Emergency Department Visits and Readmissions among Children after Gastrostomy Tube Placement.
To define the incidence of 30-day postdischarge emergency department (ED) visits and hospital readmissions following pediatric gastrostomy tube (GT) placement across all procedural services (Surgery, Interventional-Radiology, Gastroenterology) in 38 freestanding Children's Hospitals. This retrospective cohort study evaluated patients <18 years of age discharged between 2010 and 2012 after GT placement. Factors significantly associated with ED revisits and hospital readmissions within 30 days of hospital discharge were identified using multivariable logistic regression. A subgroup analysis was performed comparing patients having the GT placed on the date of admission or later in the hospital course. Of 15 642 identified patients, 8.6% had an ED visit within 30 days of hospital discharge, and 3.9% were readmitted through the ED with a GT-related issue. GT-related events associated with these visits included infection (27%), mechanical complication (22%), and replacement (19%). In multivariable analysis, Hispanic ethnicity, non-Hispanic black race, and the presence of ≥3 chronic conditions were independently associated with ED revisits; gastroesophageal reflux and not having a concomitant fundoplication at time of GT placement were independently associated with hospital readmission. Timing of GT placement (scheduled vs late) was not associated with either ED revisits or hospital readmission. GT placement is associated with high rates of ED revisits and hospital readmissions in the first 30 days after hospital discharge. The association of nonmodifiable risk factors such as race/ethnicity and medical complexity is an initial step toward understanding this population so that interventions can be developed to decrease these potentially preventable occurrences given their importance among accountable care organizations.


Genetic control over the resting brain.
The default-mode network, a coherent resting-state brain network, is thought to characterize basal neural activity. Aberrant default-mode connectivity has been reported in a host of neurological and psychiatric illnesses and in persons at genetic risk for such illnesses. Whereas the neurophysiologic mechanisms that regulate default-mode connectivity are unclear, there is growing evidence that genetic factors play a role. In this report, we estimate the importance of genetic effects on the default-mode network by examining covariation patterns in functional connectivity among 333 individuals from 29 randomly selected extended pedigrees. Heritability for default-mode functional connectivity was 0.424 +/- 0.17 (P = 0.0046). Although neuroanatomic variation in this network was also heritable, the genetic factors that influence default-mode functional connectivity and gray-matter density seem to be distinct, suggesting that unique genes influence the structure and function of the network. In contrast, significant genetic correlations between regions within the network provide evidence that the same genetic factors contribute to variation in functional connectivity throughout the default mode. Specifically, the left parahippocampal region was genetically correlated with all other network regions. In addition, the posterior cingulate/precuneus region, medial prefrontal cortex, and right cerebellum seem to form a subnetwork. Default-mode functional connectivity is influenced by genetic factors that cannot be attributed to anatomic variation or a single region within the network. By establishing the heritability of default-mode functional connectivity, this experiment provides the obligatory evidence required before these measures can be considered as endophenotypes for psychiatric or neurological illnesses or to identify genes influencing intrinsic brain function.


Higher Coffee Consumption Is Associated With Slower Cognitive Decline and Less Cerebral Aβ-Amyloid Accumulation Over 126 Months: Data From the Australian Imaging, Biomarkers, and Lifestyle Study.
Background: Worldwide, coffee is one of the most popular beverages consumed. Several studies have suggested a protective role of coffee, including reduced risk of Alzheimer's disease (AD). However, there is limited longitudinal data from cohorts of older adults reporting associations of coffee intake with cognitive decline, in distinct domains, and investigating the neuropathological mechanisms underpinning any such associations. Methods: The aim of the current study was to investigate the relationship between self-reported habitual coffee intake, and cognitive decline assessed using a comprehensive neuropsychological battery in 227 cognitively normal older adults from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study, over 126 months. In a subset of individuals, we also investigated the relationship between habitual coffee intake and cerebral Aβ-amyloid accumulation (n = 60) and brain volumes (n = 51) over 126 months. Results: Higher baseline coffee consumption was associated with slower cognitive decline in executive function, attention, and the AIBL Preclinical AD Cognitive Composite (PACC; shown reliably to measure the first signs of cognitive decline in at-risk cognitively normal populations), and lower likelihood of transitioning to mild cognitive impairment or AD status, over 126 months. Higher baseline coffee consumption was also associated with slower Aβ-amyloid accumulation over 126 months, and lower risk of progressing to "moderate," "high," or "very high" Aβ-amyloid burden status over the same time-period. There were no associations between coffee intake and atrophy in total gray matter, white matter, or hippocampal volume. Discussion: Our results further support the hypothesis that coffee intake may be a protective factor against AD, with increased coffee consumption potentially reducing cognitive decline by slowing cerebral Aβ-amyloid accumulation, and thus attenuating the associated neurotoxicity from Aβ-amyloid-mediated oxidative stress and inflammatory processes. Further investigation is required to evaluate whether coffee intake could be incorporated as a modifiable lifestyle factor aimed at delaying AD onset.


Human umbilical vein endothelial cell killing by activated neutrophils. Loss of sensitivity to injury is accompanied by decreased iron content during in vitro culture and is restored with exogenous iron.
First passage human umbilical vein endothelial cells (HUVECs) were sensitive to killing by activated neutrophils and reagent hydrogen peroxide (H2O2). Catalase and deferoxamine prevented killing whereas soybean trypsin inhibitor and superoxide dismutase did not. In these regards, HUVECs are similar to previously characterized endothelial cells from bovine and rat. Although first passage HUVECs were killed by activated neutrophils, sensitivity fell off rapidly as the cells were maintained in culture. At passage 2 (four population doublings), and beyond, HUVECs were highly resistant. The cells also became resistant to killing by reagent H2O2. The acquisition of resistance to killing was not accompanied by a failure to up-regulate neutrophil adhesion molecules or to support neutrophil adhesion. Levels of intracellular anti-oxidants (total thiols, though not glutathione, glutathione peroxidase or catalase activity) increased as a function of passage in culture. However, levels of glutathione and total thiols in late passage (resistant) HUVECs were similar to levels in late passage rat pulmonary artery endothelial cells, that were sensitive to killing by activated neutrophils. Cell-associated iron in HUVECs fell as a function of time in culture. By passage 2, the amount of total iron measurable with the Ferrozine reagent was only about 30% of the amount recovered from first passage HUVECs. The loss of iron from the cells may underlie much of the concomitant resistance to killing because when the cells were pretreated with iron under conditions in which it could be taken up, sensitivity to killing by activated neutrophils and by H2O2 was restored.


Trajectories of frailty and related factors of the older people in Taiwan.
BACKGROUND/STUDY CONTEXT: This study aimed to identify the different trajectories of frailty and factors related to frailty among older adults over time. Data were obtained from a five-wave panel composed of older Taiwanese adults from 1993 to 2007 (N = 2306). Frailty was defined as the presence of three or more of the following criteria: shrinking, weakness, exhaustion, slowness, and low physical activity. A group-based model of trajectory analysis was applied with time-dependent and time-independent variables. Three trajectory groups were identified: maintaining nonfrailty, developing frailty, and high risk of frailty. Being female, older, and having a lower level of education were risk factors for being in the developing frailty group or high risk of frailty group. Physical risk factors and psychological factors were associated with frailty within each group. Higher financial satisfaction and social participation were protective factors from frailty for the developing frailty group and high risk of frailty group, respectively. Older adults should promote their health physically, psychologically, and socially.


Prevalence of antibiotic resistant Escherichia coli isolates from fecal samples of food handlers in Qatar.
It is well documented that food handlers harbor and shed enteric foodborne pathogens causing foodborne disease outbreaks. However, little known on enteric antibiotic resistant (AR) bacteria carriage in food handlers. The objective of this study was to establish a baseline prevalence of fecal AR E. coli among food handlers in Qatar. Fecal samples were collected from 456 migrant food handlers of different nationalities arriving in Qatar on a work permit between January 2015 and December 2016. These samples (25 g each) were collected based on the availability and examination schedule at the Medical Commission facility from those consented to participate. Isolated E. coli bacteria were tested for antibiotic susceptibility against nine antibiotics using the E-test method and Double Disc Synergy Test (DDST) for extended-spectrum beta-lactamase (ESBL) production. From the 78 E. coli positive samples (17.1%, n = 456), 60% of the isolates were resistant to at least one antibiotic, whereas, 27% were multi-drug resistant (MDR). Seven isolates (9%, n = 78) were ESBL producers of which five were MDR. Individual AR E. coli frequencies to the nine antibiotics were not significantly (P > 0.05) different by nationality. Based on our findings, we revealed that individual resistant E. coli and MDR resistant E. coli were common in fecal samples of food handlers in Qatar. This may indicate that food handlers can potentially contaminate foods with AR E. coli, a possible public health concern.


Cochrane corner: sugammadex, a selective reversal medication for preventing postoperative residual neuromuscular blockade.
Sugammadex is the first selective relaxant binding agent that has been studied for reversal of neuromuscular blockade induced by rocuronium and other steroidal non-depolarizing neuromuscular blocking agents (NMBAs). To assess the efficacy and safety of sugammadex in reversing neuromuscular blockade induced by steroidal non-depolarizing NMBAs and in preventing postoperative residual neuromuscular blockade. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 3), MEDLINE (1950 to August 2008), and EMBASE (1980 to August 2008). In addition, we handsearched reference lists of relevant articles and meeting abstracts. Furthermore, we contacted the medication's manufacturer for more information. All randomized controlled trials (RCTs) on adult patients (> or = 18 years old) in which sugammadex was compared with placebo or other medications, or in which different doses of sugammadex were compared with each other. We excluded non-randomized trials and studies on healthy volunteers. We independently performed determination of trial inclusion, quality assessment, and data extraction. We applied standard meta- analytic techniques. We included18 RCTs (n=1321 patients). Seven trials were published as full-text papers, and 11 trials only as meeting abstracts. All the included trials had adequate methods of randomization and allocation concealment. The results suggest that, compared with placebo or neostigmine, sugammadex can more rapidly reverse rocuronium-induced neuromuscular blockade regardless of the depth of the block. We identified 2, 4, and 16 mg/kg of sugammadex for reversal of rocuronium-induced neuromuscular blockade at T2 reappearance , 1 to 2 post-tetanic counts, and 3 to 5 minutes after rocuronium, respectively. The number of trials are very limited regarding vecuronium and pancuronium. Serious adverse events occurred in < 1% of all patients who received the medication. There was no significant difference between sugammadex and placebo in terms of the prevalence of drug-related adverse events (RR 1.20, 95% CI 0.61 to 2.37; P=0.59, I2=0%, 5 RCTs). Also, no significant difference was found between sugammadex and neostigmine for adverse events (RR 0.98, 95% CI 0.48 to1.98; P=0.95, I2=43%, 3 RCTs). Sugammadex was shown to be effective in reversing rocuronium-induced neuromuscular blockade. This review has found no evidence of a difference in the instance of unwanted effects between sugammadex, placebo or neostigmine. These results need to be confirmed by future trials on larger patient populations and with more focus on patient-related outcomes.


