ErbB1/2 tyrosine kinase inhibitor mediates oxidative stress-induced apoptosis in inflammatory breast cancer cells.
Overexpression of epidermal growth factor receptors (ErbB) is frequently seen in inflammatory breast cancer (IBC). Treatment with ErbB1/2-targeting agents (lapatinib) mediates tumor apoptosis by downregulating ErbB1/2 phosphorylation and downstream survival signaling. In this study, using carboxy-H(2)DCFDA, DHE, and MitoSOX Red to examine changes in hydrogen peroxide radicals, cytoplasmic and mitochondrial superoxide, respectively, we observed that GW583340 (a lapatinib-analog) increases reactive oxygen species (ROS) in two models of IBC (SUM149, SUM190) that are sensitive to ErbB1/2 blockade. This significant increase in ROS levels was similar to those generated by classical oxidative agents H(2)O(2) and paraquat. In contrast, minimal to basal levels of ROS were measured in a clonal population of GW583340-resistant IBC cells (rSUM149 and rSUM190). The GW583340-resistant IBC cells displayed increased SOD1, SOD2, and glutathione expression, which correlated with decreased sensitivity to the apoptotic-inducing effects of GW583340, H(2)O(2), and paraquat. The ROS increase and cell death in the GW583340-sensitive cells was reversed by simultaneous treatment with a superoxide dismutase (SOD) mimic. Additionally, overcoming the high levels of antioxidants using redox modulators induced apoptosis in the GW583340-resistant cells. Taken together, these data demonstrate a novel mechanism of lapatinib-analog-induced apoptosis and indicate that resistant cells have increased antioxidant potential, which can be overcome by treatment with SOD modulators.


Community-centered responses to Ebola in urban Liberia: the view from below.
The West African Ebola epidemic has demonstrated that the existing range of medical and epidemiological responses to emerging disease outbreaks is insufficient, especially in post-conflict contexts with exceedingly poor healthcare infrastructures. In this context, community-based responses have proven vital for containing Ebola virus disease (EVD) and shifting the epidemic curve. Despite a surge in interest in local innovations that effectively contained the epidemic, the mechanisms for community-based response remain unclear. This study provides baseline information on community-based epidemic control priorities and identifies innovative local strategies for containing EVD in Liberia. This study was conducted in September 2014 in 15 communities in Monrovia and Montserrado County, Liberia--one of the epicenters of the Ebola outbreak. Findings from 15 focus group discussions with 386 community leaders identified strategies being undertaken and recommendations for what a community-based response to Ebola should look like under then-existing conditions. Data were collected on the following topics: prevention, surveillance, care-giving, community-based treatment and support, networks and hotlines, response teams, Ebola treatment units (ETUs) and hospitals, the management of corpses, quarantine and isolation, orphans, memorialization, and the need for community-based training and education. Findings have been presented as community-based strategies and recommendations for (1) prevention, (2) treatment and response, and (3) community sequelae and recovery. Several models for community-based management of the current Ebola outbreak were proposed. Additional findings indicate positive attitudes towards early Ebola survivors, and the need for community-based psychosocial support. Local communities' strategies and recommendations give insight into how urban Liberian communities contained the EVD outbreak while navigating the systemic failures of the initial state and international response. Communities in urban Liberia adapted to the epidemic using multiple coping strategies. In the absence of health, infrastructural and material supports, local people engaged in self-reliance in order to contain the epidemic at the micro-social level. These innovations were regarded as necessary, but as less desirable than a well-supported health-systems based response; and were seen as involving considerable individual, social, and public health costs, including heightened vulnerability to infection.


[The characteristics of the clinical picture and treatment of patients with acute kidney failure in obstetrical pathology].
The examination of 45 patients with acute renal failure (ARF) caused by obstetric problems identified 3 types of its clinical course: 1) "pure" ARF; 2) ARF in the presence of sepsis, and 3) ARF in the presence of exogenous intoxication. Types 2 and 3 were more severe and showed higher mortality rates. The average number of hemodialysis sessions per patient was 2.4, 3.6, and 9.8 with types 1, 2, and 3, respectively. The treatment was of multimodality, including suppurative focus debridement, therapeutic measures, hemodialysis, and hyperbaric oxygenation; with types 2 and 3 efforts were made to combat sepsis, hemodynamic and coagulative abnormalities, multiorgan failure. The operative risk during evolved ARF is extremely high; uterine curettage, rational bacterial therapy, refusal of nephrotoxic agents are preferred. Better treatment outcomes were due to a session of 5-10 hyperbaric oxygenation procedures which were performed in anaerobic sepsis, pulmonary edema, arterial hypoxemia. The patients who had received hyperbaric oxygenation had less severe ARF, lower incidence of complications and lower mortality rates, they tolerated hemodialysis better.


Recent Advances in Systems and Network Medicine: Meeting Report from the First International Conference in Systems and Network Medicine.
The First International Conference in Systems and Network Medicine gathered together 200 global thought leaders, scientists, clinicians, academicians, industry and government experts, medical and graduate students, postdoctoral scholars and policymakers. Held at Georgetown University Conference Center in Washington D.C. on September 11-13, 2019, the event featured a day of pre-conference lectures and hands-on bioinformatic computational workshops followed by two days of deep and diverse scientific talks, panel discussions with eminent thought leaders, and scientific poster presentations. Topics ranged from: Systems and Network Medicine in Clinical Practice; the role of -omics technologies in Health Care; the role of Education and Ethics in Clinical Practice, Systems Thinking, and Rare Diseases; and the role of Artificial Intelligence in Medicine. The conference served as a unique nexus for interdisciplinary discovery and dialogue and fostered formation of new insights and possibilities for health care systems advances.


Acceptability and effectiveness of a breast health awareness programme for rural women in India.
Breast cancer being one of the leading cancers among women in developing countries, prevention or identification of the disease at an early stage is of paramount importance in saving as well as improving the quality of life. Breast health awareness appears to be a pragmatic method for this. To determine the acceptability and effectiveness of an educational intervention programme on breast health awareness for rural women by trained female health workers. Community based non-randomised educational intervention study carried out over a period of 1 year. Three hundred and sixty rural women in the age group 30--59 years were randomly selected (and age-wise stratified), from a coastal village in Southern India. Women were educated on breast health and breast self-examination by specifically trained health workers and their awareness and proficiency levels were evaluated at the end of 1 and 3 months post-intervention. This was done using the Statistical Package for Social Sciences Version 10. Following the educational intervention, a significant increase in overall awareness regarding breast cancer (z=-15.807; P< 0.001) as well as in the performance of self-examination of the breast 321/342 (93%) was observed. Forgetfulness or being too busy appeared to be the two most frequently perceived barriers. This study clearly shows that a community oriented educational intervention programme emphasizing on proper technique can bring about the desirable behavioural change among women.


HLA-DR4 and other genetic markers in rheumatoid arthritis.
In a new series of RA patients the association with HLA-DR4 was again found to be highly significant. Also increased were the DR4 associated antigens DRw53 and DQw3. Hybridization of a DQ-beta probe to Bg1 II-digested DNA showed that a variant of DQw3, characterized by a 4.3 kb fragment and related to the serological specificity TA10, was markedly increased among DR4 positive RA patients. HLA-DR1 was also increased in RA and appeared to be independent of the increase of DR4. Although the DR1 association was weaker, it was observed in both patients with and without RF. In contrast, DR4 was found to be increased significantly only in the RF positive group of patients, as previously observed. Development of RA in multiple-case families was found to be linked to the inheritance of DR4 positive haplotypes. The possible role of risk factors associated with polymorphic markers of the T-cell receptor genes was investigated. An allelic marker associated with one of the variable gene subfamilies of the beta-chain was found to be associated with RA. The results suggest that susceptibility for development of RA is influenced by alleles of the T-cell receptor in conjunction with the class II HLA factors with which the T-cell receptor interacts in the course of the immune response.


Considerations for best practices in studies of fiber or other dietary components and the intestinal microbiome.
A 2-day workshop organized by the National Institutes of Health and U.S. Department of Agriculture included 16 presentations focused on the role of diet in alterations of the gastrointestinal microbiome, primarily that of the colon. Although thousands of research projects have been funded by U.S. federal agencies to study the intestinal microbiome of humans and a variety of animal models, only a minority addresses dietary effects, and a small subset is described in sufficient detail to allow reproduction of a study. Whereas there are standards being developed for many aspects of microbiome studies, such as sample collection, nucleic acid extraction, data handling, etc., none has been proposed for the dietary component; thus this workshop focused on the latter specific point. It is important to foster rigor in design and reproducibility of published studies to maintain high quality and enable designs that can be compared in systematic reviews. Speakers addressed the influence of the structure of the fermentable carbohydrate on the microbiota and the variables to consider in design of studies using animals, in vitro models, and human subjects. For all types of studies, strengths and weaknesses of various designs were highlighted, and for human studies, comparisons between controlled feeding and observational designs were discussed. Because of the lack of published, best-diet formulations for specific research questions, the main recommendation is to describe dietary ingredients and treatments in as much detail as possible to allow reproduction by other scientists.


Prevalence and predictors for homo- and heterosubtypic antibodies against influenza a virus.
The effectiveness of trivalent influenza vaccination has been confirmed in several studies. To date, it is not known whether repeated exposure and vaccination to influenza promote production of cross-reactive antibodies. Furthermore, how strains encountered earlier in life imprint the immune response is currently poorly understood. To determine the prevalence for human homo- and heterosubtypic antibody responses, we scrutinized serum samples from 305 healthy volunteers for hemagglutinin-binding and -neutralizing antibodies against several strains and subtypes of influenza A. Statistical analyses were then performed to establish the association of measured values with potential predictors. It was found that vaccination not only promoted higher binding and neutralizing antibody titers to homosubtypic influenza isolates but also increased heterosubtypic human immune responses. Both binding and neutralizing antibody titers in relation with age of the donors mirrored the course of the different influenza strain circulation during the last century. Advanced age appeared to be of advantage for both binding and neutralizing titers to most subtypes. In contrast, the first virus subtype encountered was found to imprint to some degree subsequent antibody responses. Antibodies to recent strains, however, primarily seemed to be promoted by vaccination. We provide evidence that vaccinations stimulate both homo- and heterosubtypic immune responses in young and middle-aged as well as more senior individuals. Our analyses suggest that influenza vaccinations not only prevent infection against currently circulating strains but can also stimulate broader humoral immune responses that potentially attenuate infections with zoonotic or antigenically shifted strains.


