Noise and crosstalk in two quorum-sensing inputs of Vibrio fischeri.
One of the puzzles in bacterial quorum sensing is understanding how an organism integrates the information gained from multiple input signals. The marine bacterium Vibrio fischeri regulates its bioluminescence through a quorum sensing mechanism that receives input from three pheromone signals, including two acyl homoserine lactone (HSL) signals. While the role of the 3-oxo-C6 homoserine lactone (3OC6HSL) signal in activating the lux genes has been extensively studied and modeled, the role of the C8 homoserine lactone (C8HSL) is less obvious, as it can either activate luminescence or block its activation. It remains unclear how crosstalk between C8HSL and 3OC6HSL affects the information that the bacterium obtains through quorum sensing. We have used microfluidic methods to measure the response of individual V.fischeri cells to combinations of C8HSL and 3OC6HSL. By measuring the fluorescence of individual V.fischeri cells containing a chromosomal gfp-reporter for the lux genes, we study how combinations of exogenous HSLs affect both the population average and the cell-to-cell variability of lux activation levels. At the level of a population average, the crosstalk between the C8HSL and 3OC6HSL inputs is well-described by a competitive inhibition model. At the level of individual cells, the heterogeneity in the lux response depends only on the average degree of activation, so that the noise in the output is not reduced by the presence of the second HSL signal. Overall we find that the mutual information between the signal inputs and the lux output is less than one bit. A nonlinear correlation between fluorescence and bioluminescence outputs from lux leads to different noise properties for these reporters. The lux genes in V.fischeri do not appear to distinguish between the two HSL inputs, and even with two signal inputs the regulation of lux is extremely noisy. Hence the role of crosstalk from the C8HSL input may not be to improve sensing precision, but rather to suppress the sensitivity of the switch for as long as possible during colony growth.


Meta-analysis of the effectiveness of parenting programmes in improving maternal psychosocial health.
The purpose of this study was to determine whether group-based parenting programmes are effective in improving maternal psychosocial health. Data sources used were English and non-English language articles published between January 1970 and July 2000, retrieved using a keyword search of a number of biomedical, social science, educational, and general reference electronic databases. Two independent reviewers selected the relevant abstracts and articles. Only controlled trials were included in which participants had been randomly allocated to an experimental and a control group, the latter being a waiting-list, no-treatment or a placebo control group. Studies had to include at least one group-based parenting programme and one standardised instrument measuring maternal psychosocial health. Means, standard deviations, and information regarding study quality were selected from the included studies by two independent reviewers. The treatment effect for each outcome in each study was standardised by dividing the mean difference in post-intervention scores for the intervention and treatment group, by the pooled standard deviation, to produce an effect size. The results were then combined in a meta-analysis using a fixed-effect model. A total of 23 studies met all the inclusion criteria and 17 of these provided sufficient data with which to calculate effect sizes. Fifteen of these studies provided data on the five main outcomes of interest: depression, anxiety/stress, self-esteem, social support, and relationship with partner. The meta-analyses show statistically significant results favouring the intervention group for depression (-0.3, 95% confidence interval [CI] = -0.4 to -0.1), anxiety/stress (-0.5, 95% CI = -0.7 to -0.3), self-esteem (-0.4, 95% CI = -0.6 to -0.1), and relationship with partner (-0.4, 95% CI = -0.7 to -0.2). However, the meta-analysis of the social support data showed no evidence of effectiveness (-0.04, 95% CI = -0.3 to 0.2). Follow-up data were available for only three of the five outcomes. The results show that there were changes favouring the intervention group for self-esteem (-0.4, 95% CI = -0.7 to -0.2), the mother's relationship with her partner (-0.3, 95% CI = -0.8 to 0.1), and depression (-0.2, 95% CI = -0.4 to 0.002), although the confidence intervals for the mother's relationship with her partner and depression both cross zero. It is concluded that parenting programmes can make a significant contribution to the short-term psychosocial health of mothers. While the limited follow-up data are promising, further evidence of their effectiveness in improving maternal mental health is required. It is also suggested that some caution should be exercised before the results are generalised to parents irrespective of the level of pathology present.


Histopathology of diode and argon laser lesions in rabbit retina. A comparative study.
Argon lasers are the most frequently used laser source for retinal photocoagulation. These are expensive, bulky and low-efficiency devices. In contrast, diode semiconductor lasers have a number of characteristics that make them attractive for medical application: compact size, high electrical-to-optical efficiency, and long operating lifetime. Comparable irradiance lesions (about 120 Wcm2), ophthalmoscopically similar to those obtained therapeutically in humans, were obtained by a diode and an argon laser. Twenty-four hours after the treatment, a study of these lesions was made by light and electron microscopy. Argon irradiations resulted in damage to both the inner and the outer retinal layers, while the diode laser radiation produced damage to the outer retina and choroid. A sufficient diode laser light passed into the choroid to induce small vessel occlusions and/or edema. The histological characteristics of the lesions produced by the two lasers suggest the use of the diode lasers, as well as argon lasers, in the treatment of retinal and subretinal pathologies.


Factors Associated With COVID-19 Disease Severity in US Children and Adolescents.
Little is known about the clinical factors associated with COVID-19 disease severity in children and adolescents. We conducted a retrospective cohort study across 45 US children's hospitals between April 2020 to September 2020 of pediatric patients discharged with a primary diagnosis of COVID-19. We assessed factors associated with hospitalization and factors associated with clinical severity (eg, admission to inpatient floor, admission to intensive care unit [ICU], admission to ICU with mechanical ventilation, shock, death) among those hospitalized. Among 19,976 COVID-19 encounters, 15,913 (79.7%) patients were discharged from the emergency department (ED) and 4063 (20.3%) were hospitalized. The clinical severity distribution among those hospitalized was moderate (3222, 79.3%), severe (431, 11.3%), and very severe (380, 9.4%). Factors associated with hospitalization vs discharge from the ED included private payor insurance (adjusted odds ratio [aOR],1.16; 95% CI, 1.1-1.3), obesity/type 2 diabetes mellitus (type 2 DM) (aOR, 10.4; 95% CI, 8.9-13.3), asthma (aOR, 1.4; 95% CI, 1.3-1.6), cardiovascular disease, (aOR, 5.0; 95% CI, 4.3- 5.8), immunocompromised condition (aOR, 5.9; 95% CI, 5.0-6.7), pulmonary disease (aOR, 5.3; 95% CI, 3.4-8.2), and neurologic disease (aOR, 3.2; 95% CI, 2.7-5.8). Among children and adolescents hospitalized with COVID-19, greater disease severity was associated with Black or other non-White race; age greater than 4 years; and obesity/type 2 DM, cardiovascular, neuromuscular, and pulmonary conditions. Among children and adolescents presenting to US children's hospital EDs with COVID-19, 20% were hospitalized; of these, 21% received care in the ICU. Older children and adolescents had a lower risk for hospitalization but more severe illness when hospitalized. There were differences in disease severity by race and ethnicity and the presence of selected comorbidities. These factors should be taken into consideration when prioritizing mitigation and vaccination strategies.


Electrospun Microfiber Scaffolds with Anti-Inflammatory Tributanoylated N-Acetyl-d-Glucosamine Promote Cartilage Regeneration.
Tissue-engineering strategies offer promising tools for repairing cartilage damage; however, these strategies suffer from limitations under pathological conditions. As a model disease for these types of nonideal systems, the inflammatory environment in an osteoarthritic (OA) joint limits the efficacy of engineered therapeutics by disrupting joint homeostasis and reducing its capacity for regeneration. In this work, we investigated a sugar-based drug candidate, a tributanoylated N-acetyl-d-glucosamine analogue, called 3,4,6-O-Bu3GlcNAc, that is known to reduce nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling in osteoarthritis. 3,4,6-O-Bu3GlcNAc not only inhibited NFκB signaling but also exerted chondrogenic and anti-inflammatory effects on chondrocytes isolated from patients with osteoarthritis. 3,4,6-O-Bu3GlcNAc also increased the expression of extracellular matrix proteins and induced cartilage tissue production in three-dimensional in vitro hydrogel culture systems. To translate these chondrogenic and anti-inflammatory properties to tissue regeneration in osteoarthritis, we implanted 3,4,6-O-Bu3GlcNAc-loaded poly(lactic-co-glycolic acid) microfiber scaffolds into rats. The drug-laden scaffolds were biocompatible, and when seeded with human OA chondrocytes, similarly promoted cartilage tissue formation. 3,4,6-O-Bu3GlcNAc combined with the appropriate structural environment could be a promising therapeutic approach for osteoarthritis.