A Novel Algorithm for Remote Photoplethysmography: Spatial Subspace Rotation.
In this paper, we propose a conceptually novel algorithm, namely "Spatial Subspace Rotation" (2SR), that improves the robustness of remote photoplethysmography. Based on the assumption of 1) spatially redundant pixel-sensors of a camera, and 2) a well-defined skin mask, our core idea is to estimate a spatial subspace of skin-pixels and measure its temporal rotation for pulse extraction, which does not require skin-tone or pulse-related priors in contrast to existing algorithms. The proposed algorithm is thoroughly assessed on a benchmark dataset containing 54 videos, which includes challenges of various skin-tones, body-motions in complex illuminance conditions, and pulse-rate recovery after exercise. The experimental results show that given a well-defined skin mask, 2SR outperforms the popular ICA-based approach and two state-of-the-art algorithms (CHROM and PBV). When comparing the pulse frequency spectrum, 2SR improves on average the SNR of ICA by 2.22 dB, CHROM by 1.56 dB, and PBV by 1.95 dB. When comparing the instant pulse-rate, 2SR improves on average the Pearson correlation and precision of ICA by 47% and 65%, CHROM by 22% and 23%, and PBV by 21% and 39%. ANOVA confirms the significant improvement of 2SR in peak-to-peak accuracy. The proposed 2SR algorithm is very simple to use and extend, i.e., the implementation only requires a few lines MATLAB code.


Heterotopic bone formation following hip arthroplasty in Paget's disease.
Heterotopic bone formation in soft tissues occurs commonly in Paget's disease patients following a primary total hip arthroplasty (THA). The nature of this heterotopic bone has not been documented. In this report, we show that the heterotopic bone removed 14 years after primary THA in a case of Paget's disease was sclerotic, contained prominent mosaic cement lines and showed increased remodelling activity on the bone surface. In addition to these typically Pagetic histological features, it was noted ultrastructurally that the osteoclasts contained characteristic intranuclear viral-like inclusions. In contrast, the foreign body macrophages found in the joint pseudocapsule and pseudomembrane, which are a population of mononuclear precursor cells from which osteoclasts can be formed, did not contain viral-like inclusions. These findings are of interest regarding the pathogenesis of heterotopic bone formation following hip arthroplasty and the ontogeny of Pagetic osteoclasts.


Ultraviolet optical and microstructural properties of MgF2 and LaF3 coatings deposited by ion-beam sputtering and boat and electron-beam evaporation.
Single layers of MgF2 and LaF3 were deposited upon superpolished fused-silica and CaF2 substrates by ion-beam sputtering (IBS) as well as by boat and electron beam (e-beam) evaporation and were characterized by a variety of complementary analytical techniques. Besides undergoing photometric and ellipsometric inspection, the samples were investigated at 193 and 633 nm by an optical scatter measurement facility. The structural properties were assessed with atomic-force microscopy, x-ray diffraction, TEM techniques that involved conventional thinning methods for the layers. For measurement of mechanical stress in the coatings, special silicon substrates were coated and analyzed. The dispersion behavior of both deposition materials, which was determined on the basis of various independent photometric measurements and data reduction techniques, is in good agreement with that published in the literature and with the bulk properties of the materials. The refractive indices of the MgF2 coatings ranged from 1.415 to 1.440 for the wavelength of the ArF excimer laser (193 nm) and from 1.435 to 1.465 for the wavelength of the F2 excimer laser (157 nm). For single layers of LaF3 the refractive indices extended from 1.67 to 1.70 at 193 nm to approximately 1.80 at 157 nm. The IBS process achieves the best homogeneity and the lowest surface roughness values (close to 1 nm(rms)) of the processes compared in the joint experiment. In contrast to MgF2 boat and e-beam evaporated coatings, which exhibit tensile mechanical stress ranging from 300 to 400 MPa, IBS coatings exhibit high compressive stress of as much as 910 MPa. A similar tendency was found for coating stress in LaF3 single layers. Experimental results are discussed with respect to the microstructural and compositional properties as well as to the surface topography of the coatings.


Ribavirin therapy for hepatitis E virus-induced acute on chronic liver failure: a preliminary report.
Hepatitis E virus (HEV) is a common cause of acute on chronic liver failure (ACLF) in HEV hyperendemic regions with high mortality. Treatment for HEV-induced ACLF is currently not available. Recently, efficacy of ribavirin in genotype 3 chronic hepatitis E patients has been reported; however, whether ribavirin is effective in genotype 1 HEV infection is not yet known. The present study includes four patients with HEV-induced ACLF treated with ribavirin in a genotype 1 HEV hyperendemic region. Diagnosis of ACLF was made by conventional criteria and HEV as the cause of ACLF was confirmed by detection of HEV RNA by reverse transcriptase PCR. Ribavirin dose ranged from 200 to 600 mg/day and was used for a median duration of 12 (range 3-24) weeks. All patients had undetectable HEV in 3-8 weeks, survived and none had serious adverse effects. This preliminary observation from a single centre indicates that ribavirin may be an effective therapeutic agent for HEV-induced ACLF and a randomized control trial is needed to establish its efficacy.


Attitudes Toward LGBT Patients Among Students in the Health Professions: Influence of Demographics and Discipline.
Health providers' personal and professional experiences may predict attitudes toward lesbian, gay, bisexual, and transgender (LGBT) individuals and can therefore serve as key targets for health professions training aimed at decreasing barriers to high-quality patient care. This study explored the relationship between professional, demographic, and training characteristics and health professions student attitudes toward LGBT patients. Students from a health sciences university and applied mental health programs in Georgia (N=475) completed a survey that included a modified version of the Attitudes Toward LGBT Patients Scale (ATLPS). Profession, sexual orientation, current financial status, religion, religiosity, spirituality, and self-reported familiarity with various religious perspectives on sex were associated with ATLPS scores. However, religiosity and self-reported familiarity with various religious perspectives on sex were the only significant predictors of ATLPS scores when these variables were included in one general linear model. Health professions students with higher levels of religiosity and lower levels of self-reported familiarity with various religious perspectives on sex reported less positive attitudes toward LGBT individuals. Results suggest that personal factors may be important to address in interprofessional curriculum related to LGBT patient care. Self-report biases and other factors may limit the accuracy and generalizability of the findings.


Role of Physical Examination in Decision Making for Selective Exploration in Patients with Penetrating Zone II Neck Injury.
To evaluate the role of physical examination in decision making for exploring patients with penetrating zone II neck injury. This was a cross-sectional study being performed in a level I trauma center between 2006 and 2010. The present study reviewed the records of 150 patients with penetrating neck injuries. Of 46 cases with zone II deep platysma neck injuries, 3 patients died before taking any significant medical measure. Thirty of 43 patients (70%) presented with hard sings while 13 (30%) did not show these sings. All patients underwent neck exploration. Two patients (4.6%) without hard sings exhibited positive findings, whereas 29 cases (67%) with hard sings reported positive on exploration. Briefly, we hold the view that it seems reasonable to follow an algorithmic approach by using physical examination of the patients with zone II penetrating neck injuries. This prevents unnecessary exploration for management of such patients.


Study of the interaction between graphene and planar terahertz metamaterial with toroidal dipolar resonance.
A planar terahertz metamaterial consisting of square split ring resonators is proposed, and the excitation of toroidal dipolar resonance is demonstrated. Moreover, we theoretically investigate the strong interaction between graphene and toroidal dipolar resonance of the metamaterial. By varying its Fermi energy, the simulations show that graphene can actively modulate the transmission amplitude of toroidal dipolar resonance and even switch it off. The interaction of the toroidal dipolar resonance with monolayer graphene further highlights the ultrasensitive sensing characteristic of the planar metamaterial, which can be utilized for other graphene-like two-dimensional materials. These intriguing properties of the proposed metamaterial may have potential applications in terahertz modulators and ultrasensitive sensors.


First Report of Awake Craniotomy of a Famous Musician: Suprasellar Tumor Surgery of Pianist Clara Haskil in 1942.
Clara Haskil (January 7, 1895-December 7, 1960) was one of the most famous female pianists of the 20th century. In her life and work she set new standards in piano playing. However, her career was beset by poor health and the adversities of two world wars. In her lifetime Haskil had three major disorders: juvenile scoliosis requiring treatment in her adolescence, a tumor of the sellar region requiring surgery at age 47 years, and a traumatic brain injury causing her death at the age of 65. Her medical history illustrates the development of surgical methods and rehabilitation in medicine before and after World War II. At an early age, she spent a year in a nursing home for orthopedic diseases due to scoliosis. In 1942, when she was 47 years old, she displayed the first symptoms of a suprasellar brain tumor: headache and hemianopsia. The famous surgeon Marcel David performed surgery on her without general anesthesia while Haskil mentally played a Mozart piano concerto as a neuronal representation to control her memory and mental abilities. Only 3 months after that operation she played a Mozart piano concerto at a concert that began her career as a great interpreter of Mozart. Her neurologic rehabilitation was remarkable and highlighted new methods in the field. In 1960, she traveled to Brussels for a concert. In the train station she stumbled on the stairs and hit her head on one of the steps. Skull fracture and intracranial hematoma were diagnosed. Doctors tried to operate on her but she lost consciousness and died. Haskil created new styles in piano playing, and her medical history offers indications of new concepts in neurosurgery.


