Coordinated control of oligodendrocyte development by extrinsic and intrinsic signaling cues.
Oligodendrocytes, the myelin-forming cells for axon ensheathment in the central nervous system, are critical for maximizing and maintaining the conduction velocity of nerve impulses and proper brain function. Demyelination caused by injury or disease together with failure of myelin regeneration disrupts the rapid propagation of action potentials along nerve fibers, and is associated with acquired and inherited disorders, including devastating multiple sclerosis and leukodystrophies. The molecular mechanisms of oligodendrocyte myelination and remyelination remain poorly understood. Recently, a series of signaling pathways including Shh, Notch, BMP and Wnt signaling and their intracellular effectors such as Olig1/2, Hes1/5, Smads and TCFs, have been shown to play important roles in regulating oligodendrocyte development and myelination. In this review, we summarize our recent understanding of how these signaling pathways modulate the progression of oligodendrocyte specification and differentiation in a spatiotemporally-specific manner. A better understanding of the complex but coordinated function of extracellular signals and intracellular determinants during oligodendrocyte development will help to devise effective strategies to promote myelin repair for patients with demyelinating diseases.


Crystallization at droplet interfaces for the fabrication of geometrically programmed synthetic magnetosomes.
Biological systems demonstrate exquisite three dimensional (3D) control over crystal nucleation and growth using soft micro/nanoenvironments, such as vesicles, for reagent transport and confinement. It remains challenging to mimic such biomineralization processes using synthetic systems. A synthetic mineralization strategy applicable to the synthesis of artificial magnetosomes with programmable magnetic domains is described. This strategy relies on the compartmentalization of precursors in surfactant-stabilized liquid microdroplets which, when contacted, spontaneously form lipid bilayers that support reagent transport and interface-confined magnetite nucleation and growth. The resulting magnetic domains are polarized and thus readily manipulated using magnetic fields or assembled using droplet-droplet interactions. This strategy presents a new, liquid phase procedure for the synthesis of vesicles with geometrically controlled inorganic features that would be difficult to produce otherwise. The artificial magnetosomes demonstrated could find use in, for example, drug/cargo delivery, droplet microfluidics, and formulation science.


The Ratón Pérez collection: Modern deciduous human teeth at the Centro Nacional de Investigación sobre la Evolución Humana (Burgos, Spain).
The aim of this report is to present the large deciduous tooth collection of identified children that is housed at the National Research Center on Human Evolution (CENIEH) in Burgos, Spain. Yearly, members of the Dental Anthropology Group of the CENIEH are in charge of collecting the teeth and registering all the relevant information from the donors at the time of collection. In compliance with Spanish Law 14/2007 of July 3, 2007, on Biomedical Research (BOE-A-2007-12945), all individuals are guaranteed anonymity and confidentiality. When the donor hands in the tooth, they fill out a Donor Information Form and sign the Informed Consent Form. At the same time, another person completes the data label for the transparent polyethylene zip lock bag where the tooth is temporarily stored. All teeth are then transferred to the CENIEH Restoration lab, where the specialists apply the same protocol as for the fossil remains. Although the sample is still growing, from the first collection campaign in 2014 to date it comprises 2977 teeth of children whose ages of tooth loss are between 2 and 15 years. Each tooth is associated with basic information of the individuals and their parents and grandparents (sex, date, and place of birth, ancestry, country of residence), as well as important data about early life history (pregnancy duration, breastfeeding, bottle-feeding) and other relevant information provided by the donors (such as if they are twins, dental loss, or dental extraction). Due to the scarcity of deciduous dental samples available, the Ratón Pérez collection represents a highly valuable sample for a wide range of disciplines such as forensic, dental, and anthropological fields among others.


Assessing children's physical activity behaviors at recess: a multi-method approach.
To better understand and promote youth physical activity (PA) it is important to determine settings and characteristics that promote or influence behavior. This study evaluated the utility of a multi-method approach (accelerometers plus direct observation) to better understand youth PA at recess. A total of 100 third through fifth grade children (52 males and 48 females) wore an Actigraph accelerometer during school recess for five consecutive days in both Fall and Spring. Trained observers coded PA behaviors at the same recess periods using the System for Observing Play and Leisure Activities (SOPLAY). Overall, gender comparisons based on both instruments indicated that boys were more active than girls. MVPA levels were higher during climbing/sliding activities (40-50%) and when the activity setting was supervised and equipped (30%). Both assessments indicated that boys were more active but the contextual data from the SOPLAY indicate that differences may vary according to the environmental context.


Analysis of spinal motion and loads during frontal impacts. Comparison between PMHS and ATD.
Quantifying the kinematics of the human spine during a frontal impact is a challenge due to the multi-degree-of-freedom structure of the vertebral column. This papers reports on a series of six frontal impacts sled tests performed on three Post Mortem Human Surrogates (PMHS). Each subject was exposed first to a low-speed, non-injurious frontal impact (9 km/h) and then to a high-speed one (40 km/h). Five additional tests were performed using the Hybrid III 50(th) percentile male ATD for comparison with the PMHS. A 3D motion capture system was used to record the 6-degree-of-freedom motion of body segments (head, T1, T8, L2, L4 and pelvis). The 3D trajectories of individual bony structures in the PMHS were determined using bone-mounted marker arrays, thus avoiding skin-attached markers and their potential measurements artifacts. The PMHS spines showed different behavior between low and high speed. While at low speed the head and upper spinal segments lagged the lower portion of the spine and pelvis in reaching their maximum forward displacement (time for maximum forward head excursion was 254.3±31.9 ms and 140.3±9 ms for the pelvis), these differences were minimal at high speed (127±2.6 ms for the head vs. 116.7±3.5 ms for the pelvis). The ATD did not exhibit this speed-dependant behavior. Furthermore, the ATD's forward displacements were consistently less than those exhibited by the PMHS, regardless of the speed. Neck loads at the atlanto-occipital joint were estimated for the PMHS using inverse dynamics techniques and compared to those measured in the ATD. It was found that the axial and shear forces and the flexion moment at the upper neck of the PMHS were higher than those measured in the ATD.


High levels of cellular retinol binding protein-1 expression in leiomyosarcoma: possible implications for diagnostic evaluation.
Retinoid bioavailability is regulated by the activity of specific cytoplasmic receptors. High levels of cellular retinol binding protein-1 (CRBP-1) have been documented during experimental arterial and wound-healing processes, but data concerning neoplastic smooth muscle tissues are scarce and/or controversial. This study reports that the expression of CRBP-1 is markedly higher in uterine and gastrointestinal leiomyosarcomas than in leiomyomas and normal myometrium; CRBP-1 was practically absent in normal gastrointestinal smooth muscle tissue. CRBP-1 positivity was particularly elevated in the epithelioid variant of leiomyosarcoma; it was associated with increased proliferative and apoptotic rates and inversely related to smooth muscle differentiation evaluated by alpha- and gamma-smooth muscle actin and desmin expression. Western blotting and reverse-transcription polymerase chain reaction confirmed the observations concerning CRBP-1 and actin isoform expression and revealed higher NF-kappa-Bp65 and RAR alpha and lower Bax protein levels in leiomyosarcoma than in the other conditions. These findings document that a high CRBP-1 expression is associated with smooth muscle malignancy and suggest that CRBP-1 expression represents a new useful marker for the classification of unusual variants of smooth muscle tumors.


Symptomatic atherosclerosis is associated with an altered gut metagenome.
Recent findings have implicated the gut microbiota as a contributor of metabolic diseases through the modulation of host metabolism and inflammation. Atherosclerosis is associated with lipid accumulation and inflammation in the arterial wall, and bacteria have been suggested as a causative agent of this disease. Here we use shotgun sequencing of the gut metagenome to demonstrate that the genus Collinsella was enriched in patients with symptomatic atherosclerosis, defined as stenotic atherosclerotic plaques in the carotid artery leading to cerebrovascular events, whereas Roseburia and Eubacterium were enriched in healthy controls. Further characterization of the functional capacity of the metagenomes revealed that patient gut metagenomes were enriched in genes encoding peptidoglycan synthesis and depleted in phytoene dehydrogenase; patients also had reduced serum levels of β-carotene. Our findings suggest that the gut metagenome is associated with the inflammatory status of the host and patients with symptomatic atherosclerosis harbor characteristic changes in the gut metagenome.


Postprandial Effect of a High-Fat Meal on Endotoxemia in Arab Women with and without Insulin-Resistance-Related Diseases.
This study determined the effects of a high-fat meal on circulating endotoxin and cardiometabolic indices in adult Arab women. The cohort consisted of 92 consenting Saudi women (18 non-diabetic (ND)) control subjects; Age 24.4 ± 7.9 year; body mass index (BMI) 22.2 ± 2.2 Kg/m2), 24 overweight/obese (referred to as overweight-plus (overweight+)) subjects (Age 32.0 ± 7.8 year; BMI 28.5 ± 1.5 Kg/m2) and 50 type 2 diabetes mellitus (T2DM) patients (Age 41.5 ± 6.2 year; BMI 35.2 ± 7.7 Kg/m2). All were given a high-fat meal (standardized meal: 75 g fat, 5 g carbohydrate, 6 g protein) after an overnight fast of 12-14 h. Anthropometrics were obtained and fasting blood glucose, lipids, and endotoxin were serially measured for four consecutive postprandial hours. Endotoxin levels were significantly elevated prior to a high-fat meal in the overweight+ and T2DM than the controls (p < 0.05). Furthermore, the postprandial cardiometabolic changes led to a more detrimental risk profile in T2DM subjects than other groups, with serial changes most notable in glucose, triglycerides, high density lipoprotein-cholesterol (HDL-cholesterol), and insulin levels (p-values < 0.05). The same single meal given to subjects with different metabolic states had varying impacts on cardiometabolic health. Endotoxemia is exacerbated by a high-fat meal in Arab subjects with T2DM, accompanied by a parallel increase in cardiometabolic risk profile, suggesting disparity in disease pathogenesis of those with or without T2DM through the altered cardiometabolic risk profile rather than variance in metabolic endotoxinaemia with a high-fat meal.