A dual binding mode for RhoGTPases in plexin signalling.
Plexins are cell surface receptors for the semaphorin family of cell guidance cues. The cytoplasmic region comprises a Ras GTPase-activating protein (GAP) domain and a RhoGTPase binding domain. Concomitant binding of extracellular semaphorin and intracellular RhoGTPase triggers GAP activity and signal transduction. The mechanism of this intricate regulation remains elusive. We present two crystal structures of the human Plexin-B1 cytoplasmic region in complex with a constitutively active RhoGTPase, Rac1. The structure of truncated Plexin-B1-Rac1 complex provides no mechanism for coupling RhoGTPase and Ras binding sites. On inclusion of the juxtamembrane helix, a trimeric structure of Plexin-B1-Rac1 complexes is stabilised by a second, novel, RhoGTPase binding site adjacent to the Ras site. Site-directed mutagenesis combined with cellular and biophysical assays demonstrate that this new binding site is essential for signalling. Our findings are consistent with a model in which extracellular and intracellular plexin clustering events combine into a single signalling output.


Controlled imbibition in a porous medium from a soft wet material (poultice).
We provide a first approach of the mechanisms of liquid imbibition in a porous medium from a wet paste in contact with this substrate. Through Magnetic Resonance Imaging (MRI) we first show that, in contrast with intuition, the liquid can invade the substrate even if it has a larger pore size than the paste, which induces a lower capillary pressure in the substrate. This phenomenon happens because the paste can easily shrink. We then show that the imbibition stops when the capillary pressure in the substrate balances the stress needed to further contract the paste. The dynamics of the process then mainly results from the competition of these two effects plus the pressure gradient associated with the liquid flow through the paste. This in particular shows that the liquid penetration in a porous medium, from a poultice in contact with this medium, may be controlled by adjusting the poultice characteristics.


The crack tip: a nanolab for studying confined liquids.
We study the equilibrium properties of a liquid phase condensed at the nanoscale between the surfaces of a sharp crack in fused silica in a moist controlled atmosphere. The extension of the condensed phase along the fracture is measured by in situ atomic force microscopy phase imaging and it is shown to be determined by a critical distance between the opposite crack surfaces, which is an increasing function of humidity. The present technique is very promising for measuring the properties of confined liquids at the nanoscale as well as for modeling the physics and chemistry of slow crack propagation in glasses.


A cross-species comparison of escape from X inactivation in Eutheria: implications for evolution of X chromosome inactivation.
Sex chromosome dosage compensation in both eutherian and marsupial mammals is achieved by X chromosome inactivation (XCI)--transcriptional repression that silences one of the two X chromosomes in the somatic cells of females. We recently used RNA fluorescent in situ hybridization (FISH) to show, in individual nuclei, that marsupial X inactivation (in the absence of XIST) occurs on a gene-by-gene basis, and that escape from inactivation is stochastic and independent of gene location. In the absence of similar data from fibroblast cell lines of eutherian representatives, a meaningful comparison is lacking. We therefore used RNA-FISH to examine XCI in fibroblast cell lines obtained from three distantly related eutherian model species: African savannah elephant (Loxodonta africana), mouse (Mus musculus) and human (Homo sapiens). We show that, unlike the orthologous marsupial X, inactivation of the X conserved region (XCR) in eutherians generally is complete. Two-colour RNA-FISH on female human, mouse and elephant interphase nuclei showed that XCR loci have monoallelic expression in almost all nuclei. However, we found that many loci located in the evolutionarily distinct recently added region (XAR) displayed reproducible locus-specific frequencies of nuclei with either one or two active X alleles. We propose that marsupial XCI retains features of an ancient incomplete silencing mechanism that was augmented by the evolution of the XIST gene that progressively stabilized the eutherian XCR. In contrast, the recently added region of the eutherian X displays an incomplete inactivation profile similar to that observed on the evolutionarily distinct marsupial X and the independently evolved monotreme X chromosomes.


Frontal lobe dysfunction in unilateral lenticulostriate infarcts. Prominent role of cortical lesions.
Most studies on frontal lobe dysfunction (FLD) in patients with striatal lesions did not consider possible associated cortical lesions not seen on computed tomographic scans. To determine the possible role of such cortical lesions, we assessed FLD in 10 patients with unilateral lenticulostriate infarct on computed tomographic scans. Magnetic resonance imaging revealed an associated cortical infarct not seen on computed tomographic scans in four patients. Using a battery of neuropsychological tests sensitive to FLD, we found that (1) the crossed tapping test was the only FLD test significantly disturbed in patients with pure unilateral lenticulostriate infarcts, (2) FLD was only present in patients with associated cortical infarct, and (3) caudate lesions only account for the number of echopraxic errors in the crossed tapping test. We conclude that unilateral isolated lenticulostriate infarcts might not lead to FLD, even though they may disturb the development of strategies involved in motor procedural learning.


Declining grouper spawning aggregations in Western Province, Solomon Islands, signal the need for a modified management approach.
Globally, groupers (Epinephelidae) that form fish spawning aggregations (FSAs) are highly vulnerable to overfishing and often require site-specific approaches to management. Over 5-years (2009-2013), we conducted underwater visual censuses (UVC) at a well-known spawning site at Njari Island, Gizo, Western Province, Solomon Islands, that supports aggregations of squaretail coralgrouper (Plectropomus areolatus), camouflage grouper (Epinephelus polyphekadion) and brown-marbled grouper (E. fuscoguttatus). Findings show that while there were species-specific variations in the duration and timing of the spawning season, aggregation densities peaked from March to June, representing the main spawning season for all three species. For P. areolatus, gonad analysis from samples taken from 2008 to 2011 confirmed reproductive activity in support of density trends observed through UVC. Over the 5-year UVC monitoring period, FSA densities declined for P. areolatus and E. polyphekadion. Conversely, following the first year of monitoring, E. fuscoguttatus densities increased. These inter-specific differences may reflect variable responses to fishing as shown elsewhere, or for example, differences in recruitment success. In response to known declines in FSAs of these species, in 2018 the Solomon Islands government placed a nationwide ban on these species' harvest and sale between October and January. As this study shows, this ban does not encompass the peak aggregation period at Njari and will offer limited protection to other FSAs of these species that are known to vary in reproductive seasonality across the Solomon Islands. A more biologically meaningful and practical management strategy would be to implement a nationwide ban on the harvest and sale of these groupers each month between full and new moons when these FSAs form consistently throughout the country. Since effective management of FSAs typically requires a combined approach, spatial management that protects both spawning sites and reproductive migratory corridors is warranted.


Flavonolignans from Aspergillus iizukae, a fungal endophyte of milk thistle (Silybum marianum).
Silybin A (1), silybin B (2), and isosilybin A (3), three of the seven flavonolignans that constitute silymarin, an extract of the fruits of milk thistle (Silybum marianum), were detected for the first time from a fungal endophyte, Aspergillus iizukae, isolated from the surface-sterilized leaves of S. marianum. The flavonolignans were identified using a UPLC-PDA-HRMS-MS/MS method by matching retention times, HRMS, and MS/MS data with authentic reference compounds. Attenuation of flavonolignan production was observed following successive subculturing of the original flavonolignan-producing culture, as is often the case with endophytes that produce plant-based secondary metabolites. However, production of 1 and 2 resumed when attenuated spores were harvested from cultures grown on a medium to which autoclaved leaves of S. marianum were added. The cycle of attenuation followed by resumed biosynthesis of these flavonolignans was replicated in triplicate.