Long-term mortality in childhood-onset epilepsy.
There are few studies on long-term mortality in prospectively followed, well-characterized cohorts of children with epilepsy. We report on long-term mortality in a Finnish cohort of subjects with a diagnosis of epilepsy in childhood. We assessed seizure outcomes and mortality in a population-based cohort of 245 children with a diagnosis of epilepsy in 1964; this cohort was prospectively followed for 40 years. Rates of sudden, unexplained death were estimated. The very high autopsy rate in the cohort allowed for a specific diagnosis in almost all subjects. Sixty subjects died (24%); this rate is three times as high as the expected age- and sex-adjusted mortality in the general population. The subjects who died included 51 of 107 subjects (48%) who were not in 5-year terminal remission (i.e., ≥5 years seizure-free at the time of death or last follow-up). A remote symptomatic cause of epilepsy (i.e., a major neurologic impairment or insult) was also associated with an increased risk of death as compared with an idiopathic or cryptogenic cause (37% vs. 12%, P<0.001). Of the 60 deaths, 33 (55%) were related to epilepsy, including sudden, unexplained death in 18 subjects (30%), definite or probable seizure in 9 (15%), and accidental drowning in 6 (10%). The deaths that were not related to epilepsy occurred primarily in subjects with remote symptomatic epilepsy. The cumulative risk of sudden, unexplained death was 7% at 40 years overall and 12% in an analysis that was limited to subjects who were not in long-term remission and not receiving medication. Among subjects with idiopathic or cryptogenic epilepsy, there were no sudden, unexplained deaths in subjects younger than 14 years of age. Childhood-onset epilepsy was associated with a substantial risk of epilepsy-related death, including sudden, unexplained death. The risk was especially high among children who were not in remission. (Funded by the Finnish Epilepsy Research Foundation.).


Computationally efficient simulation of electrical activity at cell membranes interacting with self-generated and externally imposed electric fields.
We present a computational method that implements a reduced set of Maxwell's equations to allow simulation of cells under realistic conditions: sub-micron cell morphology, a conductive non-homogeneous space and various ion channel properties and distributions. While a reduced set of Maxwell's equations can be used to couple membrane currents to extra- and intracellular potentials, this approach is rarely taken, most likely because adequate computational tools are missing. By using these equations, and introducing an implicit solver, numerical stability is attained even with large time steps. The time steps are limited only by the time development of the membrane potentials. This method allows simulation times of tens of minutes instead of weeks, even for complex problems. The extracellular fields are accurately represented, including secondary fields, which originate at inhomogeneities of the extracellular space and can reach several millivolts. We present a set of instructive examples that show how this method can be used to obtain reference solutions for problems, which might not be accurately captured by the traditional approaches. This includes the simulation of realistic magnitudes of extracellular action potential signals in restricted extracellular space. The electric activity of neurons creates extracellular potentials. Recent findings show that these endogenous fields act back onto the neurons, contributing to the synchronization of population activity. The influence of endogenous fields is also relevant for understanding therapeutic approaches such as transcranial direct current, transcranial magnetic and deep brain stimulation. The mutual interaction between fields and membrane currents is not captured by today's concepts of cellular electrophysiology, including the commonly used activation function, as those concepts are based on isolated membranes in an infinite, isopotential extracellular space. The presented tool makes simulations with detailed morphology and implicit interactions of currents and fields available to the electrophysiology community.


Use of [14C]-sodium bicarbonate/urea to measure physical activity induced increases in total energy expenditure in free-living healthy males.
The aim of this study was to evaluate the utility of the [(14)C]-sodium bicarbonate/urea technique to detect physical activity-induced increases in total energy expenditure in free-living healthy men. Thirteen healthy males aged 34.1 +/- 11.7 yrs with body mass index 24.1 +/- 3.1 kg/m(2) were studied on three separate occasions, during which [(14)C]-bicarbonate was infused over 48-hours and urine was collected during the second 24-hours. On three separate occasions and in random order, subjects either remained sedentary, or performed a bout of physical activity on an electro-magnetically braked cycle ergometer sufficient to increase energy expenditure by 7% or 11% above predicted sedentary total energy expenditure. Urine samples were analyzed to evaluate the amount of [(14)C]-bicarbonate incorporated into urinary urea, thereby reflecting the amount of CO(2) produced per day, and upon conversion, the number of kilojoules of energy expended in 24-hours. All 13 subjects successfully completed the two physical activity treatments and there were no adverse events. As measured by the [(14)C]-urea assay, mean total energy expenditure values were not significantly different between sedentary activity (17902 +/- 905 kJ/day), the physical activity treatment designed to increase TEE by 7% (17701 +/- 594 kJ/day) and the physical activity treatment designed to increase TEE by 11% (18538 +/- 485 kJ/day) (P=0.668). In conclusion, although the [(14)C]-sodium bicarbonate/urea technique was well tolerated and did not interfere with normal daily activities, it was not able to accurately measure physical activity-induced increases in EE in the range of 7-11% above predicted sedentary total energy expenditure.


Frequent fetal heart-rate monitoring for early detection of abruptio placentae in severe proteinuric hypertension.
Abruptio placentae occurred in 16 of 132 patients with severe pre-eclampsia who were admitted to an obstetric high-risk ward before 34 weeks' gestation. These 16 patients were compared with those who did not develop abruptio placentae. Systolic and diastolic blood pressure levels, proteinuria and birth weights did not differ significantly between the two groups. Apgar scores were significantly lower in the abruptio placentae group. There were 6 intra-uterine and 2 neonatal deaths in the abruptio placentae group (50% perinatal mortality (PNM] and 3 intra-uterine and 16 neonatal deaths in the other group (18% PNM). Four patients with abruptio placentae presented with abnormal fetal heart-rate patterns and 8 with abdominal pain. No warning signs were present in 3 patients and the fetal heart-rate pattern before delivery was not available in 1 patient. Abnormal fetal heart-rate patterns were present in 5 of the 8 patients who presented with pain. Abruptio placentae occurring in patients with severe proteinuric hypertension carries a high PNM. Frequent monitoring of the fetal heart rate sometimes helps to diagnose fetal distress before the clinical signs of abruption become apparent.


Sertraline as monotherapy in the treatment of psychotic and nonpsychotic depression.
Previous studies suggest that selective serotonin reuptake inhibitors (SSRIs) are effective when used alone in the treatment of unipolar depression with psychotic features. The purpose of the present study was to examine the response to sertraline for patients with and without psychotic features using standard criteria such as recovery and remission. An 8-week open-label trial of sertraline in depressed inpatients was conducted. Twenty-five subjects had DSM-IV major depressive disorder with psychotic features, and 25 had DSM-IV major depressive disorder without psychotic features. After a 1-week open washout, all subjects were rated using the Hamilton Rating Scale for Depression (HAM-D) and Brief Psychiatric Rating Scale (BPRS) at baseline. The HAM-D was administered weekly, and the BPRS was administered again only at the end of the 8-week trial. Medication dosage was started at 50 mg/day, increased to 100 mg/day after 1 week, and then increased up to 200 mg/day if subjects had not remitted. Depressed patients without psychosis responded significantly better than did depressed patients with psychosis using the criteria of remission (HAM-D score - 7; p =.001), response (HAM-D score - 50% of baseline score; p =.011), referral for electroconvulsive therapy (HAM-D score >/= 15; p =.011), or change in HAM-D scores (p =.016). Baseline HAM-D score and psychosis independently predicted response, whereas baseline BPRS scores did not, regardless of whether psychotic status was entered into the analyses. Psychotic depression responds more poorly than depression without psychosis to sertraline alone. Psychosis was a predictor of response independent of degree of depression and general psychopathology. Limitations due to an open-label design are discussed, as are differences between this study and others using SSRIs for psychotic depression.


The psychological effects of the physical healthcare environment on healthcare personnel.
The physical healthcare environment is capable of affecting patients. This concept of 'healing environments' refers to the psychological impact of environmental stimuli through sensory perceptions. It excludes more physiological effects such as those produced by ergonomic (i.e. fall prevention) or facilitative (i.e. hygiene-related) variables. The importance of an atmosphere in the healthcare environment that promotes the health and well-being of patients is evident, but this environment should not negatively affect healthcare personnel. The physical healthcare environment is part of the personnel's 'workscape'. This can make the environment an important determinant of subjective work-related outcomes like job satisfaction and well-being, as well as of objective outcomes like absenteeism or quality of care. In order to effectively build or renovate healthcare facilities, it is necessary to pay attention to the needs of both patients and healthcare personnel. To assess the psychological effects of the physical healthcare environment on healthcare personnel. We searched the Cochrane EPOC Group Specialised Register; Cochrane Central Register of Controlled Trials; Database of Abstracts and Reviews of Effects; MEDLINE; EMBASE; CINAHL; Civil Engineering Database and Compendex. We also searched the reference lists of included studies. We included randomised controlled trials (RCT), controlled clinical trials (CCT), controlled before and after studies (CBA), and interrupted time series (ITS) of psychological effects of the physical healthcare environment interventions for healthcare staff. The outcomes included measures of job satisfaction, satisfaction with the physical healthcare environment, quality of life, and quality of care. Two reviewers independently assessed studies for eligibility, extracted data, and assessed methodological quality. We identified one study, which adopted a CBA study design to investigate the simultaneous effects of multiple environmental stimuli. Staff mood improved in this study, while no effects were found on ward atmosphere or unscheduled absences. One study was included in this review. This review therefore indicates that, at present, there is insufficient evidence to support or refute the impact of the physical healthcare environment on work-related outcomes of healthcare staff. Methodological shortcomings, particularly confounding with other variables and the lack of adequate control conditions, partially account for this lack of evidence. Given these methodological issues, the field is in need of well-conducted controlled trials.