Identification of I-7 expands the repertoire of genes for resistance to Fusarium wilt in tomato to three resistance gene classes.
The tomato I-3 and I-7 genes confer resistance to Fusarium oxysporum f. sp. lycopersici (Fol) race 3 and were introgressed into the cultivated tomato, Solanum lycopersicum, from the wild relative Solanum pennellii. I-3 has been identified previously on chromosome 7 and encodes an S-receptor-like kinase, but little is known about I-7. Molecular markers have been developed for the marker-assisted breeding of I-3, but none are available for I-7. We used an RNA-seq and single nucleotide polymorphism (SNP) analysis approach to map I-7 to a small introgression of S. pennellii DNA (c. 210 kb) on chromosome 8, and identified I-7 as a gene encoding a leucine-rich repeat receptor-like protein (LRR-RLP), thereby expanding the repertoire of resistance protein classes conferring resistance to Fol. Using an eds1 mutant of tomato, we showed that I-7, like many other LRR-RLPs conferring pathogen resistance in tomato, is EDS1 (Enhanced Disease Susceptibility 1) dependent. Using transgenic tomato plants carrying only the I-7 gene for Fol resistance, we found that I-7 also confers resistance to Fol races 1 and 2. Given that Fol race 1 carries Avr1, resistance to Fol race 1 indicates that I-7-mediated resistance, unlike I-2- or I-3-mediated resistance, is not suppressed by Avr1. This suggests that Avr1 is not a general suppressor of Fol resistance in tomato, leading us to hypothesize that Avr1 may be acting against an EDS1-independent pathway for resistance activation. The identification of I-7 has allowed us to develop molecular markers for marker-assisted breeding of both genes currently known to confer Fol race 3 resistance (I-3 and I-7). Given that I-7-mediated resistance is not suppressed by Avr1, I-7 may be a useful addition to I-3 in the tomato breeder's toolbox.


Device-associated nosocomial infection rates and distribution of antimicrobial resistance in a medical-surgical intensive care unit in Turkey.
The aim of this study was to explore the rate of device-associated nosocomial infections (DANIs) and the distributions of causative agents and patterns of antibiotic resistance in the medical-surgical intensive care unit (ICU) over a 3-year period and to compare these rates with those reported by National Nosocomial Infections Surveillance System and International Nosocomial Infection Control Consortium. A total of 1,798 patients were hospitalized in our ICU for 13,942 days, of which 309 patients had DANIs, indicating an overall infection rate of 22.1 per 1,000 ICU-days. The central line-associated bloodstream infection rate was 6.4 per 1,000 catheter-days, whereas the ventilator-associated pneumonia rate was 14.3 per 1,000 ventilator-days and the catheter-associated urinary tract infection rate was 4.3 per 1,000 catheter-days. Overall, 87.4% of all Staphylococcus aureus DANIs were caused by methicillin-resistant strains. With respect to Pseudomonas aeruginosa, 30.9% of the strains were resistant to ciprofloxacin, 23.3% to amikacin, 43.1% to ceftazidime, 19.1% to piperacillin-tazobactam, and 34.7% to imipenem. Furthermore, 1.9% of the Enterococcus spp. were resistant to vancomycin, and 51.1% of Enterobacteriaceae were resistant to ceftriaxone. DANI rates decreased over the 3-year study period, which was likely in response to the infection control measures implemented in our ICU.


Transcutaneous electrical nerve stimulation (TENS) for dementia.
Transcutaneous electrical nerve stimulation (TENS) is the application of an electrical current through electrodes attached to the skin. The commonest clinical application of TENS is pain control. TENS is also used occasionally for the treatment of a range of neurological and psychiatric conditions including drug and alcohol dependence, headaches, and depression. TENS is rarely used for the treatment of dementia. However, since the early 1990s a number of studies carried out by a group in the Netherlands, and one study carried out by a group in Japan, suggest that TENS applied to the back or head may improve cognition and behaviour in patients with Alzheimer's disease or multi-infarct dementia. It was claimed that applying TENS could benefit patients with dementia by altering the activity of various neurotransmitters, or by increasing brain activity and thereby retarding neural degeneration and stimulating regenerative processes. It is claimed that application of TENS to the head may also alleviate the sleep disorders associated with dementia. The aim of this review is to determine the effectiveness and safety of transcutaneous electrical nerve stimulation (TENS) in the treatment of dementia. Secondary objectives of this review are to determine whether any effect of treatment of dementia with TENS is influenced by any treatment parameters or patient features, including: the duration of treatment, electrical waveform, current amplitude, pulse duration and frequency and the patient's type or severity of cognitive impairment. The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 10 December 2002 using the terms TENS, transcutaneous, "transcutaneous electrical nerve stimulation", and "electric stimulation". The CDCIG Specialized Register contains records from all major health care databases and many ongoing trials databases and is regularly updated. All RCTs in which TENS was used as an intervention for people with dementia were included in this review. This included peripherally applied transcutaneous electrical stimulation as well as transcutaneous electrical stimulation applied to the head (also known as cranial electrical stimulation (CES)). All RCTs that fulfilled the inclusion criteria for the review and for which sufficient data were available were included in this meta-analysis. Two reviewers extracted the data from the included trials. All except one of the included trials used similar outcome measures. Data of the same outcome measures were combined for analysis. Eight trials were included in the review but only 3 trials could be included in the meta-analysis. Sufficient data to include the other trials in the meta-analysis could not be obtained. From this limited analysis it appears that TENS produced a statistically significant improvement directly after treatment in: delayed recall of 8 words in one trial, face recognition in two trials and motivation in one trial however, no effect of TENS was found on any of the many other neuropsychological and behavioural measures evaluated either directly after TENS treatment or 6 weeks after treatment was completed. Although a number of studies suggest that TENS may produce short lived improvements in some neuropsychological or behavioural aspects of dementia, the limited presentation and availability of data from these studies does not allow definite conclusions on the possible benefits of this intervention. Since most of the currently published studies are well designed, although the numbers of subjects in each study is small, analysis of the complete original data from these and/or future studies may allow more definitive conclusions to be drawn.


Manganese-enhanced MRI of the myocardium.
Gadolinium-based contrast media are widely used in cardiovascular MRI to identify and to highlight the intravascular and extracellular space. After gadolinium, manganese has the second highest paramagnetic moment and was one of the first MRI contrast agents assessed in humans. Over the last 50 years, manganese-enhanced MRI (MEMRI) has emerged as a complementary approach enabling intracellular myocardial contrast imaging that can identify functional myocardium through its ability to act as a calcium analogue. Early progress was limited by its potential to cause myocardial depression. To overcome this problem, two clinical formulations of manganese were developed using either chelation (manganese dipyridoxyl diphosphate) or coadministration with a calcium compound (EVP1001-1, Eagle Vision Pharmaceuticals). Preclinical studies have demonstrated the efficacy of MEMRI in quantifying myocardial infarction and detecting myocardial viability as well as tracking altered contractility and calcium handling in cardiomyopathy. Recent clinical data suggest that MEMRI has exciting potential in the quantification of myocardial viability in ischaemic cardiomyopathy, the early detection of abnormalities in myocardial calcium handling, and ultimately, in the development of novel therapies for myocardial infarction or heart failure by actively quantifying viable myocardium. The stage is now set for wider clinical translational study of this novel and promising non-invasive imaging modality.


Therapeutic effect of epidurally administered lipo-prostaglandin e1 agonist in a rat spinal stenosis model.
A lipo-prostaglandin E1 agonist is effective for the treatment of neurological symptoms of spinal stenosis when administered by an oral or intravenous route. we would like to reveal the therapeutic effect of an epidural injection of lipo-prostaglandin E1 on hyperalgesia in foraminal stenosis. A total of 40 male Sprague-Dawley rats were included. A small stainless steel rod was inserted into the L5/L6 intervertebral foramen to produce intervertebral foraminal stenosis and chronic compression of the dorsal root ganglia (DRG). The rats were divided into three groups: epidural PGE1 (EP) (n = 15), saline (n = 15), and control (n = 10). In the EP group, 0.15 µg.kg-1 of a lipo-PGE1 agonist was injected daily via an epidural catheter for 10 days from postoperative day 3. In the saline group, saline was injected. Behavioral tests for mechanical hyperalgesia were performed for 3 weeks. Then, the target DRG was analyzed for the degree of chromatolysis, chronic inflammation, and fibrosis in light microscopic images. From the fifth day after lipo-PGE1 agonist injection, the EP group showed significant recovery from mechanical hyperalgesia, which was maintained for 3 weeks (P < 0.05). Microscopic analysis showed much less chromatolysis in the EP group than in the saline or control groups. An epidurally administered lipo-PGE1 agonist relieved neuropathic pain, such as mechanical hyperalgesia, in a rat foraminal stenosis model, with decreasing chromatolysis in target DRG. We suggest that epidurally administered lipo-PGE1 may be a useful therapeutic candidate for patients with spinal stenosis.


A simulation impact evaluation of a cigarette excise tax increase on licit and illicit cigarette consumption and tax revenue in 36 European countries.
To assess the impact of a simulated 10% tax-induced cigarette price increase on licit and illicit consumption and tax revenues in 36 European countries. Employing panel data for licit and illicit cigarette consumption, fixed effects regression models were applied for different income clusters. Total cigarette consumption dropped by about 3.1% as a result of the simulated tax-induced price increase. Annual illicit cigarette consumption increased by 1.52%, (95% confidence interval: 0.21, 2.83), while annual licit cigarette consumption decreased by 4.61% (95% confidence interval: -6.51, -2.72) in the observed 36 European countries. With total consumption decreasing by about 8%, the Czech Republic, Latvia, Lithuania, Poland and Slovakia were affected the most by the price hike. More specifically, licit consumption in these countries decreased by 18.43% (95% confidence interval: -19.91, -16.95) while illicit use increased by 10.99% (95% confidence interval: 6.01, 15.96). Moreover, the overall annual tobacco tax revenue increased by US$14.69 billion in the simulation. Results of the study suggest that European policy makers continue to implement tobacco taxation policies to control smoking prevalence and national health care expenditures. At the same time, efforts to kerb contraband activities along EU Eastern borders should be intensified.


Methods used for parasuicide: results of the WHO/EURO Multicentre Study on Parasuicide.
National suicide statistics show remarkable differences in the frequencies of various methods used for completed suicide. The WHO/EURO Multicentre Study on Parasuicide makes possible for the first time an international comparison of the frequencies of methods used in attempted suicide, because the data are based on geographical catchment areas of medical institutions. Ongoing standardized monitoring of attempted suicide in all medical institutions serving the catchment areas was performed in 14 centres in 12 European countries. The data analysis is based on 20,649 events involving 15,530 persons, recorded between 1989 and 1993. The comparison of rates per 100,000 shows striking differences between the centres. The highest rates for drug overdoses were found for female attempters in Oxford (347/100,000), Helsinki (238/100,000) and Stockholm (221/100,000). Guipuzcoa had the lowest rates (61/100,000). The differences were most prominent in the age group 15-24, with outstanding rates for women in Oxford (653/100,000), which was mainly due to the frequent use of analgesics. Szeged had outstandingly high rates for pesticides and solvents. In some centres the use of multiple methods was frequent. There is a need, especially for areas with high frequencies for certain methods, to understand the factors involved and to develop new and specific prevention projects and to monitor their effects. The WHO/EURO Multicentre Study on Parasuicide has proved to be a useful and reliable instrument for continuous monitoring of trends in parasuicide.