Anterior versus posterior surgical approaches to treat cervical spondylotic myelopathy: outcomes of the prospective multicenter AOSpine North America CSM study in 264 patients.
A prospective observational multicenter study. To help solve the debate regarding whether the anterior or posterior surgical approach is optimal for patients with cervical spondylotic myelopathy (CSM). The optimal surgical approach to treat CSM remains debated with varying opinions favoring anterior versus posterior surgical approaches. We present an analysis of a prospective observational multicenter study examining outcomes of surgical treatment for CSM. A total of 278 subjects from 12 sites in North America received anterior/posterior or combined surgery at the discretion of the surgeon. This study focused on subjects who had either anterior or posterior surgery (n = 264, follow-up rate, 87%). Outcome measures included the modified Japanese Orthopedic Assessment scale, the Nurick scale, the Neck Disability Index, and the Short-Form 36 (SF-36) Health Survey version 2 Physical and Mental Component Scores. One hundred and sixty-nine patients were treated anteriorly and 95 underwent posterior surgery. Anterior surgical cases were younger and had less severe myelopathy as assessed by mJOA and Nurick scores. There were no baseline differences in Neck Disability Index or SF-36 between the anterior and posterior cases. Improvement in the mJOA was significantly lower in the anterior group than posterior group (2.47 vs. 3.62, respectively, P < 0.01), although the groups started at different levels of baseline impairment. The extent of improvement in the Nurick Scale, Neck Disability Index, SF-36 version 2 Physical Component Score, and SF-36 version 2 Mental Component Score did not differ between the groups. Patients with CSM show significant improvements in several health-related outcome measures with either anterior or posterior surgery. Importantly, patients treated with anterior techniques were younger, with less severe impairment and more focal pathology. We demonstrate for the first time that, when patient and disease factors are controlled for, anterior and posterior surgical techniques have equivalent efficacy in the treatment of CSM. 3.


Evolving phenotypes of non-hospitalized patients that indicate long COVID.
For some SARS-CoV-2 survivors, recovery from the acute phase of the infection has been grueling with lingering effects. Many of the symptoms characterized as the post-acute sequelae of COVID-19 (PASC) could have multiple causes or are similarly seen in non-COVID patients. Accurate identification of PASC phenotypes will be important to guide future research and help the healthcare system focus its efforts and resources on adequately controlled age- and gender-specific sequelae of a COVID-19 infection. In this retrospective electronic health record (EHR) cohort study, we applied a computational framework for knowledge discovery from clinical data, MLHO, to identify phenotypes that positively associate with a past positive reverse transcription-polymerase chain reaction (RT-PCR) test for COVID-19. We evaluated the post-test phenotypes in two temporal windows at 3-6 and 6-9 months after the test and by age and gender. Data from longitudinal diagnosis records stored in EHRs from Mass General Brigham in the Boston Metropolitan Area was used for the analyses. Statistical analyses were performed on data from March 2020 to June 2021. Study participants included over 96 thousand patients who had tested positive or negative for COVID-19 and were not hospitalized. We identified 33 phenotypes among different age/gender cohorts or time windows that were positively associated with past SARS-CoV-2 infection. All identified phenotypes were newly recorded in patients' medical records 2 months or longer after a COVID-19 RT-PCR test in non-hospitalized patients regardless of the test result. Among these phenotypes, a new diagnosis record for anosmia and dysgeusia (OR 2.60, 95% CI [1.94-3.46]), alopecia (OR 3.09, 95% CI [2.53-3.76]), chest pain (OR 1.27, 95% CI [1.09-1.48]), chronic fatigue syndrome (OR 2.60, 95% CI [1.22-2.10]), shortness of breath (OR 1.41, 95% CI [1.22-1.64]), pneumonia (OR 1.66, 95% CI [1.28-2.16]), and type 2 diabetes mellitus (OR 1.41, 95% CI [1.22-1.64]) is one of the most significant indicators of a past COVID-19 infection. Additionally, more new phenotypes were found with increased confidence among the cohorts who were younger than 65. The findings of this study confirm many of the post-COVID-19 symptoms and suggest that a variety of new diagnoses, including new diabetes mellitus and neurological disorder diagnoses, are more common among those with a history of COVID-19 than those without the infection. Additionally, more than 63% of PASC phenotypes were observed in patients under 65 years of age, pointing out the importance of vaccination to minimize the risk of debilitating post-acute sequelae of COVID-19 among younger adults.


Polyphyly of Mussaenda inferred from ITS and trnT-F data and its implication for generic limits in Mussaendeae (Rubiaceae).
Although recognition of Mussaenda as a separate genus has been widely accepted, its generic circumscriptions have always been controversial. In this first molecular phylogenetic study focused specifically on Mussaenda sensu lato (s.l.) and its allied genera, parsimony analyses were based on both ITS and trnT-F sequence data to (1) test the monophyly of Mussaenda s.l. as presently circumscribed, (2) assess the phylogenetic relationships within the tribe Mussaendeae as currently delimited, (3) evaluate the phylogenetic value of the morphological characters traditionally and/or currently used to circumscribe Mussaendeae, (4) and make inferences on the biogeographical origin of Mussaenda. Of the 63 trnT-F and 38 ITS sequences included in our studies, 52 and 36 sequences, respectively, are newly published here. Our results highly support the polyphyly of Mussaenda s.l. as currently delimited but further support the monophyly of Mussaendeae sensu Bremer and Thulin. The Malagasy Mussaenda are more closely related to Landiopsis than they are to the African and Asian Mussaenda. Pseudomussaenda and the Afro-Asian Mussaenda clade are resolved as sister groups. Aphaenandra is nested within the Afro-Asian Mussaenda clade. As a result, we merge Aphaenandra in Mussaenda, which is now restricted to include only the African and Asian Mussaenda representatives. We describe a new genus Bremeria to accommodate all Indian Ocean (Madagascar and the Mascarenes) Mussaenda species and make 19 new combinations. The newly delimited Mussaenda is diagnosed by reduplicate-valvate aestivation and glabrous styles, whereas Bremeria can be distinguished from the remaining Mussaendeae genera by having both reduplicate- and induplicate-valvate aestivation and densely pubescent styles. Our studies strongly suggest an African origin of the newly delimited Mussaenda. Finally, descriptions of the newly circumscribed Mussaenda and Bremeria are provided.


Newborn screening for congenital heart defects: a systematic review and cost-effectiveness analysis.
To provide evidence to inform policy decisions about the most appropriate newborn screening strategy for congenital heart defects, identifying priorities for future research that might reduce important uncertainties in the evidence base for such decisions. Electronic databases. Groups of parents and health professionals. A systematic review of the published medical literature concerning outcomes for children with congenital heart defects was carried out. A decision analytic model was developed to assess the cost-effectiveness of alternative screening strategies for congenital heart defects relevant to the UK. A further study was then carried out using a self-administered anonymous questionnaire to explore the perspectives of parents and health professionals towards the quality of life of children with congenital heart defects. The findings from a structured review of the medical literature regarding parental experiences were linked with those from a focus group of parents of children with congenital heart defects. Current newborn screening policy comprises a clinical examination at birth and 6 weeks, with specific cardiac investigations for specified high-risk children. Routine data are lacking, but under half of affected babies, not previously identified antenatally or because of symptoms, are identified by current newborn screening. There is evidence that screen-positive infants do not receive timely management. Pulse oximetry and echocardiography, in addition to clinical examination, are alternative newborn screening strategies but their cost-effectiveness has not been adequately evaluated in a UK setting. In a population of 100,000 live-born infants, the model predicts 121 infants with life-threatening congenital heart defects undiagnosed at screening, of whom 82 (68%) and 83 (69%) are detected by pulse oximetry and screening echocardiography, respectively, but only 39 (32%) by clinical examination alone. Of these, 71, 71 and 34, respectively, receive a timely diagnosis. The model predicts 46 (0.5%) false-positive screening diagnoses per 100,000 infants with clinical examination, 1168 (1.3%) with pulse oximetry and 4857 (5.4%) with screening echocardiography. The latter includes infants with clinically non-significant defects. Total programme costs are predicted of pound 300,000 for clinical examination, pound 480,000 for pulse oximetry and pound 3.54 million for screening echocardiography. The additional cost per additional timely diagnosis of life-threatening congenital heart defects ranges from pound 4900 for pulse oximetry to pound 4.5 million for screening echocardiography. Including clinically significant congenital heart defects gives an additional cost per additional diagnosis of pound 1500 for pulse oximetry and pound 36,000 for screening echocardiography. Key determinants for cost-effectiveness are detection rates for pulse oximetry and screening echocardiography. Parents and health professionals place similar values on the quality of life outcomes of children with congenital heart defects and both are more averse to neurological than to cardiac disability. Adverse psychosocial effects for parents are focused around poor management and/or false test results. Early detection through newborn screening potentially can improve the outcome of congenital heart defects; however the current programme performs poorly, and lacks monitoring of quality assurance, performance management and longer term outcomes. Pulse oximetry is a promising alternative newborn screening strategy but further evaluation is needed to obtain more precise estimates of test performance and to inform optimal timing, diagnostic and management strategies. Although screening echocardiography is associated with the highest detection rate, it is the most costly strategy and has a 5% false-positive rate. Improving antenatal detection of congenital heart defects increases the cost per timely postnatal diagnosis afforded by any newborn screening strategy but does not alter the relative effects of the strategies. An improvement of timely management of screen positive infants is essential. Further research is required to refine the detection rate and other aspects of pulse oximetry, to evaluate antenatal screening strategies more directly, and to investigate the psychosocial effects of newborn screening for congenital heart defects.