Phosphorylation of mitotic kinesin-like protein 2 by polo-like kinase 1 is required for cytokinesis.
We have investigated the function of mitotic kinesin-like protein (MKlp) 2, a kinesin localized to the central spindle, and demonstrate that its depletion results in a failure of cleavage furrow ingression and cytokinesis, and disrupts localization of polo-like kinase 1 (Plk1). MKlp2 is a target for Plk1, and phosphorylated MKlp2 binds to the polo box domain of Plk1. Plk1 also binds directly to microtubules and targets to the central spindle via its polo box domain, and this interaction controls the activity of Plk1 toward MKlp2. An antibody to the neck region of MKlp2 that prevents phosphorylation of MKlp2 by Plk1 causes a cytokinesis defect when introduced into cells. We propose that phosphorylation of MKlp2 by Plk1 is necessary for the spatial restriction of Plk1 to the central spindle during anaphase and telophase, and the complex of these two proteins is required for cytokinesis.


Which representations of their gender group affect men's orientation towards care? the case of parental leave-taking intentions.
Men are currently underrepresented in traditionally female care-oriented (communal) engagement such as taking parental leave, whereas they are overrepresented in traditionally male (agentic) engagement such as breadwinning or leadership. We examined to what extent different prototypical representations of men affect men's self-reported parental leave-taking intentions and more generally the future they can imagine for themselves with regard to work and care roles (i.e., their possible selves). We expected prototypes of men that combine the two basic stereotype dimensions of agency and communion to increase men's communal intentions. In two experiments (N1 = 132, N2 = 233), we presented male participants with contrived newspaper articles that described the ideal man of today with varying degrees of agency and communion (between-subjects design with four conditions; combined agentic and communal vs. agentic vs. communal vs. control condition). Results of Experiment 1 were in line with the main hypothesis that especially presenting a combination of agency and communion increases men's expectations for communal engagement: As compared to a control condition, men expected more to engage in caretaking in the future, reported higher parental leave-taking intentions, and tended to expect taking longer parental leave. Experiment 2 only partially replicated these findings, namely for parental leave-taking intentions. Both experiments additionally provided initial evidence for a contrast effect in that an exclusive focus on agency also increased men's self-reported parental leave-taking intentions compared to the control condition. Yet, exclusively emphasizing communion in prototypes of men did not affect men's communal intentions, which were high to begin with. We further did not find evidence for preregistered mechanisms. We discuss conditions and explanations for the emergence of these mixed effects as well as implications for the communication of gendered norms and barriers to men's communal engagement more broadly.


Soil seal development under simulated rainfall: Structural, physical and hydrological dynamics.
This study delivers new insights into rainfall-induced seal formation through a novel approach in the use of X-ray Computed Tomography (CT). Up to now seal and crust thickness have been directly quantified mainly through visual examination of sealed/crusted surfaces, and there has been no quantitative method to estimate this important property. X-ray CT images were quantitatively analysed to derive formal measures of seal and crust thickness. A factorial experiment was established in the laboratory using open-topped microcosms packed with soil. The factors investigated were soil type (three soils: silty clay loam - ZCL, sandy silt loam - SZL, sandy loam - SL) and rainfall duration (2-14 min). Surface seal formation was induced by applying artificial rainfall events, characterised by variable duration, but constant kinetic energy, intensity, and raindrop size distribution. Soil porosities derived from CT scans were used to quantify the thickness of the rainfall-induced surface seals and reveal temporal seal micro-morphological variations with increasing rainfall duration. In addition, the water repellency and infiltration dynamics of the developing seals were investigated by measuring water drop penetration time (WDPT) and unsaturated hydraulic conductivity (Kun). The range of seal thicknesses detected varied from 0.6 to 5.4 mm. Soil textural characteristics and OM content played a central role in the development of rainfall-induced seals, with coarser soil particles and lower OM content resulting in thicker seals. Two different trends in soil porosity vs. depth were identified: i) for SL soil porosity was lowest at the immediate soil surface, it then increased constantly with depth till the median porosity of undisturbed soil was equalled; ii) for ZCL and SL the highest reduction in porosity, as compared to the median porosity of undisturbed soil, was observed in a well-defined zone of maximum porosity reduction c. 0.24-0.48 mm below the soil surface. This contrasting behaviour was related to different dynamics and processes of seal formation which depended on the soil properties. The impact of rainfall-induced surface sealing on the hydrological behaviour of soil (as represented by WDTP and Kun) was rapid and substantial: an average 60% reduction in Kun occurred for all soils between 2 and 9 min rainfall, and water repellent surfaces were identified for SZL and ZCL. This highlights that the condition of the immediate surface of agricultural soils involving rainfall-induced structural seals has a strong impact in the overall ability of soil to function as water reservoir.


[A comparison of the pharmacology of (-)-deprenyl to N-methylpropargylamine-1-aminoindane (J-508) and rasagiline, the desmethyl-analogue of J-508].
N-methylpropargylamine-1-aminoindane (J-508), a strong releaser of catecholamines was described 30 years ago as a more potent selective inhibitor of MAO-B than (-)-deprenyl (Knoll 1978). In 2007 the desmethyl-analogue of J-508 (rasagiline) was registered as a new selective inhibitor of MAO-B and a possible substitute for (-)-deprenyl in therapy. The discovery of the enhancer regulation, the realization that catecholaminergic and serotonergic neurons in the brain stem are enhancer-sensitive neurons, phenylethylamine (PEA) and triptamine are endogenous enhancer substances, (-)-deprenyl is a PEA-derived synthetic enhancer substance, and finally the development of (-)-BPAP, a tryptamine-derived, 100 times more potent synthetic enhancer substance than (-)-deprenyl, made it clear that the enhancer effect of (-)-deprenyl is primarily responsible for the therapeutic benefits of this drug. To compare the pharmacological spectrum of (-)-deprenyl and rasagiline was the aim of this study. The ability of rats to acquire a two way conditioned avoidance response (CAR) in the shuttle box was analyzed during 5 consecutive days. Tetrabenazine treatment (1 mg/kg, s.c.) depletes from their stores the transmitters of the catecholaminergic neurons of the brain stem. Since the activation of the cortical neurons via the noradrenergic neurons in the brain stem is sine qua non for the acquisition for a CAR, rats treated with tetrabenazine are unable to learn in the shuttle box. To block the activity of MAO-A (clorgyline) or to treat rats with an enhancer substance [(-)-BPAP] are the two possibilities to antagonize the learning deficit caused by tetrabenazine. We compared in shuttle box experiments the effect of (-)-deprenyl, (-)-desmethyl-deprenyl, J-508 and desmethyl-J-508 (rasagiline) on the learning ability of rats pretreated with tetrabenazine. We used as a reference substance clorgyline to demonstrate the effect of a selective MAO-A inhibitor, and (-)-BPAP to demonstrate the effect of a selective enhancer substance. (-)-Deprenyl and (-)-desmethyl-deprenyl acted, like (-)-BPAP, in low doses as enhancer substances and in very high doses as MAO-A inhibitors. J-508 and rasagiline proved to be devoid of the enhancer property and in doses which are known to block MAO-A, they antagonized the effect of tetrabenazine, like clorgyline. Thus, rasagiline can not be a substitute for (-)-deprenyl in therapy.


Melatonin Treatment Enhances Aβ Lymphatic Clearance in a Transgenic Mouse Model of Amyloidosis.
It has been postulated that inadequate clearance of the amyloid β protein (Aβ) plays an important role in the accumulation of Aβ in sporadic late onset Alzheimer's disease (AD). While the blood brain barrier (BBB) has taken the center stage in processes involving Aβ clearance, little information is available about the role of the lymphatic system. We previously reported that Aβ is cleared through the lymphatic system. We now assessed lymphatic Aβ clearance by treating a mouse model of AD amyloidosis with melatonin, an Aβ aggregation inhibitor and immuno-regulatory neurohormone. To confirm and expand our initial finding that Aβ is cleared through the lymphatic system. Lymphatic clearance of metabolic and cellular "waste" products from the brain into the peripheral lymphatic system has been known for a long time. However, except for our prior report, there is no additional experimental data published about Aβ being cleared into peripheral lymph nodes. For these experiments, we used a transgenic mouse model (Tg2576) that over-expresses a mutant form of the Aβ precursor protein (APP) in the brain. We examined levels of Aβ in plasma and in lymph nodes of transgenic mice as surrogate markers of vascular and lymphatic clearance, respectively. Aβ levels were also measured in the brain and in multiple tissues. Clearance of Aβ peptides through the lymphatic system was confirmed in this study. Treatment with melatonin led to the following changes: 1-A statistically significant increase in soluble monomeric Aβ40 and an increasing trend in Aβ42 in cervical and axillary lymph nodes of treated mice. 2- Statistically significant decreases in oligomeric Aβ40 and a decreasing trend Aβ42 in the brain. The data expands on our prior report that the lymphatic system participates in Aβ clearance from the brain. We propose that abnormalities in Aβ clearance through the lymphatic system may contribute to the development of cerebral amyloidosis. Melatonin and related indole molecules (i.e., indole- 3-propionic acid) are known to inhibit Aβ aggregation although they do not reverse aggregated Aβ or amyloid fibrils. Therefore, these substances should be further explored in prevention trials for delaying the onset of cognitive impairment in high risk populations.


High pressure balloon dilatation of the ureterovesical junction in primary obstructive megaureter: Infectious morbidity.
The objective of this study is to investigate the infectious morbidity associated with high-pressure balloon dilatation (HPBD) and an indwelling double J stent, in primary obstructive megaureter. We reviewed the cases of 12 patients undergoing endoscopic treatment for primary obstructive megaureter from January 2012 to January 2015. The characteristics of the infection and data concerning the patient and the intervention were analyzed. The frequency of preoperative urinary tract infection (UTI) was 58%. The procedure was feasible in 100% of cases. Two patients required a second dilatation. One patient underwent Cohen's ureteral reimplantation after failure of the second dilatation. The frequency of postoperative UTI was 25%. All these infections occurred in patients with a double J stent. None of the patients had UTI after stent removal. None of the patients developed postoperative vesicoureteral reflux (VUR) after HPBD. Endoscopic balloon dilatation has been shown to have good short- mid- and long-term outcomes. In our experience, the morbidity of this procedure mostly results from infections, exclusively related to the use of a double J stent. The placement of a double J stent has a significant medical and economic impact. A definitive decision about the utility of double J stents will require studies of further dilatation without the placement of a double J stent. 4.


Atorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke.
Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are widely used for the treatment of hypercholesterolemia and coronary heart disease and for the prevention of stroke. There have been various adverse effects, most commonly affecting muscle and ranging from myalgia to rhabdomyolysis. These adverse effects may be due to a coenzyme Q(10) (CoQ(10)) deficiency because inhibition of cholesterol biosynthesis also inhibits the synthesis of CoQ(10). To measure CoQ(10) levels in blood from hypercholesterolemic subjects before and after exposure to atorvastatin calcium, 80 mg/d, for 14 and 30 days. Prospective blinded study of the effects of short-term exposure to atorvastatin on blood levels of CoQ(10). Stroke center at an academic tertiary care hospital. Patients We examined a cohort of 34 subjects eligible for statin treatment according to National Cholesterol Education Program: Adult Treatment Panel III criteria. The mean +/- SD blood concentration of CoQ(10) was 1.26 +/- 0.47 micro g/mL at baseline, and decreased to 0.62 +/- 0.39 micro g/mL after 30 days of atorvastatin therapy (P<.001). A significant decrease was already detectable after 14 days of treatment (P<.001). Even brief exposure to atorvastatin causes a marked decrease in blood CoQ(10) concentration. Widespread inhibition of CoQ(10) synthesis could explain the most commonly reported adverse effects of statins, especially exercise intolerance, myalgia, and myoglobinuria.


Hyperbaric oxygen in diabetic gangrene treatment.
We treated a group of 18 hospitalized adult diabetic patients (all with retinopathy, 17 with symptomatic neuropathy, and 6 with macroangiopathy) presenting with gangrenous lesions of the foot by a combined regime consisting of strict metabolic control, daily debridement of necrotic tissues, and daily hyperbaric oxygen (HBO) treatments given in a multiplace oxygen chamber. Another group of 10 adult subjects with comparable foot lesions (all with retinopathy, 9 with symptomatic neuropathy, and 4 with macroangiopathy) was treated in exactly the same way except for HBO. In the test treatment group, 16 patients were healed, and the remaining 2 showed no improvement and later underwent amputation. The number of HBO treatments required for healing was significantly related to the size of gangrenous lesions. In the non-HBO-treated group, only 1 patient improved, 5 of 10 showed no change, and 4 of 10 worsened until leg amputation was unavoidable. Comparison of the two groups by chi 2-test revealed a highly significant difference (P = .001). In practical terms, HBO treatment drastically reduced leg amputations in patients so treated in the last 3 yr compared with earlier and current figures for patients not receiving HBO treatment.


The human pineal gland and melatonin in aging and Alzheimer's disease.
The pineal gland is a central structure in the circadian system which produces melatonin under the control of the central clock, the suprachiasmatic nucleus (SCN). The SCN and the output of the pineal gland, i.e. melatonin, are synchronized to the 24-hr day by environmental light, received by the retina and transmitted to the SCN via the retinohypothalamic tract. Melatonin not only plays an important role in the regulation of circadian rhythms, but also acts as antioxidant and neuroprotector that may be of importance in aging and Alzheimer's disease (AD). Circadian disorders, such as sleep-wake cycle disturbances, are associated with aging, and even more pronounced in AD. Many studies have reported disrupted melatonin production and rhythms in aging and in AD that, as we showed, are taking place as early as in the very first preclinical AD stages (neuropathological Braak stage I-II). Degeneration of the retina-SCN-pineal axis may underlie these changes. Our recent studies indicate that a dysfunction of the sympathetic regulation of pineal melatonin synthesis by the SCN is responsible for melatonin changes during the early AD stages. Reactivation of the circadian system (retina-SCN-pineal pathway) by means of light therapy and melatonin supplementation, to restore the circadian rhythm and to relieve the clinical circadian disturbances, has shown promising positive results.


Microvascular decompression for primary trigeminal neuralgia: long-term effectiveness and prognostic factors in a series of 362 consecutive patients with clear-cut neurovascular conflicts who underwent pure decompression.
The purpose of this study was to evaluate the long-term efficacy of microvascular decompression (MVD) and to identify the factors affecting outcome in patients treated for primary trigeminal neuralgia (TN). Only the cases with a clear-cut neurovascular conflict (vascular contact and/or compression of the root entry zone of the trigeminal nerve) found at surgery and treated with "pure" MVD (decompression of the root without any additional lesioning or cutting of the adjacent rootlets) were retained. The study included 362 patients who were followed up over a period of 1 to 18 years (median follow-up 7.2 years). A Kaplan-Meier survival analysis was generated at 1 and 15 years of follow-up for all of the considered factors. According to Kaplan-Meier analysis, the success rate (defined as pain-free patients without any medication) was 91% at 1 year and estimated to be 73.38% after 15 years of follow-up. None of the following patient-related factors played any significant role in prognosis: sex, patient age at surgery, history of systemic hypertension, duration of neuralgia before surgery, or history of failed trigeminal surgery. Patients with atypical neuralgia (a baseline of permanent pain) had the same outcome as those with a typical (purely spasmodic) presentation. In addition, the side and topography of the trigeminal nerve did not play a role, whereas involvement of all three divisions of the nerve had a negative effect on outcome. Concerning anatomical factors, neither the type of the compressive vessel nor its location along or around the root was found to be significant. However, the severity of compression was important-the more severe the degree of compression, the better the outcome (p = 0.002). The authors also found that presence of focal arachnoiditis had a negative influence on outcome (p = 0.002). Pure MVD can offer patients affected by a primary TN a 73.38% probability of long-term (15 years) cure of neuralgia. The presence of a clear-cut and marked vascular compression at surgery (and possibly-although not yet reliably--on preoperative magnetic resonance imaging) is the guarantee of a higher than 90% success rate.


Rethinking Sexual Citizenship.
Over the last two decades sexuality has emerged as a key theme in debates about citizenship, leading to the development of the concept of sexual citizenship. This article reviews this literature and identifies four main areas of critical framing: work that contests the significance of sexuality to citizenship; critiques that focus on the possibilities and limitations of mobilising the language of citizenship in sexual politics; analyses of sexual citizenship in relation to nationalisms and border making; and literature that critically examines western constructions of sexuality and sexual politics underpinning understandings of sexual citizenship. In order to progress the field theoretically, the article seeks to extend critiques of sexual citizenship focusing on two key aspects of its construction: the sexual citizen-subject and spaces of sexual citizenship. It argues for a critical rethink that encompasses a de-centring of a 'western-centric' focus in order to advance understandings of how sexual citizenship operates both in the Global North and South.


TH2 cells in the pathogenesis of airway remodeling: regulatory T cells a plausible panacea for asthma.
T-helper type 2 (TH2) cells are one of the hallmarks of airway remodeling. The daunting task of regaining tolerance will be to regulate airway hyperresponsiveness (AHR) and remodeling in chronic asthma by balancing the ballet of TH1 and TH2 cells. The mechanism of tolerance appears to be modulated by a specialized subset of T cells called regulatory T cells (Tregs). Currently there are six subtypes of Tregs including CD4+CD25+ naturally occurring (N-Tregs), inducible naïve CD4+CD25- T cells (TR1), TR1 memory phenotype, T-helper type 3 (TH3), CD4-CD25+DX5+ natural killer T cells (TRNKT), and CD4-CD25+CD8+ cytotoxic T cells (TRCTC). The development of Tregs is controversial as to whether they occur in the thymus or peripheral lymphoid tissue. Studies have shown that NTregs are generated in the thymus and TR1 cells occur in the periphery. Nevertheless, Tregs express an arsenal of molecular membrane markers: CD3, CD25, CD62L, CD69, BTLA, GITR, ICOS, Neuroplin- 1 (Nrp-1), and PD-1. However, the most definitive marker is Forkhead Winged-Helix Transcriptional Factor Box p3 (Foxp3). The suppression of N-Tregs occurs by cell-to-cell contact, and low levels of IL-10 and moderate levels of TGF-beta, but the primary mechanism involves the sequestration and activation of neighboring naïve CD4+CD25- T cells to become TR1 cells. In contrast, TR1 cells exert their suppressive properties by copious secretion of IL-10 and TGF- beta. These suppressive mechanisms occur by the inhibition of IL-2 production and the promotion of cell cycle arrest. The development of this specialized subset of T cells is an enigma, but their understanding will provide a plausible panacea for asthma.


[Avascular osteonecrosis of femoral head and neck in an AIDS patient].
Avascular osteonecrosis (AON) has increased in the last few years in patients infected with the human immunodeficiency virus type-1 (HIV-1). The most commonly affected bone is the femoral head and neck. Frequently these bilateral and clinical findings include moderate to severe pain and functional impotence of the affected joints. The etiology is multifactorial and highly active antiretroviral therapy (HAART) with protease inhibitors (PI) is probably related to its development. In the evolution, a total hip replacement may be needed. We present an hemophilic patient with AIDS, who developed a bilateral AON of the femoral head and neck during HAART.