Local strain distribution in real three-dimensional alveolar geometries.
Mechanical ventilation is not only a life saving treatment but can also cause negative side effects. One of the main complications is inflammation caused by overstretching of the alveolar tissue. Previously, studies investigated either global strains or looked into which states lead to inflammatory reactions in cell cultures. However, the connection between the global deformation, of a tissue strip or the whole organ, and the strains reaching the single cells lining the alveolar walls is unknown and respective studies are still missing. The main reason for this is most likely the complex, sponge-like alveolar geometry, whose three-dimensional details have been unknown until recently. Utilizing synchrotron-based X-ray tomographic microscopy, we were able to generate real and detailed three-dimensional alveolar geometries on which we have performed finite-element simulations. This allowed us to determine, for the first time, a three-dimensional strain state within the alveolar wall. Briefly, precision-cut lung slices, prepared from isolated rat lungs, were scanned and segmented to provide a three-dimensional geometry. This was then discretized using newly developed tetrahedral elements. The main conclusions of this study are that the local strain in the alveolar wall can reach a multiple of the value of the global strain, for our simulations up to four times as high and that thin structures obviously cause hotspots that are especially at risk of overstretching.


Molecular Networks of Seed Size Control in Plants.
The size of seeds affects not only evolutionary fitness but also grain yield of crops. Understanding the mechanisms controlling seed size has become an important research field in plant science. Seed size is determined by the integrated signals of maternal and zygotic tissues, which control the coordinated growth of the embryo, endosperm, and seed coat. Recent advances have identified several signaling pathways that control seed size through maternal tissues, including or involving the ubiquitin-proteasome pathway, G-protein signaling, mitogen-activated protein kinase (MAPK) signaling, phytohormone perception and homeostasis, and some transcriptional regulators. Meanwhile, growth of the zygotic tissues is regulated in part by the HAIKU (IKU) pathway and phytohormones. This review provides a general overview of current findings in seed size control and discusses the emerging molecular mechanisms and regulatory networks found to be involved.


Combined syngeneic bone marrow transplantation and immunotherapy of a murine B-cell lymphoma: active immunization with tumor-derived idiotypic immunoglobulin.
Recurrence of the underlying malignancy remains a major cause of treatment failure after autologous bone marrow transplantation (BMT) for patients with lymphoma. In this regard, we have developed an immunotherapeutic approach designed to induce resistance against residual tumor cells persisting after BMT. Previous studies in the model system of 38C13, a lethal B-cell lymphoma of C3H origin, have shown that active immunization with purified tumor-derived surface immunoglobulin (Id), as a tumor-associated antigen, produces resistance to tumor growth. Id immunization of lethally irradiated mice at 3 or 5 weeks after reconstitution with syngeneic bone marrow resulted in significantly prolonged survival after tumor challenge compared with nonspecifically immunized controls. Low levels of idiotype-specific antibody were also demonstrated in the sera of specifically immunized mice at this early time, when other functional studies in the literature of immunocompetence after syngeneic reconstitution might have predicted incomplete recovery. Immunization of mice before lethal irradiation and syngeneic marrow reconstitution also induced significant resistance to tumor challenge, suggesting the persistence of established host antitumor immunity through total body irradiation. These studies demonstrate the feasibility of id immunization in conjunction with bone marrow transplantation.


Neonatal exposure to thymotropic gross murine leukemia virus induces virus-specific immunologic nonresponsiveness.
Neonatal exposure to Gross murine leukemia virus results in a profound inhibition of the virus-specific T and B cell responses of adult animals. Animals exposed to virus as neonates exhibit a marked depression in virus-specific T cell function as measured by the virtual absence of in vivo delayed type hypersensitivity responses and in vitro proliferative responses to virally infected stimulator cells. Further, serum obtained from neonatally treated mice failed to either immunoprecipitate viral proteins or neutralize virus in an in vitro plaque assay, suggesting the concurrent induction of a state of B cell hyporesponsiveness. The specificity of this effect at the levels of both T and B cells was demonstrated by the ability of neonatally treated mice to respond normally after adult challenge with either irrelevant reovirus or influenza virus. The replication of Gross virus within both stromal and lymphocytic compartments of the neonatal thymus suggests that thymic education plays a key role in the induction of immunologic nonresponsiveness to viruses.


Enhancing prospective memory in mild cognitive impairment: The role of enactment.
Prospective memory (PM) is a fundamental requirement for independent living which might be prematurely compromised in the neurodegenerative process, namely in mild cognitive impairment (MCI), a typical prodromal Alzheimer's disease (AD) phase. Most encoding manipulations that typically enhance learning in healthy adults are of minimal benefit to AD patients. However, there is some indication that these can display a recall advantage when encoding is accompanied by the physical enactment of the material. The aim of this study was to explore the potential benefits of enactment at encoding and cue-action relatedness on memory for intentions in MCI patients and healthy controls using a behavioral PM experimental paradigm. We report findings examining the influence of enactment at encoding for PM performance in MCI patients and age- and education-matched controls using a laboratory-based PM task with a factorial independent design. PM performance was consistently superior when physical enactment was used at encoding and when target-action pairs were strongly associated. Importantly, these beneficial effects were cumulative and observable across both a healthy and a cognitively impaired lifespan as well as evident in the perceived subjective difficulty in performing the task. The identified beneficial effects of enacted encoding and semantic relatedness have unveiled the potential contribution of this encoding technique to optimize attentional demands through an adaptive allocation of strategic resources. We discuss our findings with respect to their potential impact on developing strategies to improve PM in AD sufferers.


The ConNECtion Between Abdominal Signs and Necrotizing Enterocolitis in Infants 501 to 1500 g.
Necrotizing enterocolitis (NEC) can become severe quickly, making early recognition a priority and understanding the occurrence of abdominal and clinical signs of impending NEC important. The purpose of this study was to examine relationships of abdominal signs up to 36 hours before diagnosis of NEC within subgroups treated medically, surgically, or those who died. A 3-site, descriptive correlational case-control design with retrospective data collection was used matching each NEC case to 2 controls (N = 132). NEC cases were exposed to less human milk and fed later. Among them, 61% (n = 27) had at least 1 abdominal sign 36 hours before diagnosis, with fewer numbers having 2 (18%; n = 8) or 3 (5%; n = 2). At 36 hours before NEC, abdominal distension, duskiness, higher gastric residual, and greater count of abdominal signs were associated with severe NEC. No medical NEC cases had abdominal signs 36 or 24 hours before diagnosis. Highest severity of NEC was related to more abdominal signs at the times leading up to and at diagnosis of NEC. Gastric residuals were largely unrelated to NEC except for the most severe NEC at 36 hours before diagnosis. Communicating a count of abdominal signs may support earlier recognition and treatment of NEC. More research is needed to explore timing for clinical worsening of status (eg, surgical and NEC leading to death) and to study effective clinical approaches targeting early recognition to support timely action.


Preoperative Anxiety and Its Influence on Patient and Surgeon Satisfaction in Patients Receiving Dental Implant Surgeries Performed Under Intravenous Conscious Sedation.
The aims of this study were to evaluate the relationship of age, sex, and type and duration of the surgery with preoperative anxiety in patients undergoing dental implant surgeries under intravenous conscious sedation, and to assess preoperative anxiety association with the postoperative satisfaction of both the patient and surgeon. This prospective study included 180 patients receiving dental implant surgeries under intravenous conscious sedation by means of midazolam, fentanyl, and propofol. Preoperative anxiety (Corah Dental Anxiety Scale), number of implants, duration of surgery, surgeon satisfaction (evaluated as three categories: patient too awake and nervous, adequate sedation, or patient too asleep), and patient satisfaction (classified as five levels: agreeable, neither agreeable nor disagreeable, slightly uncomfortable, unpleasant, traumatic) were recorded. All 180 patients completed the study, and 72.2% of them experienced moderate or high levels of anxiety. The mean Corah scale score was 9.2 ± 3.5. Anxiety was significantly higher among men but showed no relation to age. A significant relationship was found between patient anxiety and the number of implants: those patients who received eight or more implants, with a duration of surgery longer than 60 minutes, had lower anxiety. Surgeon satisfaction was adequate in 90% of the cases. Patients evaluated the procedure as agreeable in 34.4% of cases, neither agreeable nor disagreeable in 26.7%, slightly uncomfortable in 29.4%, unpleasant in 7.8%, and traumatic in 1.7%. High anxiety levels were related with poor patient satisfaction but not with surgeon satisfaction. Preoperative anxiety was moderate or high in two-thirds of patients undergoing dental implant surgeries, having a negative influence on patient satisfaction, but not affecting surgeon satisfaction. Additionally, the intravenous conscious sedation technique was considered a satisfactory technique by the surgeon to control anxiety.


Differential effects of equiaxial and uniaxial strain on mesenchymal stem cells.
Bone marrow mesenchymal stem cells (MSCs) can differentiate into a variety of cell types, including vascular smooth muscle cells (SMCs), and have tremendous potential as a cell source for cardiovascular regeneration. We postulate that specific vascular environmental factors will promote MSC differentiation into SMCs. However, the effects of the vascular mechanical environment on MSCs have not been characterized. Here we show that mechanical strain regulated the expression of SMC markers in MSCs. Cyclic equiaxial strain downregulated SM alpha-actin and SM-22alpha in MSCs on collagen- or elastin-coated membranes after 1 day, and decreased alpha-actin in stress fibers. In contrast, cyclic uniaxial strain transiently increased the expression of SM alpha-actin and SM-22alpha after 1 day, which subsequently returned to basal levels after the cells aligned in the direction perpendicular to the strain direction. In addition, uniaxial but not equiaxial strain induced a transient increase of collagen I expression. DNA microarray experiments showed that uniaxial strain increased SMC markers and regulated the expression of matrix molecules without significantly changing the expression of the differentiation markers (e.g., alkaline phosphatase and collagen II) of other cell types. Our results suggest that uniaxial strain, which better mimics the type of mechanical strain experienced by SMCs, may promote MSC differentiation into SMCs if cell orientation can be controlled. This study demonstrates the differential effects of equiaxial and uniaxial strain, advances our understanding of the mechanical regulation of stem cells, and provides a rational basis for engineering MSCs for vascular tissue engineering and regeneration.