Quantifying the timescales over which exogenous and endogenous conditions affect soil respiration.
Understanding how exogenous and endogenous factors and above-ground-below-ground linkages modulate carbon dynamics is difficult because of the influences of antecedent conditions. For example, there are variable lags between above-ground assimilation and below-ground efflux, and the duration of antecedent periods are often arbitrarily assigned. Nonetheless, developing models linking above- and below-ground processes is crucial for estimating current and future carbon dynamics. We collected data on leaf-level photosynthesis (Asat ) and soil respiration (Rsoil ) in different microhabitats (under shrubs vs under bunchgrasses) in the Sonoran Desert. We evaluated timescales over which endogenous and exogenous factors control Rsoil by analyzing data in the context of a semimechanistic temperature-response model of Rsoil that incorporated effects of antecedent exogenous (soil water) and endogenous (Asat ) conditions. For both microhabitats, antecedent soil water and Asat significantly affected Rsoil , but Rsoil under shrubs was more sensitive to Asat than that under bunchgrasses. Photosynthetic rates 1 and 3 d before the Rsoil measurement were most important in determining current-day Rsoil under bunchgrasses and shrubs, respectively, indicating a significant lag effect. Endogenous and exogenous controls are critical drivers of Rsoil , but the relative importance and the timescale over which each factor affects Rsoil depends on above-ground vegetation and ecosystem structure characteristics.


[Distinctive features of orofacial pain perception].
In the widely used German pain questionnaire, qualitative pain characteristics are assessed by the Schmerzbeschreibungsliste (SBL). In clinical practice these adjectives insufficiently cover the spectrum of orofacial pain perceptions (OFP) and have not been proven by data. The aim of this study was the analysis of a questionnaire focussing on OFP (ZZM-FB) in which nine additional pain descriptors were amended to the SBL (SBL-OF). The objectives of this work were to (1) compare selection frequencies between the items of the SBL and the SBL-OF and (2) test the null hypothesis that the SBL and SBL-OF item selection is not influenced by gender, age, pain features (intensity, duration, time pattern, distribution), hospital anxiety and depression scale (HADS) and diagnosis. A total of 224 patients consecutively referred to the interdisciplinary OFP unit between 2010 and 2012 completed a ZZM-FB. The corresponding diagnosis was obtained from the clinical reports. In all, 209 OFP-Q were anonymized and data retrospectively analysed at a significance level of p ≤ 0.01. The descending rank order of the 12 most frequently selected items was as follow: pressing (SBL), dull (SBL), pulling (SBL), stinging (SBL), dreadful (SBL), miserable (SBL), exhausting (SBL-OF), grueling (SBL-OF), agonizing (SBL-OF), atrocious (SBL), horrible (SBL), pulsating (SBL). The null hypothesis was rejected for all parameters except for age. The selection frequency was significantly influenced by gender, pain intensity, duration and distribution, time pattern, HADS values and diagnosis. In this cohort, some ADD descriptors were selected more frequently than some SBL items, indicating that the SBL does not adequately capture the characteristics of OFP. These results will be considered in the construction of a revised ZZM-FB, which is currently in development.


Human trk oncogenes activated by point mutation, in-frame deletion, and duplication of the tyrosine kinase domain.
Malignant activation of the human trk proto-oncogene, a member of the tyrosine protein kinase receptor family, has been implicated in the development of certain human cancers, including colon and thyroid papillary carcinomas. trk oncogenes have also been identified in cultured cells transfected with various DNAs. In this study, we report the characterization of three in vitro-generated trk oncogenes, trk2, trk4, and trk5 (R. Oskam, F. Coulier, M. Ernst, D. Martin-Zanca, and M. Barbacid, Proc. Natl. Acad. Sci. USA 85:2964-2968, 1988), in an effort to understand the spectrum of mutational events that can activate the human trk gene. Nucleotide sequence analysis of cDNA clones of trk2 and trk4 revealed that these oncogenes were generated by a head-to-tail arrangement of two trk tyrosine protein kinase domains connected by a purine-rich region. These oncogenes code for cytoplasmic molecules of 67,000 (p67trk2) and 69,000 (p69trk4) daltons. In contrast, the product of the trk5 oncogene, gp95trk5, is a cell surface glycoprotein of 95,000 daltons. This oncogene was generated by a 153-base-pair in-frame deletion within sequences coding for the extracellular domain of the trk receptor. This activating deletion encompasses a triplet coding for one of the nine cysteine residues that the trk receptor shares with the product of the highly related trkB tyrosine protein kinase gene. Introduction of a single point mutation (TGT----AGT) in this codon resulted in a novel trk oncogene whose product, gp140S345, differs from the nontransforming trk proto-oncogene receptor in a single amino acid residue, Ser-345 instead of Cys-345. These results illustrate that multiple molecular mechanisms, including point mutation, internal deletion, and kinase domain duplication, can result in the malignant activation of the human trk proto-oncogene.


Targeted crisis resource management training improves performance among randomized nursing and medical students.
In this study designed with adequate statistical power to detect relevant training effects, investigators evaluated Crisis Resource Management (CRM) training during a simulated patient crisis. This study is guided by the Team Effectiveness Conceptual Model by Kozlowski and Ilgen. An experimental pretest/posttest design was used. Four-member, interdisciplinary teams, each composed of nursing and medical students, were randomly assigned to experimental or control conditions: Basic Life Support plus CRM training or Basic Life Support only, respectively. Team process (task management, teamworking, situation awareness, and interprofessional attitude) and team effectiveness (team error rate and response times) were the outcomes of interest. Experimental teams demonstrated significant improvement in team process measures compared with control teams. CRM training predicted 13% of the variance in task management (P = 0.05), 15% of the variance in teamworking (P = 0.04), and 18% of the variance in situation awareness (P = 0.03). CRM training and task management predicted 22% of the variance (P = 0.04) in team error rate; CRM training and teamworking predicted 35% of the variance (P = 0.01), while CRM training and situation awareness predicted 20% of the variance (P = 0.04) in response time to chest compressions. Both experimental and control teams demonstrated significant improvement in team effectiveness measures. CRM team training and team practice in an environment of high-fidelity simulation and facilitated debriefing have significant effects on team process and team effectiveness. The conceptual framework is potentially adaptable to additional settings and populations for team-related research and education.


Specific Roles of NMDA Receptor Subunits in Mental Disorders.
N-methyl-D-aspartate (NMDA) receptor plays important roles in learning and memory. NMDA receptors are a tetramer that consists of two glycine-binding subunits GluN1, two glutamate-binding subunits (i.e., GluN2A, GluN2B, GluN2C, and GluN2D), a combination of a GluN2 subunit and glycine-binding GluN3 subunit (i.e., GluN3A or GluN3B), or two GluN3 subunits. Recent studies revealed that the specific expression and distribution of each subunit are deeply involved in neural excitability, plasticity, and synaptic deficits. The present article summarizes reports on the dysfunction of NMDA receptors and responsible subunits in various neurological and psychiatric disorders, including schizophrenia, autoimmune-induced glutamatergic receptor dysfunction, mood disorders, and autism. A key role for the GluN2D subunit in NMDA receptor antagonist-induced psychosis has been recently revealed.


First Report of Beet severe curly top virus in Jalapeño Pepper in Chihuahua, Mexico.
Curly top is a serious problem in many irrigated crops in the semiarid areas in the western United States. The disease is caused by a complex of leafhopper-transmitted curtoviruses, one of which, Beet mild curly top virus (BMCTV), was previously found in chili pepper in Zacatecas and Aguascalientes, Mexico (3). During the past few years, sporadic symptoms similar to curly top disease were observed in jalapeño pepper in the south-central area of Chihuahua State. Symptomatic plants were scattered in otherwise healthy looking pepper stands and displayed stunting and yellowing. Affected leaves were brittle, showed upward curling, and a distinct green vein pattern with interveinal yellowing. In June and August of 2010, field surveys were conducted in Cordillera-Escuadra, Meoqui-Estacion Consuelo, Meoqui-Lomas del Consuelo, and Delicias-Presa Francisco I Madero. Ninety-four leaf samples were collected from symptomatic jalapeño pepper plants and subjected to ELISA and PCR testing for curly top. Of the 94 samples, 11 were found to be positive by triple-antibody sandwich-ELISA with polyclonal antibodies against curly top (2). To confirm the identification of curly top and type the specific curtovirus identified, four ELISA-positive samples were subjected to a PCR analysis using a virus-specific primer set for curtovirus typing designed by Chen et al. (1). All four samples tested produced a single 720-bp band with primers BSCTVv2688 and BGc396 (1) characteristic of the Beet severe curly top virus (BSCTV). These curly top-specific PCR amplicons were sequenced and found to be 99% similar to the BSCTV nucleotide sequence in the C1 gene region (GenBank Accession No. X97203); corresponding sequences were deposited in GenBank under Accession Nos. JF437870 to JF437873. To our knowledge, this is the first report of the curly top virus in the State of Chihuahua, demonstrating that curly top is established and common in jalapeño pepper here and will need surveillance in other vegetable crops under irrigation. References: (1) L. F. Chen et al. Plant Dis. 94:99, 2010. (2) J. Durrin et al. Plant Dis. 94:972, 2010. (3) R. Velásquez-Valle et al. Plant Dis. 92:650, 2008.