Activity of PD-1 Inhibitor Combined With Anti-Angiogenic Therapy in Advanced Sarcoma: A Single-Center Retrospective Analysis.
Background: Immune checkpoint inhibitors (ICIs) are employed to treat various cancers, including soft tissue sarcomas (STSs), and less than 20% of patients benefit from this treatment. Vascular endothelial growth factor (VEGF) promotes the immunosuppressive tumor microenvironment and contributes to ICI-resistant therapy. Anti-VEGF receptor tyrosine-kinase inhibitors (TKIs) combined with ICIs have shown antitumor activity in patients with alveolar soft-part sarcoma (ASPS). However, they have not been extensively studied to treat other STS subtypes, such as leiomyosarcoma (LMS), dedifferentiated liposarcoma (DDLPS), undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), and angiosarcoma (AS). Methods: In this retrospective study, we collected data from 61 patients who were diagnosed with advanced STS based on imaging and histology, including LMS, DDLPS, and UPS. Among them, 41 patients were treated with ICIs combined with TKIs and 20 patients received ICI therapy. The endpoints of progression-free survival (PFS) and overall response rate (ORR) were analyzed in the two groups, and the overall response [partial response (PR), stable disease (SD), and progressive disease (PD)] of each patient was determined using RECIST 1.1 evaluation criteria. Results: In total, 61 STS patients had the following subtypes: LMS (n = 20), DDLPS (n = 17), UPS (n = 8), ASPS (n = 7), MFS (n = 7), and AS (n = 2). The median PFS (mPFS) was significantly prolonged after ICI treatment in combination with TKIs (11.74 months, 95% CI 4.41-14.00) compared to ICI treatment alone (6.81 months, 95% CI 5.43-NA) (HR 0.5464, p = 0.043). The 12-month PFS rates of patients who received ICI-TKI treatment were increased from 20.26% (95% CI 0.08-0.53) to 42.90% (95% CI 0.27-0.68). In the combination therapy group, 12 patients (30%) achieved PR, 25 patients (62.5%) achieved SD, and 3 patients (7.5%) achieved PD for 3 months or longer. In the non-TKI-combination group, 2 patients (9.5%) achieved PR, 14 patients (66.7%) achieved SD, and 5 patients (23.8%) achieved PD within 3 months. The ORRs in the two groups were 30.0% (ICI-TKI combination) and 9.5% (ICI only), respectively. A notable ORR was observed in the ICI-TKI combination group, especially for subtypes ASPS (66.7%), MFS (42.9%), and UPS (33.3%). The PD-L1 expression (n = 33) and tumor mutation burden (TMB, n = 27) were determined for each patient. However, our results showed no significant difference in PFS or response rates between the two groups. Conclusion: This study suggests that ICI-TKI treatment has antitumor activity in patients with STS, particularly the ASPS and MFS subtypes. Moreover, effective biomarkers to predict clinical outcomes are urgently needed after combination therapy in the STS subtypes.


Emerging and re-emerging infectious diseases in Japan: epidemiology and infection prevention measures.
In recent years, emerging and re-emerging infectious diseases, such as the Ebola virus disease and Middle East Respiratory Syndrome (MERS), have been frequently reported. In this review, we summarize the representative outbreaks of emerging and re-emerging infectious diseases since 2000 and outbreaks of various infectious diseases that have occurred around the world and in Japan. Moreover, the emerging and re-emerging infectious diseases that could develop in Japan are also summarized. Especially, for mosquito-borne infectious diseases, viral hemorrhagic fever and severe fever with thrombocytopenia syndrome, and avian Influenza and MERS, the disease features, routes of infection, and infection prevention measures are reviewed in this article. Healthcare workers are at high risk of infection, and therefore, a sufficient understanding of disease features and routes of infection and the appropriate infection prevention measures are needed to increase self-protection.


Observations on asthma mortality.
The rate of death from asthma in the United States has been increasing over the last decade, but such deaths still remain uncommon. Mortality rates differ markedly by region and ethnicity, and case-fatality rates are highest in black men living in inner cities. In general, patients in greatest jeopardy are those with severe, unstable disease who are not being objectively monitored; however, death can occur in anyone if the attack is intense enough. Sudden catastrophic episodes of asthma occur but are very rare. Failure to recognize the seriousness of the terminal episode or to treat the episode appropriately remains the chief contributing cause of poor outcome. Little compelling evidence shows that adverse effects of medications play much of a role in asthma-related death. The disease characteristics that place patients at risk remain inadequately defined. Of those suggested, only a history of recurrent hospitalization and the need for ventilatory assistance are specific enough to be helpful. These characteristics, however, are found in only 36% and 6% of cases, respectively; thus, their absence is of no value in assessing risk. The prognosis after a near-fatal episode of asthma is poor, and approximately 10% of patients die in the year after the event. Given the current state of knowledge, it is wise to view all exacerbations of asthma that last longer than a few days as potentially fatal and to treat them accordingly. This is especially true in patients who have previously had a severe episode of asthma.


Effects of flexibility training on eccentric exercise-induced muscle damage.
This study investigated whether flexibility training would attenuate muscle damage induced by maximal eccentric exercise. Thirty untrained young men were allocated to static stretching (SS), proprioceptive neuromuscular facilitation (PNF), or control group (n = 10 per group). The SS consisted of 30 sets of a 30-s standard SS with a 30-s rest between sets, and the PNF included 5 sets of the 30-s standard SS followed by 3 sets of three "contract-relax-agonist-contract" procedures. These were performed three times a week for 8 wk, and all subjects performed six sets of 10 maximal isokinetic (30°·s) lengthening contractions of the knee flexors after the 8-wk training or 8 wk after the baseline measures (control). Changes in indirect markers of muscle damage before and for 5 d after the eccentric exercise were compared among the groups. The range of motion (ROM) of the hip joint increased by 25°, and the optimum angle of the knee flexors shifted (P < 0.05) to a longer muscle length by 10° after training, without significant differences between SS and PNF. No significant changes in these variables were evident for the control group. Compared with the control group, the SS and PNF groups showed significantly (P < 0.05) smaller decreases and faster recovery of knee flexor muscle strength and smaller changes in optimum angle, ROM, muscle soreness, and plasma creatine kinase activity and myoglobin concentration without significant differences between the groups. The preeccentric exercise ROM or optimum angle was significantly (P < 0.05) correlated with the changes in the muscle damage markers. These results suggest that both SS and PNF training are effective in attenuating eccentric exercise-induced muscle damage and that flexible muscles are less susceptible to the damage.


A modified fourier transform method for multiple scattering calculations in a plane parallel mie atmosphere.
A method for evaluating characteristics of the scattered radiation emerging from a plane parallel atmosphere containing large spherical particles is described. In this method, the normalized phase function for scattering is represented as a Fourier series whose maximum required number of terms depends upon the zenith angles of the directions of incident and of scattered radiation. Some results are presented to show that this method can be used to obtain reliable numerical values in a reasonable amount of computer time.


The social construction of violence among Northern Plains tribal members with antisocial personality disorder and alcohol use disorder.
Whereas recent reports from national studies have presented extremely high rates for many personality disorders in American Indian communities, persistent concerns about the meaning of these symptoms have left many troubled by these reports. American Indians as a group are known to suffer disproportionately from a number of violent experiences, but the dynamics of this violence have received little attention. This paper examines perspectives on violence in the lives of 15 northern plains tribal members who met criteria for antisocial personality disorder and comorbid alcohol use disorder. It explores how study participants constructed and understood their own violent encounters, as well as the motivations they described (characterized here as reputation, leveling, retaliation, catharsis, and self-defense). Violence was gendered in this study, with men generally presenting as perpetrators and women as victims. Men often described themselves as ready participants in a violent world, while women were quite clear that aggression for them was often simply required as they tried to defend themselves from male violence. While this analysis does not replace clinical analyses of violence in antisocial personality disorder, it does reveal an underlying cultural logic that may play a role in shaping the recourse to violence for that minority of individuals for whom it appears to be the obvious choice.


Bactericidal activity of a monocytic cell line (THP-1) against common respiratory tract bacterial pathogens is depressed after infection with respiratory syncytial virus.
Non-typable Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis and respiratory syncytial virus (RSV) are commonly isolated from patients during the course of chronic obstructive pulmonary disease (COPD). Earlier studies found that virus infection enhanced binding of bacterial respiratory pathogens to epithelial cells in vitro. The objective of the present study was to assess the effect of RSV infection of a human monocytic cell line on bactericidal activity and cytokine production in response to these bacterial respiratory pathogens. The effect of RSV infection on binding, uptake and intracellular killing of bacteria by a human monocytic leukaemia cell line, THP-1, was assessed. Cell culture supernates were examined with a mouse fibroblast cell assay for tumour necrosis factor-alpha (TNF-alpha) bioactivity. Expression of CD14, CD11a, CD18, CD15 and CD29 on uninfected and RSV-infected THP-1 cells was assessed by flow cytometry in relation to differences in bacterial binding. RSV infection of THP-1 cells significantly decreased their ability to bind and kill bacteria. Compared with uninfected cells, fewer bacteria bound to RSV-infected THP-1 cells and the surface antigens that have been reported to bind bacteria were expressed at lower levels on RSV-infected cells. RSV-infected cells incubated with bacteria exhibited less TNF-alpha bioactivity than uninfected cell incubated with bacteria. The results elucidate some of the mechanisms involved in the increased susceptibility of virus-infected patients to secondary bacterial infection. Reduced bacterial killing by virus-infected monocytes might contribute to reduced clearance of bacteria from the respiratory tract and damage elicited by the bacteria or cytokine response in COPD patients.


Characterization of two glyceraldehyde-3-phosphate dehydrogenase isoenzymes from the pentalenolactone producer Streptomyces arenae.
Pentalenolactone (PL) irreversibly inactivates the enzyme glyceraldehyde-3-phosphate dehydrogenase [D-glyceraldehyde-3-phosphate:NAD+ oxidoreductase (phosphorylating)] (EC 18.104.22.168) and thus is a potent inhibitor of glycolysis in both procaryotic and eucaryotic cells. We showed that PL-producing strain Streptomyces arenae TU469 contains a PL-insensitive glyceraldehyde-3-phosphate dehydrogenase under conditions of PL production. In complex media no PL production was observed, and a PL-sensitive glyceraldehyde-3-phosphate dehydrogenase, rather than the insensitive enzyme, could be detected. The enzymes had the same substrate specificity but different catalytic and molecular properties. The apparent Km values of the PL-insensitive and PL-sensitive enzymes for glyceraldehyde-3-phosphate were 100 and 250 microM, respectively, and the PL-sensitive enzyme was strongly inhibited by PL under conditions in which the PL-insensitive enzyme was not inhibited. The physical properties of the PL-insensitive enzyme suggest that the protein is an octamer, whereas the PL-sensitive enzyme, like other glyceraldehyde-3-phosphate dehydrogenases, appears to be a tetramer.


A genome triplication associated with early diversification of the core eudicots.
Although it is agreed that a major polyploidy event, gamma, occurred within the eudicots, the phylogenetic placement of the event remains unclear. To determine when this polyploidization occurred relative to speciation events in angiosperm history, we employed a phylogenomic approach to investigate the timing of gene set duplications located on syntenic gamma blocks. We populated 769 putative gene families with large sets of homologs obtained from public transcriptomes of basal angiosperms, magnoliids, asterids, and more than 91.8 gigabases of new next-generation transcriptome sequences of non-grass monocots and basal eudicots. The overwhelming majority (95%) of well-resolved gamma duplications was placed before the separation of rosids and asterids and after the split of monocots and eudicots, providing strong evidence that the gamma polyploidy event occurred early in eudicot evolution. Further, the majority of gene duplications was placed after the divergence of the Ranunculales and core eudicots, indicating that the gamma appears to be restricted to core eudicots. Molecular dating estimates indicate that the duplication events were intensely concentrated around 117 million years ago. The rapid radiation of core eudicot lineages that gave rise to nearly 75% of angiosperm species appears to have occurred coincidentally or shortly following the gamma triplication event. Reconciliation of gene trees with a species phylogeny can elucidate the timing of major events in genome evolution, even when genome sequences are only available for a subset of species represented in the gene trees. Comprehensive transcriptome datasets are valuable complements to genome sequences for high-resolution phylogenomic analysis.