Aerosols and criteria gases in an underground mine that uses FAME biodiesel blends.
The contribution of heavy-duty haulage trucks to the concentrations of aerosols and criteria gases in underground mine air and the physical properties of those aerosols were assessed for three fuel blends made with fatty acid methyl esters biodiesel and petroleum-based ultra-low-sulfur diesel (ULSD). The contributions of blends with 20, 50, and 57% of biodiesel as well as neat ULSD were assessed using a 30-ton truck operated over a simulated production cycle in an isolated zone of an operating underground metal mine. When fueled with the B20 (blend of biodiesel with ULSD with 20% of biodiesel content), B50 (blend of biodiesel with ULSD with 50% of biodiesel content), and B57 (blend of biodiesel with ULSD with 57% of biodiesel content) blends in place of ULSD, the truck's contribution to mass concentrations of elemental and total carbon was reduced by 20, 50, and 61%, respectively. Size distribution measurements showed that the aerosols produced by the engine fueled with these blends were characterized by smaller median electrical mobility diameter and lower peak concentrations than the aerosols produced by the same engine fueled with ULSD. The use of the blends resulted in number concentrations of aerosols that were 13-29% lower than those when ULSD was used. Depending on the content of biodiesel in the blends, the average reductions in the surface area concentrations of aerosol which could be deposited in the alveolar region of the lung (as measured by a nanoparticle surface area monitor) ranged between 6 and 37%. The use of blends also resulted in slight but measurable reductions in CO emissions, as well as an increase in NOX emissions. All of the above changes in concentrations and physical properties were found to be correlated with the proportion of biodiesel in the blends.


Intrauterine growth patterns in rural Ethiopia compared with WHO and INTERGROWTH-21st growth standards: A community-based longitudinal study.
Children's well-being is highly influenced by their fetal growth. Adequate intrauterine growth (IUG) is a basic feature of a healthy pregnancy. The aim of our study was to assess IUG patterns in a rural and drought-affected population in the Rift Valley area of the Adami Tullu district in Oromia, Ethiopia. We conducted a longitudinal, community-based study of IUG patterns utilizing serial ultrasound measurements. Data were collected for 17 months, from July 2016 to November 2017. We included 675 singleton foetuses ≤ 24 weeks old, based on ultrasound-derived estimates of gestational age, and followed them until delivery. We obtained head circumference, biparietal diameter, abdominal circumference, femur length, and estimated fetal weight at 26, 30, and 36 weeks. Fetal weight was estimated using the Hadlock algorithm, and the 5th, 10th, 25th, 50th, 75th, 90th, and 95th centiles were developed from this model. We compared the biometric measurements and fetal weight data from our study to the World Health Organization (WHO) and INTERGROWTH-21st fetal growth reference standards. Distribution of the biometric measurements and estimated fetal weights in our study were similar to those for the WHO and INTERGROWTH-21st references. Most measurements were between -2 and +2 of the reference z-scores. Based on the smoothed percentiles, the 5th, 50th, and 95th percentiles of our study had similar distribution patterns to the WHO chart, and the 50th percentile had a similar pattern to the INTERGROWTH-21st chart. Our study determined fetal growth patterns in a drought-affected rural community of Ethiopia using common ultrasound biometric measurements. We found similar IUG patterns to those indicated in the WHO and INTERGROWTH-21st fetal growth reference standards.


Attenuation of fluorocarbons released from foam insulation in landfills.
Chlorofluorocarbons (CFCs), hydrochlorofluorocarbons (HCFCs), and hydrofluorocarbons (HFCs) have been used as blowing agents (BAs) for foam insulation in home appliances and building materials, which after the end of their useful life are disposed of in landfills. The objective of this project was to evaluate the potential for degradation of BAs in landfills, and to develop a landfill model, which could simulate the fate of BAs in landfills. The investigation was performed by use of anaerobic microcosm studies using different types of organic waste and anaerobic digested sludge as inoculum. The BAs studied were CFC-11, CFC-12, HCFC-141b, HFC-134a, and HFC-245fa. Experiments considering the fate of some of the expected degradations products of CFC-11 and CFC-12 were included like HCFC-21, HCFC-22, HCFC-31, HCFC-32, and HFC-41. Degradation of all studied CFCs and HCFCs was observed regardless the type of waste used. In general, the degradation followed first-order kinetics. CFC-11 was rapidly degraded from 590 microg L(-1) to less than 5 microg L(-1) within 15-20 days. The degradation pattern indicated a sequential production of HCFC-21, HCFC-31, and HFC-41. However, the production of degradation products did not correlate with a stoichiometric removal of CFC-11 indicating that other degradation products were produced. HCFC-21 and HCFC-31 were further degraded whereas no further degradation of HFC-41 was observed. The degradation rate coefficient was directly correlated with the number of chlorine atoms attached to the carbon. The highest degradation rate coefficient was obtained for CFC-11, whereas lower rates were seen for HCFC-21 and HCFC-31. Equivalent results were obtained for CFC-12. HCFC-141b was also degraded with rates comparable to HCFC-21 and CFC-12. Anaerobic degradation of the studied HFCs was not observed in any of the experiments within a run time of up to 200 days. The obtained degradation rate coefficients were used as input for an extended version of an existing landfill fate model incorporating a time dependent BA release from co-disposed foam insulation waste. Predictions with the model indicate that the emission of foam released BAs may be strongly attenuated by microbial degradation reactions. Sensitivity analysis suggests that there is a need for determination of degradation rates under more field realistic scenarios.


In vitro and in vivo activities of Peganum harmala extract against Leishmania major.
In vitro and in vivo antileishmanial activities of crude hydroalcoholic extract of peganum harmala seeds were investigated against Leishmania major. The extract of aerial parts of P harmala was obtained by maceration. The in vitro experiments were performed on promastigotes to assess antileishmanial activity of the extract using amphotericin B as a reference. The in vivo studies were carried out on cutaneous leishmaniasis in outbred mice to evaluate the effects of topical application of the ointment-based extract. The in vitro experiments showed a concentration-dependent decrease of parasites number caused by the extract with an IC50 value of 59.4 μg/ml. In vivo studies demonstrated a significant post-treatment decrease in the lesion size and parasite count in infected animals, compared to placebo and control groups. High performance liquid chromatography (HPLC) of the crude extract demonstrated the existence of harmaline and harmine as beta-carboline alkaloids. P harmala seeds extract showed significant in vitro and in vivo antileishmanial activities. Most biological activity of the extract could be attributed to its beta-carboline content. However, another alkaloid of P harmala seeds extract, peganine, has also been reported to have antileishmanial activity. These beneficial effects can be attributed to the cumulative effects of various biologically active components present in it.


Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism.
Chronic infection and inflammation are risk factors for the development of cholangiocarcinoma, a highly malignant, generally fatal adenocarcinoma originating from biliary epithelia. However, the link between inflammation and carcinogenesis in these disorders is obscure. Because nitric oxide (NO) is generated in inflamed tissues by inducible nitric oxide synthase (iNOS) and because DNA repair proteins are potentially susceptible to NO-mediated nitrosylation, we formulated the hypothesis that inflammatory cytokines induce iNOS and sufficient NO to inhibit DNA repair enzymes leading to the development and progression of cholangiocarcinoma. iNOS and nitrotyrosine were demonstrated in 18/18 cholangiocarcinoma specimens. Furthermore, iNOS and NO generation could be induced in vitro by inflammatory cytokines (mixture of interleukin-1beta, IFN-gamma, and tumor necrosis factor alpha) in three human cholangiocarcinoma cell lines. NO-dependent DNA damage as assessed by the comet assay was demonstrated during exposure of the three cholangiocarcinoma cell lines to cytokines. Moreover, global DNA repair activity was inhibited by 70% by a NO-dependent process after exposure of cells to cytokines. Our data indicate that activation of iNOS and excess production of NO in response to inflammatory cytokines cause DNA damage and inhibit DNA repair proteins. NO inactivation of DNA repair enzymes may provide a link between inflammation and the initiation, promotion, and/or progression of cholangiocarcinoma.


Consumer Adoption of Future MyData-Based Preventive eHealth Services: An Acceptance Model and Survey Study.
Constantly increasing health care costs have led countries and health care providers to the point where health care systems must be reinvented. Consequently, electronic health (eHealth) has recently received a great deal of attention in social sciences in the domain of Internet studies. However, only a fraction of these studies focuses on the acceptability of eHealth, making consumers' subjective evaluation an understudied field. This study will address this gap by focusing on the acceptance of MyData-based preventive eHealth services from the consumer point of view. We are adopting the term "MyData", which according to a White Paper of the Finnish Ministry of Transport and Communication refers to "1) a new approach, a paradigm shift in personal data management and processing that seeks to transform the current organization centric system to a human centric system, 2) to personal data as a resource that the individual can access and control." The aim of this study was to investigate what factors influence consumers' intentions to use a MyData-based preventive eHealth service before use. We applied a new adoption model combining Venkatesh's unified theory of acceptance and use of technology 2 (UTAUT2) in a consumer context and three constructs from health behavior theories, namely threat appraisals, self-efficacy, and perceived barriers. To test the research model, we applied structural equation modeling (SEM) with Mplus software, version 7.4. A Web-based survey was administered. We collected 855 responses. We first applied traditional SEM for the research model, which was not statistically significant. We then tested for possible heterogeneity in the data by running a mixture analysis. We found that heterogeneity was not the cause for the poor performance of the research model. Thus, we moved on to model-generating SEM and ended up with a statistically significant empirical model (root mean square error of approximation [RMSEA] 0.051, Tucker-Lewis index [TLI] 0.906, comparative fit index [CFI] 0.915, and standardized root mean square residual 0.062). According to our empirical model, the statistically significant drivers for behavioral intention were effort expectancy (beta=.191, P<.001), self-efficacy (beta=.449, P<.001), threat appraisals (beta=.416, P<.001), and perceived barriers (beta=-.212, P=.009). Our research highlighted the importance of health-related factors when it comes to eHealth technology adoption in the consumer context. Emphasis should especially be placed on efforts to increase consumers' self-efficacy in eHealth technology use and in supporting healthy behavior.


