Clinical feasibility of umbilical cord tissue-derived mesenchymal stem cells in the treatment of multiple sclerosis.
Multiple sclerosis (MS) is a progressively debilitating neurological condition in which the immune system abnormally erodes the myelin sheath insulating the nerves. Mesenchymal stem cells (MSC) have been used in the last decade to safely treat certain immune and inflammatory conditions. A safety and feasibility study was completed on the use of umbilical cord MSC (UCMSC) as a treatment for MS. In this 1-year study, consenting subjects received seven intravenous infusions of 20 × 106 UCMSC over 7 days. Efficacy was assessed at baseline, 1 month and 1 year after treatment, including magnetic resonance imaging (MRI) scans, Kurtzke Expanded Disability Status Scale (EDSS), Scripps Neurological Rating Scale, Nine-Hole Peg Test, 25-Foot Walk Test, and RAND Short Form-36 quality of life questionnaire. Twenty subjects were enrolled in this study. No serious adverse events were reported. Of the mild AEs denoted as possibly related to treatment, most were headache or fatigue. Symptom improvements were most notable 1 month after treatment. Improvements were seen in EDSS scores (p < 0.03), as well as in bladder, bowel, and sexual dysfunction (p < 0.01), in non-dominant hand average scores (p < 0.01), in walk times (p < 0.02) and general perspective of a positive health change and improved quality of life. MRI scans of the brain and the cervical spinal cord showed inactive lesions in 15/18 (83.3%) subjects after 1 year. Treatment with UCMSC intravenous infusions for subjects with MS is safe, and potential therapeutic benefits should be further investigated. Trial registration ClinicalTrials.gov NCT02034188. Registered Jan 13, 2014. https://clinicaltrials.gov/ct2/show/NCT02034188.


Action of vasodilator agents on inner and outer muscle of bovine coronary arteries.
Noradrenaline and adrenaline (via beta-receptors), adenosine, and prostacyclin all relaxed inner more than outer muscle in coronary arteries contracted by histamine. In submaximal concentrations, noradrenaline, and usually the other dilator hormones, produced proportionately even greater relaxation of inner than outer muscle. Inner and outer strips contracted by 5-hydroxytryptamine showed similar but smaller differences in response to noradrenaline. Outer strips contracted by methacholine were little affected by noradrenaline, though inorganic nitrite relaxed them.


Electrogenesis of increased norepinephrine sensitivity of arterial vascular muscle in hypertension.
The possibility that the vascular muscle cell might contribute to the development of essential hypertension by being more responsive to norepinephrine because of an inherently lower membrane potential (Em) was investigated. Experiments were designed to test the hypothesis that Em of arterial vascular muscle cells from spontaneously hypertensive rats (SHR) are less negative than those from matched Kyoto normotensive rats (KNR). The caudal artery, a muscular, densely innervated regulating artery 300-400 mum in outside diameter, which is activated by graded (nonspiking) depolarization to produce a maintained contraction, was studied. Vascular muscle cells from SHR always had less negative Em than those from KNR at 16 degrees C, but not at 36 degrees C, over a range of K+ concentrations from 2.7 mM to 150 mM. From the relationship between Em and K+ concentration, intracellular K+ concentration ([K+]i) was estimated to be 150 mM for SHR and 170 mM for KNR. The caudal artery undergoes a large depolarization when K+ is removed from the superfusing solution and a transient hyperpolarization that exceeds the calculated EK (potassium equilibrium potential) when K+ is replaced. The magnitude of the hyper-polarization on returning to 30 mM or 50 mM K+ always was greater for vascular muscle of SHR than KNR. The apparently lower [K+]i and more active (compensating) electrogenic ion transport in the SHR vascular muscle cells thus result in an unaltered Em at body temperature in the physiological range of K+ concentrations. However, depolarization by norepinephrine was greater over the middle of the dose-response curve, and this greater depolarization caused the contractions of SHR arteries to be greater. The altered electrogenesis of the SHR vascular muscle cells is postulated to provide a mechanism for the increased reactivity of arteries to norepinephrein in hypertension.


Treatment of psoriatic arthritis at the Dead Sea.
To evaluate the effectiveness of balneotherapy (mud packs and sulfur baths) on patients with psoriasis and psoriatic arthritis (PsA). One hundred and sixty-six patients with psoriasis and PsA were treated at the Dead Sea for a period of 3 weeks. The patients were divided into 2 groups. Both groups had the regular regimen of bathing in Dead Sea water and exposure to the sun's ultraviolet rays. The study group, which consisted of 146 patients also was treated with mud packs and sulfur baths. The control group, which had no additional therapy, consisted of 20 patients. The main clinical variables assessed were duration of morning stiffness, grip strength, activities of daily living, subjective patient assessment of disease severity, number of active joints, number of effluent joints. Ritchie index, psoriasis area and severity index score, cervical, thoracic, and lumbar spine pain and limitations of movement. Statistically significant improvement was found in most variables in both groups. However, better results were observed in the study group. In 2 variables, reduction of spinal pain and range of movement in the lumbar spine, significant improvement (p < 0.001 and p = 0.022, respectively) was observed in the study group only. Treatment of psoriasis and PsA at the Dead Sea area is very efficacious and the addition of balneotherapy can have additional beneficial effects on patients with PsA. Other controlled studies with longer followup periods are needed to verify our results.


Drosophila neuroligin 1 regulates synaptic growth and function in response to activity and phosphoinositide-3-kinase.
Neuroligins are postsynaptic neural cell adhesion molecules that mediate synaptic maturation and function in vertebrates and invertebrates, but their mechanisms of action and regulation are not well understood. At the Drosophila larval neuromuscular junction (NMJ), previous analysis demonstrated a requirement for Drosophila neuroligin 1 (dnlg1) in synaptic growth and maturation. The goal of the present study was to better understand the effects and mechanisms of loss-of-function and overexpression of dnlg1 on synapse size and function, and to identify signaling pathways that control dnlg1 expression. Consistent with reduced synapse size, evoked excitatory junctional currents (EJCs) were diminished in dnlg1 mutants but displayed normal Ca(2+) sensitivity and short-term plasticity. However, postsynaptic function was also perturbed, in that glutamate receptor staining and the distribution of amplitudes of miniature excitatory junctional currents (mEJCs) were abnormal in mutants. All the above phenotypes were rescued by a genomic transgene. Overexpression of dnlg1 in muscle resulted in synaptic overgrowth, but reduced the amplitudes of EJCs and mEJCs. Overgrowth and reduced EJC amplitude required Drosophila neurexin 1 (dnrx1) function, suggesting that increased DNlg1/DNrx1 signaling attenuates synaptic transmission and regulates growth through a retrograde mechanism. In contrast, reduced mEJC amplitude was independent of dnrx1. Synaptic overgrowth, triggered by neuronal hyperactivity, absence of the E3 ubiquitin ligase highwire, and increased phosphoinositide-3-kinase (PI3K) signaling in motor neurons reduced synaptic DNlg1 levels. Likewise, postsynaptic attenuation of PI3K, which increases synaptic strength, was associated with reduced DNlg1 levels. These observations suggest that activity and PI3K signaling pathways modulate growth and synaptic transmission through dnlg1-dependent mechanisms.


DP-1: a cell cycle-regulated and phosphorylated component of transcription factor DRTF1/E2F which is functionally important for recognition by pRb and the adenovirus E4 orf 6/7 protein.
The cellular transcription factor DRTF1/E2F integrates cell cycle events with the transcription apparatus through its cyclical interactions with important regulators of cellular proliferation. Two sequence-specific DNA binding proteins, DP-1 and E2F-1, are components of DRTF1/E2F which synergistically interact in a DP-1/E2F-1 heterodimer. Here, we show that DP-1 is a very frequent, possibly universal, component of DRTF1/E2F in 3T3 cells since it is present in all forms of the DNA binding activity that occur during cell cycle progression. Furthermore, the DP-1 polypeptide, which is phosphorylated, undergoes a phosphorylation-dependent mobility shift during the cell cycle suggesting that its level of phosphorylation is regulated during cell cycle progression. A C-terminal region in DP-1 can interact with pRb which, in the context of the DP-1/E2F-1 heterodimer, contributes to the efficiency of pRb binding. The DP-1/E2F-1 heterodimer specifically interacts with the adenovirus type 5 E4 orf 6/7 protein, to produce a DNA binding activity which binds co-operatively to, and transcriptionally activates through, two appropriately positioned E2F sites in a manner which resembles the regulation of DRTF1/E2F by E4 orf 6/7 during adenovirus infection. We conclude that DP-1 is a frequent and cell cycle-regulated component of DRTF1/E2F, and that in the DP-1/E2F-1 heterodimer it is functionally important for recognition by pRb and the E4 orf 6/7 protein.


Effects of Perfluorooctanoic Acid on Metabolic Profiles in Brain and Liver of Mouse Revealed by a High-throughput Targeted Metabolomics Approach.
Perfluorooctanoic acid (PFOA), a perfluoroalkyl acid, can result in hepatotoxicity and neurobehavioral effects in animals. The metabolome, which serves as a connection among transcriptome, proteome and toxic effects, provides pathway-based insights into effects of PFOA. Since understanding of changes in the metabolic profile during hepatotoxicity and neurotoxicity were still incomplete, a high-throughput targeted metabolomics approach (278 metabolites) was used to investigate effects of exposure to PFOA for 28 d on brain and liver of male Balb/c mice. Results of multivariate statistical analysis indicated that PFOA caused alterations in metabolic pathways in exposed individuals. Pathway analysis suggested that PFOA affected metabolism of amino acids, lipids, carbohydrates and energetics. Ten and 18 metabolites were identified as potential unique biomarkers of exposure to PFOA in brain and liver, respectively. In brain, PFOA affected concentrations of neurotransmitters, including serotonin, dopamine, norepinephrine, and glutamate in brain, which provides novel insights into mechanisms of PFOA-induced neurobehavioral effects. In liver, profiles of lipids revealed involvement of β-oxidation and biosynthesis of saturated and unsaturated fatty acids in PFOA-induced hepatotoxicity, while alterations in metabolism of arachidonic acid suggesting potential of PFOA to cause inflammation response in liver. These results provide insight into the mechanism and biomarkers for PFOA-induced effects.