Removal of disinfection by-products formation potential by biologically intensified process.
The removal of disinfection by-products formation potential (DBPFP) in artificially intensified biological activated carbon (IBAC) process which is developed on the basis of traditional ozone granular activated carbon was evaluated. By IBAC removals of 31% and 68% for THMFP and HAAFP were obtained respectively. Under identical conditions, the removals of the same substances were 4% and 32% respectively only by the granular activated carbon (GAC) process. Compared with GAC, the high removal rates of the two formed potential substances were due to the increasing of bioactivity of the media and the synergistic capabilities of biological degradation cooperating with lactivated carbon adsorption of organic compounds. A clear linear correlation (R2 = 0.9562 and R2 = 0.9007) between DOC HAAFP removal rate and Empty Bed Contact Time (EBCT) of IBAC process was observed, while that between THMFP removal rate and EBCT of GAC was R2 = 0.9782. In addition certain linear correlations between THMFP, HAAFP and UV254 (R2 = 0.855 and R2 = 0.7702) were found for the treated water. For IBAC process there are also more advantages such as long backwashing cycle time, low backwashing intensity and prolonging activated carbon lifetime and so on.


Effect of 1 month of zopiclone on obstructive sleep apnoea severity and symptoms: a randomised controlled trial.
Hypnotic use in obstructive sleep apnoea (OSA) is contraindicated due to safety concerns. Recent studies indicate that single-night hypnotic use worsens hypoxaemia in some and reduces OSA severity in others depending on differences in pathophysiology. However, longer clinical trial data are lacking. This study aimed to determine the effects of 1 month of zopiclone on OSA severity, sleepiness and alertness in patients with low-moderate respiratory arousal thresholds without major overnight hypoxaemia.69 participants completed a physiology screening night with an epiglottic catheter to quantify arousal threshold. 30 eligible patients (apnoea-hypopnoea index (AHI) 22±11 events·h-1) then completed standard in-laboratory polysomnography (baseline) and returned for two additional overnight sleep studies (nights 1 and 30) after receiving either nightly zopiclone (7.5 mg) or placebo during a 1-month, double-blind, randomised, parallel trial (ANZCTR identifier ANZCTRN12613001106729).The change in AHI from baseline to night 30 was not different between zopiclone versus placebo groups (-5.9±10.2 versus -2.4±5.5 events·h-1; p=0.24). Similarly, hypoxaemia, next-day sleepiness and driving simulator performance were not different.1 month of zopiclone does not worsen OSA severity, sleepiness or alertness in selected patients without major overnight hypoxaemia. As the first study to assess the effect of a hypnotic on OSA severity and sleepiness beyond single-night studies, these findings provide important safety data and insight into OSA pathophysiology.


Cost of interventions to control schistosomiasis: A systematic review of the literature.
Schistosomiasis, a disease caused by blood flukes of the genus Schistosoma, belongs to the neglected tropical diseases. Left untreated, schistosomiasis can lead to severe health problems and even death. An estimated 800 million people are at risk of schistosomiasis and 250 million people are infected. The global strategy to control and eliminate schistosomiasis emphasizes large-scale preventive chemotherapy with praziquantel targeting school-age children. Other tools are available, such as information, education, and communication (IEC), improved access to water, sanitation, and hygiene (WASH), and snail control. Despite available evidence of the effectiveness of these control measures, analyses estimating the most cost-effective control or elimination strategies are scarce, inaccurate, and lack standardization. We systematically reviewed the literature on costs related to public health interventions against schistosomiasis to strengthen the current evidence-base. In adherence to the PRISMA guidelines, we systematically searched three readily available electronic databases (i.e., PubMed, WHOLIS, and ISI Web of Science) from inception to April 2019 with no language restrictions. Relevant documents were screened, duplicates eliminated, specific rules on studies to consider were defined, and the eligible studies fully reviewed. Costs of schistosomiasis interventions were classified in three groups: (i) preventive chemotherapy; (ii) preventive chemotherapy plus an individual diagnostic test to identify at-risk population; and (iii) test-and-treat interventions. Fifteen articles met our inclusion criteria. In general, it was hard to compare the reported costs from the different studies due to different approaches used to estimate and classify the costs of the intervention assessed. Costs varied considerably from one study to another, ranging from US$ 0.06 to US$ 4.46 per person treated. The difference between financial and opportunity costs only played a minimal role in the explanation of the costs' variation, even if delivery costs were two times higher in the analyses including economic costs. Most of the studies identified in our systematic review focused on sub-Saharan African countries. The degree of transparency of most of the costing studies of schistosomiasis interventions found in the current review was limited. Hence, there is a pressing need for strategies to improve the quality of cost analyses, and higher reporting standards and transparency that should be fostered by peer-review journal policies. Cost information on these interventions is crucial to inform resource allocation decisions and those regarding the affordability of scaling-up interventions.


Extreme Glacial Legacies: A Synthesis of the Antarctic Springtail Phylogeographic Record.
We review current phylogeographic knowledge from across the Antarctic terrestrial landscape with a focus on springtail taxa. We describe consistent patterns of high genetic diversity and structure among populations which have persisted in glacial refugia across Antarctica over both short (10 Mya) timescales. Despite a general concordance of results among species, we explain why location is important in determining population genetic patterns within bioregions. We complete our review by drawing attention to the main limitations in the field of Antarctic phylogeography, namely that the scope of geographic focus is often lacking within studies, and that large gaps remain in our phylogeographic knowledge for most terrestrial groups.


Price dynamics in political prediction markets.
Prediction markets, in which contract prices are used to forecast future events, are increasingly applied to various domains ranging from political contests to scientific breakthroughs. However, the dynamics of such markets are not well understood. Here, we study the return dynamics of the oldest, most data-rich prediction markets, the Iowa Electronic Presidential Election "winner-takes-all" markets. As with other financial markets, we find uncorrelated returns, power-law decaying volatility correlations, and, usually, power-law decaying distributions of returns. However, unlike other financial markets, we find conditional diverging volatilities as the contract settlement date approaches. We propose a dynamic binary option model that captures all features of the empirical data and can potentially provide a tool with which one may extract true information events from a price time series.


Transcervical approach to percutaneous endoscopic gastrostomy tube insertion in a patient with head and neck cancer.
This is the case of a 48-year-old woman with recurrent head and neck cancer. Six years before presenting at our institution, she was diagnosed with a moderately differentiated squamous cell carcinoma involving the right maxilla and underwent surgical resection followed by chemoradiation. More recently, she presented at our institution with oral bleeding and pain. Examination revealed severe trismus, and biopsy demonstrated recurrent squamous cell carcinoma. She underwent surgical resection with a plan for simultaneous placement of a feeding gastrostomy tube. Owing to the near non-existent mouth opening, traditional per-oral placement of a percutaneous endoscopic gastrostomy (PEG) tube was impossible. Intraoperatively, following tumor resection, endoscopy was performed via direct pharyngeal access through a right cervical incision. The PEG tube was then placed uneventfully. Numerous studies have shown the superiority of PEG tubes over either radiologically or surgically placed gastrostomy tubes. This report describes an approach to PEG placement in a patient in whom per-oral placement was not feasible.