Cultural competence education for practicing physicians: lessons in cultural humility, nonjudgmental behaviors, and health beliefs elicitation.
Although numerous studies have examined cultural competence training, debate still exists about efficacious approaches to this training. Furthermore, little focus has been placed on training and evaluating practicing physicians. A skills-based course on culturally competent diabetes care was developed and subsequently tested in a controlled trial of primary physicians caring for patients enrolled in one state's Medicaid program. We hypothesized that physicians completing the course would show higher levels of self-reported cultural competence as measured by a Cultural Competence Assessment Tool (CCAT) than those in the control group. Differences in CCAT subscale scores were also compared. Ninety physicians completed the study, with 41 in the control and 49 in the intervention group. Most were female (66%), with an average age of 44, and 12 years in practice. There were no significant differences on total CCAT score (212.7 ± 26.7 for control versus 217.2 ± 28.6 for intervention, p = .444) or subscales measuring cultural knowledge. There were significant positive differences on the subscales measuring physicians' nonjudgmental attitudes/behaviors (subscale score 2.38 ± 0.46 for control versus 2.69 ± 0.52 for intervention, p = .004) and future likelihood of eliciting patients' beliefs about diabetes and treatment preferences (3.11 ± 0.53 for control versus 3.37 ± 0.45 for intervention, p = .014). There was, however, a significant negative difference on the subscale measuring cultural self-awareness (3.48 ± 0.36 for control versus 3.26 ± 0.48 for intervention, p = .018). A predominantly skills-based approach to training physicians did not change aggregate measures of cultural competence, but did affect key attitudes and behaviors, which may better reflect the goals of cultural competence training.


A rat model of chronic pressure-induced optic nerve damage.
To develop unilateral, chronically elevated intraocular pressure in rats, episcleral veins were injected with hypertonic saline and the intraocular pressure was monitored with a Tono-Pen XL tonometer. Histologic analyses of eyes with differing degrees and durations of intraocular pressure elevation were performed to ascertain the effects of these pressures on the optic nerve. Out of 20 consecutive animals, nine had elevations of intraocular pressure following a single injection, while subsequent injections raised intraocular pressure in seven others. One eye became hypotonous. In the remaining animals, subsequent injections sufficient to raise intraocular pressure were deliberately withheld, to determine the possible direct effects of injections on the optic nerve. Mean sustained pressure elevations ranged from 7 to 28 mm Hg and the retinal vasculature remained perfused in all eyes. Optic nerve cross sections from eyes without intraocular pressure elevation appeared identical to those from uninjected eyes, while nerves from eyes with the greatest intraocular pressure rise demonstrated axonal damage that involved 100% of the neural area. Eyes with either less severe pressure elevations or shorter durations showed partial damage, ranging from 0.5% to 10.4% of the neurla area. In 70% of these nerves, damage was concentrated in the superior temporal region. Within the optic nerve head, often associated with astrocytes, axons contained abnormal accumulations of membrane-bound vesicles and mitochondria. The anterior chamber angles showed sclerosis of the trabecular meshwork with anterior synechiae, but Schlemm's canal, collector channels and aqueous veins appeared patent. Unilateral sclerosis of the trabecular meshwork produces sustained elevation of intraocular pressure in rats with optic nerve damage that in many ways resembles that seen in human glaucoma. Understanding the mechanism of nerve damage in this model may provide new insights into the pathogenesis of human glaucoma.


Anti-TNF Therapy Induces CD4+ T-Cell Production of IL-22 and Promotes Epithelial Repairs in Patients With Crohn's Disease.
Anti-tumor necrosis factor (TNF) therapy appears to be effective in the treatment of Crohn's disease (CD), a chronic inflammatory disease of the gastrointestinal tract. However, the mechanisms involved are not completely understood. Fifty-seven active CD patients were enrolled, and cytokine profiles in colonic biopsies of patients with active CD receiving anti-TNF monoclonal antibody (mAb) (infliximab [IFX]) treatment were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Colonic biopsies of active CD patients and healthy donors were cultured with IFX in vitro, and cytokine profiles were measured by qRT-PCR. Peripheral blood (PB)-CD4+ T cells were stimulated with anti-CD3 and anti-CD28 mAbs in the presence of human immunoglobin (HIg), IFX, recombinant human TNF-α converting enzyme (rhTACE), and aryl hydrocarbon receptor (AhR) inhibitor (CH-223191), respectively, to determine interleukin (IL)-22 expression by CD4+ T cells. Caco2 cells were also utilized to study their potential role in modulating epithelial cell barrier repairs in vitro. IFX therapy markedly upregulated IL-22 mRNA expression in the gut mucosa of CD patients. In vitro treatment with IFX greatly promoted CD CD4+ T cells to express IL-22, which was inhibited by rhTACE, indicating that reverse signaling through binding to membrane-bound TNF mediates anti-TNF-induced IL-22 expression of CD CD4+ T cells. However, blockade of AhR markedly inhibited anti-TNF-induced IL-22+CD4+ T (Th22) cell differentiation in CD patients. Moreover, treatment with IL-22 induced intestinal epithelial cell expression of tight junction proteins (eg, claudin1 and ZO-1) and facilitated transepithelial resistance, indicating that IL-22 protects intestinal mucosa from inflammation via maintenance of epithelial barrier integrity. Our results uncover a novel mechanism whereby anti-TNF therapy upregulates IL-22 production in CD patients through promoting Th22 cell differentiation and contributes to intestinal epithelial barrier repairs.


Resonant energy transfer in a van der Waals stacked MoS2 - functionalized graphene quantum dot composite with ab initio validation.
Graphene-based van der Waals (vdW) heterostructures can facilitate exciting charge transfer dynamics in between structural layers with the emission of excitonic quasi-particles. However, the chemical formation of such heterostructures has been elusive thus far. In this work, a simple chemical approach is described to form such van der Waals (vdW) heterostructures using few layer MoS2 sheet embedded quantum dots (QDs) and amine-functionalized graphene quantum dots (GQDs) to probe the energy transfer mechanism for tunable photoluminescence (PL). Our findings reveal an interesting non-radiative Förster-type energy transfer with the quenching of functional GQD PL intensity after GQD/MoS2 composite formation, which validates the existing charge transfer dynamics analogous to 0D and 2D systems. The non-radiative type of energy transfer characteristic from GQD into the MoS2 layer through vdW interactions has been confirmed by photoluminescence, time decay analyses and ab initio calculations with the shifting of the Fermi level in the density of states towards the conduction band in the stacked configuration. These results are encouraging for the fundamental exploration of optical properties in other chemically prepared QD/2D based heterostructures to understand the charge transfer mechanism and fingerprint luminescence quenching for future optoelectronic device and optical sensing applications.


Determinants and mechanisms of attentional modulation of neural processing.
This review contrasts the most-studied variety of attention, visuospatial attention, with several types of nonspatial visual attention. We: 1) discuss the manner in which spatial and nonspatial varieties of attention are experimentally defined, and the ecological validity of the paradigms in which they are studied, 2) review and compare differing effects of spatial and nonspatial attention on neural processing, 3) discuss the manner in which attention operates within the framework of an anatomical visual hierarchy, as well as 4) how attention relates to the temporal dynamics of visual processing, 5) describe cellular circuits and physiological processes that appear to be involved in attention effects, 6) discuss the relationship of attentional physiology to the perceptual and cognitive effects of attention, and 7) consider the strengths and limitations of several current models of selective attention. Throughout, we attempt to integrate the findings of monkey and human studies whenever possible. We have three main conclusions. First, two models, the Neural Specificity Model of Harter and colleagues and the Feature Similarity Gain Model of Treue and colleagues best incorporate findings in relation to both spatial and nonspatial varieties of attention. Significantly, these models explicitly note that the specific neuronal components used in attentional modulation of processing are flexible and determined by task demands. Second, current evidence also provides strong bases for deriving testable hypotheses about the specific brain mechanisms utilized by attention. Cellular processes, brain circuits and neurotransmitter components can and should be incorporated into our models of attention. Finally, it is increasingly evident that we can and should analyze temporal patterns of attentional modulation, both within and across brain areas. These patterns provide critical information on the dynamics of attention.


Survival in breast cancer related to tumour oestrogen receptor status and immunohistochemical staining for NCRC 11.
NCRC 11 is a monoclonal antibody raised against dissociated breast cancer cells. Using this antibody, it has been shown in an earlier study that staining of a high proportion of tumour cells is strongly associated with superior survival. Many investigators have found that positive tumour oestrogen receptor (OER) status is associated with better survival in breast cancer. In the present study of 136 breast cancer patients followed up for a minimum of 30 months, tumour oestrogen receptor assays were carried out, and using the indirect immunoperoxidase technique, histological sections of paraffin embedded material were stained for NCRC 11; for the purpose of this study, tumours showing 25 per cent or less cells staining were regarded as 'negative'. Patients whose tumours were OER positive had a significantly better prognosis (logrank test P less than 0.05). Patients whose tumours were graded as negative for NCRC 11 had a poorer prognosis compared with the positive group but this did not attain significance. Our failure to demonstrate convincingly a better prognosis for the NCRC 11 positive patients may relate to the shorter duration of our study, or to different tissue fixation techniques. In this study staining for NCRC 11 was positively correlated with oestrogen receptor status (P less than 0.02).


Proteomic response of inflammatory stimulated intestinal epithelial cells to in vitro digested plums and cabbages rich in carotenoids and polyphenols.
Due to their anti-oxidant and anti-inflammatory potential, polyphenol and carotenoid-rich plant foods have been suggested as promising phytochemicals in the prevention of or as adjuvants regarding inflammatory bowel diseases (IBD). In the present study, we investigated whether plum (Italian Plum, Prunus cocomilla), or cabbage (Kale, Brassica oleracea var. sabellica), selected for their high phytochemical content, are able to reduce inflammation in cellular models of the intestinal epithelium, employing proteomic methods. For this purpose, plum/cabbage (carotenoid content: 1.9 mg per 100 g resp. 13 mg per 100 g; polyphenol content: 83 mg per 100 g resp. 27 mg per 100 g) were gastro-intestinally digested, and aliquots exposed (18 h) to either a monoculture (Caco-2) or a triple culture (Caco-2/HT-29-MTX (90 : 10, v/v) with THP-1 like macrophages), stimulated (with LPS, TNF-α, and IL-1β) to induce inflammation. Cells (Caco-2, Caco-2/HT-29-MTX, and THP-1) were then harvested separately, and proteomic analyses of total cell extracts were carried out by 2D-DIGE. In the monoculture, 68 protein-spots were significantly (p < 0.05, expression ratio >1.5) differentially regulated due to the Kale and Italian plum digesta, and in the co-culture 206 protein-spots, compared to digesta without plum/cabbage. These belonged to 27 (monoculture) and 76 (coculture) uniquely identified proteins, suggesting the coculture to be a more sensitive model. Proteins included antioxidant enzymes such as catalase, superoxide dismutase and glutathione-S-transferases. Only 3 proteins were differentially regulated in the THP-1 cells, perhaps as these were only indirectly exposed. The results show promise regarding some aspects related to IBD complications, however, employing phytochemical-rich food items should be further investigated in in vivo trials.