Involvement of oxidative stress in NF-kappaB activation in endothelial cells treated by photodynamic therapy.
In human endothelial cells ECV 304 and HMEC-1 photosensitized by pyropheophorbide-a methylester (PPME) in sublethal conditions transcription factor Nuclear Factor kappa B (NF-kappaB) activation takes place for several hours. Activated NF-kappaB was functional because it stimulated the transcriptional activation of either a transfected reporter gene or the endogenous gene encoding interleukin (IL)-8. Concomitant with NF-kappaB activation, inhibitor of NF-kappaB alpha (IkappaB alpha) was degraded during photosensitization and IkappaB beta, p100, p105 and IkappaB epsilon were slightly modified. Reactive oxygen species (ROS) were shown to be crucial intermediates in the activation because antioxidants strongly decreased NF-kappaB activation. Using both a fluorescent probe and isotope substitution, it was shown that ROS, and especially singlet oxygen (1O2), were important in the activation process. Because NF-kappaB activation in the presence of ROS was suspected to proceed through a pathway independent of the IkappaB kinases (IKK), we demonstrated that the IKK were indeed not activated by photosensitization but required an intact tyrosine residue at position 42 on IkappaB alpha, suggesting the involvement of a tyrosine kinase in the activation process. This was further reinforced by the demonstration that herbimycin A, a tyrosine kinase inhibitor, prevented NF-kappaB activation by photosensitization but not by TNF alpha, a cytokine known to activate NF-kappaB through an IKK-dependent mechanism.


Chrysotile asbestos and H2O2 increase permeability of alveolar epithelium.
The alveolar epithelium contains tight junctions and provides a barrier to passage of potentially injurious substances into the pulmonary interstitium. Alveolar epithelial injury is hypothesized to be an important early event in the pathogenesis of asbestosis. Mechanisms that may contribute to alveolar epithelial cell injury following asbestos exposure include the physicochemical interactions between asbestos fibers and cells, and the generation of reactive oxygen species such as hydrogen peroxide (H2O2). The present study examined changes in transepithelial resistance (Rt) (a measure of barrier function) and permeability of alveolar epithelium after chrysotile asbestos and H2O2 exposure. Alveolar epithelial cell monolayers, obtained from isolation of rat alveolar type II cells and grown on porous supports, were exposed to chrysotile asbestos or polystyrene beads (control) at concentrations of 5, 10, and 25 micrograms/cm2 for 24 h. In separate experiments, monolayers were exposed to H2O2 at concentrations of 50, 75, and 100 microM for 1 h Rt was measured using a voltohmmeter. Prior to treatment, monolayers had a high Rt (> 2000 ohms.cm2). Permeability was assessed by measuring flux of [3H]sucrose from apical to basolateral compartments. Cytotoxicity was evaluated by lactate dehydrogenase (LDH) and preincorporated [14C]adenine release. The morphological integrity of the monolayers was evaluated by scanning electron microscopy. Chrysotile asbestos and H2O2 exposure resulted in dose-dependent decrease in alveolar epithelial Rt and increases in permeability under conditions that did not result in over cytotoxicity. These results demonstrate that both chrysotile asbestos and H2O2 have effects on alveolar epithelial Rt and permeability and suggest a potential role for the alveolar epithelium in mediation of asbestos-induced pulmonary interstitial disease.


The challenges of ending AIDS in Asia: outcomes of the Thai National AIDS Universal Coverage Programme, 2000-2014.
We sought to determine Thai National AIDS Program (NAP) outcomes and gaps, and success in reaching the WHO 90:90:90 goals. Retrospective study of treatment outcomes, mortality and loss to follow-up (LTFU), of all individuals aged >15 years who registered to the NAP from 2000 to 2014. We focused outcomes on data from 2008 when the NAP was linked to the death registry. A total of 429,294 patients registered to the NAP up to November 2014, and 309,313 patients aged >15 years started ART. Median (IQR) age was 37 (31-43) years; 51% were male. From 2008 to 2014, long-term follow-up rates per 100 person-years were 3.2 in those who started ART vs 3.5 in those who did not (P<0.001) and mortality rates per 100 person-years were 3.5 in those who started ART vs 4.9 in those who did not (P<0.001). Mortality reduced from 16% in 2008 to 3% in 2014 for those who started ART. For patients starting treatment since 2000, 87% of those alive and with a recent viral load (VL) result had <50 copies/mL, and 6% had VL ≥1000 copies/mL. In a continuum-of-care analysis from 2008 to 2014, 68% were living and retained on ART, and 46% of diagnosed individuals were virally suppressed at <50 copies/mL. In the Thai NAP, death and LTFU are major factors disrupting the care-continuum, and many patients initiate ART with low CD4 cell counts. Rolling out systems for early detection and treatment for all, regardless of CD4 cell count, are essential and under way.


Is there plasticity in developmental instability? The effect of daily thermal fluctuations in an ectotherm.
Diversified bet-hedging (DBH) by production of within-genotype phenotypic variance may evolve to maximize fitness in stochastic environments. Bet-hedging is generally associated with parental effects, but phenotypic variation may also develop throughout life via developmental instability (DI). This opens for the possibility of a within-generation mechanism creating DBH during the lifetime of individuals. If so, DI could in fact be a plastic trait itself; if a fluctuating environment indicates uncertainty about future conditions, sensing such fluctuations could trigger DI as a DBH response. However, this possibility has received little empirical attention. Here, we test whether fluctuating environments may elicit such a response in the clonally reproducing crustacean Daphnia magna. Specifically, we exposed genetically identical individuals to two environments of different thermal stability (stable vs. pronounced daily realistic temperature fluctuations) and tested for effects on DI in body mass and metabolic rate shortly before maturation. Furthermore, we also estimated the genetic variation in DI. Interestingly, fluctuating temperatures did not affect body mass, but metabolic rate decreased. We found no evidence for plasticity in DI in response to environmental fluctuations. The lack of plasticity was common to all genotypes, and for both traits studied. However, we found considerable evolvability for DI, which implies a general evolutionary potential for DBH under selection for increased phenotypic variance.


Neuroendocrine-related effects of long-term, 'binge' cocaine administration: diminished individual differences in stress-induced corticosterone response.
Acute cocaine administration activates behavioral and neuroendocrine processes associated with the stress response. However, much less is known about the effects of chronic, long-term cocaine administration on neuroendocrine adaptations and individual vulnerability to stress. We hypothesized that chronic 'binge' cocaine administration may serve as a chronic pharmacological stressor leading to a hyperactivity of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis and alterations in its feedback mechanisms. In order to test this hypothesis, the effects of long-term (3 and 6 weeks) 'binge' pattern cocaine administration (3x15 mg/kg cocaine, i.p., daily, during the early phase of the light cycle) on body weight, adrenal gland weight, basal and stress-induced activity of the corticosterone (CORT) and basal plasma testosterone (T) levels were measured. Both 3 and 6 weeks 'binge' cocaine administration decreased body weight gain, increased the weight of adrenal glands and increased basal CORT levels. Plasma T levels were suppressed by both 3 and 6 weeks of cocaine treatment. No correlation was found between elevated CORT and low T levels at any time point. Neither chronic saline nor cocaine administration altered stress-induced CORT secretion. CORT levels 60 min following the restraint stress (recovery) were significantly lower than pre-stress basal levels after 3 and 6 weeks of cocaine, but not saline, administration. Moreover, initial individual differences in stress-induced CORT response, i.e. low and high responsivity to restraint prior to any saline or cocaine injections, were maintained in control rats but became diminished in cocaine-treated rats. These results indicate that chronic binge cocaine administration leads to sustained activation of the HPA axis and alters processes underlying individual vulnerability to stress.


The influence of visual search efficiency on the time-course of identity-based SR-compatibility.
Three experiments were conducted to investigate the impact of stimulus-driven control on the time-course of stimulus-response (SR) compatibility. Participants responded to the presence or absence of a singleton arrow that was presented among multiple nontargets. When the singleton arrow was present, observers pressed a button with their right index finger, when it was absent they pressed with their left-index finger. SR-compatibility depended on the relation between the identity of the target and the present response: Even though the identity of the target singleton arrow (whether it was pointing to the right or left) was irrelevant to the task, the direction could be corresponding (right arrow) or noncorresponding (left arrow) with a target present response (the right hand). To examine the time-course of performance target-distractor similarity was varied to increase or decrease visual search efficiency and accordingly response latency. There were three main findings. First, the results of Experiment 1 showed that observers were no faster to respond 'present' when the singleton arrow pointed to the right (corresponding to the right hand) than when it pointed left (noncorresponding to the right hand) in a simple present-absent detection task. Second, only when observers were encouraged to process the identity of the arrow singleton, an effect of an SR-compatibility effect was found which developed over time. Third, the time-course of SR-compatibility was not influenced by visual search efficiency. The results of the present work suggest that visual selection and response selection occur in different stages.


Incidence and mortality of hip fractures in the United States.
Understanding the incidence and subsequent mortality following hip fracture is essential to measuring population health and the value of improvements in health care. To examine trends in hip fracture incidence and resulting mortality over 20 years in the US Medicare population. Observational study using data from a 20% sample of Medicare claims from 1985-2005. In patients 65 years or older, we identified 786,717 hip fractures for analysis. Medication data were obtained from 109,805 respondents to the Medicare Current Beneficiary Survey between 1992 and 2005. Age- and sex-specific incidence of hip fracture and age- and risk-adjusted mortality rates. Between 1986 and 2005, the annual mean number of hip fractures was 957.3 per 100,000 (95% confidence interval [CI], 921.7-992.9) for women and 414.4 per 100,000 (95% CI, 401.6-427.3) for men. The age-adjusted incidence of hip fracture increased from 1986 to 1995 and then steadily declined from 1995 to 2005. In women, incidence increased 9.0%, from 964.2 per 100,000 (95% CI, 958.3-970.1) in 1986 to 1050.9 (95% CI, 1045.2-1056.7) in 1995, with a subsequent decline of 24.5% to 793.5 (95% CI, 788.7-798.3) in 2005. In men, the increase in incidence from 1986 to 1995 was 16.4%, from 392.4 (95% CI, 387.8-397.0) to 456.6 (95% CI, 452.0-461.3), and the subsequent decrease to 2005 was 19.2%, to 369.0 (95% CI, 365.1-372.8). Age- and risk-adjusted mortality in women declined by 11.9%, 14.9%, and 8.8% for 30-, 180-, and 360-day mortality, respectively. For men, age- and risk-adjusted mortality decreased by 21.8%, 25.4%, and 20.0% for 30-, 180-, and 360-day mortality, respectively. Over time, patients with hip fracture have had an increase in all comorbidities recorded except paralysis. The incidence decrease is coincident with increased use of bisphosphonates. In the United States, hip fracture rates and subsequent mortality among persons 65 years and older are declining, and comorbidities among patients with hip fractures have increased.