[Bacteremia by enterobacteria in adults from a university hospital: a five year analysis].
Bacteremia continues to be one of the main causes of morbidity and mortality in adult patients despite the existence of numerous antimicrobial agents and an increase in support measures. The aim of this study was to analyze the cases of community and hospital-acquired bacteremia, by evaluating the prevalence of species, risk factors, source of infection and antimicrobial susceptibility of the microorganisms involved. From January 2000 to December 2004, 129 cases of bacteremia due to enterobacteria were detected in 45 outpatients (35%) and 84 inpatients (65%). The most common risk factors were neoplasia (33.3%) and diabetes (12.4%); being urinary (29.5%) and abdominal (13.9%) the most frequently found sources of infection. E. coli was the most common enterobacteria isolated in both populations, followed by Klebsiella spp. (21.7%), and Enterobacter spp. (12.4%). Klebsiella spp. bacteremia was most common in ICU patients and, together with Enterobacter spp., constituted the most antibiotic-resistant microorganisms.


All in the Blood: A Review of Aboriginal Australians' Cultural Beliefs About Blood and Implications for Biospecimen Research.
Public participation in medical research and biobanking is considered key to advances in scientific discovery and translation to improved health care. Cultural concerns relating to blood have been found to affect the participation of indigenous peoples and minorities in research, but such concerns are rarely specified in the literature. This article presents a review of the role of blood in Australian Aboriginal cultures. We discuss the range of meanings and uses of blood in traditional culture, including their use in ceremonies, healing, and sorcery. We draw on more recent literature on Aboriginal Australians and biomedicine to consider how traditional beliefs may be changing over time. These findings provide an empirical basis for researchers and bioethicists to develop culturally grounded strategies to boost the participation of Aboriginal Australians in biomedical research. They also serve as a model for integrating anthropological literature with bioethical concerns that could be applied to other indigenous and minority groups.


The structure of YqeH. An AtNOS1/AtNOA1 ortholog that couples GTP hydrolysis to molecular recognition.
AtNOS1/AtNOA1 was identified as a nitric oxide-generating enzyme in plants, but that function has recently been questioned. To resolve issues surrounding AtNOA1 activity, we report the biochemical properties and a 2.36 A resolution crystal structure of a bacterial AtNOA1 ortholog (YqeH). Geobacillus YqeH fused to a putative AtNOA1 leader peptide complements growth and morphological defects of Atnoa1 mutant plants. YqeH does not synthesize nitric oxide from L-arginine but rather hydrolyzes GTP. The YqeH structure reveals a circularly permuted GTPase domain and an unusual C-terminal beta-domain. A small N-terminal domain, disordered in the structure, binds zinc. Structural homology among the C-terminal domain, the RNA-binding regulator TRAP, and the hypoxia factor pVHL define a recognition module for peptides and nucleic acids. TRAP residues important for RNA binding are conserved by the YqeH C-terminal domain, whose positioning is coupled to GTP hydrolysis. YqeH and AtNOA1 probably act as G-proteins that regulate nucleic acid recognition and not as nitric-oxide synthases.


Beyond hypomethylating agents failure in patients with myelodysplastic syndromes.
Although hypomethylating agents (HMAs) significantly improve outcomes in myelodysplastic syndromes (MDS), only half the patients achieve objective responses, and most responders lose response within 1-2 years. Azacitidine prolongs survival by a median of only 9.5 months. Failure of HMA therapy is associated with a very dismal prognosis. Therefore, novel therapeutic approaches are clearly needed. The sequential use of the alternative HMA after failure of first line HMA is associated with modest efficacy. The improved understanding of the biologic underpinnings of the disease have opened the door to study investigational agents that target disrupted molecular pathways critical to the pathogenesis of MDS. Combination treatment strategies using an azacitidine backbone are demonstrating promising early results. Expanding the applicability of allogeneic stem cell transplantation (alloSCT), the only curative modality, by reducing toxicity and relapse rates is another area of active research. Sequential switching to the alternative HMA, clinical trials of novel targeted therapies, azacitidine-based combination therapeutic strategies, and improvements in the alloSCT platform are the main directions in improving outcomes of MDS post HMA failure.


Argumentation and the diffusion of counter-intuitive beliefs.
Research in cultural evolution has focused on the spread of intuitive or minimally counterintuitive beliefs. However, some very counterintuitive beliefs can also spread successfully, at least in some communities-scientific theories being the most prominent example. We suggest that argumentation could be an important factor in the spread of some very counterintuitive beliefs. A first experiment demonstrates that argumentation enables the spread of the counterintuitive answer to a reasoning problem in large discussion groups, whereas this spread is limited or absent when participants can show their answers to each other but cannot discuss. A series of experiments using the technique of repeated transmission show that, in the case of the counterintuitive belief studied: (a) arguments can help spread this belief without loss; (b) conformist bias does not help spread this belief; and (c) authority or prestige bias play a minimal role in helping spread this belief. Thus, argumentation seems to be necessary and sufficient for the spread of some counterintuitive beliefs. (PsycINFO Database Record


Uncovering the role of VDAC in the regulation of cell life and death.
Proper cell activity requires an efficient exchange of molecules between mitochondria and cytoplasm. Lying in the outer mitochondrial membrane, VDAC assumes a crucial position in the cell, forming the main interface between the mitochondrial and the cellular metabolisms. As such, it has been recognized that VDAC plays a crucial role in regulating the metabolic and energetic functions of mitochondria. Indeed, down-regulation of VDAC1 expression by shRNA leads to a decrease in energy production and cell growth. VDAC has also been recognized as a key protein in mitochondria-mediated apoptosis through its involvement in the release of apoptotic proteins located in the inter-membranal space and as the proposed target of pro- and anti-apoptotic members of the Bcl2-family and of hexokinase. Questions, however, remain as to if and how VDAC mediates the transfer of apoptotic proteins from the inter-membranal space to the cytosol. The diameter of the VDAC pore is only about 2.5-3 nm, insufficient for the passage of a folded protein like cytochrome c. New work, however, suggests that pore formation involves the assembly of homo-oligomers of VDAC or hetero-oligomers composed of VDAC and pro-apoptotic proteins, such as Bax. Thus, VDAC appears to represent a convergence point for a variety of cell survival and cell death signals. This review provides insight into the central role of VDAC in mammalian cell life and death, emphasizing VDAC function in the regulation of mitochondria-mediated apoptosis and, as such, its potential as a rational target for new therapeutics.


Calpain-2 activates Akt via TGF-β1-mTORC2 pathway in pulmonary artery smooth muscle cells.
Calpain is a family of calcium-dependent nonlysosomal neutral cysteine endopeptidases. Akt is a serine/threonine kinase that belongs to AGC kinases and plays important roles in cell survival, growth, proliferation, angiogenesis, and cell metabolism. Both calpain and Akt are the downstream signaling molecules of platelet-derived growth factor (PDGF) and mediate PDGF-induced collagen synthesis and proliferation of pulmonary artery smooth muscle cells (PASMCs) in pulmonary vascular remodeling. We found that inhibitions of calpain-2 by using calpain inhibitor MDL28170 and calpain-2 small interfering RNA attenuated Akt phosphorylations at serine-473 (S473) and threonine-308 (T308), as well as collagen synthesis and cell proliferation of PASMCs induced by PDGF. Overexpression of calpain-2 in PASMCs induced dramatic increases in Akt phosphorylations at S473 and T308. Moreover, knockout of calpain attenuated Akt phosphorylations at S473 and T308 in smooth muscle of pulmonary arterioles of mice with chronic hypoxic pulmonary hypertension. The cell-permeable-specific transforming growth factor (TGF)-β receptor inhibitor SB431542 attenuated Akt phosphorylations at both S473 and T308 induced by PDGF and by overexpressed calpain-2 in PASMCs. Furthermore, SB-431452 and knocking down activin receptor-like kinase-5 significantly reduced PDGF-induced collagen synthesis and cell proliferation of PASMCs. Nevertheless, neutralizing extracellular TGF-β1 using a cell-impermeable TGF-β1 neutralizing antibody did not affect PDGF-induced Akt phosphorylations at S473 and T308. Furthermore, inhibition of mammalian target of rapamycin complex 2 (mTORC2) by knocking down its component protein Rictor prevented Akt phosphorylations at S473 and T308 induced by PDGF and by overexpressed calpain-2. These data provide first evidence supporting that calpain-2 upregulates PDGF-induced Akt phosphorylation in pulmonary vascular remodeling via an intracrine TGF-β1/mTORC2 mechanism.