Poor lung function and tonsillectomy in childhood are associated with mortality from age 18 to 44.
The aim of this analysis was to examine associations between lung health in childhood and mortality between ages 18 and 44 years in the Tasmanian Longitudinal Health Study (TAHS). The 1961 Tasmanian birth cohort who attended school in 1968 (n=8583) were linked to the Australian National Death Index (NDI) to identify deaths. Additional deaths were notified by families through a 37 year follow-up postal questionnaire. Information on lung health at age 7 years and on potential confounders was obtained from the original 1968 TAHS survey and school medical records. Cox proportional hazards modelling was used to assess determinants of mortality. A total of 264 (3%) deaths were identified. The principal causes of death were external injury (56.1%, n=97) and cancer (17.9%, n=31). Males were more likely than females to have died (p=<0.1). Only two (1.1%) participants had died from respiratory conditions. Having an FEV(1)<80% predicted at 7 years of age was associated with a 2-fold increased incidence of death. Tonsillectomy before age 7 years was associated with a 1.5-fold increase in mortality (p=0.05); being male with a 3.6-fold increase in mortality (p=0.0001); and repeated chest illnesses at age 7 years causing >30 days confinement in the last year, was associated with a 2.2-fold increase in mortality (p=0.03). Childhood lung health appears to be associated with increased mortality in adulthood, perhaps by affecting the ability to survive trauma, major illnesses and other physical stresses.


Hollow mesoporous aluminosilica spheres with perpendicular pore channels as catalytic nanoreactors.
The design and synthesis of hollow/yolk-shell mesoporous structures with catalytically active ordered mesoporous shells can infuse new vitality into the applications of these attractive structures. In this study, we report that hollow/yolk-shell structures with catalytically active ordered mesoporous aluminosilica shells can be easily prepared by using silica spheres as the silica precursors. By simply treating with a hot alkaline solution in the presence of sodium aluminate (NaAlO(2)) and cetyltrimethylammonium bromide (CTAB), solid silica spheres can be directly converted into high-quality hollow mesoporous aluminosilica spheres with perpendicular pore channels. On the basis of the proposed formation mechanism of etching followed by co-assembly, the synthesis strategy developed in this work can be extended as a general strategy to prepare ordered mesoporous yolk-shell structures with diverse compositions and morphologies simply by replacing solid silica spheres with silica-coated nanocomposites. The reduction of 4-nitrophenol with yolk-shell structured Au@ordered mesoporous aluminosilica as the catalyst has clearly demonstrated that the highly permeable perpendicular pore channels of mesoporous aluminosilica can effectively prevent the catalytically active yolk from aggregating. Furthermore, with accessible acidity, the yolk-shell structured ordered mesoporous aluminosilica spheres containing Pd yolk exhibit high catalytic activity and recyclability in a one-pot two-step synthesis involving an acid catalysis and subsequent catalytic hydrogenation for desired benzimidazole derivative, which makes the proposed hollow ordered aluminosilica spheres a versatile and practicable scaffold for advanced catalytic nanoreactor systems.


Inventory and treatment of compost maturation emissions in a municipal solid waste treatment facility.
Emissions of volatile organic compounds (VOCs) from the compost maturation building in a municipal solid waste treatment facility were inventoried by solid phase microextraction and gas chromatography-mass spectrometry. A large diversity of chemical classes and compounds were found. The highest concentrations were found for n-butanol, methyl ethyl ketone and limonene (ppmv level). Also, a range of compounds exceeded their odor threshold evidencing that treatment was needed. Performance of a chemical scrubber followed by two parallel biofilters packed with an advanced packing material and treating an average airflow of 99,300 m(3) h(-1) was assessed in the treatment of the VOCs inventoried. Performance of the odor abatement system was evaluated in terms of removal efficiency by comparing inlet and outlet abundances. Outlet concentrations of selected VOCs permitted to identify critical odorants emitted to the atmosphere. In particular, limonene was found as the most critical VOC in the present study. Only six compounds from the odorant group were removed with efficiencies higher than 90%. Low removal efficiencies were found for most of the compounds present in the emission showing a significant relation with their chemical properties (functionality and solubility) and operational parameters (temperature, pH and inlet concentration). Interestingly, benzaldehyde and benzyl alcohol were found to be produced in the treatment system.


A pilot study of surgical telementoring for leg fasciotomy.
Acute extremity compartment syndrome requires rapid decompression. In remote locations, distance, weather and logistics may delay the evacuation of patients with extremity trauma beyond the desired timeline for compartment release. The aim of this study was to establish the feasibility of performing telementored surgery for leg compartment release and to identify methodological issues relevant for future research. Three anaethetists and one critical care physician were recruited as operators. They were directed to perform a two-incision leg fasciotomy on a Thiel-embalmed cadaver under the guidance of a remotely located orthopaedic surgeon. The operating physician and the surgeon (mentor) were connected through software that allows for real-time supervision and the use of a virtual pointer overlaid onto the surgical field. Two experienced orthopaedic traumatologists independently assessed the adequacy of compartment decompression and the presence of iatrogenic complications. 14 of 16 compartments (in four leg specimens) were felt to have been completely released. The first evaluator considered that the deep posterior compartment was incompletely released in two specimens. The second evaluator considered that the superficial posterior compartment was incompletely released in two specimens. The only complication was a large laceration of the soleus muscle that occurred during a period of blurred video signal attributed to a drop in bandwidth. This study suggests that surgical telementoring may enable physicians to safely perform two-incision leg fasciotomy in remote environments. This could improve the chances of limb salvage when compartment syndrome occurs far from surgical care. We found interobserver variation in the assessment of compartment release, which should be considered in the design of future research protocols.


Emerging and re-emerging rickettsial infections.
Rickettsial organisms are a diverse group of obligate intracellular bacteria; all species known to cause human disease are dependent on an arthropod vector and many are considered zoonotic diseases. Typical vectors of rickettsia are fleas, ticks, mites or lice. Humans become infected either when bitten or upon contact of broken skin or mucous membranes by infected secretions from an arthropod vector. The emergence and re-emergence of rickettsial diseases is a serious public health concern in the United States and abroad. Herein, the clinical and pathologic features of rickettsial diseases are described in tandem with the current scientific underpinnings. The histopathology of emerging and re-emerging rickettsiosis with species-specific discussion relating to vector issues and control are explored. Concepts of endemicity are addressed in the context of climate change and its impact on vector and sylvatic reservoirs, underscoring the need for clinical vigilance and broad consideration for encounters with these potentially life threating human pathogens.


Enhancement of the upconversion photoluminescence of hexagonal phase NaYF4:Yb3+,Er3+ nanoparticles by mesoporous gold films.
Efficient enhancement of photoluminescence in rare-earth activated upconversion materials is of great significance for their practical applications in various fields. In this work, three-dimensional mesoporous gold films were fabricated by a low-cost and facile dealloying approach to improve the upconversion photoluminescence efficiency. The mesoporous Au films exhibit good chemical stability, large-area uniformity and abundant distribution of porous nanospaces. Varying the time of the dealloying process leads to modification of the pore size distribution, surface roughness and residual Ag content, resulting in effective tuning of the wavelength of the broadband localized surface plasmon resonance (LSPR). Enhancement factors were identified to be a function of the dealloying time. With the optimized upconversion photoluminescence enhancement, a 41-fold increase was achieved with the mesoporous gold substrate which had been dealloyed for 8 days. These results pave the way to overcome the limitation of poor upconversion efficiency for widespread practical applications in life science and energy fields.


A CONTRIBUTION TO THE STUDY OF HUMAN NEUROGLIA.
THE RESULTS AND CONCLUSIONS OF THE ABOVE INVESTIGATION ARE: 1. The term glio-sarcoma should be dropped, as unscientific and misleading in its significance. 2. The problems regarding neuroglia demand varied methods for their adequate study. 3. With all the means at our command, the absolute determination of the relation of cells and fibres in individual cases remains difficult and at times impossible. 4. No criterion has yet been offered to determine a fundamental distinction between glioma and sarcoma (Stroebe); and secondly, between glioma and so-called gliosis (Weigert). 5. The development of neuroglia in all probability is from cells with protoplasmic processes to cells with differentiated and independent fibres. 6. Herein lies a possible reconciliation of the conflicting views concerning the ultimate structure of human neuroglia.