Plasma ghrelin concentrations in patients with polycystic ovary syndrome before and after 6months therapy: correlation with androgen levels.
Ghrelin is a natural ligand of the growth hormone secretagogue receptor and has been shown to be a potent stimulant of GH secretion. It has also orexigenic effects and regulates energy homeostasis. Recent studies claim that ghrelin influences the androgen level and probably takes part in PCOS pathomechanism. The aim of the study was an assessment of ghrelin level in plasma in women with PCOS before and after the treatment and ghrelin's influence on androgen level change. The study included 25 women with the diagnosed PCOS (mean age 25.3+/-4.05 yr). The tests were done twice: before the treatment and after 6-month therapy with Diane 35 (cyproterone acetate 2 mg with ethinylestradiol 35 mug). Following hormones were measured: ghrelin, free testosterone, androstendione, dehydroepiandrosterone sulfate, 17-OH-progesterone and estradiol. The received results in both groups were compared with the control group (11 healthy women, mean age 26.0+/-2.6 yr). No statistically significant differences in ghrelin levels before (187.8+/-8.1 fmol/ml) and after the therapy (185.6+/-9.5 fmol/ml) were found. Similar results were received when two groups of women compared with the control (186.5+/-8.7 fmol/ml). No correlations between ghrelin and androgen levels were confirmed. Final conclusion is that there is no direct impact of ghrelin level on PCOS pathogenesis, however, its role in development of obesity, hyperinsulinemia and insulin resistance co-occurring with metabolic disorders syndrome cannot be excluded.


The face that sank the Essex: potential function of the spermaceti organ in aggression.
'Forehead to forehead I meet thee, this third time, Moby Dick!' [Ahab (Melville, 1851)] Herman Melville's fictional portrayal of the sinking of the Pequod was inspired by instances in which large sperm whales sank whaling ships by ramming the ships with their heads. Observations of aggression in species of the four major clades of cetacean and the artiodactyl outgroup suggest that head-butting during male-male aggression is a basal behavior for cetaceans. We hypothesize that the ability of sperm whales to destroy stout wooden ships, 3-5 times their body mass, is a product of specialization for male-male aggression. Specifically, we suggest that the greatly enlarged and derived melon of sperm whales, the spermaceti organ, evolved as a battering ram to injure an opponent. To address this hypothesis, we examined the correlation between relative melon size and the level of sexual dimorphism in body size among cetaceans. We also modeled impacts between two equal-sized sperm whales to determine whether it is physically possible for the spermaceti organ to function as an effective battering ram. We found (i) that the evolution of relative melon size in cetaceans is positively correlated with the evolution of sexual dimorphism in body size and (ii) that the spermaceti organ of a charging sperm whale has enough momentum to seriously injure an opponent. These observations are consistent with the hypothesis that the spermaceti organ has evolved to be a weapon used in male-male aggression.


Management of Severe Curly Top in Sugar Beet with Insecticides.
Curly top, caused by Curtovirus spp., is a widespread disease problem vectored by the beet leafhopper in semiarid sugar beet production areas. The insecticide seed treatment Poncho Beta has proven to be effective in controlling curly top in sugar beet but was only evaluated under light to moderate disease pressure. Thus, the insecticide seed treatments Poncho Beta, NipsIt INSIDE, and Cruiser Force were evaluated under severe curly top pressure (six viruliferous beet leafhoppers per plant) in field studies during the 2010 and 2011 growing seasons on two commercial sugar beet cultivars. In addition, the foliar insecticides Movento, Provado, and Scorpion were also evaluated. The seed treatments and Scorpion reduced curly top symptoms by 33 to 41% (P < 0.0001) and increased root yield by 55 to 95% (P < 0.0001), sucrose content by 6.5 to 7.2% (P = 0.0013 to <0.0001), and estimated recoverable sucrose by 58 to 96% (P < 0.0001) when compared with the untreated check. Movento and Provado did not improve control beyond that provided by Poncho Beta. Even under severe disease pressure 50 to 55 days after planting, neonicotinoid seed treatments can effectively reduce curly top, increase yield, and help protect against early-season insect pest pressure.


Effect of X-irradiation on Citrus Canker Pathogen Xanthomonas citri subsp. citri of Satsuma Mandarin Fruits.
Citrus canker caused by Xanthomonas citri subsp. citri (Xcc) is one of the most important bacterial diseases of citrus. Because citrus canker is not found in many countries including European Union and Australia, Xcc is strictly regulated in order to prevent its spread. In this study, the effects of X-irradiation on Xcc growth either in the suspension or on the surface of citrus fruits were investigated. The suspension containing 1×10(7) cfu/ml of Xcc was irradiated with different absorbed doses of X-irradiation ranging from 50 to 400 Gy. The results showed that Xcc was fully dead at 400 Gy of X-irradiation. To determine the effect of X-irradiation on quarantine, the Xcc-inoculated citrus fruits were irradiated with different X-ray doses at which Xcc was completely inhibited by an irradiation dose of 250 Gy. The D10 value for Xcc on citrus fruits was found to be 97 Gy, indicating the possibility of direct application on citrus quarantine without any side sterilizer. Beside, presence of Xcc on the surface of asymptomatic citrus fruits obtained from citrus canker-infected orchards was noted. It indicated that the exporting citrus fruits need any treatment so that Xcc on the citrus fruits should be completely eliminated. Based on these results, ionizing radiation can be considered as an alternative method of eradicating Xcc for export of citrus fruits.


Enhanced efficacy of therapeutic cancer vaccines produced by co-treatment with Mycobacterium tuberculosis heparin-binding hemagglutinin, a novel TLR4 agonist.
Effective activation of dendritic cells (DCs) toward T helper (Th)-1 cell polarization would improve DC-based antitumor immunotherapy, helping promote the development of immunotherapeutic vaccines based on T-cell immunity. To achieve this goal, it is essential to develop effective immune adjuvants that can induce powerful Th1 cell immune responses. The pathogenic organism Mycobacterium tuberculosis includes certain constitutes, such as heparin-binding hemagglutinin (HBHA), that possess a strong immunostimulatory potential. In this study, we report the first clarification of the functions and precise mechanism of HBHA in immune stimulation settings relevant to cancer. HBHA induced DC maturation in a TLR4-dependent manner, elevating expression of the surface molecules CD40, CD80, and CD86, MHC classes I and II and the proinflammatory cytokines IL-6, IL-12, IL-1β, TNF-α, and CCR7, as well as stimulating the migratory capacity of DCs in vitro and in vivo. Mechanistic investigations established that MyD88 and TRIF signaling pathways downstream of TLR4 mediated secretion of HBHA-induced proinflammatory cytokines. HBHA-treated DCs activated naïve T cells, polarized CD4(+) and CD8(+) T cells to secrete IFN-γ, and induced T-cell-mediated cytotoxicity. Notably, systemic administration of DCs that were HBHA-treated and OVA(251-264)-pulsed ex vivo greatly strengthened immune priming in vivo, inducing a dramatic regression of tumor growth associated with long-term survival in a murine E.G7 thymoma model. Together, our findings highlight HBHA as an immune adjuvant that favors Th1 polarization and DC function for potential applications in DC-based antitumor immunotherapy.


UK Healthcare Workers' Experiences of Major System Change in Elective Surgery During the COVID-19 Pandemic: Reflections on Rapid Service Adaptation.
The coronavirus disease 2019 (COVID-19) pandemic disrupted the delivery of elective surgery in the United Kingdom. The majority of planned surgery was cancelled or postponed in March 2020 for the duration of the first wave of the pandemic. We investigated the experiences of staff responsible for delivering rapid changes to surgical services during the first wave of the pandemic in the United Kingdom, with the aim of developing lessons for future major systems change (MSC). Using a rapid qualitative study design, we conducted 25 interviews with frontline surgical staff during the first wave of the pandemic. Framework analysis was used to organise and interpret findings. Staff discussed positive and negative experiences of rapid service organisation. Clinician-led decision-making, the flexibility of individual staff and teams, and the opportunity to innovate service design were all seen as positive contributors to success in service adaptation. The negative aspects of rapid change were inconsistent guidance from national government and medical bodies, top-down decisions about when to cancel and restart surgery, the challenges of delivering emergency surgical care safely and the complexity of prioritising surgical cases when services re-started. Success in the rapid reorganisation of elective surgical services can be attributed to the flexibility and adaptability of staff. However, there was an absence of involvement of staff in wider system-level pandemic decision-making and competing guidance from national bodies. Involving staff in decisions about the organisation and delivery of MSC is essential for the sustainability of change processes.


Dorsolateral prefrontal cortex magnetic resonance imaging measurements and cognitive performance in autism.
This study examined the relationships between volumetric measurements of frontal lobe structures and performance on executive function tasks in individuals with autism. Magnetic resonance imaging (MRI) scans were obtained from 38 individuals with autism and 40 matched controls between the ages of 8 and 45 years. Executive function was assessed using neuropsychological measures including the Wisconsin Card Sorting Test and Tower of Hanoi. Differences in performance on the neuropsychological tests were found between the 2 groups. However, no differences in dorsolateral prefrontal cortex volumes were observed between groups. No correlations between volumetric measurements and performance on the neuropsychological tests were found. Findings from this study suggest that executive function deficits observed in autism are related to functional but not anatomical abnormalities of the frontal lobe. The absence of correlations suggests that executive dysfunction is not the result of focal brain alterations but, rather, is the result of a distributed neural network dysfunction.


