges more metabolites from tomato. This integrated metabolic model for the P. infestans-tomato interaction provides a framework to integrate data and generate hypotheses about in planta nutrition of P. infestans throughout its infection cycle.IMPORTANCE Late blight disease caused by the oomycete pathogen Phytophthora infestans leads to extensive yield losses in tomato and potato cultivation worldwide. To effectively control this pathogen, a thorough understanding of the mechanisms shaping the interaction with its hosts is paramount. While considerable work has focused on exploring host defense mechanisms and identifying P. infestans proteins contributing to virulence and pathogenicity, the nutritional strategies of the pathogen are mostly unresolved. Genome-scale metabolic models (GEMs) can be used to simulate metabolic fluxes and help in unravelling the complex nature of metabolism. We integrated a GEM of tomato with a GEM of P. infestans to simulate the metabolic fluxes that occur during infection. This yields insights into the nutrients that P. infestans obtains during different phases of the infection cycle and helps in generating hypotheses about nutrition in planta.


Design strategies for bioorthogonal smart probes.
Bioorthogonal chemistry has enabled the selective labeling and detection of biomolecules in living systems. Bioorthogonal smart probes, which become fluorescent or deliver imaging or therapeutic agents upon reaction, allow for the visualization of biomolecules or targeted delivery even in the presence of excess unreacted probe. This review discusses the strategies used in the development of bioorthogonal smart probes and highlights the potential of these probes to further our understanding of biology.


Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences the circadian clock.
In animals, circadian oscillators are based on a transcription-translation circuit that revolves around the transcription factors CLOCK and BMAL1. We found that the JumonjiC (JmjC) and ARID domain-containing histone lysine demethylase 1a (JARID1a) formed a complex with CLOCK-BMAL1, which was recruited to the Per2 promoter. JARID1a increased histone acetylation by inhibiting histone deacetylase 1 function and enhanced transcription by CLOCK-BMAL1 in a demethylase-independent manner. Depletion of JARID1a in mammalian cells reduced Per promoter histone acetylation, dampened expression of canonical circadian genes, and shortened the period of circadian rhythms. Drosophila lines with reduced expression of the Jarid1a homolog, lid, had lowered Per expression and similarly altered circadian rhythms. JARID1a thus has a nonredundant role in circadian oscillator function.


Value of the SYNTAX score in patients treated by primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: The MI SYNTAXscore study.
The aims of this study were to evaluate the SYNTAX score (SXscore) calculated at 2 stages during a primary percutaneous intervention (PPCI), that is, SXscore I (diagnostic) and SXscore II (postwiring), and assess its additional value to standard clinical risk scores in acute myocardial infarction. SXscores I and II were applied to 736 consecutive acute ST-elevation myocardial infarction patients referred for PPCI between November 2006 and February 2008. SXscore changed significantly before (I: 16, interquartile range 9.5-23) and after wiring (II: 11, interquartile range 6-19), P < .001. Kaplan-Meier methods were used to compare the primary end point major adverse coronary events (MACE; composite of repeat MI, target vessel revascularization [TVR], and mortality) and secondary end point mortality at 1.5 years in tertiles of SXscore I and SXscore II. Major adverse coronary event was highest in the higher SXscore I tertile (11% vs 15% vs 23%, log-rank <0.01), driven primarily by increased rate of mortality (9% vs 11% vs 17%, log-rank 0.02). Major adverse coronary event was also highest in SXscore II tertile, by a combination of increased mortality and also TVR (TVR rate 2% vs 3% vs 9%, log-rank <0.01). Predictive Cox regression models for mortality and MACE were significantly and similarly improved by the addition of either SXscore I or SXscore II (hazard ratio 1.63, 95% CI 1.18-2.26, P < .01 for MACE) with respective c indices of 0.61 and 0.63 for MACE and 0.60 and 0.61 for mortality. SXscore during PPCI is a useful tool that provides additional risk stratification to known risk factors of long-term mortality and MACE in patients with ST-elevation myocardial infarction.