Cooperative strategies and the evolution of communication.
Using communication is not the only cooperative strategy that can evolve when organisms need to solve a problem together. This article describes a model that extends MacLennan and Burghardt's [37] synthetic ethology simulation to show that using a spatial world in a simulation allows a wider range of strategies to evolve in response to environmental demands. The model specifically explores the interaction between population density and resource abundance and their effect on the kinds of cooperative strategies that evolve. Signaling strategies evolve except when population density is high or resource abundance is low.


Evaluation and management of knee pain in young athletes: overuse injuries of the knee.
Recurrent or chronic activity related knee pain is common in young athletes. Numerous intrinsic conditions affecting the knee can cause such pain. In addition, knee pain can be referred pain from low back, hip or pelvic pathology. The most common cause of knee pain in young athletes is patellofemoral pain syndrome, or more appropriately termed idiopathic anterior knee pain. Although, numerous anatomical and biomechanical factors have been postulated to contribute the knee pain in young athletes, the most common underlying reason is overuse injury. In this paper, we have reviewed selected conditions that case knee pain in athletes, including anterior knee pain syndrome, Osgood-Schlatter disease, Sinding-Larsen-Johanssen syndrome, juvenile osteochondritis dissecans (JOCD), bipartite patella, plica syndrome, and tendonitis around the knee.


Occurrence of a 16SrIV Group Phytoplasma not Previously Associated with Palm Species in Yucatan, Mexico.
The occurrence of 16SrIV group phytoplasmas in palm species Sabal mexicana and Pseudophoenix sargentii is reported here for the first time. Palm trees showed leaf decay and leaf yellowing syndromes, respectively. An amplification product (1.4 kb) was obtained in symptomatic S. mexicana (18 of 21) and symptomatic P. sargentii (1 of 1) palm trees sampled in different locations in Yucatan State, Mexico; five of the positive S. mexicana and the positive P. sargentii trees died. The identity of the phytoplasmas from these species was determined by restriction fragment length polymorphism profiling with restriction enzymes AluI and HinfI, showing there could be two phytoplasma strains of the 16SrIV group. In one S. mexicana palm, the profile was the same as observed with these enzymes for phytoplasmas of 16SrIV-A subgroup, previously associated with Cocos nucifera palm trees and, in the rest of the trees, including the P. sargentii palm, the profile was for phytoplasmas of the 16SrIV-D subgroup. These identities were supported by analyses of the amplicons obtained by nested polymerase chain reaction by nucleotide-nucleotide BLAST analysis. Geographical distribution of the association S. mexicana/16SrIV group phytoplasmas was found widely dispersed in Yucatan State. A potential role of S. mexicana palm trees as a permanent source of phytoplasma inoculum is suggested. In addition to P. sargentii, other palm species (Thrinax radiata and C. nucifera) coexisting with S. mexicana trees were also sampled and analyzed.


Ubc9- and mms21-mediated sumoylation counteracts recombinogenic events at damaged replication forks.
The Ubc9 SUMO-conjugating enzyme and the Siz1 SUMO ligase sumoylate several repair and recombination proteins, including PCNA. Sumoylated PCNA binds Srs2, a helicase counteracting certain recombination events. Here we show that ubc9 mutants depend on checkpoint, recombination, and replication genes for growth. ubc9 cells maintain stalled-fork stability but exhibit a Rad51-dependent accumulation of cruciform structures during replication of damaged templates. Mutations in the Mms21 SUMO ligase resemble the ubc9 mutations. However, siz1, srs2, or pcna mutants altered in sumoylation do not exhibit the ubc9/mms21 phenotype. Like ubc9/mms21 mutants, sgs1 and top3 mutants also accumulate X molecules at damaged forks, and Sgs1/BLM is sumoylated. We propose that Ubc9 and Mms21 act in concert with Sgs1 to resolve the X structures formed during replication. Our results indicate that Ubc9- and Mms21-mediated sumoylation functions as a regulatory mechanism, different from that of replication checkpoints, to prevent pathological accumulation of cruciform structures at damaged forks.


The importance of the diurnal and annual cycle of air traffic for contrail radiative forcing.
Air traffic condensation trails, or contrails, are believed to have a net atmospheric warming effect, although one that is currently small compared to that induced by other sources of human emissions. However, the comparably large growth rate of air traffic requires an improved understanding of the resulting impact of aircraft radiative forcing on climate. Contrails have an effect on the Earth's energy balance similar to that of high thin ice clouds. Their trapping of outgoing longwave radiation emitted by the Earth and atmosphere (positive radiative forcing) is partly compensated by their reflection of incoming solar radiation (negative radiative forcing). On average, the longwave effect dominates and the net contrail radiative forcing is believed to be positive. Over daily and annual timescales, varying levels of air traffic, meteorological conditions, and solar insolation influence the net forcing effect of contrails. Here we determine the factors most important for contrail climate forcing using a sophisticated radiative transfer model for a site in southeast England, located in the entrance to the North Atlantic flight corridor. We find that night-time flights during winter (December to February) are responsible for most of the contrail radiative forcing. Night flights account for only 25 per cent of daily air traffic, but contribute 60 to 80 per cent of the contrail forcing. Further, winter flights account for only 22 per cent of annual air traffic, but contribute half of the annual mean forcing. These results suggest that flight rescheduling could help to minimize the climate impact of aviation.


Efficacy and cost of an exercise program for functionally impaired older patients with heart failure: a randomized controlled trial.
Little is known about the optimum way to deliver exercise to older, functionally impaired patients with heart failure. We tested whether an exercise program tailored to the needs of these patients could improve exercise capacity and quality of life or reduce costs to the National Health Service. The study design was a parallel-group, single-blind, randomized controlled trial. Patients aged ≥70 years with symptomatic heart failure and left ventricular systolic dysfunction were randomized to either 24 weeks of exercise training or usual care. Six-minute walk distance was the primary outcome; markers of physical function, quality of life, health status, and daily activity were measured at baseline and 8 and 24 weeks. Carer strain and healthcare costs were also recorded. A total of 107 participants were randomized (mean age, 80 years; men, 72 [67%]). Six-minute walk distance did not improve compared to that of the control group at 8 weeks (-16.9 m; 95% CI, -41.8 to 7.9 m; P=0.18) or at 24 weeks (-5.3 m; 95% CI, -32.6 to 22.0 m; P=0.70). For secondary outcomes, only the sit-to-stand test improved significantly at 24 weeks (-6.4 s; 95% CI, -12.2 to 0.6 s; P=0.03); there was no difference in change for the Minnesota Living With Heart Failure score (0.1 points; 95% CI, -0.9 to 1.1 points; P=0.83) at 24 weeks. Carer strain did not decrease at 24 weeks (difference, -0.5 points; 95% CI, -8.3 to 7.3 points; P=0.80), and there was no difference in overall healthcare costs. This exercise intervention did not improve exercise capacity or quality of life in older patients with heart failure and was not cost saving to the National Health Service. Clinical Trial Registration- URL: http://www.controlled-trials.com. Unique identifier: ISRCTN51615566.


Variation in KRTAP6-1 affects wool fibre diameter in New Zealand Romney ewes.
Variation in KRTAP6-1 has been reported to affect wool fibre traits in Merino cross-breed sheep and Chinese Tan sheep, but little is known about whether these effects persist in other breeds. In this study, variation in KRTAP6-1 was investigated in 290 New Zealand (NZ) Romney ewes sired by 16 different rams. Polymerase chain reaction single-stranded conformational polymorphism (PCR-SSCP) analysis revealed four variants ( A , B , E and F ) of KRTAP6-1, and nine genotypes (AA, AB, AE, AF, BB, BE, BF, EE and FF) in these ewes. Among the 243 ewes that had genotypes with a frequency of over 5 % (i.e. AA, AB and BB), the presence of A was found to be associated with reduced mean fibre diameter (MFD) and increased coefficient of variation in fibre diameter (CVFD), whereas the presence of B had a trend of association with decreased coarse edge measurement (CEM). A genotype effect was also detected for MFD and CVFD. No associations were detected for fibre diameter standard deviation (FDSD), mean fibre curvature (MFC) and medulation. These results suggest that variation in KRTAP6-1 affects wool fibre diameter in NZ Romney ewes, confirming the finding in Merino cross-breed sheep.


Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer.
Preclinical studies in animal models have demonstrated tumor regression following intratumoral administration of an adenovirus vector containing wild-type p53 complementary DNA (Ad-p53). Therefore, in a phase I clinical trial, we administered Ad-p53 to 28 patients with non-small-cell lung cancer (NSCLC) whose cancers had progressed on conventional treatments. Patients received up to six, monthly intratumoral injections of Ad-p53 by use of computed tomography-guided percutaneous fine-needle injection (23 patients) or bronchoscopy (five patients). The doses ranged from 10(6) plaque-forming units (PFU) to 10(11) PFU. Polymerase chain reaction (PCR) analysis showed the presence of adenovirus vector DNA in 18 (86%) of 21 patients with evaluable posttreatment biopsy specimens; vector-specific p53 messenger RNA was detected by means of reverse transcription-PCR analysis in 12 (46%) of 26 patients. Apoptosis (programmed cell death) was demonstrated by increased terminal deoxynucleotide transferase-mediated biotin uridine triphosphate nick-end labeling (TUNEL) staining in posttreatment biopsy specimens from 11 patients. Vector-related toxicity was minimal (National Cancer Institute's Common Toxicity Criteria: grade 3 = one patient; grade 4 = no patients) in 84 courses of treatment, despite repeated injections (up to six) in 23 patients. Therapeutic activity in 25 evaluable patients included partial responses in two patients (8%) and disease stabilization (range, 2-14 months) in 16 patients (64%); the remaining seven patients (28%) exhibited disease progression. Repeated intratumoral injections of Ad-p53 appear to be well tolerated, result in transgene expression of wild-type p53, and seem to mediate antitumor activity in a subset of patients with advanced NSCLC.