A social-cognitive model of trait and state levels of gratitude.
Three studies tested a new model of gratitude, which specified the generative mechanisms linking individual differences (trait gratitude) and objective situations with the amount of gratitude people experience after receiving aid (state gratitude). In Study 1, all participants (N = 253) read identical vignettes describing a situation in which they received help. People higher in trait gratitude made more positive beneficial appraisals (seeing the help as more valuable, more costly to provide, and more altruistically intended), which fully mediated the relationship between trait and state levels of gratitude. Study 2 (N = 113) replicated the findings using a daily process study in which participants reported on real events each day for up to 14 days. In Study 3, participants (N = 200) read vignettes experimentally manipulating objective situations to be either high or low in benefit. Benefit appraisals were shown to have a causal effect on state gratitude and to mediate the relationship between different prosocial situations and state gratitude. The 3 studies demonstrate the critical role of benefit appraisals in linking state gratitude with trait gratitude and the objective situation.


Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial.
Mesenchymal stem cells (MSCs) are under evaluation as a therapy for ischemic cardiomyopathy (ICM). Both autologous and allogeneic MSC therapies are possible; however, their safety and efficacy have not been compared. To test whether allogeneic MSCs are as safe and effective as autologous MSCs in patients with left ventricular (LV) dysfunction due to ICM. A phase 1/2 randomized comparison (POSEIDON study) in a US tertiary-care referral hospital of allogeneic and autologous MSCs in 30 patients with LV dysfunction due to ICM between April 2, 2010, and September 14, 2011, with 13-month follow-up. Twenty million, 100 million, or 200 million cells (5 patients in each cell type per dose level) were delivered by transendocardial stem cell injection into 10 LV sites. Thirty-day postcatheterization incidence of predefined treatment-emergent serious adverse events (SAEs). Efficacy assessments included 6-minute walk test, exercise peak VO2, Minnesota Living with Heart Failure Questionnaire (MLHFQ), New York Heart Association class, LV volumes, ejection fraction (EF), early enhancement defect (EED; infarct size), and sphericity index. Within 30 days, 1 patient in each group (treatment-emergent SAE rate, 6.7%) was hospitalized for heart failure, less than the prespecified stopping event rate of 25%. The 1-year incidence of SAEs was 33.3% (n = 5) in the allogeneic group and 53.3% (n = 8) in the autologous group (P = .46). At 1 year, there were no ventricular arrhythmia SAEs observed among allogeneic recipients compared with 4 patients (26.7%) in the autologous group (P = .10). Relative to baseline, autologous but not allogeneic MSC therapy was associated with an improvement in the 6-minute walk test and the MLHFQ score, but neither improved exercise VO2 max. Allogeneic and autologous MSCs reduced mean EED by −33.21% (95% CI, −43.61% to −22.81%; P < .001) and sphericity index but did not increase EF. Allogeneic MSCs reduced LV end-diastolic volumes. Low-dose concentration MSCs (20 million cells) produced greatest reductions in LV volumes and increased EF. Allogeneic MSCs did not stimulate significant donor-specific alloimmune reactions. In this early-stage study of patients with ICM, transendocardial injection of allogeneic and autologous MSCs without a placebo control were both associated with low rates of treatment-emergent SAEs, including immunologic reactions. In aggregate, MSC injection favorably affected patient functional capacity, quality of life, and ventricular remodeling. clinicaltrials.gov Identifier: NCT01087996.


Improving Newborn Survival in Southern Tanzania (INSIST) trial; community-based maternal and newborn care economic analysis.
Despite health systems improvements in Tanzania, gaps in the continuum of care for maternal, newborn and child health persist. Recent improvements have largely benefited those over one month of age, leading to a greater proportion of under-five mortality in newborns. Community health workers providing home-based counselling have been championed as uniquely qualified to reach the poorest. We provide financial and economic costs of a volunteer home-based counselling programme in southern Tanzania. Financial costs of the programme were extracted from project accounts. Ministry of Health and Social Welfare costs associated with programme implementation were collected based on staff and project monthly activity plans. Household costs associated with facility-based delivery were also estimated based on exit interviews with post-natal women. Time spent on the programme by implementers was assessed by interviews conducted with volunteers and health staff. The programme involved substantial design and set-up costs. The main drivers of set-up costs were activities related to volunteer training. Total annualized costs (design, set-up and implementation) amounted to nearly US$300 000 for financial costs and just over US$400 000 for economic costs. Volunteers (n = 842) spent just under 14 hours per month on programme-related activities. When volunteer time was valued under economic costs, this input amounted to just under half of the costs of implementation. The economic consequences of increased service use to households were estimated at US$36 985. The intervention cost per mother-newborn pair visited was between US$12.60 and US$19.50, and the incremental cost per additional facility-based delivery ranged from US$85.50 to US$137.20 for financial and economic costs (with household costs). Three scale-up scenarios were considered, with the financial cost per home visit respectively varying from $1.44 to $3.21 across scenarios. Cost-effectiveness compares well with supply-side initiatives to increase coverage of facility-based deliveries, and the intervention would benefit from substantial economies of scale.


Refractive index measurement of turbid media by transmission of backscattered light near the critical angle.
We investigate experimentally the determination of the effective refractive index (RI) of a turbid particle suspension from the angle dependence of light scattered by the particles and then transmitted into a transparent prism of higher RI. We assembled a versatile experimental device that may be recognized as an Abbe-type refractometer in which the sample is illuminated from the prism side and use it to measure the intensity profile of diffuse light refracted into the prism around the critical angle. By fitting a recently proposed theoretical model we extract the complex RI of turbid suspensions of particles from the measured intensity profiles. We show that the real part of the effective RI is readily obtained with good precision regardless of how the sample is illuminated, whereas obtaining the imaginary part is done with less precision but nevertheless useful measurements can be obtained. The effective RI obtained with this method compares very well with the so-called van de Hulst effective RI and the one derived from Keller's model of the effective propagation constant.


Anti-Psoriatic Drug Monomethylfumarate Increases Nuclear Factor Erythroid 2-Related Factor 2 Levels and Induces Aquaporin-3 mRNA and Protein Expression.
Oxidative stress contributes to inflammatory skin diseases, including psoriasis. Monomethylfumarate (MMF) is an antipsoriatic agent with a poorly understood mechanism of action. In other cell types MMF increases the expression of nuclear factor erythroid-derived 2-like 2 (Nrf2), a transcription factor that regulates cellular antioxidant responses, to reduce oxidative stress like that observed in inflammatory disorders such as multiple sclerosis. We tested the hypothesis that MMF enhances Nrf2 activity in keratinocytes, thereby improving their capacity to counteract environmental stresses. We used Western analysis, immunofluorescence, and real-time quantitative reverse-transcription polymerase chain reaction to examine the effect of MMF on the expression of Nrf2 and its targets. We also measured intracellular reactive oxygen species (ROS) levels following MMF treatment. Our data show that MMF increased total and nuclear Nrf2 levels in primary mouse keratinocytes and enhanced mRNA expression of several Nrf2-downstream effectors, including heme oxygenase-1 and peroxiredoxin-6. Moreover, MMF treatment attenuated the generation of ROS following hydrogen peroxide treatment. On the other hand, the expression and membranous localization of aquaporin-3 (AQP3), a glycerol channel implicated in keratinocyte differentiation, was stimulated by MMF, which also enhanced keratinocyte glycerol uptake. The Nrf2 activator sulforaphane also increased AQP3 levels, suggesting that AQP3 expression may be regulated by Nrf2. We show for the first time that MMF stimulates Nrf2 and AQP3 expression and function/activity in keratinocytes. This effect may account, in part, for the previously observed ability of MMF to inhibit proliferation and inflammatory mediator production and promote differentiation in keratinocytes and to treat psoriasis.


Activation of the epidermal growth factor receptor in macrophages regulates cytokine production and experimental colitis.
Macrophages regulate innate immunity to maintain intestinal homeostasis and play pathological roles in intestinal inflammation. Activation of the epidermal growth factor receptor (EGFR) promotes cellular proliferation, differentiation, survival, and wound closure in several cell types. However, the impact of EGFR in macrophages remains unclear. This study was to investigate whether EGFR activation in macrophages regulates cytokine production and intestinal inflammation. We found that EGFR was activated in colonic macrophages in mice with dextran sulfate sodium (DSS)-induced colitis and in patients with ulcerative colitis. DSS-induced acute colitis was ameliorated, and recovery from colitis was promoted in Egfr(fl/fl)LysM-Cre mice with myeloid cell-specific deletion of EGFR, compared with LysM-Cre mice. DSS treatment increased IL-10 and TNF levels during the acute phase of colitis, and increased IL-10 but reduced TNF levels during the recovery phase in Egfr(fl/fl)LysM-Cre mice. An anti-IL-10 neutralizing Ab abolished these effects of macrophage-specific EGFR deletion on DSS-induced colitis in Egfr(fl/fl)LysM-Cre mice. LPS stimulated EGFR activation and inhibition of EGFR kinase activity enhanced LPS-stimulated NF-κB activation in RAW 264.7 macrophages. Furthermore, induction of IL-10 production by EGFR kinase-blocked RAW 264.7 cells, in response to LPS plus IFN-γ, correlated with decreased TNF production. Thus, although selective deletion of EGFR in macrophages leads to increases in both pro- and anti-inflammatory cytokines in response to inflammatory stimuli, the increase in the IL-10 level plays a role in suppressing proinflammatory cytokine production, resulting in protection of mice from intestinal inflammation. These results reveal an integrated response of macrophages regulated by EGFR in intestinal inflammatory disorders.