ON THE HEXON BASES OF LIVER TISSUE UNDER NORMAL AND CERTAIN PATHOLOGICAL CONDITIONS.
The results above reported lead to the conclusion that while in the degenerating cells chemical changes are taking place tending toward a diminution of the hexon bases as a whole, they affect the arginin especially. One may picture the process either as a partial or as a complete breaking down of certain proteid. material more or less rich in hexon bases, leaving behind. proteid matter poorer in bases. The meaning of these changes is, however, obscure, and with the limited number of known facts bearing upon the subject, it would seem idle even to attempt to formulate an hypothesis to explain them. Certain work of other investigators is, however, suggestive in this connection. Kossel and Dakin, for instance, as illustrated by their work upon the simple proteid body clupein, found that a partial destruction of the proteid molecule, involving the arginin group, is brought about by a ferment furnished by the animal organism. When subjected to the hydrolytic action of a mineral acid, clupein yields arginin in considerable abundance. But if the clupein is first acted upon by the ferment arginase found in the liver, and then subjected to acid hydrolysis, the yield of arginin is appreciably diminished. Among the cleavage products in the latter instance are the components of arginin, namely, omithin and urea. It would seem, therefore, as if the ferment had loosened the union between the omithin and urea in the arginin group, so that upon subsequent hydrolysis a diminution of arginin resulted. In the cases studied by me, it may be that the conditions were favorable for some such ferment action as that above described, and hence the relatively low yield of arginin. No attempt, however, was made to ascertain if omithin were present in the urine. Its presence there would seem not wholly unlikely when one considers the diminished power of oxidation of the phosphorus-poisoned cell, although Thompson has shown that arginin or omithin when administered to a healthy dog as food or by hypodermic injection is eliminated for the most part as urea, no ornithin being found. There might seem to be a conflict between this view and the results recently published by Wohlgemuth, but it must be borne in mind that the influences at work causing the breaking down of the proteid molecule are probably quite diverse in character. Wohlgemuth has recently shown for the first time that a diamino acid may actually find its way into the urine in phosphorus poisoning. He found arginin in the urine not only in rabbits poisoned with phosphorus but also in a patient suffering from phosphorus poisoning. On the other hand, he was unable to find lysin in the urine. This fact is of especial interest in view of the evidence set forth in this paper that the arginin base is lost to the proteid molecule more rapidly than the lysin base. The correspondence between the findings in the liver and in the urine is thus a close one. How much of the arginin liberated from the proteid molecule may find its way into the urine is of course uncertain. It seems reasonable to suppose that a portion of the base is acted upon by the arginase ferment in the manner already described. Of the seventeen to eighteen cleavage products of the proteid molecule thus far isolated, the hexon bases are among the most stable. One or more of these bases have been found in practically all proteid matter thus far investigated; in fact arginin is so uniformly present that Kossel has made the suggestion that it is the kernel of the proteid molecule. At all events, the question may be asked, whether, if the influences at work in the altered liver tissue were of a general character causing a diminution of the hexon bases, the monoamino acid groups would not suffer even a greater diminution; and since the pathological condition is undoubtedly associated with impaired oxidation, their presence should not be expected in the urine. As a matter of fact, Ignatowski found considerable quantities of monoamino acids in the urine of patients suffering from gout, pneumonia, and leukaemia, though under normal conditions no monoamino acids were found in the urine, indeed, not even after the subcutaneous injection of glycokoll. Furthermore, the loosening of the amino acids from the proteid molecule is suggested by the fact that Taylor found such acids in the liver of a patient who died from a hepatic disease of obscure etiology, but which he was inclined to attribute to chloroform poisoning. Taylor found not only leucin and tyrosin in the liver, but also arginin, a fact not without interest in view of the diminished arginin content found in the livers of the chloroformed dogs after acid hydrolysis. Moreover, the falling off of the hexon bases under the conditions studied seems quite in accordance with some results recently reported by Levene. He has shown that certain cleavage products obtained by the action of mineral acids upon self-digested pancreas, spleen, and liver, are much diminished when compared with the products obtained from the fresh glands. The lysin and arginin of the digested liver, for example, showed a diminution of over 50 per cent. It is now well established that in course of the process of aseptic autolysis, the proteids of the liver cell undergo decomposition into simpler substances, and Jacoby showed that during life autolysis may go on in portions of the liver in which the circulation has been hindered. But of greater significance still in this connection, is the observation made by Jacoby on the autolytic changes in the liver during phosphorus poisoning. He found that when the normal liver substance is permitted to autolyse the solution of the liver substance is a slow one. On the other hand, under similar conditions the liver of a phosphorus-poisoned animal undergoes rapid and almost complete solution. The difference in the behavior of the normal and damaged liver points to an increase of normal ferment action in the case of the poisoned organ. It thus seems reasonable to suppose that in phosphorus poisoning we have during life an exaggerated breaking down of the proteid molecule associated with an over-action of certain ferments, and among them probably arginase. The pathological process in the liver during life may, therefore, be thought of as proceeding in the same general direction as the process of post-morten autolytic decomposition. By means of further studies along lines indicated in this paper, it should be possible to gain a deeper insight into numerous pathological processes. The changes in amyloid degeneration are among those which promise to be better understood through the application of the new methods of chemical analysis. Moreover, it cannot be doubted that pharmacology as well as toxicology has much to gain from a study of what happens to the proteid molecule under the influence of poisons.


Joint medicine-information and pharmacovigilance services could improve detection and communication about drug-safety problems.
RELIS is a Norwegian network of four regional medicine-information and pharmacovigilance centers where pharmacists and clinical pharmacologists provide feedback to health care professionals in spontaneous drug-related questions and adverse drug-reaction (ADR) reports published in a question-answer pair (QAP) database (the RELIS database) and the Norwegian ADR database, respectively. To describe the potential of RELIS's dual service to improve detection and communication of drug-safety problems. We searched the RELIS database for QAPs about ADRs with use of the Norwegian ADR database as a reference. We also searched the Norwegian ADR database for reports that used the RELIS database as a reference. Both searches were limited to the years 2003-2012. We then selected the example of pregabalin and drug abuse after the marketing of Lyrica in Norway in September 2004 to illustrate RELIS's potential to detect new drug-safety information through a limited number of QAPs and ADR reports. A total of 5,427 (26%) of 21,071 QAPs in the RELIS database concerned ADRs. QAPs from this database were used as references in 791 (4%) of a total of 22,090 reports in the Norwegian ADR database. The Norwegian ADR database was used as a reference in 363 (7%) of 5,427 QAPs that concerned ADRs. Between September 2004 and September 2008, RELIS received eleven questions and 13 ADR reports about suspicion of Lyrica (pregabalin) and different aspects of abuse. RELIS processes data through two databases that facilitate communication about ADRs. Our service also has the potential to detect new drug-safety problems with a limited number of questions and ADR reports.


Cost-effectiveness of Osimertinib in the First-Line Treatment of Patients With EGFR-Mutated Advanced Non-Small Cell Lung Cancer.
The survival of patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) gene mutations has improved substantially in the last decade with the development of targeted tyrosine kinase inhibitors (TKIs). Osimertinib, a third-generation TKI that is approved by the US Food and Drug Administration for the treatment of patients who develop EGFR T790M mutations, has recently shown improved clinical outcomes compared with gefitinib and erlotinib for treatment-naive patients. The aim of this study was to assess the cost-effectiveness of osimertinib for the first-line treatment of patients with EGFR-mutated NSCLC. For this cost-effectiveness analysis, we extracted individual patient data from the FLAURA randomized clinical trial and used findings of our earlier meta-analysis to develop a decision-analytic model and determine the cost-effectiveness of osimertinib (AZD9291) compared with first- and second-generation EGFR-TKIs over a 10-year time horizon. All direct costs were based on US and Brazilian payer perspectives. The main outcome of this study was the incremental cost-effectiveness ratio (ICER) expressed as cost per quality-adjusted life-year (QALY) gained by using osimertinib compared with first- or second-generation EGFR-TKIs in previously untreated EGFR-mutated NSCLC. In the base case using the data as reported in the FLAURA trial, the incremental QALY for osimertinib was 0.594 compared with the first- and second-generation EGFR-TKIs. In the United States, the osimertinib ICERs were $226 527 vs erlotinib, $231 123 vs gefitinib, and $219 874 vs afatinib. In Brazil, the ICERs were $162 329, $180 804, and $175 432, respectively. The overall survival (95% CI) reported in the FLAURA trial (hazard ratio, 0.63; 95% CI, 0.45-0.88) had the strongest association with the ICER (ranging from $84 342 to $859 771). Osimertinib price adjustments to the FLAURA trial data improved cost-effectiveness. For example, a discount of 10% on osimertinib acquisition cost was associated with a 20% decreased ICER compared with the base case ICER, and a discount of 20% on osimertinib acquisition cost was associated with a 40% decreased ICER compared with the base case ICER. At current costs, by World Health Organization cost-effectiveness threshold criteria, osimertinib is not cost-effective for first-line therapy of EGFR-mutated NSCLC in either the United States or Brazil.


Fiber types and myosin types in human atrial and ventricular myocardium. An anatomical description.
Hybridomas were prepared from mice immunized with myosin from the enlarged left ventricle of a 53-year-old female with an obstructive cardiomyopathy. The specificity of 15 monoclonal antibodies to myosin heavy chains was assessed by the reactivity of muscle extracts and of chymotryptic myosin fragments of different sizes with these antibodies, as determined by the immune replicate technique; some of the monoclonal antibodies cross-reacted only with the ventricular V3-type myosin from hypothyroid rats, whereas the other antibodies cross-reacted both with the latter and with the ventricular V1-type myosins from normal young rats. Immunological heterogeneity of the fibers from human atrial muscles and from human ventricular muscles was detected by some of the antimyosin antibodies by means of indirect immunofluorescence. Histochemical fiber heterogeneity was also detected by adenosine triphosphatase staining of the same tissues. Because of the close correspondence observed between the immunological and histochemical responses of atrial fibers, it has been postulated that at least two distinct types of myosin exist in the human atrium, each myosin form being histochemically related to either alpha- or beta-like ventricular myosin heavy chains. In contrast, there was no direct correspondence between the two experimental approaches in human ventricles, and it is postulated that at least three distinct types of myosin exist within the human ventricles, one V1-type myosin, presumably corresponding to the very rare fibers with an alkaline-stable adenosine triphosphatase activity, and two other V3-type myosins corresponding to immunologically different fibers, each having an alkaline-labile adenosine triphosphatase activity. Monoclonal antibodies that can distinguish among the different myosin variants were further used to provide the basis for an anatomical description of fiber types and myosin types within the human atrial and ventricular myocardium in the whole hearts of two young boys who died sudden violent deaths. Small zones of myosin variation were seen to be scattered, but probably not randomly distributed, within large areas of myocardium in which the cellular distribution of myosin was constant; the large areas had one myosin distribution specific for each cardiac cavity. No clear-cut conclusions can yet be made concerning the physiological role of the regional variations observed in the distribution of the different molecular forms of myosin.