The relationship between maternal self-efficacy, compliance and outcome in a trial of vitamin D supplementation in pregnancy.
In a randomised controlled trial of vitamin D during pregnancy, we demonstrated that women with lower self-efficacy were more likely to experience practical problems with taking the trial medication and that this was associated with lower compliance and achieved 25(OH)-vitamin D concentrations. The relationship between self-efficacy (the belief that one can carry out a behaviour), compliance with study protocol and outcome was explored within a randomised, double-blind, placebo-controlled trial of vitamin D supplementation in pregnancy. In the Maternal Vitamin D Osteoporosis Study (MAVIDOS) trial, women with circulating plasma 25(OH)-vitamin D of 25-100 nmol/l in early pregnancy were randomised to either 1000 IU cholecalciferol/day or matched placebo from 14 weeks until delivery. Circulating 25(OH)-vitamin D concentrations were assessed at 14 and 34 weeks' gestation. A sequential sub-sample completed Schwarzer's General Self-Efficacy Scale at 14 and 34 weeks and the Problematic Experiences of Therapy Scale at 34 weeks. Women were interviewed about their experiences of the trial and interview transcripts analysed thematically. In 203 women, those with higher self-efficacy were less likely to experience practical problems taking the study medication (odds ratio (OR) 0.81 (95 % confidence interval (CI) 0.69-0.95), p = 0.01). Over half reported practical problems associated with poorer compliance with the protocol requiring women to take the medication daily. Compliance in women who experienced practical problems was 94 % compared with 98 % for those with no problems (p < 0.001). Poorer compliance was also associated with lower concentrations of 25(OH)-D in late pregnancy in the treatment group (β = 0.54 nmol/l (95 % CI 0.18-0.89), p = 0.003). Thematic analysis suggested common difficulties were remembering to take the medication every day and swallowing the large capsules. These findings suggest that differences in self-efficacy influence trial outcomes. Such information may help clinicians anticipate responses to routine vitamin D supplementation in pregnancy and identify those who may need more support to comply. ISRCTN82927713, registered 11/04/2008.


Activation of PPARδ prevents endothelial dysfunction induced by overexpression of amyloid-β precursor protein.
Existing evidence suggests that amyloid-β precursor protein (APP) causes endothelial dysfunction and contributes to pathogenesis of atherosclerosis. In the present study, experiments were designed to: (1) determine the mechanisms underlying endothelial dysfunction and (2) define the effects of peroxisome proliferator-activated receptor delta (PPARδ) ligand on endothelial function in transgenic Tg2576 mice overexpressing mutated human APP. Confocal microscopy and western blot analyses of wild-type mice aortas provided evidence that APP protein is mainly present in endothelial cells. Overexpression of APP significantly impaired endothelium-dependent relaxations to acetylcholine and phosphorylation of endothelial nitric oxide synthase at Ser(1177) in aortas. HPLC analysis revealed that tetrahydrobiopterin (BH(4)) levels were reduced in Tg2576 mice aortas. This was caused by increased oxidation of BH(4) and reduced expression and activity of GTP-cyclohydrolase I. Furthermore, gp91phox protein expression and superoxide anion production were increased in aortas of Tg2576 mice. This augmented superoxide formation was completely prevented by the NADPH oxidase inhibitor VAS2870. Expression of copper-/zinc-superoxide dismutase (Cu/ZnSOD) and extracellular SOD was downregulated. Treatment with PPARδ ligand GW501516 (2 mg/kg/day) for 14 days significantly increased BH(4) bioavailability and improved endothelium-dependent relaxations in Tg2576 mice aortas. GW501516 also normalized protein expression of gp91(phox) and SODs, thereby reducing production of superoxide anion in the aortas. Our results suggest that in APP transgenic mice loss of nitric oxide and increased oxidative stress are the major causes of endothelial dysfunction. The vascular protective effects of GW501516 in Tg2576 mice appear to be critically dependent on prevention of superoxide anion production.


Targeting integrins in malignant glioma.
The integrin family of cell adhesion receptors is emerging as a promising target of anticancer therapy. AlphaVbeta3 and alphaVbeta5 integrins are overexpressed on both glioma cells and tumor vasculature. Cilengitide, the most advanced specific integrin inhibitor in oncology, has shown antitumor activity against glioma in early clinical trials. Durable remissions have been observed in phase I and phase II trials for recurrent glioblastoma (GBM) with both lower and higher doses of cilengitide. Pilot trials in newly diagnosed glioblastoma in conjunction with standard chemoradiotherapy have been encouraging. Preclinical data suggest synergy with concomitant chemo- and radiation therapy. A pivotal phase III study (CENTRIC) in newly diagnosed GBM patients is currently recruiting. This paper summarizes the current understanding of the role of integrins and their inhibition in gliomagenesis. The background and design of ongoing trials are outlined.


Space-time nature of causality.
In a causal world the direction of the time arrow dictates how past causal events in a variable X produce future effects in Y. X is said to cause an effect in Y, if the predictability (uncertainty) about the future states of Y increases (decreases) as its own past and the past of X are taken into consideration. Causality is thus intrinsic dependent on the observation of the past events of both variables involved, to the prediction (or uncertainty reduction) of future event of the other variable. We will show that this temporal notion of causality leads to another natural spatiotemporal definition for it, and that can be exploited to detect the arrow of influence from X to Y, either by considering shorter time-series of X and longer time-series of Y (an approach that explores the time nature of causality) or lower precision measured time-series in X and higher precision measured time-series in Y (an approach that explores the spatial nature of causality). Causality has thus space and time signatures, causing a break of symmetry in the topology of the probabilistic space, or causing a break of symmetry in the length of the measured time-series, a consequence of the fact that information flows from X to Y.


Appreciative Inquiry as an intervention to change nursing practice in in-patient settings: An integrative review.
High profile accounts of failures in patient care reflect an urgent need for transformational development in healthcare. Appreciative Inquiry is promoted as an approach to exploring and bringing about change in social systems. Appreciative Inquiry has been used extensively in North American business since the late 1980s. The application of Appreciative Inquiry may have merit in the complex world of human health experiences. To identify, evaluate and synthesise the evidence about the impact of Appreciative Inquiry on changing clinical nursing practice in in-patient settings. An integrative review and narrative synthesis. In-patient settings including paediatrics, maternity and mental health. Nurses of all grades, patients, carers, relatives, other healthcare professionals including allied healthcare staff, management and students. An electronic search of the following electronic databases was performed in January 2015 and updated in July 2015: MEDLINE, EMBASE, Cochrane Library (Cochrane database of systematic reviews), Cumulative Index of Nursing and Allied Health Literature, PsychINFO, PsychARTICLES, Amed, Assia, Scopus and Web of Science. Hand searching of reference lists of included studies was undertaken. Limits were set to include literature published in English only and publications from 1990 to July 2015. Three reviewers independently assessed eligibility for inclusion and extracted data. Full text articles were systematically appraised using a standardised data extraction instrument in conjunction with criteria to assess whether change using Appreciative Inquiry is transformational. Eight studies (reported in 11 papers) met the inclusion criteria. Overall, these studies demonstrate poor application of Appreciative Inquiry criteria in a nursing context. This makes judgement of the impact difficult. One study achieved transformation against agreed criteria for Appreciative Inquiry. Other included studies demonstrated that Appreciative Inquiry is being perceived as a gateway to knowledge translation rather than transformative change in practice. Appreciative Inquiry offers potential for nurse practice development and change but not without cognisance of the pivotal components. If Appreciative Inquiry is to be perceived as a legitimate research endeavour, there must be engagement and attention to rigour. Findings suggest caution is required against the choreography of Appreciative Inquiry where participant experiences are moulded to fit a previously drafted master plan. Further research is needed to explore the role of expert facilitation in securing and sustaining successful outcomes of Appreciative Inquiry.


ming is expressed in neuroblast sublineages and regulates gene expression in the Drosophila central nervous system.
Cell diversity in the Drosophila central nervous system (CNS) is primarily generated by the invariant lineage of neural precursors called neuroblasts. We used an enhancer trap screen to identify the ming gene, which is transiently expressed in a subset of neuroblasts at reproducible points in their cell lineage (i.e. in neuroblast 'sublineages'), suggesting that neuroblast identity can be altered during its cell lineage. ming encodes a predicted zinc finger protein and loss of ming function results in precise alterations in CNS gene expression, defects in axonogenesis and embryonic lethality. We propose that ming controls cell fate within neuroblast cell lineages.


A web-based intervention for carers of individuals with anorexia nervosa (We Can): Trial protocol of a randomised controlled trial investigating the effectiveness of different levels of support.
Anorexia nervosa (AN) is a life-threatening mental disorder that is associated with substantial caregiver burden. Carers of individuals with AN report high levels of distress and self-blame, and insufficient knowledge to help their loved ones. However, carers can have a very important role to play in aiding recovery from AN, and are often highly motivated to assist in the treatment process. This manuscript presents the protocol for a randomised controlled trial (RCT) of We Can, a web-based intervention for carers for people with AN. The study aims to investigate the effectiveness of We Can delivered with different intensities of support. The study takes the form of a multi-site, two-country, three group RCT, comparing We Can (a) with clinician messaging support (We Can-Ind), (b) with moderated carer chatroom support (We Can-Chat) and (c) with online forum only (We Can-Forum). Participants will be 303 carers of individuals with AN as well as, where possible, the individuals with AN themselves. Recruitment will be via specialist eating disorder services and carer support services in the UK and Germany. Randomisation of carers to one of the three intervention conditions in a 1:1:1 ratio will be stratified by whether or not the individual with AN has (a) agreed to participate in the study and (b) is a current inpatient. The We Can intervention will be provided to carers online over a period of 12 weeks. Participants will complete self-report questionnaires at pre-intervention (T1), mid-intervention (mediators only; 4-weeks post-randomisation), post-intervention (T2; 3-months post randomisation), and 6 months (T3) and 12 months (T4) after randomisation. The primary outcome variables are carer symptoms of depression and anxiety. Secondary outcome variables will be measured in both carers and individuals with AN. Secondary carer outcome variables will include alcohol and drug use and quality of life, caregiving behaviour, and the acceptability and use of We Can and associated supports. Secondary outcomes measured in individuals with AN will include eating disorder symptoms, and symptoms of depression and anxiety. The study will also evaluate the cost-effectiveness of the three We Can conditions, and test for mediators and moderators of the effects of We Can. The trial is registered at the International Standard Randomisation Controlled Trial Number (ISRCTN) database, registration number: ISRCTN11399850. The study will provide insight into the effectiveness of We Can and its optimal method/s of delivery.