Leptin inhibits insulin binding in isolated rat adipocytes.
Leptin is secreted from adipose tissue, and is thought to act as a 'lipostat', signalling the body fat levels to the hypothalamus resulting in adjustments to food intake and energy expenditure to maintain body weight homeostasis. In addition, plasma leptin concentrations have been shown to be related to insulin sensitivity independent of body fat content, suggesting that the hyperleptinemia found in obesity could contribute to the insulin resistance. We investigated the effects of leptin on insulin binding by isolated adipocytes. Adipocytes isolated from Sprague-Dawley rats exhibited a dose-dependent reduction in the uptake of 125I-labelled insulin when incubated with various concentrations of exogenous leptin. For example, addition of 50 nM leptin reduced total insulin binding in isolated adipocytes by 19% (P < 0.05). Analysis of displacement curve binding data suggested that leptin reduced maximal insulin binding in a dose-dependent manner, but had no significant effect on the affinity of insulin for its binding site. We conclude that leptin directly inhibited insulin binding by adipocytes, and the role of leptin in the development of insulin resistance in obese individuals requires further investigation.


The AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), but not metformin, prevents inflammation-associated cachectic muscle wasting.
Activation of AMPK has been associated with pro-atrophic signaling in muscle. However, AMPK also has anti-inflammatory effects, suggesting that in cachexia, a syndrome of inflammatory-driven muscle wasting, AMPK activation could be beneficial. Here we show that the AMPK agonist AICAR suppresses IFNγ/TNFα-induced atrophy, while the mitochondrial inhibitor metformin does not. IFNγ/TNFα impair mitochondrial oxidative respiration in myotubes and promote a metabolic shift to aerobic glycolysis, similarly to metformin. In contrast, AICAR partially restored metabolic function. The effects of AICAR were prevented by the AMPK inhibitor Compound C and were reproduced with A-769662, a specific AMPK activator. AICAR and A-769662 co-treatment was found to be synergistic, suggesting that the anti-cachectic effects of these drugs are mediated through AMPK activation. AICAR spared muscle mass in mouse models of cancer and LPS induced atrophy. Together, our findings suggest a dual function for AMPK during inflammation-driven atrophy, wherein it can play a protective role when activated exogenously early in disease progression, but may contribute to anabolic suppression and atrophy when activated later through mitochondrial dysfunction and subsequent metabolic stress.


Bipartite and tripartite Cucumber mosaic virus-based vectors for producing the Acidothermus cellulolyticus endo-1,4-β-glucanase and other proteins in non-transgenic plants.
Using plant viruses to produce desirable proteins in plants allows for using non-transgenic plant hosts and if necessary, the ability to make rapid changes in the virus construct for increased or modified protein product yields. The objective of this work was the development of advanced CMV-based protein production systems to produce Acidothermus cellulolyticus endo-1, 4-β-glucanase (E1) in non-transgenic plants. We used two new Cucumber mosaic virus (CMV)-based vector systems for producing the green fluorescent protein (GFP) and more importantly, the Acidothermus cellulolyticus endo-1, 4-β-glucanase (E1) in non-transgenic Nicotiana benthamiana plants. These are the inducible CMVin (CMV-based inducible) and the autonomously replicating CMVar (CMV-based advanced replicating) systems. We modified a binary plasmid containing the complete CMV RNA 3 cDNA to facilitate insertion of desired sequences, and to give modifications of the subgenomic mRNA 4 leader sequence yielding several variants. Quantitative RT-PCR and immunoblot analysis showed good levels of CMV RNA and coat protein accumulation for some variants of both CMVin and CMVar. When genes for E1 or GFP were inserted in place of the CMV coat protein, both were produced in plants as shown by fluorescence (GFP) and immunoblot analysis. Enzymatic activity assays showed that active E1 was produced in plants with yields up to ~ 11 μg/g fresh weight (FW) for specific variant constructs. We also compared in vitro CMV genomic RNA reassortants, and CMV RNA 3 mutants which lacked the C' terminal 33 amino acids of the 3A movement protein in attempts to further increase E1 yield. Taken together specific variant constructs yielded up to ~21 μg/g FW of E1 in non-transgenic plants. Intact, active E1 was rapidly produced in non-transgenic plants by using agroinfiltration with the CMV-based systems. This reduces the time and cost compared to that required to generate transgenic plants and still gives the comparable yields of active E1. Our modifications described here, including manipulating cloning sites for foreign gene introduction, enhance the ease of use. Also, N. benthamiana, which is particularly suitable for agroinfiltration, is a very good plant for transient protein production.


Oral treatment with probiotics reduces allergic symptoms in ovalbumin-sensitized mice: a bacterial strain comparative study.
Evidence demonstrating an important role of the intestinal microbiota in the incidence of allergic disorders has led to the concept of using probiotics as possible antiallergic therapy. This study aimed to select a bacterial strain with the best antiallergic treatment effects from a panel of 6 bacterial strains in a mouse model of ovalbumin(OVA)-allergic asthma. OVA-sensitized BALB/c mice were orally administered the bacterial strains Bifidobacterium breve M-16V, B. infantis NumRes251, B. animalis NumRes252 and NumRes253, Lactobacillus plantarum NumRes8 and L. rhamnosus NumRes6. After challenge by OVA inhalation in the lungs, the response to methacholine was measured. Pulmonary inflammation was assessed by analyzing bronchoalveolar lavage fluid for the presence of eosinophils, neutrophils, macrophages and lymphocytes and for interleukin 4, interleukin 5, interleukin 10 and interferon-gamma. OVA-specific IgE, IgG1 and IgG2a were measured in serum. Next, the effect on acute allergic skin reaction was measured after treatment with B. breve M-16V and L. plantarum NumRes8. Of the panel of 6 strains, B. breve M-16V and L. plantarum NumRes8 inhibited (1) the response to methacholine, (2) reduced the number of eosinophils in the bronchoalveolar lavage fluid, (3) reduced both OVA-specific IgE and (4) OVA-specific IgG1, whereas the other strains did not affect all these parameters simultaneously. B. breve M-16V but not L. plantarum NumRes8 reduced interleukin 4, interleukin 5 and interleukin 10. Furthermore, B. breve M-16V but not L. plantarum NumRes8 reduced acute allergic skin reactions to OVA. B. breve M-16V was identified as the most potent antiallergic strain.


Neural Signatures of Controlled and Automatic Retrieval Processes in Memory-based Decision-making.
Decision-making often requires retrieval from memory. Drawing on the neural ACT-R theory [Anderson, J. R., Fincham, J. M., Qin, Y., & Stocco, A. A central circuit of the mind. Trends in Cognitive Sciences, 12, 136-143, 2008] and other neural models of memory, we delineated the neural signatures of two fundamental retrieval aspects during decision-making: automatic and controlled activation of memory representations. To disentangle these processes, we combined a paradigm developed to examine neural correlates of selective and sequential memory retrieval in decision-making with a manipulation of associative fan (i.e., the decision options were associated with one, two, or three attributes). The results show that both the automatic activation of all attributes associated with a decision option and the controlled sequential retrieval of specific attributes can be traced in material-specific brain areas. Moreover, the two facets of memory retrieval were associated with distinct activation patterns within the frontoparietal network: The dorsolateral prefrontal cortex was found to reflect increasing retrieval effort during both automatic and controlled activation of attributes. In contrast, the superior parietal cortex only responded to controlled retrieval, arguably reflecting the sequential updating of attribute information in working memory. This dissociation in activation pattern is consistent with ACT-R and constitutes an important step toward a neural model of the retrieval dynamics involved in memory-based decision-making.


Solvent-free oxidation of primary alcohols to aldehydes using Au-Pd/TiO2 catalysts.
The oxidation of alcohols to aldehydes with O2 in place of stoichiometric oxygen donors is a crucial process for the synthesis of fine chemicals. However, the catalysts that have been identified so far are relatively inactive with primary alkyl alcohols. We showed that Au/Pd-TiO2 catalysts give very high turnover frequencies (up to 270,000 turnovers per hour) for the oxidation of alcohols, including primary alkyl alcohols. The addition of Au to Pd nanocrystals improved the overall selectivity and, using scanning transmission electron microscopy combined with x-ray photoelectron spectroscopy, we showed that the Au-Pd nanocrystals were made up of a Au-rich core with a Pd-rich shell, indicating that the Au electronically influences the catalytic properties of Pd.


Nanomaterials and autophagy: new insights in cancer treatment.
Autophagy represents a cell's response to stress. It is an evolutionarily conserved process with diversified roles. Indeed, it controls intracellular homeostasis by degradation and/or recycling intracellular metabolic material, supplies energy, provides nutrients, eliminates cytotoxic materials and damaged proteins and organelles. Moreover, autophagy is involved in several diseases. Recent evidences support a relationship between several classes of nanomaterials and autophagy perturbation, both induction and blockade, in many biological models. In fact, the autophagic mechanism represents a common cellular response to nanomaterials. On the other hand, the dynamic nature of autophagy in cancer biology is an intriguing approach for cancer therapeutics, since during tumour development and therapy, autophagy has been reported to trigger both an early cell survival and a late cell death. The use of nanomaterials in cancer treatment to deliver chemotherapeutic drugs and target tumours is well known. Recently, autophagy modulation mediated by nanomaterials has become an appealing notion in nanomedicine therapeutics, since it can be exploited as adjuvant in chemotherapy or in the development of cancer vaccines or as a potential anti-cancer agent. Herein, we summarize the effects of nanomaterials on autophagic processes in cancer, also considering the therapeutic outcome of synergism between nanomaterials and autophagy to improve existing cancer therapies.