Screening questionnaires for problem drinking in adolescents: performance of AUDIT, AUDIT-C, CRAFFT and POSIT.
Only rather few data on the validity of screening questionnaires to detect problem drinking in adolescents exist. The aim of this study was to compare the performance of the Alcohol Use Disorders Identification Test (AUDIT), its short form AUDIT-C, the Substance Module of the Problem Oriented Screening Instrument for Teenagers (POSIT), and CRAFFT (acronym for car, relax, alone, forget, family, and friends). The questionnaires were filled in by 9th and 10th graders from two comprehensive schools. All students received an interview using the alcohol section of the Composite International Diagnostic Interview. Alcohol abuse and alcohol dependence according to DSM-IV as well as episodic heavy drinking served as criteria to validate the screening instruments. All 9th and 10th graders (n=225) of both schools participated. No significant differences were found for areas under the receiver operating characteristic curves ranging from 0.810 to 0.872. Cronbach's alpha was satisfactory (0.77-0.80) but poor for CRAFFT (0.64). Different cut-offs are discussed. Considering validity as well as reliability, AUDIT, AUDIT-C and POSIT performed well; however, the POSIT is quite lengthy. AUDIT-C showed good psychometric properties and has clear advantages because of its brevity.


The use of ion mobility mass spectrometry to probe modulation of the structure of p53 and of MDM2 by small molecule inhibitors.
Developing drug-like molecules to inhibit the interactions formed by disordered proteins is desirable due to the high correlation of disorder with protein implicated in disease, but is challenging due in part to the lack of atomistically resolved and resolvable structures from conformationally dynamic systems. Ion mobility mass spectrometry (IM-MS) is well-positioned to assess protein ligand interactions along with the effect of a given inhibitor on conformation. Here we demonstrate the use of IM-MS to characterize the effect of two inhibitors RITA and Nutlin-3 on their respective binding partners: p53 and MDM2. RITA binds N-terminal transactivation domain of p53 (Np53) weakly, preventing direct observation of the complex in the gas phase. Nonetheless, upon incubation with RITA, we observe an alteration in the charge state distribution and in the conformational distributions adopted by Np53 in the gas phase. This finding supports the hypothesis that RITAs mode of action proceeds via a conformational change in p53. Circular dichroism corroborates our gas phase findings, showing a slight increase in secondary structure content on ligand incubation, and HDX-MS experiments also highlight the dynamic properties of this protein. Using the same approach we present data to show the effect of Nutlin-3 binding to the N-terminal domain of MDM2 (N-MDM2), N-MDM2 presents as at least two conformational families in the absence of Nutlin-3. Upon Nutlin-3 binding, the protein undergoes a compaction event similar to that exhibited by RITA on Np53. This multi-technique approach highlights the inherent disorder in these systems; and in particular exemplifies the power of IM-MS as a technique to study transient interactions between small molecule inhibitors and intrinsically disordered proteins.


Structural analysis and anti-obesity effect of a pectic polysaccharide isolated from Korean mulberry fruit Oddi (Morus alba L.).
A water-soluble polysaccharide JS-MP-1 was isolated from Korean mulberry fruits Oddi (Morus alba L.). Sugar linkage analysis and NMR data confirmed that it is a rhamnogalacturonan type I (RG I) polymer carrying arabinan and arabinogalactan (AG II) side chains. JS-MP-1 reduced dose-dependently the viability of 3T3-L1 pre-adipocyte cells, significantly stimulated the cleavage of caspases 9 and 3 and poly (ADP-ribose) polymerase (PARP) and decreased the ratio of Bcl-2 to Bax expression level that led to mitochondrial dysfunction and apoptosis in pre-adipocyte cells. The apoptotic death was mediated by stimulation of MAPKs (ERK and p38) signalling pathway. These results suggest that JS-MP-1 is able to reduce the number of fat cells and the mass of adipose tissue via inhibition of pre-adipocyte proliferation and thus JS-MP-1 itself or a crude aqueous Oddi extract containing this polysaccharide can be used as functional ingredient of health-beneficial food supplements for the treatment or prevention of obesity disorders.


The social licence for research: why care.data ran into trouble.
In this article we draw on the concept of a social licence to explain public concern at the introduction of care.data, a recent English initiative designed to extract data from primary care medical records for commissioning and other purposes, including research. The concept of a social licence describes how the expectations of society regarding some activities may go beyond compliance with the requirements of formal regulation; those who do not fulfil the conditions for the social licence (even if formally compliant) may experience ongoing challenge and contestation. Previous work suggests that people's cooperation with specific research studies depends on their perceptions that their participation is voluntary and is governed by values of reciprocity, non-exploitation and service of the public good. When these conditions are not seen to obtain, threats to the social licence for research may emerge. We propose that care.data failed to adequately secure a social licence because of: (i) defects in the warrants of trust provided for care.data, (ii) the implied rupture in the traditional role, expectations and duties of general practitioners, and (iii) uncertainty about the status of care.data as a public good. The concept of a social licence may be useful in explaining the specifics of care.data, and also in reinforcing the more general lesson for policy-makers that legal authority does not necessarily command social legitimacy.


Recovery from an acute infection in C. elegans requires the GATA transcription factor ELT-2.
The mechanisms involved in the recognition of microbial pathogens and activation of the immune system have been extensively studied. However, the mechanisms involved in the recovery phase of an infection are incompletely characterized at both the cellular and physiological levels. Here, we establish a Caenorhabditis elegans-Salmonella enterica model of acute infection and antibiotic treatment for studying biological changes during the resolution phase of an infection. Using whole genome expression profiles of acutely infected animals, we found that genes that are markers of innate immunity are down-regulated upon recovery, while genes involved in xenobiotic detoxification, redox regulation, and cellular homeostasis are up-regulated. In silico analyses demonstrated that genes altered during recovery from infection were transcriptionally regulated by conserved transcription factors, including GATA/ELT-2, FOXO/DAF-16, and Nrf/SKN-1. Finally, we found that recovery from an acute bacterial infection is dependent on ELT-2 activity.


Validity and usability testing of a health systems guidance appraisal tool, the AGREE-HS.
Health systems guidance (HSG) provides recommendations to address health systems challenges. No tools exist to inform HSG developers and users about the components of high quality HSG and to differentiate between HSG of varying quality. In response, we developed a tool to assist with the development, reporting and appraisal of HSG - the Appraisal of Guidelines for Research and Evaluation-Health Systems (AGREE-HS). This paper reports on the validity, usability and initial measurement properties of the AGREE-HS. To establish face validity (Study 1), stakeholders completed a survey about the AGREE-HS and provided feedback on its content and structure. Revisions to the tool were made in response. To establish usability (Study 2), the revised tool was applied to 85 HSG documents and the appraisers provided feedback about their experiences via an online survey. An initial test of the revised tool's measurement properties, including internal consistency, inter-rater reliability and criterion validity, was conducted. Additional revisions to the tool were made in response. In Study 1, the AGREE-HS Overview, User Manual, quality item content and structure, and overall assessment questions were rated favourably. Participants indicated that the AGREE-HS would be useful, feasible to use, and that they would apply it in their context. In Study 2, participants indicated that the quality items were easy to understand and apply, and the User Manual, usefulness and usability of the tool were rated favourably. Study 2 participants also indicated intentions to use the AGREE-HS. The AGREE-HS comprises a User Manual, five quality items and two overall assessment questions. It is available at agreetrust.org.


SU-E-J-16: Prostate Bed Motion during Post-Prostatectomy Radiotherapy.
To report the inter-fractional prostate bed motion (PBM) during post-prostatectomy radiotherapy using cone-beam CT (CBCT). The correlations between PBM, anterior rectal wall and posterior bladder wall shifts were also investigated. Seventy CBCT and 8 planning CT scans from 8 patients treated with prostate bed radiotherapy were retrospectively analyzed. For each CBCT-CT pair, two rigid image registrations were performed: one based on surgical clips and the other based on pelvic bony anatomy. Each registration gives a displacement vector. The difference between the two registration displacements represents the PBM. In addition, rectum/bladder contours on CT and CBCT scans were compared to identify the organ wall motion. Shifts of the anterior rectal wall and posterior bladder wall were assessed by averaging the slice-by-slice distances between contours on two image sets, measured along an anterior-posterior line passing through the symphysis pubis. The prostate bed motion in the left-right (LR), anterior-posterior (AP) and superior-inferior (SI) directions was (0.1±0.9)mm, (0.9±1.6)mm, and (-0.4±1.9)mm, respectively. The derived PTV-CTV margin for LR, AP and SI motion was 3mm, 5mm, and 6mm, respectively. Pearson's correlation coefficients between PBM and anterior rectal wall (whole length) shifts, PBM and the cranial half of anterior rectal wall shifts, and PBM and posterior bladder wall shifts, were 0.43, 0.47, and 0.67, respectively. The magnitude of PBM relative to pelvic bony anatomy in all three directions was small. The correlation between average anterior rectal wall shifts and PBM was weak-to-moderate, which may be due to rectum contouring inconsistency. Possible sources for this inconsistency include: non-uniform rectal wall motion through its length, low CBCT image contrast, and artifacts due to filling. Significant correlation between average posterior bladder wall shifts and PBM suggests bladder wall motion may also be a suitable surrogate for PBM in the AP direction.


Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: new developments and revised recommendations.
The publication of the Australasian Creatinine Consensus Working Group's position statements in 2005 and 2007 resulted in automatic reporting of estimated glomerular filtration rate (eGFR) with requests for serum creatinine concentration in adults, facilitated the unification of units of measurement for creatinine and eGFR, and promoted the standardisation of assays. New advancements and continuing debate led the Australasian Creatinine Consensus Working Group to reconvene in 2010. The working group recommends that the method of calculating eGFR should be changed to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, and that all laboratories should report eGFR values as a precise figure to at least 90 mL/min/1.73 m(2). Age-related decision points for eGFR in adults are not recommended, as although an eGFR < 60 mL/min/1.73 m(2) is very common in older people, it is nevertheless predictive of significantly increased risks of adverse clinical outcomes, and should not be considered a normal part of ageing.If using eGFR for drug dosing, body size should be considered, in addition to referring to the approved product information. For drugs with a narrow therapeutic index, therapeutic drug monitoring or a valid marker of drug effect should be used to individualise dosing. The CKD-EPI formula has been validated as a tool to estimate GFR in some populations of non-European ancestry living in Western countries. Pending publication of validation studies, the working group also recommends that Australasian laboratories continue to automatically report eGFR in Aboriginal and Torres Strait Islander peoples. The working group concluded that routine calculation of eGFR is not recommended in children and youth, or in pregnant women. Serum creatinine concentration (preferably using an enzymatic assay for paediatric patients) should remain as the standard test for kidney function in these populations.