Nutritional significance of rice bran oil.
India is the second largest producer of rice in the world and has the high potential to produce rice bran oil (RBO), a by-product of the rice milling industry. Since RBO is, an unconventional oil, the chemical composition, nutrient evaluation and toxicological safety were assessed. The fatty acid composition RBO is very close to that of groundnut oil (GNO). Though RBO has high unsaponifiable matter (4.2%), it is rich In minor constituents such as phytosterols, triterpene alcohols, tocopherols and tocotrienols. Experimental as well as human studies have demonstrated the hypolipidaemic effects of RBO. Further, It was established that minor constituents present in unsaponifiable fraction of RBO were responsible for its hypolipidaemic effects. Nutritional evaluation studies, carried out with 10 per cent RBO and 20 per cent protein, indicated that growth, feed efficiency and mineral balance were comparable to GNO-fed animals. Toxicological studies had shown that there were no abnormalities In animals fed either RBO or GNO. The reproductive performance was also found to be normal as compared with that of GNO-fed animals in all three generations. In addition, neither RBO nor the foods deepfried in it showed any mutagenicity as judged by Ames test. In view of its safety and hypolipidaemic activity, RBO could be considered as an alternative source of edible oil.


Informed consent for exome sequencing research in families with genetic disease: the emerging issue of incidental findings.
Genomic sequencing technology is increasingly used in genetic research. Studies of informed consent for exome and genome sequencing (ES/GS) research have largely involved hypothetical scenarios or healthy individuals enrolling in population-based studies. Studies have yet to explore the consent experiences of adults with inherited disease. We conducted a qualitative interview study of 15 adults recently enrolled in a large-scale ES/GS study (11 affected adults, four parents of affected children). Our study had two goals: (1) to explore three theoretical barriers to consent for ES/GS research (interpretive/technical complexity, possibility of incidental findings, and risks of loss of privacy); and (2) to explore how interviewees experienced the consent process. Interviewees could articulate study goals and processes, describe incidental findings, discuss risks of privacy loss, and reflect on their consent experience. Few expected the study would identify the genetic cause of their condition. All elected to receive incidental findings. Interviewees acknowledged paying little attention to potential implications of incidental findings in light of more pressing goals of supporting research regarding their own medical conditions. Interviewees suggested that experience living with a genetic condition prepared them to adjust to incidental findings. Interviewees also expressed little concern about loss of confidentiality of study data. Some experienced the consent process as very long. None desired reconsent prior to return of study results. Families with inherited disease likely would benefit from a consent process in which study risks and benefits were discussed in the context of prior experiences with genetic research and genetic disease.


Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib.
Following the initial success of imatinib as frontline therapy for chronic myeloid leukemia (CML), several second-generation therapeutics have been developed with increased potency and the ability to inhibit the majority of imatinib-resistant mutations. Here, we review the current knowledge about the target specificity of the two new inhibitors nilotinib and dasatinib in comparison to imatinib, including the recent large-scale chemical proteomics screens.


Memory for lists of sounds by the bottle-nosed dolphin: convergence of memory processes with humans?
After listening to a list of as many as six discriminably different 2-second sounds, a bottle-nosed dolphin classified a subsequent probe sound as either "old" (from the list) or "new." The probability of recognizing an old probe was close to 1.0 if it matched the most recent sound in the list and decreased sigmoidally for successively earlier list sounds. Memory span was estimated to be at least four sounds. Overall probabilities of correctly classifying old and new probes corresponded closely, as if recognition decisions were made according to an optimum maximum likelihood criterion. The data bore many similarities to data obtained from humans tested on probe recognition tasks.


Anabolic hormone profiles in elite military men: Robust associations with age, stress, and fatigue.
We recently established stable daily profiles of the anabolic hormones dehydroepiandrosterone (DHEA) and testosterone in 57 elite military men. In this follow-on study, we explored associations of salivary anabolic hormone profiles with demographic (i.e., age, body mass index [BMI]) and biobehavioral health indices (i.e., blood pressure, sleep, perceived stress, fatigue) via correlational models. Next, nuanced patterns were constructed using quartile splits followed by one-way analysis of variance and post hoc subgroup comparisons. Both DHEA (r range: -0.33 to -0.49) and testosterone (r range: -0.19 to -0.41) were inversely associated with age. Quartile comparisons revealed that age-related declines in DHEA were linear, curvilinear, or sigmoidal, depending on the summary parameter of interest. Anabolic hormone profiles did not associate with BMI, blood pressure, or sleep efficiency. Robust linear associations were observed between testosterone and perceived stress (r range: -0.29 to -0.36); concentration-dependent patterns were less discernible. Lower DHEA (r range: -0.22 to -0.30) and testosterone (r range: -0.22 to -0.36) concentrations associated with higher fatigue. Subsequent quartile comparisons suggested a concentration-dependent threshold with respect to evening testosterone. Specifically, those individuals within the lowest quartile (≤68.4pg/mL) endorsed the highest fatigue of the four groups (p=0.01), while the remaining three groups did not differ from each other. This study not only showed that anabolic hormone profiles have distinctive age trajectories, but are also valuable predictors of stress and fatigue in elite military men. This highlights the importance of routine monitoring of anabolic hormone profiles to sustain and optimize health and readiness in chronically stressed populations.