Choice in fertility preservation in girls and adolescent women with cancer.
With the cure rate for many pediatric malignancies now between 70% and 90%, infertility becomes an increasingly important issue. Strategies for preserving fertility in girls and adolescent women occur in two distinct phases. The first phase includes oophorectomy (usually unilateral) and cryopreservation of ovarian cortex slices or individual oocytes; ultrasound-guided needle aspiration of oocytes, with or without in vitro maturation (IVM), followed by cryopreservation; and ovarian autografting to a distant site. The second phase occurs if the woman chooses to pursue pregnancy, and includes IVM of the oocytes, followed by in vitro fertilization (IVF) and transfer of any created embryos to the woman's uterus (or to a surrogate's uterus if the cancer patient's uterus has been surgically removed or the endometrium destroyed by radiotherapy). For ovarian autografting, the woman would undergo menotropin ovarian stimulation and retrieval of matured oocytes (likely by laparotomy, but possibly by ultrasound-guided needle aspiration if the ovary is positioned in an inaccessible location). The ethical challenges with each of these phases are many of fertility preservation and include issues of informed choice (consent or refusal). The lack of proven benefit with these strategies and the associated potential physical and psychological harms require careful attention to the key elements of informed choice, which include decisional capacity, disclosure, understanding and voluntariness, and to the benefits of in-depth counseling to promote free and informed choice at a time that is emotionally difficult for the decision makers.


Pilot study to evaluate ecological momentary assessment of tinnitus.
Because audiometric evaluation, symptom histories, questionnaires, and similar standard assessment tools may not adequately sample the effects of chronic tinnitus on day-to-day activities, there is a need for alternative methodological approaches to study the impact of tinnitus on day-to-day life. An innovative methodological approach that has shown great promise in the study of chronic health problems characterized by reported temporal and/or situational variability in symptoms and distress is known as ecological momentary assessment (EMA). EMA involves the real-time measurement of states, situational factors, and symptoms by individuals as they go about their day-to-day activities. The objective of this pilot investigation was to explore the feasibility of using EMA methods to examine within- and between-day effects of tinnitus. This study was conducted in three phases: (1) design and development of an EMA methodology that could be used to assess effects of tinnitus; (2) refinement of the methodology through the use of two focus groups; and (3) field-test the methodology with individuals who experienced bothersome tinnitus. For Phase 3, each of the 24 participants wore, throughout their waking hours for 2 weeks, a personal digital assistant that produced alerts four times a day. The alerts prompted participants to respond to 19 questions, including 9 relating to situational and mood factors and 10 comprising the Tinnitus Handicap Inventory-Screening version (THI-S). To evaluate for potential reactive effects of performing the EMA protocol, each participant completed the paper-and-pencil version of the full 25-item THI before and after the 2-week EMA period. Participants responded to the alerts with a 90% compliance rate, providing a total of 1210 completed surveys. At the time of their response, participants indicated that they were in their house or apartment (67.7%), alone (50.2%), happy (50%), and calm (54.5%). Across most responses, participants could hear their tinnitus (97%), and the loudness of their tinnitus averaged 4.7 on a 7-point increasing-loudness scale. The mean THI-S index score (out of a possible maximum 40 points for greatest tinnitus severity) was 17.0 (moderate self-perceived tinnitus handicap). Repeated THI-S index scores varied considerably both within and between participants. Mean 25-item THI scores were not significantly different before and after the EMA period, suggesting little reactivity of the EMA. The high compliance rate, positive feedback from participants, lack of reactivity as a result of performing the EMA protocol, and data collected indicate that EMA methodology is feasible with patients who have tinnitus. Outcome data obtained with this methodology cannot be obtained any other way because retrospective questionnaires cannot capture the day-to-day reactions. This methodology has the potential to provide more in-depth and accurate assessments of patients receiving therapy for tinnitus.


Nicardipine improves the antidepressant action of ECT but does not improve cognition.
Cognitive impairment, the most important adverse effect of electroconvulsive therapy (ECT), may involve elevated intracellular calcium ion signaling. Animal research suggests that calcium channel-blocking agents, which attenuate excessive intracellular calcium activity, may reduce cognitive dysfunction caused by ECT. The lipid-soluble calcium channel-blocking drug nicardipine or matching placebo were randomly assigned to 26 patients with major depressive disorder receiving ECT. A rater blind to the experimental condition administered the Hamilton Depression Rating Scale, the Montgomery-Asberg Depression Rating Scale, the Beck Depression Inventory, the Mini-Mental State Examination and a comprehensive battery of neuropsychological tests prior to ECT, at the completion of ECT, and 6 months after ECT completion. Compared with patients receiving placebo, patients taking nicardipine had significantly lower scores on the Hamilton and Montgomery-Asberg but not the Beck Depression rating scale scores at the completion of ECT. There were no differences between placebo and nicardipine groups in depression scores 6 months after ECT. Cognitive function declined over the course of ECT and improved over the next 6 months in both groups, but changes were statistically significant for only two subtests on the neuropsychological battery. Changes in Mini-Mental State Examination scores were small and were not significant at any point. There were no significant differences between nicardipine and placebo treated groups in any assessment of cognition. Standard approaches to ECT in younger patients without preexisting neurological impairment do not produce cognitive side effects of sufficient severity for calcium channel-blocking agents to reduce these side effects demonstrably. Studies of treatments for cognitive impairment should be conducted in patients with risk factors for more severe cognitive impairment such as geriatric patients or patients with a history of interictal delirium during previous treatment with ECT. A possible effect of nicardipine in enhancing the antidepressant action of ECT requires further investigation in a study designed to test this action.


Protocols for in vivo measurement of the ion transport defects in cystic fibrosis nasal epithelium.
New treatments for cystic fibrosis (CF), including gene therapy, are currently being assessed. These aim to correct the basic defects of increased sodium absorption and decreased chloride secretion in airway epithelia. Assessment of these bioelectric parameters, particularly in the nasal epithelium, is likely to be used as a measure of treatment efficacy. However, the optimal in vivo protocol to discriminate cystic fibrosis from non-cystic fibrosis subjects is unclear. We have, therefore, compared three protocols for measurement of the cystic fibrosis ion transport defects in vivo in the nasal epithelium. Sodium absorption was measured using both the baseline potential difference and the response to the sodium channel blocker, amiloride. Chloride secretion was assessed in the presence of amiloride, using perfusion with isoprenaline, or terbutaline, or a low chloride solution followed by isoprenaline. Baseline potential difference (PD) and the absolute response to amiloride clearly differentiated the increased sodium absorption in the cystic fibrosis subjects. The responses both to terbutaline (delta PD: non-CF: -0.8 (SEM 0.7) mV; CF: -3.6 (0.5) mV) and isoprenaline (non-CF: 1.5 (0.6) mV; CF: -2.9 (0.6) mV) differentiated the two groups of subjects, but there was considerable overlap of values. Perfusion with a low chloride solution (non-CF: 12.6 (1.2) mV; CF: 0.6 (0.4) mV), as well as subsequent perfusion with isoprenaline (non-CF: 10.0 (1.1) mV; CF: -1.4 (0.4) mV) allowed clear separation of the two groups, with no overlap of values. Some CF subjects showed a transient hyperpolarization to these stimuli, which could clearly be differentiated from the sustained responses seen in non-cystic fibrosis subjects.(ABSTRACT TRUNCATED AT 250 WORDS)


Graph-Based Word Alignment for Clinical Language Evaluation.
Among the more recent applications for natural language processing algorithms has been the analysis of spoken language data for diagnostic and remedial purposes, fueled by the demand for simple, objective, and unobtrusive screening tools for neurological disorders such as dementia. The automated analysis of narrative retellings in particular shows potential as a component of such a screening tool since the ability to produce accurate and meaningful narratives is noticeably impaired in individuals with dementia and its frequent precursor, mild cognitive impairment, as well as other neurodegenerative and neurodevelopmental disorders. In this article, we present a method for extracting narrative recall scores automatically and highly accurately from a word-level alignment between a retelling and the source narrative. We propose improvements to existing machine translation-based systems for word alignment, including a novel method of word alignment relying on random walks on a graph that achieves alignment accuracy superior to that of standard expectation maximization-based techniques for word alignment in a fraction of the time required for expectation maximization. In addition, the narrative recall score features extracted from these high-quality word alignments yield diagnostic classification accuracy comparable to that achieved using manually assigned scores and significantly higher than that achieved with summary-level text similarity metrics used in other areas of NLP. These methods can be trivially adapted to spontaneous language samples elicited with non-linguistic stimuli, thereby demonstrating the flexibility and generalizability of these methods.


A Finite Element Model for Mixed Porohyperelasticity with Transport, Swelling, and Growth.
The purpose of this manuscript is to establish a unified theory of porohyperelasticity with transport and growth and to demonstrate the capability of this theory using a finite element model developed in MATLAB. We combine the theories of volumetric growth and mixed porohyperelasticity with transport and swelling (MPHETS) to derive a new method that models growth of biological soft tissues. The conservation equations and constitutive equations are developed for both solid-only growth and solid/fluid growth. An axisymmetric finite element framework is introduced for the new theory of growing MPHETS (GMPHETS). To illustrate the capabilities of this model, several example finite element test problems are considered using model geometry and material parameters based on experimental data from a porcine coronary artery. Multiple growth laws are considered, including time-driven, concentration-driven, and stress-driven growth. Time-driven growth is compared against an exact analytical solution to validate the model. For concentration-dependent growth, changing the diffusivity (representing a change in drug) fundamentally changes growth behavior. We further demonstrate that for stress-dependent, solid-only growth of an artery, growth of an MPHETS model results in a more uniform hoop stress than growth in a hyperelastic model for the same amount of growth time using the same growth law. This may have implications in the context of developing residual stresses in soft tissues under intraluminal pressure. To our knowledge, this manuscript provides the first full description of an MPHETS model with growth. The developed computational framework can be used in concert with novel in-vitro and in-vivo experimental approaches to identify the governing growth laws for various soft tissues.