Analysis of Anti-Doping Rule Violations That Have Impacted Medal Results at the Summer Olympic Games 1968-2012.
Since 2004, the International Olympic Committee (IOC) store all samples collected at summer Olympic Games (OG) for retrospective re-analysis with more advanced analytical techniques to catch doping athletes. All announced Anti-Doping Rule Violations (ADRVs) from IOC re-tests of the 2004, 2008 and 2012 OG (via IOC, International Federations and Athletics Integrity Unit public data) and other ADRVs confirmed to impact OG results from 1968 to 2012 (via the list of Doping Irregularities on olympedia.org) were collated to investigate how many medals have been impacted by ADRVs, when the ADRV was identified relative to the OG in question and its cause. One hundred and thirty-four medals were impacted by ADRVs but only 26% of these ADRVs were identified at the time of the OG. Most ADRVs impacting medal results (74%) were identified retrospectively, either from events prior to the OG (17%) or via IOC re-tests of samples from 2004, 2008 and 2012 (57%). ADRVs impacting medal results from these re-tests took a mean of 6.8 ± 2.0 years to be announced relative to the end of the OG in which the medal was originally won. Exogenous Anabolic Androgenic Steroid metabolites were present in 90% of all athlete (n = 142) samples from IOC re-tests with dehydrochloromethyltestosterone and stanozolol accounting for 79% of detected substances. Athletics (n = 64) and weightlifting (n = 62) were the most affected sports. This analysis shows the frequency of targeted pre-OG Out-of-Competition testing should increase. We advocate for long-term sample storage to continue and additionally incorporate novel and potentially complementary technologies/sample matrices.


"I can't understand your information sheet, doc!" Readability of limited-reach media materials for the lay population.
Patients are provided limited-reach media materials, such as information sheets and pamphlets, as reinforcement of information when the oral healthcare professional is no longer face-to-face. Patients are more likely to use the printed information if text complexity and reader's ability match, or if their need to know the content provokes an urge to read. A number of researchers have developed readability tests. This study used the Fry Readability Graph to plot the results of three independent raters' averages of the number of sentences and the words (syllables) of continuous (prose) and non-continuous (matrix-style) pre-selected passages from several reputable sources. These limited-reach materials are frequently used in academic institutions' community engagement efforts. Several of the limited-reach materials we studied were ranked above the fifth-grade reading level, so consideration must be given to future distribution of these documents in communities where the average reading proficiency is lower. Several limitations, such as the quality of illustrations and measuring the reading level of individuals, were not investigated and must be considered as the authors continue to distribute literature in certain urban and suburban locales. This study is the genesis of an academic institution's community engagement efforts to provide information to clinicians and improve its outreach distribution of limited-reach media for patients who have varying levels of general and health literacy backgrounds.


Recruiting older people to a randomised controlled dietary intervention trial--how hard can it be?
The success of a human intervention trial depends upon the ability to recruit eligible volunteers. Many trials fail because of unrealistic recruitment targets and flawed recruitment strategies. In order to predict recruitment rates accurately, researchers need information on the relative success of various recruitment strategies. Few published trials include such information and the number of participants screened or approached is not always cited. This paper will describe in detail the recruitment strategies employed to identify older adults for recruitment to a 6-month randomised controlled dietary intervention trial which aimed to explore the relationship between diet and immune function (The FIT study). The number of people approached and recruited, and the reasons for exclusion, will be discussed. Two hundred and seventeen participants were recruited to the trial. A total of 7,482 letters were sent to potential recruits using names and addresses that had been supplied by local Family (General) Practices. Eight hundred and forty three potential recruits replied to all methods of recruitment (528 from GP letters and 315 from other methods). The eligibility of those who replied was determined using a screening telephone interview, 217 of whom were found to be suitable and agreed to take part in the study. The study demonstrates the application of multiple recruitment methods to successfully recruit older people to a randomised controlled trial. The most successful recruitment method was by contacting potential recruits by letter on NHS headed note paper using contacts provided from General Practices. Ninety percent of recruitment was achieved using this method. Adequate recruitment is fundamental to the success of a research project, and appropriate strategies must therefore be adopted in order to identify eligible individuals and achieve recruitment targets.


Rapid onset of vascular wall protein synthesis with increase in lability of blood pressure in rabbits.
1. Structural and functional changes resulting from baroreceptor denervation were studied in rabbits 4 days after surgery. 2. After section of the aortic and carotid sinus nerves, arterial pressure was characteristically labile although the mean pressures were not significantly different from those of control animals. 3. The responsiveness of isolated ear arteries and cephalic veins from deafferented animals to noradrenaline and electrical stimulation of their sympathetic innervation was similar in both groups. 4. Neuronal uptake of noradrenaline into arterial tissue was similar in both groups, although uptake into the cephalic veins of deafferented animals was less than in the control group. 5. [3H]Thymidine uptake, an index of DNA synthesis, was similar in both groups, radioautography revealing no difference in smooth muscle cell labelling. 6. Uptake of [3H]proline, an indicator of protein synthesis, by aorta, ear, brachial, basilar and renal arteries from deafferented animals was greater than in control animals. 7. Baroreceptor denervation altered protein metabolism in the arterial wall.


Downregulation of Survivin contributes to cell-cycle arrest during postnatal cardiac development in a severe spinal muscular atrophy mouse model.
Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality, characterized by progressive degeneration of spinal-cord motor neurons, leading to atrophy of skeletal muscles. However, accumulating evidence indicates that it is a multi-system disorder, particularly in its severe forms. Several studies delineated structural and functional cardiac abnormalities in SMA patients and mouse models, yet the abnormalities have been primarily attributed to autonomic dysfunction. Here, we show in a severe mouse model that its cardiomyocytes undergo G0/G1 cell-cycle arrest and enhanced apoptosis during postnatal development. Microarray and real-time RT-PCR analyses revealed that a set of genes associated with cell cycle and apoptosis were dysregulated in newborn pups. Of particular interest, the Birc5 gene, which encodes Survivin, an essential protein for heart development, was down-regulated even on pre-symptomatic postnatal day 0. Interestingly, cultured cardiomyocytes depleted of SMN recapitulated the gene expression changes including downregulation of Survivin and abnormal cell-cycle progression; and overexpression of Survivin rescued the cell-cycle defect. Finally, increasing SMN in SMA mice with a therapeutic antisense oligonucleotide improved heart pathology and recovered expression of deregulated genes. Collectively, our data demonstrate that the cardiac malfunction of the severe SMA mouse model is mainly a cell-autonomous defect, caused by widespread gene deregulation in heart tissue, particularly of Birc5, resulting in developmental abnormalities through cell-cycle arrest and apoptosis.


Role of dopamine in the physiology of T-cells and dendritic cells.
Dendritic cells (DCs) are responsible for priming T-cells and for promoting their differentiation from naïve T-cells into appropriate effector cells. Because of their fundamental roles in controlling immunity, DCs and T-cells require tight regulatory mechanisms. Several studies have shown that dopamine, not only mediate interactions into the nervous system, but can also contribute to the modulation of immunity. Here, we review the emerging role of this neurotransmitter as a regulator of DC and T-cell physiology and, in turn, immune response. Moreover, we discuss how alterations in the dopamine-mediated immune regulatory mechanisms could contribute to the onset of immune-related disorders.


Analysis of bacterial adhesion using a gradient force analysis method and colloid probe atomic force microscopy.
The atomic force microscope (AFM) has been used to examine the stickiness of bacteria on the basis of the analysis of approach and retraction force curves between the AFM tip and the bacterial surface. One difficulty in analyzing approach curve data is that the distance between the AFM tip and the surface of the bacterium is difficult to define. The exact distances are difficult to determine because the surface of the bacterium deforms during force imaging, producing a highly nonlinear region in the approach curve. In this study, AFM approach and retraction curves were obtained using a colloid probe AFM for three strains of Escherichia coli (D21, D21f2, and JM109). These strains differed in their relative adhesion to glass surfaces, on the basis of measurements of sticking coefficients in packed bed flow through column tests. A gradient force curve analysis method was developed to model the interactions between the colloid probe and a surface. Gradient analysis of the approach curve revealed four different regions of colloid-surface interactions during the approach and contact of the probe with the bacterial surface: a noninteraction region, a noncontact phase, a contact phase, and a constant compliance region. The noncontact phase, which ranged from 28 to 59 nm for the three bacterial strains, was hypothesized to arise primarily from steric repulsion of the colloid by extracellular polymers on the bacterial surface. The contact phase, spanning 59-113 nm, was believed to arise from the initial pressure of the colloid on the outer membrane of the cell. The constant compliance region likely reflected the response of the colloid probe to the stiff peptidoglycan layer that confers strength and rigidity to gram negative bacteria. It was shown that the sticking coefficients reported for the three E. coli strains were correlated with the length of the noncontact phase but not the properties of the other phases. Sticking coefficients were also not correlated with any parameters determined from retraction force curves such as pull-off distances or separation energies. These results show that gradient analysis is useful for studying the contribution of the length of the exopolymers on the cell surface to bacterial adhesion to glass surfaces.


Fourier transform emission lifetime spectrometer.
We report a rapid and low cost Fourier transform spectrometer that uses a path length modulated Michelson interferometer to simultaneously measure excitation spectra and excitation wavelength-dependent emission lifetimes. Excitation spectra and lifetimes of excited tris(2,2'-bipyridyl) ruthenium(II) measured using this technique corresponded to values known in the literature. Excitation-dependent lifetimes of porous silicon measured with this technique suggest the influence of quantum confinement effects. This method may be useful for measuring mixtures of emitting species with closely spaced lifetimes as well as studying excitation wavelength-dependent emission phenomena.


Calsyntenins are secretory granule proteins in anterior pituitary gland and pancreatic islet alpha cells.
Calsyntenins are members of the cadherin superfamily of cell adhesion molecules. They are present in postsynaptic membranes of excitatory neurons and in vesicles in transit to neuronal growth cones. In the current study, calsyntenin-1 (CST-1) and calsyntenin-3 (CST-3) were identified by mass spectrometric analysis (LC-MS/MS) of integral membrane proteins from highly enriched secretory granule preparations from bovine anterior pituitary gland. Immunofluorescence microscopy on thin frozen sections of rat pituitary revealed that CST-1 was present only in gonadotropes where it colocalized with follicle-stimulating hormone in secretory granules. In contrast, CST-3 was present not only in gonadotrope secretory granules but also in those of somatotropes and thyrotropes. Neither protein was detected in mammatropes. In addition, CST-1 was also localized to the glucagon-containing secretory granules of alpha cells in the pancreatic islets of Langerhans. Results indicate that calsyntenins function outside the nervous system and potentially are modulators of endocrine function.