Integrated treatment of co-occurring mental illness and addiction: clinical intervention, program, and system perspectives.
Individuals with mental illness and addiction comprise at least half of the patients in most mental health treatment systems. This combination results in increased risk for frequent psychiatric relapses, poor medication compliance, violence, suicide, legal problems, and high utilization of the emergency room or inpatient services. Traditional mental health and addiction treatments have not adequately addressed these co-occurring disorders due to clinical interventions, programs, and system flaws that have not addressed the individual's needs. Integrated treatment requires both an understanding of mental illness and addiction and the means to integrate and modify the traditional treatment approaches in both the mental health and addiction treatment fields. There is strong evidence to support the efficacy and effectiveness of integrated treatment in this population. All mental health clinicians should become experienced and skilled in the core psychotherapy approaches to treating substance use disorders, including motivational enhancement therapy, relapse prevention (cognitive-behavioral therapy), and 12-step facilitation. In addition, integrated treatment includes integrating medications for both addiction and mental illness with the behavioral therapies and other psychosocial interventions. This article reviews the clinical intervention, program, and system components of integrated treatment and specific clinical interventions for this population.


Complex formation of APP with GABAB receptors links axonal trafficking to amyloidogenic processing.
GABAB receptors (GBRs) are key regulators of synaptic release but little is known about trafficking mechanisms that control their presynaptic abundance. We now show that sequence-related epitopes in APP, AJAP-1 and PIANP bind with nanomolar affinities to the N-terminal sushi-domain of presynaptic GBRs. Of the three interacting proteins, selectively the genetic loss of APP impaired GBR-mediated presynaptic inhibition and axonal GBR expression. Proteomic and functional analyses revealed that APP associates with JIP and calsyntenin proteins that link the APP/GBR complex in cargo vesicles to the axonal trafficking motor. Complex formation with GBRs stabilizes APP at the cell surface and reduces proteolysis of APP to Aβ, a component of senile plaques in Alzheimer's disease patients. Thus, APP/GBR complex formation links presynaptic GBR trafficking to Aβ formation. Our findings support that dysfunctional axonal trafficking and reduced GBR expression in Alzheimer's disease increases Aβ formation.


Chronic intrahypothalamic rather than subcutaneous liraglutide treatment reduces body weight gain and stimulates the melanocortin receptor system.
The GLP-1 receptor agonist liraglutide is marketed for obesity treatment where it induces body weight reduction possibly via the hypothalamus, which regulates energy homeostasis. In animal studies, acute liraglutide treatment triggers satiety, weight loss and activates thermogenesis in adipose tissue. However, the precise mechanisms how liraglutide affects in particular chronic weight loss are still under investigation. We aimed to evaluate whether chronic hypothalamic or chronic subcutaneous administration of liraglutide induces sustained weight loss through altered adipose tissue function and to what extent hypothalamic neuronal appetite regulators are involved in the liraglutide-induced weight loss in healthy lean rats on a normal diet. We continuously administered liraglutide either intrahypothalamically (10 μg per day) or subcutaneously (200 μg kg-1 per day) for 28 days to lean Sprague Dawley rats (n=8 each). We assessed changes in body weight, adipose tissue mass, adipocyte size and adipose tissue volume in the abdominal region by using micro-CT. We analyzed genetic expression patterns of browning, thermogenic and adipocyte differentiation regulators in adipose tissues as well as particular neuronal appetite regulators in the hypothalamus. Intrahypothalamic liraglutide administration induced an 8% body weight reduction at day 9 compared with the control group (P<0.01) and a 7% body weight loss at day 9 compared with subcutaneous liraglutide treatment (P<0.01), supported by a significant reduction in adipose tissue mass and volume with intrahypothalamic liraglutide administration (P<0.05). Our data show that chronic intrahypothalamic liraglutide treatment triggered an 18-fold induction of the hypothalamic mc4r gene (P<0.01) accompanied by a significant increase in circulating thyroxine (T4) levels (P<0.05). Chronic intrahypothalamic liraglutide administration resulted in a profound reduction in body weight and fat mass loss most likely mediated by the hypothalamic melanocortin system rather than by adipose tissue browning or improved thermogenesis.