Acute spinal cord injury, part I: pathophysiologic mechanisms.
Spinal cord injury (SCI) is a devastating and common neurologic disorder that has profound influences on modern society from physical, psychosocial, and socioeconomic perspectives. Accordingly, the present decade has been labeled the Decade of the Spine to emphasize the importance of SCI and other spinal disorders. Spinal cord injury may be divided into both primary and secondary mechanisms of injury. The primary injury, in large part, determines a given patient's neurologic grade on admission and thereby is the strongest prognostic indicator. However, secondary mechanisms of injury can exacerbate damage and limit restorative processes, and hence, contribute to overall morbidity and mortality. A burgeoning body of evidence has facilitated our understanding of these secondary mechanisms of injury that are amenable to pharmacological interventions, unlike the primary injury itself. Secondary mechanisms of injury encompass an array of perturbances and include neurogenic shock, vascular insults such as hemorrhage and ischemia-reperfusion, excitotoxicity, calcium-mediated secondary injury and fluid-electrolyte disturbances, immunologic injury, apoptosis, disturbances in mitochondrion function, and other miscellaneous processes. Comprehension of secondary mechanisms of injury serves as a basis for the development and application of targeted pharmacological strategies to confer neuroprotection and restoration while mitigating ongoing neural injury. The first article in this series will comprehensively review the pathophysiology of SCI while emphasizing those mechanisms for which pharmacologic therapy has been developed, and the second article reviews the pharmacologic interventions for SCI.


Hepatocarcinogenic potential of the glucocorticoid antagonist RU486 in B6C3F1 mice: effect on apoptosis, expression of oncogenes and the tumor suppressor gene p53.
Glucocorticoids inhibit hepatocellular proliferation and modulate the expression of oncogenes and tumor suppressor genes via mechanisms involving the glucocorticoid receptor. Glucocorticoids also produce a receptor-mediated inhibitory effect on both basal and hormone-stimulated expression of a newly discovered family of molecules important for shutting off cytokine action. We therefore hypothesized that inhibiting glucocorticoid receptors may disturb hepatocellular growth and apoptosis. Consequently, we investigated the effect of RU486, a potent antagonist of the glucocorticoid receptor, on basal levels of hepatocellular proliferation and apoptosis in male B6C3F1 mice. Furthermore, we evaluated the effect of this compound on cellular genes involved in the regulation of these important processes. Data show that treatment of male B6F3C1 mice with RU486 (2 mg/kg/d, ip) for 7 days dramatically inhibited liver cell proliferation by about 45% and programmed hepatocellular death by approximately 66%. RU 486 also significantly increased hepatic expression of the oncogenes mdm2 and JunB, while reducing that of the tumor suppressor gene p53. Exposure to RU486 may ultimately enhance the susceptibility of the liver to cancer risk by diminishing its ability to purge itself of pre-cancerous cells via apoptosis. This effect may be mediated through increases in the hepatic expression of the oncogene mdm2, coupled with decreases in that of the tumor suppressor gene p53. The decrease in hepatocellular proliferation caused by RU 486 may be related to effects other than its anti-glucocorticoid activity.


Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin.
The most common inherited form of Frontotemporal Lobar Degeneration (FTLD) known stems from Progranulin (GRN) mutation and exhibits TDP-43 plus ubiquitin aggregates. Despite the causative role of GRN haploinsufficiency in FTLD-TDP, the neurobiology of this secreted glycoprotein is unclear. Here, we examined PGRN binding to the cell surface. PGRN binds to cortical neurons via its C terminus, and unbiased expression cloning identifies Sortilin (Sort1) as a binding site. Sort1⁻/⁻ neurons exhibit reduced PGRN binding. In the CNS, Sortilin is expressed by neurons and PGRN is most strongly expressed by activated microglial cells after injury. Sortilin rapidly endocytoses and delivers PGRN to lysosomes. Mice lacking Sortilin have elevations in brain and serum PGRN levels of 2.5- to 5-fold. The 50% PGRN decrease causative in FTLD-TDP cases is mimicked in GRN+/⁻ mice, and is fully normalized by Sort1 ablation. Sortilin-mediated PGRN endocytosis is likely to play a central role in FTLD-TDP pathophysiology.


Fabrication of Metal Nanoparticles from Fungi and Metal Salts: Scope and Application.
Fungi secrete enzymes and proteins as reducing agents which can be used for the synthesis of metal nanoparticles from metal salts. Large-scale production of nanoparticles from diverse fungal strains has great potential since they can be grown even in vitro. In recent years, various approaches have been made to maximize the yield of nanoparticles of varying shape, size, and stability. They have been characterized by thermogravimetric analysis, X-ray diffractometry, SEM/TEM, zeta potential measurements, UV-vis, and Fourier transform infrared (FTIR) spectroscopy. In this review, we focus on the biogenic synthesis of metal nanoparticles by fungi to explore the chemistry of their formation extracellularly and intracellularly. Emphasis has been given to the potential of metal nanoparticles as an antimicrobial agent to inhibit the growth of pathogenic fungi, and on other potential applications.


Two-color trapped-particle optical microscopy.
We demonstrate a method for nonintrusive scanned near-field optical microscopy. The microscope utilizes an optical trap to position accurately a 50-100-nm-diameter lithium niobate particle. The infrared trapping beam is frequency doubled in the particle, resulting in a visible microscopic optical probe. By separation of the trapping and detection wavelengths, objects that are transparent in the infrared (e.g., biological) may be positioned close to the particle, resulting in high resolution. The current experimental resolution is limited to approximately 500 nm by the properties of the test objects. The theoretical resolution is less than 100 nm.


Implementation strategy and cost of Mozambique's HPV vaccine demonstration project.
Cost is an important determinant of health program implementation. In this study, we conducted a comprehensive evaluation of the implementation strategy of Mozambique's school-based HPV vaccine demonstration project. We sought to estimate the total costs for the program, cost per fully immunized girl (FIG), and compute projections for the total cost of implementing a similar national level vaccination program. We collected primary data through document review, participatory observation, and key informant interviews at all levels of the national health system and Ministry of Education. We used a combination of micro-costing methods-identification and measurement of resource quantities and valuation by application of unit costs, and gross costing-for consideration of resource bundles as they apply to the number of vaccinated girls. We extrapolated the cost per FIG to the HPV-vaccine-eligible population of Mozambique, to demonstrate the projected total annual cost for two scenarios of a similarly executed HPV vaccine program. The total cost of the Mozambique HPV vaccine demonstration project was $523,602. The mean cost per FIG was $72 (Credibility Intervals (CI): $62 - $83) in year one, $38 (CI: $37 - $40) in year two, and $54 CI: $49 - $61) for years one and two. The mean cost per FIG with the third HPV vaccine dose excluded from consideration was $60 (CI: $50 - $72) in year one, $38 (CI: $31 - $46) in year two, and $48 (CI: $42 - $55) for years one and two. The mean cost per FIG when only one HPV vaccine dose is considered was $30 (CI: $27 - $33)) in year one, $19 (CI: $15-$23) in year two, and $24 (CI: $22-$27) for both years. The projected annual cost of a two-and one-dose vaccine program targeting all 10-year-old girls in the country was $18.2 m (CI: $15.9 m - $20.7 m) and $9 m (CI: $8 m - $10 m) respectively. National adaptation and scale-up of Mozambique's school-based HPV vaccine strategy may result in substantial costs depending on dosing. For sustainability, stakeholders will need to negotiate vaccine price and achieve higher efficiency in startup activities and demand creation.


Invasion and extinction in the west Indian ant fauna: evidence from the dominican amber.
Of 37 genera and well-defined subgenera identified in the amber of the Dominican Republic (late Oligocene or early Miocene), 34 have survived somewhere in the New World tropics to the present, although the species studied thus far are extinct. Of the surviving genera and subgenera, 22 persist on Hispaniola. Fifteen genera and subgenera have colonized the island since amber times, restoring the number of genera and well-defined subgenera now present on Hispaniola to 37. A higher extinction rate has occurred in genera and subgenera that are either highly specialized or possess less colonizing ability, as evidenced by their restriction to the New World.


Indoleamine 2,3 dioxygenase, age, and immune activation in people living with HIV.
Immune activation complicates HIV despite antiretroviral therapy (ART). Indoleamine 2,3 dioxygenase (IDO) catabolizes tryptophan (T) to kynurenine (K), regulating immune activity, and IDO activity increases with age. This study examines the relationship of IDO activity, bacterial translocation, and aging in people living with HIV (PLWH) on ART. Samples and data from PLWH on ART from the Centers for AIDS Research Network of Integrated Clinical Systems and from matched HIV-uninfected patients (controls) from the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study were analyzed. The ratio of K to T (K:T) and neopterin were indicators of inflammation; 16S ribosomal DNA (16S rDNA) and lipopolysaccharide (LPS) were markers of bacterial translocation. Samples and data from 205 PLWH and 99 controls were analyzed. PLWH had higher K:T values across all ages, with a significant relationship between age and K:T for both groups. CD4 count or CD4 nadir had no association with K:T. There was no positive association between level of 16S rDNA or LPS detection and K:T. K:T and neopterin were associated. PLWH had elevated IDO activity, at younger ages, despite ART. This study suggests K:T ratio increases with age in both groups and is elevated in PLWH at all ages compared with age-matched controls.


Does modification of the Innsbruck and the Glasgow Coma Scales improve their ability to predict functional outcome?
The accurate prediction of functional outcome requires the development of multivariate models. To enhance their contribution to such models, the predictive power of each component must be optimized. To improve the predictive power of coma scales as the first step in building more sophisticated multivariate models to predict specific levels of functional outcome. Prospective descriptive study. Neurology and neurosurgery intensive care unit (NNICU) in a tertiary care academic center. Eighty-four patients with acute traumatic brain injury, intracerebral hemorrhage, subarachnoid hemorrhage, or ischemic stroke. None. The Glasgow Coma Scale (GCS) and Innsbruck Coma Scale (ICS) were administered within 24 hours of admission to the NNICU and then at 48-hour intervals until discharge of the patient from the NNICU. The assessments were performed by 3 occupational therapy graduate students working under the supervision of the medical director of the NNICU. The functional outcome at 3 months after discharge from the hospital was assessed by telephone by the same nurse using the following categories: (1) dead, (2) receiving nursing home or custodial care, (3) home with help, or (4) independent. Cronbach's alpha estimates of reliability for each scale were computed using all scores obtained during the study. The analyses indicated that the verbal response item of the GCS and the oral automatisms item of the ICS were less reliable in this patient population. The scales were modified by deleting those items, and predictive validity for the original and modified scales was computed using a discriminant function of the admission scores. Before modification, both scales were best at predicting independence (GCS and ICS, 71% correct) and mortality (GCS, 60% correct; ICS, 56% correct). The modifications produced a modest improvement in the ability of both scales to better predict levels of outcome (modified GCS: home with help, 33% correct, independent, 71% correct; modified ICS: home with help, 0% correct, independent, 74% correct). By deleting items with low reliability from the ICS and the GCS we achieved improved reliability and predictive validity. The improvement in predictive power, however, was inadequate to accurately predict functional outcome. Combining clinical scales with other demographic, physiological, functional, and radiographic data will be needed to achieve useful predictions of functional outcome.