Dynamics of MDR Enterobacter cloacae outbreaks in a neonatal unit in Nepal: insights using wider sampling frames and next-generation sequencing.
There are limited data on Enterobacter cloacae outbreaks and fewer describing these in association with NDM-1. With whole-genome sequencing, we tested the hypothesis that a cluster of 16 E. cloacae bacteraemia cases in a Nepali neonatal unit represented a single clonal outbreak, using a wider set of epidemiologically unrelated clinical E. cloacae isolates for comparison. Forty-three isolates were analysed, including 23 E. cloacae and 3 Citrobacter sp. isolates obtained from blood cultures from 16 neonates over a 3 month period. These were compared with two contemporaneous community-associated drug-resistant isolates from adults, a unit soap dispenser isolate and a set of historical invasive isolates (n=14) from the same geographical locality. There were two clear neonatal outbreaks and one isolated case in the unit. One outbreak was associated with an NDM-1 plasmid also identified in a historical community-associated strain. The smaller, second outbreak was likely associated with a contaminated soap dispenser. The two community-acquired adult cases and three sets of historical hospital-associated neonatal isolates represented four additional genetic clusters. E. cloacae infections in this context represent several different transmission networks, operating at the community/hospital and host strain/plasmid levels. Wide sampling frames and high-resolution typing methods are needed to describe the complex molecular epidemiology of E. cloacae outbreaks, which is not appropriately reflected by routine susceptibility phenotypes. Soap dispensers may represent a reservoir for E. cloacae and bacterial strains and plasmids may persist in hospitals and in the community for long periods, sporadically being involved in outbreaks of disease.


The role of aldosterone blockade in murine lupus nephritis.
The purpose of this study was to examine the effect of aldosterone receptor blockade on the immunopathogenesis and progression of nephritis in the (NZB x NZW) F1 murine lupus model. Female NZB/W F1 mice (11 weeks old) were treated daily with 25 or 50 mg/kg oral spironolactone or vehicle. Proteinuria, renal function, and serum autoantibody levels were monitored. Renal histopathology, immune complex deposition, and immunohistochemistry were analyzed at various time points. Targeted microarray analysis was performed on renal tissue, with subsequent real-time PCR analysis of several differentially expressed genes. Treatment with spironolactone was well tolerated by the mice throughout the course of their disease progression, with no significant differences in azotemia or serum potassium levels between vehicle-treated and spironolactone-treated animals. By 36 weeks of age, fewer spironolactone-treated mice developed nephrotic range proteinuria as compared with the control mice (control 70.8%, 25 mg/kg spironolactone 51.3%, and 50 mg/kg spironolactone 48.6%). Compared with control mice, mice treated with 25 mg/kg spironolactone had significantly lower serum anti-single-stranded DNA levels (2,042 microg/ml versus 1,036 microg/ml; P = 0.03) and anti-double-stranded DNA levels (3,433 microg/ml versus 614 microg/ml; P = 0.05). Spironolactone-treated mice exhibited decreased histopathologic evidence of inflammation and tissue damage, as compared with control mice. Additionally, spironolactone treatment resulted in decreased expression in the kidney of several inflammatory and proapoptotic genes, including those encoding interferon-gamma, B lymphocyte stimulator (BlyS), tumor necrosis factor related apoptosis inducing ligand (TRAIL), tumor necrosis factor related weak inducer of apoptosis (TWEAK), and Fas ligand. Aldosterone receptor blockade is safe and well tolerated in progressive murine lupus nephritis, and it results in decreased levels of clinical proteinuria, lower serum levels of autoantibodies, and decreased kidney damage. It appears to modulate inflammatory changes during the progression of glomerulonephritis and may also have a previously undescribed role in attenuating apoptosis.


Integrated RNA and DNA sequencing improves mutation detection in low purity tumors.
Identifying somatic mutations is critical for cancer genome characterization and for prioritizing patient treatment. DNA whole exome sequencing (DNA-WES) is currently the most popular technology; however, this yields low sensitivity in low purity tumors. RNA sequencing (RNA-seq) covers the expressed exome with depth proportional to expression. We hypothesized that integrating DNA-WES and RNA-seq would enable superior mutation detection versus DNA-WES alone. We developed a first-of-its-kind method, called UNCeqR, that detects somatic mutations by integrating patient-matched RNA-seq and DNA-WES. In simulation, the integrated DNA and RNA model outperformed the DNA-WES only model. Validation by patient-matched whole genome sequencing demonstrated superior performance of the integrated model over DNA-WES only models, including a published method and published mutation profiles. Genome-wide mutational analysis of breast and lung cancer cohorts (n = 871) revealed remarkable tumor genomics properties. Low purity tumors experienced the largest gains in mutation detection by integrating RNA-seq and DNA-WES. RNA provided greater mutation signal than DNA in expressed mutations. Compared to earlier studies on this cohort, UNCeqR increased mutation rates of driver and therapeutically targeted genes (e.g. PIK3CA, ERBB2 and FGFR2). In summary, integrating RNA-seq with DNA-WES increases mutation detection performance, especially for low purity tumors.


Quantitative correlation between susceptibility and OprJ production in NfxB mutants of Pseudomonas aeruginosa.
Various Pseudomonas aeruginosa PAO1 NfxB mutants were isolated on agar plates containing cefpirome and ofloxacin. They were classified into type A and type B, based on the degrees of changes in their susceptibilities. Type A mutants were four to eight times more resistant to ofloxacin, erythromycin, and new zwitterionic cephems, i.e., cefpirome, cefclidin, cefozopran, and cefoselis, than was the parent strain, PAO1. In contrast, type B mutants were more resistant to tetracycline and chloramphenicol, as well as ofloxacin, erythromycin, and the new zwitterionic cephems, than was PAO1, and they were four to eight times more susceptible to carbenicillin, sulbenicillin, imipenem, panipenem, biapenem, moxalactam, aztreonam, gentamicin, and kanamycin that was PAO1. The changes in susceptibilities of type B mutants were greater than those of type A mutants. The susceptibilities of both type A and type B mutants were restored to the level of PAO1 by transformation with plasmid pNF111, which contained the wild-type nfxB gene, demonstrating that they are NfxB mutants. Immunoblot analysis with a monoclonal antibody to OprJ revealed that type B mutants produced larger amounts of outer membrane protein OprJ than did type A mutants and that PAO1 produced an undetectable amount of it. Moreover, transconjugants obtained with the different types of NfxB mutants as the donor strains showed almost the same phenotypes as the corresponding donor strains. These results suggest that there are at least two nfxB mutations that show different phenotypes and that production of OprJ is associated with changes in susceptibilities of NfxB mutants.


Maternal Characteristics Affect Fetal Growth Response in the Women First Preconception Nutrition Trial.
The objective of this secondary analysis was to identify maternal characteristics that modified the effect of maternal supplements on newborn size. Participants included 1465 maternal-newborn dyads in Guatemala, India, and Pakistan. Supplementation commenced before conception (Arm 1) or late 1st trimester (Arm 2); Arm 3 received usual care. Characteristics included body mass index (BMI), stature, anemia, age, education, socio-economic status (SES), parity, and newborn sex. Newborn outcomes were z-scores for length (LAZ), weight (WAZ), and weight to length ratio-for-age (WLRAZ). Mixed-effect regression models included treatment arm, effect modifier, and arm * effect modifier interaction as predictors, controlling for site, characteristics, and sex. Parity (para-0 vs. para ≥1), anemia (anemia/no anemia), and sex were significant effect modifiers. Effect size (95% CI) for Arm 1 vs. 3 was larger for para-0 vs. ≥1 for all outcomes (LAZ 0.56 (0.28, 0.84, p < 0.001); WAZ 0.45 (0.20, 0.07, p < 0.001); WLRAZ 0.52 (0.17, 0.88, p < 0.01) but only length for Arm 2 vs. 3. Corresponding effects for para ≥1 were >0.02. Arm 3 z-scores were all very low for para-0, but not para ≥1. Para-0 and anemia effect sizes for Arm 1 were > Arm 2 for WAZ and WLRAZ, but not LAZ. Arm 1 and 2 had higher WAZ for newborn boys vs. girls. Maternal nulliparity and anemia were associated with impaired fetal growth that was substantially improved by nutrition intervention, especially when commenced prior to conception.


SynSeg-Net: Synthetic Segmentation Without Target Modality Ground Truth.
A key limitation of deep convolutional neural networks (DCNN) based image segmentation methods is the lack of generalizability. Manually traced training images are typically required when segmenting organs in a new imaging modality or from distinct disease cohort. The manual efforts can be alleviated if the manually traced images in one imaging modality (e.g., MRI) are able to train a segmentation network for another imaging modality (e.g., CT). In this paper, we propose an end-to-end synthetic segmentation network (SynSeg-Net) to train a segmentation network for a target imaging modality without having manual labels. SynSeg-Net is trained by using (1) unpaired intensity images from source and target modalities, and (2) manual labels only from source modality. SynSeg-Net is enabled by the recent advances of cycle generative adversarial networks (CycleGAN) and DCNN. We evaluate the performance of the SynSeg-Net on two experiments: (1) MRI to CT splenomegaly synthetic segmentation for abdominal images, and (2) CT to MRI total intracranial volume synthetic segmentation (TICV) for brain images. The proposed end-to-end approach achieved superior performance to two stage methods. Moreover, the SynSeg-Net achieved comparable performance to the traditional segmentation network using target modality labels in certain scenarios. The source code of SynSeg-Net is publicly available 2.


MIC and MBC of Honey and Gold Nanoparticles against methicillin-resistant (MRSA) and vancomycin-resistant (VRSA) coagulase-positive S. aureus isolated from contagious bovine clinical mastitis.
Staphylococcus aureus is one of the major causative agents of the bovine clinical mastitis. This study aimed to isolate and identify S. aureus from cases of bovine clinical mastitis followed by phenotypic detection of MRSA and VRSA. The genotypic detection of MRSA was done through PCR detection of the resistance mecA gene. Furthermore, this study aimed to investigate the in vitro MIC and MBC of the Dodonaea angustifolia plant extract, Honey, and AuNPs against the clinically isolated MRSA and VRSA. Of 93 mastitis milk samples examined, 54 (58.1%) S. aureus were isolated and identified {CP S. aureus = 46 (85.2%) and CN S. aureus = 8 (14.8%)}. The whole MRSA, VRSA, MSSA, and VSSA detected were 19 (35.2%), 7 (13%), 35 (65%), and 47 (87%) respectively. The mean counts of S. aureus were between 8.6 × 104 ± 3.5 × 105 CFU/ml. The oxacillin and vancomycin MICs against MRSA and VRSA respectively, were >256 µg/ml. AuNPs sized 30 nm produce observable in vitro anti-MRSA and anti-VRSA activities. Imtenan® citrus blossom honey has also antibacterial activities against MRSA and VRSA with general MBC and MIC range values were observed at a concentration of 0.625, 1.25, 2.5, and 5 (%v/v). In the present study, the most significant result obtained when AuNPs was mixed with Imtenan® citrus blossom honey (1:1 = v:v) with the best MBC was observed at the concentration of 0.56 × 109:0.3 (NP/ml: honey %v/v).