Prehospital care of left ventricular assist device patients by emergency medical services.
Left ventricular assist devices (LVADs) are frequently implanted as permanent (bridge to destination [BTD]) or temporary (bridge to transplantation [BTT]) cardiac support. When LVAD patients are discharged to home, they are very likely to require emergency medical services (EMS), but there is very little literature on out-of-hospital emergency care for patients with LVADs. We present two typical cases of LVAD patients for whom EMS was called. In the first case, the patient was in an ambulance two hours distant from our university hospital when a pulsatile system malfunctioned. In the second case, EMS was called to an unconscious LVAD patient. Emergency reference cards, training programs for emergency medical staff, and a 24-hour emergency hotline for the local VAD team are advisable.


microRNA-21 regulates astrocytic response following spinal cord injury.
Astrogliosis following spinal cord injury (SCI) involves an early hypertrophic response that serves to repair damaged blood-brain barrier and a subsequent hyperplastic response that results in a dense scar that impedes axon regeneration. The mechanisms regulating these two phases of astrogliosis are beginning to be elucidated. In this study, we found that microRNA-21 (miR-21) increases in a time-dependent manner following SCI in mouse. Astrocytes adjacent to the lesion area express high levels of miR-21 whereas astrocytes in uninjured spinal cord express low levels of miR-21. To study the role of miR-21 in astrocytes after SCI, transgenic mice were generated that conditionally overexpress either the primary miR-21 transcript in astrocytes or a miRNA sponge designed to inhibit miR-21 function. Overexpression of miR-21 in astrocytes attenuated the hypertrophic response to SCI. Conversely, expression of the miR-21 sponge augmented the hypertrophic phenotype, even in chronic stages of SCI recovery when astrocytes have normally become smaller in size with fine processes. Inhibition of miR-21 function in astrocytes also resulted in increased axon density within the lesion site. These findings demonstrate a novel role for miR-21 in regulating astrocytic hypertrophy and glial scar progression after SCI, and suggest miR-21 as a potential therapeutic target for manipulating gliosis and enhancing functional outcome.


Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis.
Besides its role in glycolysis, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) initiates a cell death cascade. Diverse apoptotic stimuli activate inducible nitric oxide synthase (iNOS) or neuronal NOS (nNOS), with the generated nitric oxide (NO) S-nitrosylating GAPDH, abolishing its catalytic activity and conferring on it the ability to bind to Siah1, an E3-ubiquitin-ligase with a nuclear localization signal (NLS). The GAPDH-Siah1 protein complex, in turn, translocates to the nucleus and mediates cell death; these processes are blocked by procedures that interfere with GAPDH-Siah1 binding. Nuclear events induced by GAPDH to kill cells have been obscure. Here we show that nuclear GAPDH is acetylated at Lys 160 by the acetyltransferase p300/CREB binding protein (CBP) through direct protein interaction, which in turn stimulates the acetylation and catalytic activity of p300/CBP. Consequently, downstream targets of p300/CBP, such as p53 (Refs 10,11,12,13,14,15), are activated and cause cell death. A dominant-negative mutant GAPDH with the substitution of Lys 160 to Arg (GAPDH-K160R) prevents activation of p300/CBP, blocks induction of apoptotic genes and decreases cell death. Our findings reveal a pathway in which NO-induced nuclear GAPDH mediates cell death through p300/CBP.


An open, randomized comparative trial of two antivenoms for the treatment of envenoming by Sri Lankan Russell's viper (Daboia russelii russelii).
Russell's viper (Daboia russelii russelii) is an important cause of morbidity and mortality in Sri Lanka. In a study in 1985, Haffkine equine polyspecific antivenom in doses up to 20 g proved ineffective in clearing antigenaemia and caused a high incidence of anaphylactoid reactions. A new, monospecific ovine Fabantivenom (Polonga TAb) has been developed against the venom of Sri Lankan Russell's viper and, to assess its safety and efficacy, we carried out (in 1997) an open, randomized comparison of this with the Haffkine antivenom currently in use in the country. Patients with systemic envenoming following Russell's viper bite were randomized to receive an initial intravenous dose of either 1 g of Polonga TAb (n = 23) or 10 g of Haffkine antivenom (n = 20). One dose of Polonga TAb permanently restored blood coagulability in only 9 (41%) of 22 patients and 13 needed repeated doses, whereas the majority (14/20; 70%) had restored coagulability after 1 dose of Haffkine antivenom. There was a tendency towards more rapid resolution of local swelling and systemic manifestations in the Haffkine group. Venom antigenaemia was eliminated more quickly in the Haffkine group and ovine Fab was cleared from the circulation more rapidly than equine F(ab')2. To evaluate safety, patients were closely observed for adverse reactions. Following a severe reaction with Haffkine antivenom all subsequent patients in this group were treated prophylactically with hydrocortisone and chlorpheniramine. Despite this, the incidence of adverse reactions was significantly higher in the Haffkine group compared with the PolongaTAb group (81% compared with 48%) and 4 patients had a severe anaphylactic reaction in the former group. In conclusion, the new antivenom is safer than Haffkine antivenom but, to avoid repeated doses, an initial dose higher than 1 g is needed in the treatment of Sri Lankan Russell's viper envenoming. The safety of this larger dose is the subject of further studies.


A new method for the detection of phospholipase A2 variants: identification of isozymes in the venoms of newborn and adult Bothrops asper (terciopelo) snakes.
A new method for the identification of phospholipase A2 isozymes in snake venoms is described. The technique is based on the separation of the venom components by isoelectric focusing in agarose gels, transfer of the protein bands by diffusion onto nitrocellulose paper and detection of the phospholipolytic activity of the enzymes by a hemolytic assay either in agarose gels or by benzidine reaction on a solid matrix. Striking differences in the electrophoretic patterns of the phospholipase A2 isozymes between the Atlantic and Pacific venoms and between the newborn and adult venoms from Bothrops asper specimens were observed. The method allowed the detection of 9 different phospholipase A2 isozymes in the venom of adult Atlantic, 7 isozymes in the venom of adult Pacific, and 2-3 isozymes in the venoms of newborn specimens. Horse polyvalent antivenom varied in its capacity to neutralize the phospholipolytic activity of the different isozymes in the same venom and among different venoms.


Impact of reducing portion sizes in worksite cafeterias: a stepped wedge randomised controlled pilot trial.
Reducing the portion sizes of foods available in restaurants and cafeterias is one promising approach to reducing energy intake, but there is little evidence of its impact from randomised studies in field settings. This study aims to i. examine the feasibility and acceptability, and ii. estimate the impact on energy purchased, of reducing portion sizes in worksite cafeterias. Nine worksites in England were recruited to reduce by at least 10% the portion sizes of foods available in their cafeterias from targeted categories (main meals, sides, desserts, cakes). In a stepped wedge randomised controlled pilot trial, each site was randomised to a date of implementation, staggered fortnightly, following a baseline period of four weeks. Impact on energy purchased was analysed using generalised linear mixed modelling. We also assessed feasibility, acceptability, and fidelity of intervention implementation. Data from six of the nine randomised sites were analysed, with three sites excluded for not providing sufficient data and/or not implementing the intervention. The extent to which the intervention was implemented varied by site, with between 6 and 49% of products altered within targeted categories. Feedback following the intervention suggested it was broadly acceptable to customers and cafeteria staff. For the primary outcome of daily energy (kcal) purchased from intervention categories, there was no statistically significant change when data from all six sites were pooled: percentage change - 8.9% (95% CI: -16.7, - 0.4; p = 0.081). Each of these six sites showed reductions in energy purchased, ranging from - 15.6 to - 0.3%, which were borderline statistically significant at two sites (respective percentage changes (95% CIs): - 15.6% (- 26.7, - 2.8); - 14.0% (- 25.0, - 1.2)). Secondary outcome data are suggestive of a compensatory increase in energy purchased from food categories not targeted by the intervention, with no overall effect observed on energy purchased across all categories. The results of this pilot trial suggest that reducing portion sizes could be effective in reducing energy purchased and consumed from targeted food categories, and merits investigation in a larger trial. Future studies will need to address factors that prevented optimal implementation including site dropout and application across a limited range of products. ( ISRCTN52923504 ). Registered on 20th September 2016.


Handwriting features of children with developmental coordination disorder--results of triangular evaluation.
Developmental coordination disorders (DCD) is one of the most common disorders affecting school-aged children. The study aimed to characterize the handwriting performance of children with DCD who write in Arabic, based on triangular evaluation. Participants included 58 children aged 11-12 years, 29 diagnosed with DCD based on the DSM-IV criteria and the M-ABC, and 29 matched typically developed controls. Children were asked to copy a paragraph on a sheet of paper affixed to a digitizer supplying objective measures of the handwriting process. The handwriting proficiency screening questionnaire (HPSQ) was completed by their teachers while observing their performance and followed by evaluation of their final written product. Results indicated that compared to controls, children with DCD required significantly more on-paper and in-air time per stroke while copying. In addition, global legibility, unrecognizable letters and spatial arrangement measures of their written product were significantly inferior. Significant group differences were also found between the HPSQ subscales scores. Furthermore, 82.8% of all participants were correctly classified into groups based on one discriminate function which included two handwriting performance measures. These study results strongly propose application of triangular standardized evaluation to receive better insight of handwriting deficit features of individual children with DCD who write in Arabic.


An in vivo model of somatic cell gene therapy for human severe combined immunodeficiency.
Deficiency of adenosine deaminase (ADA) results in severe combined immunodeficiency (SCID), a candidate genetic disorder for somatic cell gene therapy. Peripheral blood lymphocytes from patients affected by ADA- SCID were transduced with a retroviral vector for human ADA and injected into immunodeficient mice. Long-term survival of vector-transduced human cells was demonstrated in recipient animals. Expression of vector-derived ADA restored immune functions, as indicated by the presence in reconstituted animals of human immunoglobulin and antigen-specific T cells. Retroviral vector gene transfer, therefore, is necessary and sufficient for development of specific immune functions in vivo and has therapeutic potential to correct this lethal immunodeficiency.


tailup, a LIM-HD gene, and Iro-C cooperate in Drosophila dorsal mesothorax specification.
The LIM-HD gene tailup (tup; also known as islet) has been categorised as a prepattern gene that antagonises the formation of sensory bristles on the notum of Drosophila by downregulating the expression of the proneural achaete-scute genes. Here we show that tup has an earlier function in the development of the imaginal wing disc; namely, the specification of the notum territory. Absence of tup function causes cells of this anlage to upregulate different wing-hinge genes and to lose expression of some notum genes. Consistently, these cells differentiate hinge structures or modified notum cuticle. The LIM-HD co-factors Chip and Ssdp are also necessary for notum specification. This suggests that Tup acts in this process in a complex with Chip and Ssdp. Overexpression of tup, together with araucan, a 'pronotum' gene of the iroquois complex (Iro-C), synergistically reinforces the weak capacity of either gene, when overexpressed singly, to induce ectopic notum-like development. Whereas the Iro-C genes are activated in the notum anlage by EGFR signalling, tup is positively regulated by Dpp signalling. Our data support a model in which the EGFR and Dpp signalling pathways, with their respective downstream Iro-C and tup genes, converge and cooperate to commit cells to the notum developmental fate.


DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers.
Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors, associated with highly variable postoperative evolution. The scarcity of reliable PPGL prognostic markers continues to complicate patient management. In this study, we explored genome-wide DNA methylation patterns in the context of PPGL malignancy to identify novel prognostic markers. We retrospectively investigated DNA methylation patterns in PPGL with and without metastases using high-throughput DNA methylation profiling data (Illumina 27K) from two large, well-characterized discovery (n = 123; 24 metastatic) and primary validation (n = 154; 24 metastatic) series. Additional validation of candidate CpGs was performed by bisulfite pyrosequencing in a second independent set of 33 paraffin-embedded PPGLs (19 metastatic). Of the initial 86 candidate CpGs, we successfully replicated 52 (47 genes), associated with metastatic PPGL. Of these, 48 CpGs showed significant associations with time to progression even after correcting for SDHB genotype, suggesting their value as prognostic markers independent of genetic background. Hypermethylation of RDBP (negative elongation factor complex member E) in metastatic tumors was further validated by bisulfite pyrosequencing [Δβmetastatic-benign = 0.29, P = 0.003; HR, 1.4; 95% confidence interval (CI), 1.1-2.0; P = 0.018] and may alter transcriptional networks involving (RERG, GPX3, and PDZK1) apoptosis, invasion, and maintenance of DNA integrity. This is the first large-scale study of DNA methylation in metastatic PPGL that identifies and validates prognostic markers, which could be used for stratifying patients according to risk of developing metastasis. Of the three CpGs selected for further validation, one (RDBP) was clearly confirmed and could be used for stratifying patients according to the risk of developing metastases.


A huge mitral valve tumor and its vascularity--a case report.
Primary cardiac tumors of the mitral valve are extremely rare; however, they present a major risk of embolization. Therefore, prompt diagnosis and urgent treatment is obligatory. The authors report the case of a 60-year-old man with a huge mitral valve mass and its vascularity, which was diagnosed by transthoracic echocardiography and selective coronary arteriography. Our patient's mitral valve tumor had a size of 5.9 x 2.9 cm, which was the largest size reported up to this time in this location. The patient died from a major cerebrovascular event before surgical excision could be performed.


Emerging drugs for the treatment of myelofibrosis.
Myelofibrosis (MF) is a myeloproliferative neoplasm associated with significant disease burden composed of splenomegaly, constitutional symptoms and a reduced life expectancy. The advent of targeted treatments has provided new means by which to improve MF associated splenomegaly, symptoms, health-related quality of life and even mortality. We discuss the spectrum of targeted treatments currently under investigation for MF. We furthermore compare their effects on improving anemia, reducing fibrosis and splenomegaly and enhancing symptom control. MF is a complex disorder, partly attributable to its heterogeneity. Although the severity of patient symptoms correlates with risk category, high symptom burden may also be observed in low-risk patients. Serial use of PRO tools allows clinicians to objectively evaluate the MF symptom burden, compare efficacy of therapies and adjust medications to improve symptom control. Novel targeted agents have proven superior to historic treatment regimens for symptom management. Promising treatment categories include JAK2 inhibitors, histone deacetylase inhibitors, hypomethylating agents, heat shock protein-90 inhibitors, hedgehog inhibitors, PI3-AKT-mTOR inhibitors, antifibrosing agents and telomerase inhibitors. The majority of therapies remain under investigation, either alone or in combination with other treatments. It is anticipated that these agents will be increasingly integrated into standard treatment algorithms for MF symptom management.


Interleukin-1β induced nuclear factor-κB binds to a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 9 promoter in human chondrosarcoma cells.
Nuclear factor-κB (NF-κB) is involved in the regulation of inflammation‑associated genes. NF-κB forms dimers which bind with sequences referred to as NF-κB sites (9-11 bp). A disintegrin-like and metalloproteinase with thrombospondin type 1 motif 9 (ADAMTS9) is a type of proteoglycanase, which proteolytically cleaves versican and aggrecan. ADAMTS9 is a cytokine-inducible gene that contains binding sites for NF-κB within its promoter region. Interleukin-1β (IL-1β) affects cartilage metabolism and is involved in the NF-κB pathway. It is therefore hypothesized that NF-κB binding with ADAMTS9 promoters may activate IL-1β, thereby promoting chondrocytic cell growth. In the present study, the OUMS-27 chondrocytic human chondrosarcoma cell line was treated with IL-1β with or without inhibitors of NF-κB signaling pathways. Chromatin immunoprecipitation (ChIP) and electromobility shift assays (EMSA) were conducted order to analyze the binding of NF-κB with the ADAMTS9 promoter region. NF-κB-p65 subunit phosphorylation was promoted in IL-1β-treated cells, which were not treated with inhibitors of NF-κB signaling pathways. By contrast, NF-κB-p65 subunit phosphorylation was inhibited in cells that had been treated with BAY-117085, an NF-κB pathway inhibitor. ChIP and EMSA assays demonstrated that, following treatment with IL-1β, NF-κB‑p65 bound to elements located at -1177 and -1335 in the ADAMTS9 promoter region, in contrast to the untreated samples. The results of the present study suggested that NF-κB may be involved in IL-1β-induced activation of ADAMTS9 in human chondrocytes.


Abnormal glucose metabolism is associated with reduced left ventricular contractile reserve and exercise intolerance in patients with chronic heart failure.
To investigate the associations between glucose metabolism, left ventricular (LV) contractile reserve, and exercise capacity in patients with chronic systolic heart failure (HF). From an outpatient HF clinic, 161 patients with systolic HF were included (mean age 70 ± 10 years, 69% male, 59% had ischaemic heart disease, mean LV ejection fraction (LVEF) 37 ± 9%). Thirty-four (21%) patients had known diabetes mellitus (DM). Oral glucose tolerance testing (OGTT) classified patients without a prior DM diagnosis as normal glucose tolerance (NGT), impaired glucose tolerance or new DM. All patients completed low-dose dobutamine echocardiography (LDDE) and 154 patients a 6-min walking distance test (6MWD). Compared with patients with NGT, patients with known DM had lower resting LVEF (33.4 vs. 39.1%, P < 0.05) and higher E/e' (13.9 vs. 11.4, P < 0.05). During LDDE, an increase in LVEF could be observed in all glycemic groups (mean 8.2% absolute increase), but the contractile reserve was lower in patients with known DM (-5.4%, P = 0.001) and new DM (-3.5%, P = 0.035) compared to patients with NGT. 6MWD was lower in known DM (349 m) and new DM (379 m) compared with NGT (467 m) (P < 0.001). Differences in clinical variables, resting echocardiographic parameters or contractile reserve, did not explain the exercise intolerance related to diabetes. Diabetes, known or newly detected by OGTT, is independently associated with reduced LV contractile reserve and exercise intolerance in outpatients with systolic HF. These findings may offer one explanation for the excess mortality related to diabetes in HF.


Appropriateness of imaging studies ordered by emergency medicine residents: results of an online survey.
The purpose of this study is to determine the proficiency of emergency medicine residents in selecting appropriate radiologic examinations for specific clinical scenarios and to ascertain whether their training improves competency in this area over the course of their residency. An online multiple-choice questionnaire was created. It included 10 clinical scenarios excerpted from the American College of Radiology Appropriateness Criteria guidelines and instructed residents to select the most appropriate initial imaging study. A link and invitation to the survey were e-mailed to the residency program directors and coordinators of all American Council for Graduate Medical Education-accredited emergency medicine residency training programs with the request that they be forwarded to their current residents. Responses were graded, with correct answers derived from the American College of Radiology guidelines. Results were stratified by year of emergency medicine training, and an analysis of variance was performed. A total of 583 residents from at least 77 different emergency medicine residency training programs completed the survey. Overall, the average number of questions answered correctly was 7.1 of 10 (SD, 1.2). First-through fourth-year residents averaged 6.9 (SD, 1.3), 7.1 (SD, 1.2), 7.1 (SD, 1.1), and 7.5 (SD, 1.1) correct answers, respectively. Analysis of variance found no significant difference between the scores of the four classes (p = 0.09). Emergency medicine residents do not show significant improvement over the course of their residency in their ability to choose appropriate imaging studies. This finding suggests that there is a role for more-rigorous focused instruction to better familiarize residents with appropriateness guidelines for diagnostic imaging selection.


Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials.
Low-carbohydrate diets have become increasingly popular for weight loss. However, evidence from individual trials about benefits and risks of these diets to achieve weight loss and modify cardiovascular risk factors is preliminary. We used the Cochrane Collaboration search strategy to identify trials comparing the effects of low-carbohydrate diets without restriction of energy intake vs low-fat diets in individuals with a body mass index (calculated as weight in kilograms divided by the square of height in meters) of at least 25. Included trials had to report changes in body weight in intention-to-treat analysis and to have a follow-up of at least 6 months. Two reviewers independently assessed trial eligibility and quality of randomized controlled trials. Five trials including a total of 447 individuals fulfilled our inclusion criteria. After 6 months, individuals assigned to low-carbohydrate diets had lost more weight than individuals randomized to low-fat diets (weighted mean difference, -3.3 kg; 95% confidence interval [CI], -5.3 to -1.4 kg). This difference was no longer obvious after 12 months (weighted mean difference, -1.0 kg; 95% CI, -3.5 to 1.5 kg). There were no differences in blood pressure. Triglyceride and high-density lipoprotein cholesterol values changed more favorably in individuals assigned to low-carbohydrate diets (after 6 months, for triglycerides, weighted mean difference, -22.1 mg/dL [-0.25 mmol/L]; 95% CI, -38.1 to -5.3 mg/dL [-0.43 to -0.06 mmol/L]; and for high-density lipoprotein cholesterol, weighted mean difference, 4.6 mg/dL [0.12 mmol/L]; 95% CI, 1.5-8.1 mg/dL [0.04-0.21 mmol/L]), but total cholesterol and low-density lipoprotein cholesterol values changed more favorably in individuals assigned to low-fat diets (weighted mean difference in low-density lipoprotein cholesterol after 6 months, 5.4 mg/dL [0.14 mmol/L]; 95% CI, 1.2-10.1 mg/dL [0.03-0.26 mmol/L]). Low-carbohydrate, non-energy-restricted diets appear to be at least as effective as low-fat, energy-restricted diets in inducing weight loss for up to 1 year. However, potential favorable changes in triglyceride and high-density lipoprotein cholesterol values should be weighed against potential unfavorable changes in low-density lipoprotein cholesterol values when low-carbohydrate diets to induce weight loss are considered.


Acute pain services in Hong Kong: facilities, volume, and quality.
Acute pain services in public hospitals in Hong Kong were studied. Audit data on the volume and quality of acute pain services were collected prospectively from 1997 to 1999, and data on related facilities were collected in 2000. About 20% of patients undergoing a major operation received an acute pain service; of these, 78.6% were satisfied with the treatment provided. In 2000, 86% (18/21) of hospitals providing anaesthetic services were running an acute pain service. Staffing was better in hospitals providing a high volume of acute pain services, ranging from a full-time specialist anaesthesiologist assisted by a half-time trainee to a half-time specialist assisted by a full- or half-time trainee. However, only four hospitals were staffed with pain nurses. In total, 57% of patients received intravenous patient-controlled analgesia and 32% epidural analgesia. The mean duration of acute pain service treatment was 3.1 days. Currently anaesthesiologist-based acute pain services take care of a limited number of patients. To expand the coverage, there should be a move towards an anaesthesiologist-led, pain nurse-based, acute pain service. The present shortage of pain nurses should be addressed.


Human glutathione S-transferase P1-1 interacts with TRAF2 and regulates TRAF2-ASK1 signals.
Human glutathione S-transferase P1-1 (GSTP1-1) is an ubiquitously expressed protein that plays an important role in the detoxification and xenobiotics metabolism. It has been shown that GSTP1-1 interacts with c-Jun NH(2)-terminal kinase (JNK) and suppresses its activity. Here, we report a novel function of GSTP1-1 in regulating tumor necrosis factor-alpha (TNF-alpha)-triggered signaling. The present experiments showed that GSTP1-1 physically associated with tumor necrosis factor receptor-associated factor 2 (TRAF2) in vivo and in vitro. Overexpression of GSTP1-1 inhibited TRAF2-induced activation of both JNK and p38 but not of nuclear factor-kappaB (NF-kappaB). Glutathione S-transferase P1-1 also attenuated TRAF2-enhanced apoptosis signal-regulating kinase 1 (ASK1) autophosphorylation and inhibited TRAF2-ASK1-induced cell apoptosis by suppressing the interaction of TRAF2 and ASK1. Conversely, silencing of GSTP1-1 expression through RNA interference (RNAi) resulted in increase of TNF-alpha-dependent TRAF2-ASK1 association followed by hyper-activation of ASK1 and JNK. A mutant GSTP1-1 lacking TRAF domain-binding motif exhibited a significant decline of capacity to bind TRAF2 and block TRAF2-ASK1 signaling compared with the wild type of GSTP1-1. Moreover, the glutathione-conjugating activity of GSTP1-1 was not involved in the regulation of TRAF2 signaling. These findings indicate that GSTP1-1 plays an important regulatory role in TNF-alpha-induced signaling by forming ligand-binding interactions with TRAF2, which provides a new insight for analysing the protective effects of GSTP1-1 in tumor cells.


Mena binds α5 integrin directly and modulates α5β1 function.
Mena is an Ena/VASP family actin regulator with roles in cell migration, chemotaxis, cell-cell adhesion, tumor cell invasion, and metastasis. Although enriched in focal adhesions, Mena has no established function within these structures. We find that Mena forms an adhesion-regulated complex with α5β1 integrin, a fibronectin receptor involved in cell adhesion, motility, fibronectin fibrillogenesis, signaling, and growth factor receptor trafficking. Mena bound directly to the carboxy-terminal portion of the α5 cytoplasmic tail via a 91-residue region containing 13 five-residue "LERER" repeats. In fibroblasts, the Mena-α5 complex was required for "outside-in" α5β1 functions, including normal phosphorylation of FAK and paxillin and formation of fibrillar adhesions. It also supported fibrillogenesis and cell spreading and controlled cell migration speed. Thus, fibroblasts require Mena for multiple α5β1-dependent processes involving bidirectional interactions between the extracellular matrix and cytoplasmic focal adhesion proteins.


Addition of propolis to irinotecan therapy prolongs survival in ehrlich ascites tumor-bearing mice.
We investigated possible synergistic action of anticancer drug Irinotecan (IRI) combined with ethanolic (EEP) and water-soluble (WSDP) derivate of propolis on Swiss albino mice injected with Ehrlich ascites tumor (EAT). For survival analysis mice were administered WSDP and EEP (100 mg/kg) daily for 3 consecutive days, beginning on 3rd day after EAT cell (1×10⁶) injection. IRI was administered at a dose of 50 mg/kg on days 1, 13, and 19. We simultaneously studied peripheral white blood cell count, cell types washed from the peritoneal cavity, functional activity of macrophages from peritoneal cavity, and the level of primary DNA damage in leukocytes, kidney, and liver cells using the alkaline comet assay. Three out of 9 mice per group survived the entire duration of the experiment (90 days) in groups treated with IRI combined with WSDP and EEP. All test components increased survival of mice by 7.53% to 231.54%. Combined treatment with IRI and/or WSDP and EEP significantly decreased percentage of tumor cells in the peritoneal cavity as compared to nontreated EAT-injected mice. All treated animals had significantly higher percentage of neutrophils in the peritoneal cavity in comparison to nontreated EAT-injected mice. We observed significantly higher value of DNA damage in leukocytes of mice treated with IRI and combination of IRI and/or WSDP and EEP as compared to nontreated EAT-injected mice, while the same treatment decreased DNA damage in kidney. Our results showed that addition of propolis to IRI treatment enhanced antitumor activity of IRI and prolongs survival in EAT-bearing mice, which definitely deserve further studies to clarify the possible mechanisms of antitumor actions of combined herb-drug treatments.


Billions for biodefense: Federal Agency biodefense funding, FY2006-FY2007.
Since 2001, the United States government has spent substantial resources on preparing the nation against a bioterrorist attack. Earlier articles in this series analyzed the civilian biodefense funding by the federal government from fiscal years 2001 through 2006. This article updates those figures with budgeted amounts for fiscal year 2007, specifically analyzing the budgets and allocations for biodefense at the Department of Health and Human Services, the Department of Homeland Security, the Department of Agriculture, the Environmental Protection Agency, the Department of State, and the National Science Foundation.


Ice age paleotopography.
A gravitationally self-consistent theory of postglacial relative sea level change is used to infer the variation of surface ice and water cover since the Last Glacial Maximum (LGM). The results show that LGM ice volume was approximately 35 percent lower than suggested by the CLIMAP reconstruction and the maximum heights of the main Laurentian and Fennoscandian ice complexes are inferred to have been commensurately lower with respect to sea level. Use of these Ice Age boundary conditions in atmospheric general circulation models will yield climates that differ significantly from those previously inferred on the basis of the CLIMAP data set.


Effect of replacing calcium salts of palm oil distillate with extruded linseeds on milk fatty acid composition in Jersey and Holstein cows.
Clinical and biomedical studies have provided evidence for the critical role of n-3 fatty acids on the reduction of chronic disease risk in humans, including cardiovascular disease. In the current experiment, the potential to enhance milk n-3 content in two breeds with inherent genetic differences in mammary lipogenesis and de novo fatty acid synthesis was examined using extruded linseeds. Six lactating cows (three Holstein and three Jersey) were used in a two-treatment switchback design with 3 × 21-day experimental periods to evaluate the effect of iso-energetic replacement of calcium salts of palm oil distillate (CPO) in the diet (34 g/kg dry matter (DM)) with 100 g/kg DM extruded linseeds (LIN). For both breeds, replacing CPO with LIN had no effect (P > 0.05) on DM intake or milk yield, but reduced (P < 0.05) milk fat and protein yield (on average, from 760 to 706 and 573 to 552 g/day, respectively). Relative to CPO, the LIN treatment reduced (P < 0.01) total saturated fatty acid content and enhanced (P < 0.001) 18:3n-3 in milk, whereas breed by diet interactions were significant for milk fat 16:0, total trans fatty acid and conjugated linoleic acid concentrations. Increases in 18:3n-3 intake derived from LIN in the diet were transferred into milk with a mean marginal transfer efficiency of 1.8%. Proportionate changes in milk fatty acid composition were greater in the Jersey, highlighting the importance of diet-genotype interactions on mammary lipogenesis. More extensive studies are required to determine the role of genotype on milk fat composition responses to oilseeds in the diet.


Pain in older people with cancer: attitudes and self-management strategies.
Cancer is predominantly a disease of older people. It is also frequently a painful condition. However, the ageing process brings with it any number of other painful conditions, so it can be difficult to quantify the number of older people who are in pain solely because of cancer. In this article, we present a review of the literature concerning issues specifically related to the management of pain in older people. Three main areas are considered: the use of analgesics; the attitudes of older people in relation to pain management and their utilization of pain management strategies. We suggest that although a great deal is known about the efficacy of analgesia, there is relatively little information relating to the subjective experience of older individuals as they engage with treatment processes. This is important because social, psychological and cultural factors can have a significant influence on the effective management of cancer pain in this age group.