Dietary polyphenol quercetin targets pancreatic cancer stem cells.
According to the cancer stem cell hypothesis the aggressive growth and early metastasis of pancreatic cancer may arise through dysregulation of self-renewal of stem cells in the tissue. Since recent data suggest targeting of cancer stem cells by some dietary agents we studied the effect of quercetin, a major polyphenol and flavonoid commonly detected in many fruits and vegetables. Using in vitro and in vivo models of pancreatic cancer stem cells we found quercetin-mediated reduction of self-renewal as measured by spheroid and colony formation. Quercetin diminished ALDH1 activity and reverted apoptosis resistance as detected by substrate assays, FACS and Western blot analysis. Importantly, combination of quercetin with sulforaphane, an isothiocyanate enriched in broccoli, had synergistic effects. Although quercetin led to enhanced binding of the survival factor NF-kappaB, co-incubation with sulforaphane completely eliminated this pro-proliferative feature. Moreover, quercetin prevented expression of proteins involved in the epithelial-mesenchymal transition, which was even stronger in presence of sulforaphane, suggesting the blockade of signaling involved in early metastasis. In vivo, quercetin inhibited growth of cancer stem cell-enriched xenografts associated with reduced proliferation, angiogenesis, cancer stem cell-marker expression and induction of apoptosis. Co-incubation with sulforaphane increased these effects and no pronounced toxicity on normal cells or mice was observed. Our data suggest that food ingredients complement each other in the elimination of cancer stem cell-characteristics. Since carcinogenesis is a complex process, combination of bioactive dietary agents with complementary activities may be most effective.


The landscape of RNA polymerase II-associated chromatin interactions in prostate cancer.
Transcriptional dysregulation is a hallmark of prostate cancer (PCa). We mapped the RNA polymerase II-associated (RNA Pol II-associated) chromatin interactions in normal prostate cells and PCa cells. We discovered thousands of enhancer-promoter, enhancer-enhancer, as well as promoter-promoter chromatin interactions. These transcriptional hubs operate within the framework set by structural proteins - CTCF and cohesins - and are regulated by the cooperative action of master transcription factors, such as the androgen receptor (AR) and FOXA1. By combining analyses from metastatic castration-resistant PCa (mCRPC) specimens, we show that AR locus amplification contributes to the transcriptional upregulation of the AR gene by increasing the total number of chromatin interaction modules comprising the AR gene and its distal enhancer. We deconvoluted the transcription control modules of several PCa genes, notably the biomarker KLK3, lineage-restricted genes (KRT8, KRT18, HOXB13, FOXA1, ZBTB16), the drug target EZH2, and the oncogene MYC. By integrating clinical PCa data, we defined a germline-somatic interplay between the PCa risk allele rs684232 and the somatically acquired TMPRSS2-ERG gene fusion in the transcriptional regulation of multiple target genes - VPS53, FAM57A, and GEMIN4. Our studies implicate changes in genome organization as a critical determinant of aberrant transcriptional regulation in PCa.


Sensory and descending motor circuitry during development and injury.
Proprioceptive sensory input and descending supraspinal projections are two major inputs that feed into and influence spinal circuitry and locomotor behaviors. Here we review their influence on each other during development and after spinal cord injury. We highlight developmental mechanisms of circuit formation as they relate to the sensory-motor circuit and its reciprocal interactions with local spinal interneurons, as well as competitive interactions between proprioceptive and descending supraspinal inputs in the setting of spinal cord injury.


Global solutions to regional problems: Collecting global expertise to address the problem of harmful cyanobacterial blooms. A Lake Erie case study.
In early August 2014, the municipality of Toledo, OH (USA) issued a 'do not drink' advisory on their water supply directly affecting over 400,000 residential customers and hundreds of businesses (Wilson, 2014). This order was attributable to levels of microcystin, a potent liver toxin, which rose to 2.5μgL-1 in finished drinking water. The Toledo crisis afforded an opportunity to bring together scientists from around the world to share ideas regarding factors that contribute to bloom formation and toxigenicity, bloom and toxin detection as well as prevention and remediation of bloom events. These discussions took place at an NSF- and NOAA-sponsored workshop at Bowling Green State University on April 13 and 14, 2015. In all, more than 100 attendees from six countries and 15 US states gathered together to share their perspectives. The purpose of this review is to present the consensus summary of these issues that emerged from discussions at the Workshop. As additional reports in this special issue provide detailed reviews on many major CHAB species, this paper focuses on the general themes common to all blooms, such as bloom detection, modeling, nutrient loading, and strategies to reduce nutrients.


Cancer screening practices among physicians in the national breast and cervical cancer early detection program.
The National Breast and Cervical Cancer Early Detection Program (NBCCEDP) provides low-income, uninsured women with screening and diagnostic services for breast and cervical cancer. Our study was conducted to describe the demographic and practice characteristics of participating and nonparticipating physicians, as well as their beliefs, adoption of new screening technologies, and recommendations for breast and cervical cancer screening. From a 2006-2007 nationally representative survey, we identified 1,111 practicing primary care physicians who provide breast and cervical cancer screenings and assessed their recommendations using clinical vignettes related to screening initiation, frequency, and cessation. Responses of physicians participating in the NBCCEDP were compared with those from nonparticipating physicians. Of the physicians surveyed, 15% reported participation in the NBCCEDP, 65% were not participants, and 20% were not sure or did not respond to this question. Program physicians were significantly more likely to practice in multispecialty settings, in a rural location, and in a hospital or clinic setting and had more patients who were female and insured by Medicaid or uninsured compared with nonprogram physicians. Beliefs about the effectiveness of screening tools or procedures in reducing breast or cervical cancer mortality were similar by program participation. Adoption of new technologies, including digital mammography and human papillomavirus (HPV) testing, and making guideline-consistent recommendations for screening initiation, frequency, and cessation did not differ significantly by program participation. Although there may be differences in physician characteristics and practice settings, the beliefs and screening practices for both breast and cervical cancer are similar between program and nonprogram providers.


Microglial and astrocyte chemokines regulate monocyte migration through the blood-brain barrier in human immunodeficiency virus-1 encephalitis.
The numbers of immune-activated brain mononuclear phagocytes (MPs) affect the progression of human immunodeficiency virus (HIV)-1-associated dementia (HAD). Such MPs originate, in measure, from a pool of circulating monocytes. To address the mechanism(s) for monocyte penetration across the blood-brain barrier (BBB), we performed cross-validating laboratory, animal model, and human brain tissue investigations into HAD pathogenesis. First, an artificial BBB was constructed in which human brain microvascular endothelial and glial cells-astrocytes, microglia, and/or monocyte-derived macrophages (MDM)-were placed on opposite sides of a matrix-coated porous membrane. Second, a SCID mouse model of HIV-1 encephalitis (HIVE) was used to determine in vivo monocyte blood-to-brain migration. Third, immunohistochemical analyses of human HIVE tissue defined the relationships between astrogliosis, activation of microglia, virus infection, monocyte brain infiltration, and beta-chemokine expression. The results, taken together, showed that HIV-1-infected microglia increased monocyte migration through an artificial BBB 2 to 3.5 times more than replicate numbers of MDM. In the HIVE SCID mice, a marked accumulation of murine MDM was found in areas surrounding virus-infected human microglia but not MDM. For human HIVE, microglial activation and virus infection correlated with astrogliosis, monocyte transendothelial migration, and beta-chemokine expression. Pure cultures of virus-infected and activated microglia or astrocytes exposed to microglial conditioned media produced significant quantities of beta-chemokines. We conclude that microglial activation alone and/or through its interactions with astrocytes induces beta-chemokine-mediated monocyte migration in HAD.


Detection of Pseudomonas pseudomallei antigen in urine for the diagnosis of melioidosis.
An enzyme-linked immunosorbent assay using a fluorescein isothiocyanate (FITC)-anti-FITC amplification system, has been developed to detect Pseudomonas pseudomallei antigen in urine. The assay was evaluated in 135 patients with acute melioidosis, 194 hospitalized patients with other disorders, and 40 healthy controls. Antigen was detected in the urine of 123 (91%) patients with melioidosis. Urinary antigen was found in 85 (96%) of 89 patients with septicemic melioidosis, all six patients with P. pseudomallei urinary tract infection, and 32 (80%) of 40 patients with other localized infections. Antigen was not detected in the urine of 40 healthy individuals, but the urine of 16 (8%) of 194 hospitalized patients with diagnoses other than melioidosis gave a positive result. Of the false-positive results, 13 of 16 were associated with bacteriuria > or = 10(4) colony-forming units/ml. At a cutoff titer of 1:10, the sensitivity and specificity of the test were 81% and 96%, respectively. Enzyme immunoassay detection of urinary antigen is a valuable and rapid laboratory test for the early diagnosis of acute melioidosis.


Extreme temperatures and mortality in the North of Spain.
To study the relationship between mortality and temperature in Cantabria, a Spanish region that includes both rural and urban areas. Meteorological data (2003-2006) were obtained from the Spanish Meteorological Agency and daily numbers of deaths were obtained from the Spanish Institute for Statistics. A graphical approach using locally weighted regression smoothing was used to explore the relationship between mortality and temperatures and to identify temperature thresholds; we estimated the excess of mortality due to extreme temperatures in both warm and cold periods using Poisson regression models, and we simulated a situation with increased temperatures. Raising maximum or minimum temperatures by 1ºC was associated with a 2% excess in mortality risk in the whole population throughout the warm period, and we found no effect in mortality on the cold season; almost all changes in mortality occur in people aged 65 or more. Women are more sensitive to temperature changes in the warmer months. The deleterious effect of increasing temperatures in summer is more pronounced than the beneficial effect of a similar increase in winter.