Prevalence of Bovine Viral Diarrhoea Virus (BVDV), Bovine Herpes Virus 1 (BHV 1), Leptospirosis and Neosporosis, and associated risk factors in 161 Irish beef herds.
There are limited data available, in Ireland or elsewhere, to determine the extent of exposure to various endemic diseases among beef cows and factors associated with exposure to causative pathogens. The objectives of this study were to determine the herd and within herd prevalence of Bovine Viral Diarrhoea Virus (BVDV), Bovine Herpes Virus 1 (BHV-1), Leptospirosis and Neosporosis in a large scale study of commercial beef herds on the island of Ireland, and to examine herd level factors associated with exposure to these pathogens in these herds. The average number of cows tested per herd was 35.5 (median 30). Herd level seroprevalence to Bovine Herpesvirus-1(BHV-1), Bovine Viral-Diarrhoea Virus (BVDV), Leptospirosis and Neosporosis was 90%, 100%, 91% and 67%, respectively, while the mean within herd prevalence for the these pathogens was 40%, 77.7%, 65.7% and 5.7%, respectively. The study confirms that the level of seroconversion for the four pathogens of interest increases with herd size. There was also evidence that exposure to one pathogen may increase the risk of exposure to another pathogen. Herd level seroprevalences were in excess of 90% for BVDV, BHV-1 and Leptosporosis. Larger herds were subject to increased exposure to disease pathogens. This study suggests that exposure to several pathogens may be associated with the further exposure to other pathogens.


Brazilian adults' sedentary behaviors by life domain: population-based study.
There is rapidly-emerging evidence on the harmful health effects of sedentary behaviors. The aim of this paper was to quantify time in sedentary behaviors and document socio-demographic variations in different life domains among adults. A population-based survey was carried out in 2012 through face-to-face interviews with Brazilian adults aged 20+ years (N = 2,927). Information about time spent sedentary in a typical weekday was collected for five different domains (workplace, commuting, school/university, watching TV, and computer use at home). Descriptive and bivariate analyses examined variations in overall and domain-specific sedentary time by gender, age, educational attainment and socioeconomic position. On average, participants reported spending 5.8 (SD 4.5) hours per day sitting. The median value was 4.5 (interquartile range: 2.5-8) hours. Men, younger adults, those with higher schooling and from the wealthiest socioeconomic groups had higher overall sedentary scores. TV time was higher in women, older adults and among those with low schooling and socioeconomic position. Sedentary time in transport was higher in men, younger adults, and participants with high schooling and high socioeconomic position. Computer use at home was more frequent among young adults and those from high socioeconomic groups. Sitting at work was higher in those with higher schooling and from the wealthiest socioeconomic groups. Sedentary behavior at school was related inversely to age and directly to schooling. Patterns of sedentary behavior are different by life domains. Initiatives to reduce prolonged sitting among Brazilian adults will be required on multiple levels for different life domains.


Formalization and computation of quality measures based on electronic medical records.
Ambiguous definitions of quality measures in natural language impede their automated computability and also the reproducibility, validity, timeliness, traceability, comparability, and interpretability of computed results. Therefore, quality measures should be formalized before their release. We have previously developed and successfully applied a method for clinical indicator formalization (CLIF). The objective of our present study is to test whether CLIF is generalizable--that is, applicable to a large set of heterogeneous measures of different types and from various domains. We formalized the entire set of 159 Dutch quality measures for general practice, which contains structure, process, and outcome measures and covers seven domains. We relied on a web-based tool to facilitate the application of our method. Subsequently, we computed the measures on the basis of a large database of real patient data. Our CLIF method enabled us to fully formalize 100% of the measures. Owing to missing functionality, the accompanying tool could support full formalization of only 86% of the quality measures into Structured Query Language (SQL) queries. The remaining 14% of the measures required manual application of our CLIF method by directly translating the respective criteria into SQL. The results obtained by computing the measures show a strong correlation with results computed independently by two other parties. The CLIF method covers all quality measures after having been extended by an additional step. Our web tool requires further refinement for CLIF to be applied completely automatically. We therefore conclude that CLIF is sufficiently generalizable to be able to formalize the entire set of Dutch quality measures for general practice.


Molecular phylogeny and systematics of native North American lumbricid earthworms (Clitellata: Megadrili).
The family Lumbricidae is arguably the most well-known and well-studied earthworm group due to its dominance in the European earthworm fauna and its invasion in temperate regions worldwide. However, its North American members, especially the genus Bimastos Moore, 1893, are poorly understood. We revised the systematics of the genus Bimastos and tested the hypothesis of the monophyly of North American lumbricids using morphological characters and eight molecular markers. Phylogenetic analyses based on our extensive sampling of Bimastos and inclusion of Dendrodrilus and Allolobophoridella indicated a well-supported clade containing Bimastos and Eisenoides Gates, 1969, and provided the first evidence supporting that North American lumbricids are monophyletic. Assuming the available divergence time estimations and dating of land bridges are correct, it would suggest that the ancestor of this clade arrived North America through Beringia or the De Geer route during Late Cretaceous, and since then the clade has diverged from its Eurasian sister group, Eisenia. The peregrine genera Dendrodrilus and Allolobophoridella are nested within the Bimastos clade; we propose to treat them as junior synonyms of the genus Bimastos, and, contradictory to the commonly held belief of being European, they are indeed part of the indigenous North American earthworm fauna. Morphological characters, such as red-violet pigmentation, proclinate U-shaped nephridial bladders and calciferous diverticula in segment 10 further support this placement. The East Mediterranean-Levantine Spermophorodrilus Bouché, 1975 and Healyella Omodeo & Rota, 1989 are nested within the Dendrobaena sensu lato clade; therefore their close relationship with the North American Bimastos is refuted. Species fit the revised diagnosis of Bimastos are reviewed and keyed, and a new species, Bimastos schwerti sp. nov., is described.


KRAS and EGFR Amplifications Mediate Resistance to Rociletinib and Osimertinib in Acquired Afatinib-Resistant NSCLC Harboring Exon 19 Deletion/T790M in EGFR.
The critical T790M mutation in EGFR, which mediates resistance to first- and second-generation EGFR tyrosine kinase inhibitors (TKI; gefitinib, erlotinib, and afatinib), has facilitated the development of third-generation mutation-selective EGFR TKIs (rociletinib and osimertinib). We previously reported heterogeneous afatinib-resistant mechanisms, including emergence of T790M-EGFR, and responses to third-generation EGFR TKIs. Here, we used afatinib-resistant lung adenocarcinoma cells [AfaR (formerly AFR3) cells], carrying exon 19 deletion/T790M in EGFR To identify the novel resistance mechanisms in post-afatinib treatment, RocR1/RocR2 and OsiR1/OsiR2 cells were established using increasing concentrations of rociletinib and osimertinib, respectively. Attenuation of exon 19 deletion and T790M was confirmed in both rociletinib-resistant cells; in addition, EGFR and KRAS amplification was observed in RocR1 and RocR2, respectively. Significant KRAS amplification was observed in the osimertinib-resistant cell lines, indicating a linear and reversible increase with increased osimertinib concentrations in OsiR1 and OsiR2 cells. OsiR1 cells maintained osimertinib resistance with KRAS amplification after osimertinib withdrawal for 2 months. OsiR2 cells exhibited KRAS attenuation, and osimertinib sensitivity was entirely recovered. Phospho-EGFR (Y1068) and growth factor receptor-bound protein 2 (GRB2)/son of sevenless homolog 1 (SOS1) complex was found to mediate osimertinib resistance in OsiR1 cells with sustained KRAS activation. After 2 months of osimertinib withdrawal, this complex was dissociated, and the EGFR signal, but not the GRB2/SOS1 signal, was activated. Concomitant inhibition of MAPK kinase and EGFR could overcome osimertinib resistance. Thus, we identified a heterogeneous acquired resistance mechanism for third-generation EGFR TKIs, providing insights into the development of novel treatment strategies.


Development of pattern ERG and pattern VEP spatial resolution in kittens with unilateral esotropia.
To follow the development of strabismic amblyopia longitudinally by comparing mean amplitudes and the visual spatial resolving ability of retinal and cortical pattern responses at various stages of postnatal development in unilateral iatrogenic convergent strabismic kittens. Surgery to produce iatrogenic convergent strabismus was performed on 20 kittens at 3 weeks of age; three kittens were used for controls. The monocular transient pattern electroretinogram (PERG) and pattern visual evoked potential (PVEP) were recorded simultaneously on the 23 kittens throughout development. The PVEPs of the strabismic eyes were very reduced at 4 to 5 postnatal weeks (P < 0.01). The reduction increased at 6 to 16 weeks but was even worse at 17 to 30 weeks. The PERG of the squinting eye showed only a slight reduction in the first 4 to 5 weeks of age (P > 0.05), the decrease of responses was significant (P < 0.01) at 6 to 16 weeks and 17 to 30 weeks. At 4 to 8 weeks of age, the PVEP evoked through the unoperated eye in kittens consisted mainly of two positive components of similar amplitude. During development, the slow component decreased in comparison to the fast one, and its peak shifted forward until it merged into the fast (P100) component. Esotropic amblyopia did affect the PERG and the PVEP in the amblyopic eye, but the effect on the PERG was less severe, had slower onset, and did not continue as long as for the PVEP.


The role and regulation of complement activation as part of the thromboinflammation elicited in cell therapies.
Cell therapies in which the cells come into direct contact with blood and other body fluids are emerging treatment procedures for patients with various diseases, such as diabetes mellitus, liver insufficiency, and graft-versus-host disease. However, despite recent progress, these procedures are associated with tissue loss caused by thromboinflammatory reactions. These deleterious reactions involve the activation of the complement and coagulation cascades and platelet and leukocyte activation, ultimately resulting in clot formation and damage to the implanted cells. In this concept review, we discuss the basic mechanisms underlying the thrombininflammatory process, with special reference to the engagement of complement and emerging strategies for the therapeutic regulation of these reactions that include the use of selective systemic inhibitors and various procedures to coat the surfaces of the cells. The coating procedures may also be applied to other treatment modalities in which similar mechanisms are involved, including whole organ transplantation, treatment with biomaterials in contact with blood, and extracorporeal procedures.


Three-Dimensional Paper-Based Microfluidic Analytical Devices Integrated with a Plasma Separation Membrane for the Detection of Biomarkers in Whole Blood.
Paper-based microfluidic analytical devices (μPADs) have recently attracted attention as a point-of-care test kit because of their low cost and nonrequirement for external forces. To directly detect biomarkers in whole blood, however, they need to be assembled with a filter such as a plasma separation membrane (PSM) because the color of the blood cells interferes with the colorimetric assay. However, this assembly process is rather complicated and cumbersome, and the fluid does not uniformly move to the detection zone when the adhesion between the paper and PSM is not perfect. In this study, we report a simple three-dimensional (3D) printing method for fabricating PSM-integrated 3D-μPADs made of plastics without the need for additional assembly. In detail, PSM was coated with parylene C to prevent its dissolution from organic solvent during 3D printing. Then, the coated PSM was superimposed on the paper. Detection zones and a reservoir were printed on the paper and PSM via liquid photopolymerization, using a digital light processing printer. The limit of detection of the PSM-integrated 3D-μPADs for glucose in whole blood was 0.3 mM, and these devices demonstrated clinically relevant performance on diabetes patient blood samples. Our 3D-μPADs can also simultaneously detect multiple metabolic disease markers including glucose, cholesterol, and triglycerides in whole blood. Our results suggest that our printing method is useful for fabricating 3D-μPADs integrated with PSM for the direct detection of biomarkers in whole blood.


Mothering a child with hidden impairments.
When a mother has a child with a chronic impairment, the occupational demands of mothering extend to address the specialized needs of that child. This research explores how the type of hidden impairment in a child influences family routines and occupations. This qualitative study consisted of interviews with 22 mothers of children with attention deficit hyperactivity disorder (ADHD), a behavioral disorder, and 22 mothers of children with cystic fibrosis, a physical disorder. Open-ended questions were used to explore family demands, resources, time use, routines, concerns, and support. The transcripts of these interviews were analyzed in terms of consistency with existing literature on parenting the child with hidden disability, and for emergent themes. In this analysis the experiences of mothers of children with cystic fibrosis were consistent with research findings on other chronic conditions, with these mothers reporting that family provides them with extensive physical and emotional support. Although mothers of children with cystic fibrosis reported a persistent emotional sorrow, they felt they were able to "normalize" their daily routines. In contrast, mothers of children with ADHD reported little family support, high perception of child-related demands, and less confidence in their success in mothering these children. In describing their daily routines, these mothers often stated that there was no such thing as a "normal" day. They felt constantly "on alert" and did not feel that they had "normal" routines. Based on this study, mothers of children with ADHD felt distress because their child did not easily conform to social standards, and were likely to express exhaustion in their role as "mother." The pattern of responses offered by these participants differs significantly from that of the participants whose children have cystic fibrosis, and from the usual pattern of coping with chronic childhood disability documented in the literature.


Localized Ewing sarcoma of the tibia.
Ewing sarcoma (ES) is a high-grade malignant primary round cell tumour of bone in which there is commonly extension into extraosseous soft tissues at the time of diagnosis. This report details the clinical, radiological and pathological features of a case of ES of the tibia in which there was extensive osseous involvement but no infiltration beyond the periosteum into surrounding soft tissue. We also record the findings of one other ES case that exhibited similar behaviour. Both cases were male, involved the tibia and had the characteristic t (11;22) (q24;q12) translocation. No recurrence of tumour or metastasis has been seen in these two cases, both of which have had 6 years follow-up. Our findings indicate that there is heterogeneity in the behaviour of ES and show that localized ES is associated with a good prognosis.


Unresolved issues in the first five years of the rubella immunization program.
Despite extensive use of atttenuated rubella vaccine during the past five years, the degree of fetal risk in susceptible women inoculated early in pregnancy is still an unresolved issue. Although there is considerable evidence of chronic vaccine virus infection of the products of gestation in aborted fetuses, congenital defects have not yet been reported in the newborn infants of susceptible vaccinated pregnant women. The normal findings in the newborn infant can be misleading with respect to the safety of the vaccines in early pregnancy, because they represent only a small selected group of reported cases. The immediate need is for more complete reporting of all relevant cases wherever they occur in order to determine without many more years of delay whether the fetal risk has public health significance or is so low as to be of negligible importance.


Cardiovascular fat in women at midlife: effects of race, overall adiposity, and central adiposity. The SWAN Cardiovascular Fat Study.
Cardiovascular fat (CF) is associated with greater coronary heart disease (CHD) risk. Postmenopausal women have greater CF volumes than premenopausal women, and the association between specific CF depot volumes and CHD risk is more pronounced after menopause. Race, central adiposity, and visceral adiposity are important factors that could impact CF volumes. Whether racial differences in CF volumes and in their associations with central (visceral fat [VAT]) and general adiposity (body mass index [BMI]) exist in midlife women have not been addressed before. In all, 524 participants from the Study of Women's Health Across the Nation (mean age: 50.9 ± 2.9 years; 62% White and 38% Black) who had data on CF volumes (epicardial fat [EAT], paracardial fat [PAT], total heart fat, and aortic perivascular fat), VAT, and BMI were studied. In models adjusted for age, study site, menopausal status, comorbid conditions, alcohol consumption, and physical activity, Black women had 19.8% less EAT, 24.5% less PAT, 20.4% less total heart fat, and 13.2% less perivascular fat than White women (all P < 0.001). These racial differences remained significant after additional adjustment for BMI or VAT. Race significantly modified associations between adiposity measures and CF volumes. Every 1-SD higher BMI was associated with 66.7% greater PAT volume in White compared with 42.4% greater PAT volume in Black women (P = 0.004), whereas every 1-SD higher VAT was associated with 32.3% greater EAT volume in Black compared with 25.3% greater EAT volume in White women (P = 0.039). Racial differences were found in CF volumes and in their associations with adiposity measures among midlife women. Future research should determine how race-specific changes in CF volumes impact CHD risk in women.


Applying 'omics technologies in chemicals risk assessment: Report of an ECETOC workshop.
Prevailing knowledge gaps in linking specific molecular changes to apical outcomes and methodological uncertainties in the generation, storage, processing, and interpretation of 'omics data limit the application of 'omics technologies in regulatory toxicology. Against this background, the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) convened a workshop Applying 'omics technologies in chemicals risk assessment that is reported herein. Ahead of the workshop, multi-expert teams drafted frameworks on best practices for (i) a Good-Laboratory Practice-like context for collecting, storing and curating 'omics data; (ii) the processing of 'omics data; and (iii) weight-of-evidence approaches for integrating 'omics data. The workshop participants confirmed the relevance of these Frameworks to facilitate the regulatory applicability and use of 'omics data, and the workshop discussions provided input for their further elaboration. Additionally, the key objective (iv) to establish approaches to connect 'omics perturbations to phenotypic alterations was addressed. Generally, it was considered promising to strive to link gene expression changes and pathway perturbations to the phenotype by mapping them to specific adverse outcome pathways. While further work is necessary before gene expression changes can be used to establish safe levels of substance exposure, the ECETOC workshop provided important incentives towards achieving this goal.


Patient-reported outcomes in meta-analyses-part 2: methods for improving interpretability for decision-makers.
Systematic reviews and meta-analyses of randomized trials that include patient-reported outcomes (PROs) often provide crucial information for patients, clinicians and policy-makers facing challenging health care decisions. Based on emerging methods, guidance on improving the interpretability of meta-analysis of patient-reported outcomes, typically continuous in nature, is likely to enhance decision-making. The objective of this paper is to summarize approaches to enhancing the interpretability of pooled estimates of PROs in meta-analyses. When differences in PROs between groups are statistically significant, decision-makers must be able to interpret the magnitude of effect. This is challenging when, as is often the case, clinical trial investigators use different measurement instruments for the same construct within and between individual randomized trials. For such cases, in addition to pooling results as a standardized mean difference, we recommend that systematic review authors use other methods to present results such as relative (relative risk, odds ratio) or absolute (risk difference) dichotomized treatment effects, complimented by presentation in either: natural units (e.g. overall depression reduced by 2.4 points when measured on a 50-point Hamilton Rating Scale for Depression); minimal important difference units (e.g. where 1.0 unit represents the smallest difference in depression that patients, on average, perceive as important the depression score was 0.38 (95% CI 0.30 to 0.47) units less than the control group); or a ratio of means (e.g. where the mean in the treatment group is divided by the mean in the control group, the ratio of means is 1.27, representing a 27% relative reduction in the mean depression score).


Myeloid cell-specific deletion of epidermal growth factor receptor aggravates acute cardiac injury.
Myeloid cells, including macrophages, play important roles as first responders to cardiac injury and stress. Epidermal growth factor receptor (EGFR) has been identified as a mediator of macrophage responsiveness to select diseases, though its impact on cardiac function or remodeling following acute ischemic injury is unknown. We aimed to define the role of myeloid cell-specific EGFR in the regulation of cardiac function and remodeling following acute myocardial infarction (MI)-induced injury. Floxed EGFR mice were bred with homozygous LysM-Cre (LMC) transgenic mice to yield myeloid-specific EGFR knockout (mKO) mice. Via echocardiography, immunohistochemistry, RNA sequencing and flow cytometry, the impact of myeloid cell-specific EGFR deletion on cardiac structure and function was assessed at baseline and following injury. Compared with LMC controls, myeloid cell-specific EGFR deletion led to an increase in cardiomyocyte hypertrophy at baseline. Bulk RNASeq analysis of isolated cardiac Cd11b+ myeloid cells revealed substantial changes in mKO cell transcripts at baseline, particularly in relation to predicted decreases in neovascularization. In response to myocardial infarction, mKO mice experienced a hastened decline in cardiac function with isolated cardiac Cd11b+ myeloid cells expressing decreased levels of the pro-reparative mediators Vegfa and Il10, which coincided with enhanced cardiac hypertrophy and decreased capillary density. Overall, loss of EGFR qualitatively alters cardiac resident macrophages that promotes a low level of basal stress and a more rapid decrease in cardiac function along with worsened repair following acute ischemic injury.


Effect of progesterone elevation in follicular phase of IVF-cycles on the endometrial receptivity.
The premature rise of progesterone during the late follicular phase in stimulated IVF cycles is a frequent event, and emerging evidence shows that premature progesterone rise does negatively affect the outcome of assisted reproductive techniques. The effect of elevated peripheral progesterone levels in the late follicular phase seems to be on the endometrium and the window of implantation, which may lead to asynchrony between the endometrium and the developing embryo. In stimulated cycles, endometrial maturation is advanced on the day of oocyte retrieval, and patients with a progesterone level above 1.5 ng/ml on the day of final oocyte maturation have different endometrial gene expression profiles. This progesterone level seems to represent the critical threshold, at which a negative effect on the ongoing pregnancy rate in fresh IVF cycles can be observed. Moreover, no association exists between progesterone elevation in the fresh cycle, and the probability of pregnancy after transfer of frozen-thawed embryos, originating from that cycle. The causes of premature progesterone elevation during ovarian stimulation are still unclear; however, recent studies point towards enhanced FSH-stimulation as a cause for progesterone elevation.


Learning from people with long-term conditions: new insights for governance in primary healthcare.
The introduction of top-down centrally driven solutions to governance of healthcare, at the same time as increasing policy emphasis on greater 'bottom up' patient and public involvement in all aspects of healthcare, has set up complex tensions for policy implementation and healthcare practice. This paper explores the interplay of these agendas in the context of changes in primary healthcare services provided by the National Health Service in England. Specifically, it looks at service user involvement in a qualitative study of the professional response to changes in the governance and incentives in the care of people with long-term conditions. Service users influenced and guided the study at local and national levels. Vignettes of patient stories developed by service users informed in-depth interviews with 56 health and social care professionals engaged in the development of local policies and services for people with complex long-term illness, and themes generated by cross case analysis were validated through service users. The findings presented here focus on four themes about risk and comparison of professionals' and service users' perspectives of the issues: managing risks/consistent support, the risks of letting go/feeling in control, professional identity/helping people to help themselves, and managing expectations/professionals losing out. In this study, service user involvement added value by validating understandings of governance, framing debates to focus on what matters at the point of care and enabling perspective sharing and interaction. We suggest that more collaborative forms of governance in healthcare that take account of service user perspectives and enable interaction with professional groups could help validate processes of quality assurance and provide motivation for continuous quality improvement. We offer a model for 'opening up' collaborative projects to evaluation and critical reflection of the interrelationships between the context, methods and outcomes of service user involvement.


A differential diagnosis for left atrial mass on transthoracic echocardiography: hiatus hernia.
Hiatus hernia is a common medical condition. An elderly woman being investigated for dyspnoea of unknown aetiology had a transthoracic echocardiogram as part of her investigations. This alarmingly demonstrated a large left atrial mass. Further assessment with cardiac magnetic resonance imaging revealed a large hiatus hernia compressing the left atrium and no intra-cardiac mass. The case succinctly highlights gastrointestinal pathology simulating cardiac symptoms and masses.


Correlates of expected positive and negative support for smoking cessation among a sample of chronically ill veterans.
To examine demographic, relationship, and smoking history factors related to expected positive and negative support for quitting smoking among chronically ill veterans. Data for this report comes from baseline data from a randomized controlled trial of a support-based smoking cessation intervention for veterans with chronic diseases (cancer, cardiovascular disease, hypertension, diabetes, and chronic obstructive pulmonary disease). We used separate multiple linear regression models to analyze relationships between positive and negative support and variables selected for model entry. Veterans in our sample expected high positive and negative support for quitting. Veterans who were married/living as married, had some college education, were female, or named a female support person expected higher levels of positive support. Veterans who named a female or a nonsmoker as a support person expected higher levels of negative support. Males and non-Caucasians also reported higher levels of expected negative support. Individual differences that influence perceptions of expected support are likely to influence intervention participation and engagement. Thus, understanding factors associated with expected positive and negative support is necessary to optimize future implementation of support-based cessation interventions through better treatment matching.


Role of endogenous prostaglandin E2 in erythropoietin production and dome formation by human renal carcinoma cells in culture.
Studies were carried out on the role of endogenous prostaglandin E2 (PGE2) in erythropoietin (Ep) production and dome formation in primary monolayer cultures of a human renal carcinoma from a patient with erythrocytosis that has been serially transplanted into BALB/c athymic nude mice. The metabolism of [14C]arachidonic acid (14C-AA) by cultured renal carcinoma cells, which were plated in 25-cm2 flasks at a density of 2 X 10(4) cells/cm2 and grown for 6, 12 (confluence, 13 X 10(4) cells/cm2), 16, 24, and 30 d in Eagle's minimum essential medium (MEM) supplemented with 10% fetal bovine serum, was examined by using radiometric thin-layer chromatography (TLC). TLC revealed PGE2 to be the major metabolite of 14C-AA produced by the cultured cells throughout the 30 d of cultivation. In addition, the cultured cells at each time period were incubated for 24 h in 5 ml of serum-free Eagle's MEM and the levels of PGE2 and Ep in the incubated media were measured via radioimmunoassay. PGE2 levels in the serum-free media incubated with the cultured cells grown for 6 d were significantly (P less than 0.001) elevated (174 +/- 2.5 pg/ml, n = 5), compared with the unincubated control media (1.5 +/- 0.19 pg/ml, n = 5) and gradually decreased at each time period to 97.6 +/- 4.4 pg/ml (n = 5) at 30 d. On the other hand, the levels of Ep in the incubated media of the cells grown for 6 d were 11.5 +/- 0.52 mU/ml (n = 5) compared with 7.6 +/- 0.62 mU/ml (n = 5) in the control media. However, after the cultured cells became confluent, the levels of Ep in the incubated media showed a marked increase to 222.9 +/- 5.26 mU/ml (n = 5) at 30 d of cultivation. Multicellular hemicysts (domes) developed after the cultured cells reached confluence and their numbers increased with increasing time in confluence in parallel with the increase in Ep. Meclofenamate (MF) (3 X 10(-6)-3 X 10(-5) M), a prostaglandin synthesis inhibitor, produced a significant dose-related decrease in PGE2, Ep, and dome formation without producing a significant effect on cell viability in the 30-d cells. This inhibitory effect of MF on Ep production and dome formation was completely abolished by the addition of 10(-8) M PGE2 to the incubation medium. In conclusion, endogenous PGE2 plays an important role in supporting and/or stimulating Ep production and dome formation in cultured renal carcinoma cells.


Structures, metal ion affinities, and fluorescence properties of soluble derivatives of tris((6-phenyl-2-pyridyl)methyl)amine.
Metal complexes of tris((6-phenyl-2-pyridyl)methyl)amine (2) have hydrophobic cavities that potentially accommodate small molecules. However, the utility of this attractive motif has been hampered by the poor solubility of such complexes in many common solvents. In this study, two tripodal ligands (3, tris-[6-(3,4,5-trimethoxy-phenyl)-pyridin-2-ylmethyl]-amine, and 4, tris((6-(3,4,5-tris(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)pyridin-2-yl)methyl)amine) derived from 2 were prepared with enhanced solubility in organic and aqueous solvents. The X-ray crystallographic analyses of selected ligands and complexes revealed that the hydrophobic cavities inside the zinc complexes were retained after derivatization. Fluorescence, nuclear magnetic resonance (NMR), and potentiometric titration studies, which were enabled by the improved solubility, were performed to investigate the binding properties of the soluble ligands (3 and 4) with metal ions such as Zn(2+) and Cu(2+). When saturating quantities of Zn(2+) ions are added to ligand 3 in acetonitrile, the fluorescence emission maximum exhibits a pronounced red shift of approximately 80 nm (from 376 to 457 nm) and is enhanced by a factor of >100 when measured at 520 nm. The fluorescence properties of the Zn(2+) ion-coordinated ligands in the Zn(3) complex are consistent with a charge-transfer character in the excited state, with possible contributions from a planarization of the pyridyl-trimethoxyphenyl groups in the excited state, and from excitonic interactions.


Alcohol and error processing.
A recent study indicates that alcohol consumption reduces the amplitude of the error-related negativity (ERN), a negative deflection in the electroencephalogram associated with error commission. Here, we explore possible mechanisms underlying this result in the context of two recent theories about the neural system that produces the ERN - one based on principles of reinforcement learning and the other based on response conflict monitoring.


Estrogen Receptor Status Predicts Late-Onset Skeletal Recurrence in Breast Cancer Patients.
Estrogen receptor-positive (ER+) breast cancer (BCa) often recurs after long latency, and is known to favor bone as a metastatic site. We hypothesized that skeletal recurrence of ER+ BCa follows a different chronological pattern from that of nonskeletal recurrence.We retrospectively evaluated 434 matched pairs of ER+ and ER- female patients who underwent surgery for clinically localized BCa between 2005 and 2009. Patient age, tumor size, lymph node involvement, and adjuvant treatment biases were adjusted by the propensity score method. We conducted competing risk analysis to determine the prognostic significance of ER expression status on the risk of overall recurrence and late recurrence (after 3 years). We also compared chronological patterns of ER+ and ER- tumor recurrence, stratified by the first metastatic site (skeletal vs nonskeletal).After 3 postoperative years, ER+ tumor had a significantly higher risk of overall distant recurrence than ER- tumor (P = 0.02). When further stratified by first site of metastasis, only late skeletal recurrence was significantly associated with ER status (P = 0.029). In multivariate analysis, ER and lymph node involvement status were significant prognostic factors for late skeletal recurrence, with adjusted hazard ratios of 5.2 (95% CI = 1.2-22.4, P = 0.025) and 5.2 (1.7-16.3, P = 0.005), respectively. For nonskeletal distant recurrence, tumor size (>2 cm) was the only significant risk factor with adjusted hazard ratio of 2.8 (1.4-5.7, P = 0.005). Annual hazard of skeletal recurrence events of ER+ tumors continued to exist up to 10 years, while annual hazard of nonskeletal recurrences decreased after peaking at 5 years. ER- tumor recurrences exhibited similar annual hazard patterns across skeletal and nonskeletal sites.ER expression and lymph node involvement status were strong predictors of BCa late-onset (>3 years) recurrences, especially in skeletal sites. Therefore, skeletal system surveillance is mandatory for long-term follow-up of this subpopulation.


Change in teachers' ratings of attention problems and subsequent change in academic achievement: a prospective analysis.
Recent research has documented a link between attention problems at school entry and later academic achievement. Little is known about the association of change in attention problems during the early school years with subsequent change in academic achievement. A community-based cohort was followed up and assessed for attention problems at ages 6 and 11 (Teacher Report Form; TRF) and for academic achievement in math and reading at ages 11 and 17 (Woodcock-Johnson Psycho-Educational Battery). Complete data were available on 590 children (72% of the initial sample). Ordinary least squares regressions were used to estimate change in academic achievement from age 11 to age 17 in relation to change in TRF-attention problems from age 6 to age 11. Children's IQ and family factors were statistically controlled. Change in teachers' ratings of attention problems from age 6 to age 11 was negatively associated with change in math and reading from age 11 to age 17, controlling for children's IQ and family factors. Externalizing problems had no significant association with change in math or reading, when added to the multivariable model. Increases in teacher-rated attention problems from age 6 to age 11 were followed by declines in academic achievement from age 11 to age 17; decreases were followed by gains. The results underscore the need for research on the course of attention problems, the testing of interventions to address children's early attention problems and the evaluation of their effects on subsequent academic achievement.