OPTN/SRTR 2011 Annual Data Report: liver.
The current liver allocation system, introduced in 2002, decreased the importance of waiting time for allocation priorities; the number of active wait-listed candidates and median waiting times were immediately reduced. However, the total number of adult wait-listed candidates has increased since 2002, and median waiting time has increased since 2006. Pretransplant mortality rates have been stable, but the number of candidates withdrawn from the list as being too sick to undergo transplant nearly doubled between 2009 and 2011. Deceased donation rates have remained stable, with an increasing proportion of expanded criteria donors. Living donation has decreased over the past 10 years. Transplant outcomes remain robust, with continuously improving graft survival rates for deceased donor, living donor, and donation after circulatory death livers. Numbers of new and prevalent pediatric candidates on the waiting list have decreased. Pediatric pretransplant mortality has decreased, most dramatically for candidates aged less than 1 year. The transplant rate has increased since 2002, and is highest in candidates aged less than 1 year. Graft survival continues to improve for pediatric recipients of deceased donor and living donor livers. Incidence of acute rejections increases with time after transplant. Posttransplant lymphoproliferative disorder remains an important concern in pediatric recipients.


Perception of peer physical examination in two Australian osteopathy programs.
Peer physical examination (PPE) is an efficient and practical educational approach whereby students can practise their examination skills on each other before commencing clinical practice with actual patients. Little is known about the use of PPE in osteopathy education. Students in Year 1 of the osteopathy programs at Victoria University (Melbourne, Australia) and Southern Cross University (Lismore, Australia) completed the Examining Fellow Students and the Peer Physical Examination questionnaires prior to, and at the completion of, their first 12-week teaching session. Descriptive statistics were generated for each questionnaire. The McNemar and sign tests were used to evaluate differences between each questionnaire administration. Logistic regression was used to evaluate the influence of demographics on responses to both questionnaires. Results showed that students in both programs were generally willing to examine non-sensitive areas both before and after the 12-week teaching session. Students' were less apprehensive about PPE at the end of the teaching session, and this was reinforced by results for previous exposure to PPE in other courses. Consistent with previous studies, unwillingness to participate in PPE was associated with being female, being born outside Australia, holding religious beliefs, and being older. This is the first study to explore students' perceptions of PPE in this cohort and provides a basis for further work, including evaluating longer term changes in student perception of PPE, and whether these perceptions extend to practising manual therapy techniques. This study demonstrates that perceptions about PPE reported in medicine and other disciplines, namely that unwillingness to participate in PPE is associated with being female, being born outside Australia, holding religious beliefs, and being older, also apply to osteopathy. These findings are significant for all manual therapy students who spend a substantial portion of their course developing skills in PPE and practising manual therapy techniques. They highlight the need for curriculum development that acknowledges the importance of good practice in PPE, including discussions about body image, feedback skills training for educators, and providing detailed information to students about what to expect in practical skills classes before they commence their course.


Lack of efficacy of Haemophilus b polysaccharide vaccine in Minnesota.
We evaluated the efficacy of Haemophilus b polysaccharide vaccine in children in Minnesota using a case-control study. The vaccine became available in Minnesota in August 1985. During the subsequent 28 months, 88 cases of invasive H influenzae type b disease were identified in children 24 to 71 months of age, the group targeted for vaccination. Of the 88 cases, 36 (41%) occurred in vaccinated children. Fifty-eight (33%) of 176 controls were vaccinated during a similar period. The vaccine's protective efficacy for children with any history of vaccination was -58% (95% confidence interval = -204% to 18%). The vaccine's protective efficacy for children who were most likely to be protected by vaccination was -55% (95% confidence interval = -238% to 29%). Our results indicate that vaccination with Haemophilus b polysaccharide vaccine had no effect in preventing H influenzae type b disease in Minnesota children.


Coexistence among Epiphytic Bacterial Populations Mediated through Nutritional Resource Partitioning.
The levels of coexistence between Pseudomonas syringae and various nonpathogenic epiphytic species in the phyllosphere of beans (Phaseolus vulgaris) were assessed by using replacement series. The epiphytic species Pseudomonas fluorescens, Pantoea agglomerans, Stenotrophomonas maltophilia, and Methylobacterium organophilum were all capable of exhibiting higher levels of coexistence with P. syringae than was observed with a near-isogenic P. syringae strain pair. The ecological similarity of the epiphytes was estimated with niche overlap indices derived from in vitro carbon source utilization profiles. The level of coexistence of the epiphytes was inversely correlated with the ecological similarity of the strains. Hence, the level of coexistence between the epiphytes was proportional to the degree of niche differentiation, defined as the ability to utilize carbon sources not utilized by a competing strain. Comparisons of utilization profiles for groups of carbon sources (amino acids, organic acids, and carbohydrates) indicated the types of carbon sources for which the strains likely competed in the bean phyllosphere. P. fluorescens and P. syringae strains probably competed for most carbon sources. S. maltophilia and M. organophilum strains probably competed with P. syringae for most organic acids but few amino acids or carbohydrates. P. agglomerans strains probably competed with P. syringae for most amino acids and organic acids but few carbohydrates. A variable level of coexistence observed between P. agglomerans and P. syringae probably reflected the variability in abundance in the bean phyllosphere of the carbohydrates that P. agglomerans utilized exclusively.


Expression pattern of the Brachyury gene in whole-mount TWis/TWis mutant embryos.
The murine Brachyury (T) gene is required in mesoderm formation. Mutants carrying different T alleles show a graded severity of defects correlated with gene dosage along the body axis. The phenotypes range from shortening of the tail to the malformation of sacral vertebrae in heterozygotes, and to disruption of trunk development and embryonic death in homozygotes. Defects include a severe disturbance of the primitive streak, an early cessation of mesoderm formation and absence of the allantois and notochord, the latter resulting in an abnormality of the neural tube and somites. The T gene is expressed in nascent mesoderm and in the notochord of wild-type embryos. Here the expression of T in whole-mount mutant embryos homozygous for the T allele TWis is described. The TWis gene product is altered, but the TWis/TWis phenotype is very similar to that of T/T embryos which lack T. In early TWis/TWis embryos T expression is normal, but ceases prematurely during early organogenesis coincident with a cessation of mesoderm formation. The archenteron/node region is disrupted and the extension of the notochord precursor comes to a halt, followed by a decrease and finally a complete loss of T gene expression in the primitive streak and the head process/notochord precursor. It appears that the primary defect of the mutant embryo is the disruption of the notochord precursor in the node region which is required for axis elongation. Thus the T gene product is directly or indirectly involved in the organization of axial development.


Field application of a planted fixed bed reactor (PFR) for support media and rhizosphere investigation using undisturbed samples from full-scale constructed wetlands.
This study presents a novel method for investigations on undisturbed samples from full-scale horizontal subsurface-flow constructed wetlands (HSSFCW). The planted fixed bed reactor (PFR), developed at the Helmholtz Center for Environmental Research (UFZ), is a universal test unit for planted soil filters that reproduces the operational conditions of a constructed wetland (CW) system in laboratory scale. The present research proposes modifications on the PFR original configuration in order to allow its operation in field conditions. A mobile device to obtain undisturbed samples from real-scale HSSFCW was also developed. The experimental setting is presented with two possible operational configurations. The first allows the removal and replacement of undisturbed samples in the CW bed for laboratory investigations, guaranteeing sample integrity with a mobile device. The second allows the continuous operation of the PFR and undisturbed samples as a fraction of the support media, reproducing the same environmental conditions outside the real-scale system. Investigations on the hydrodynamics of the adapted PFR were carried out with saline tracer tests, validating the proposed adaptation. Six adapted PFR units were installed next to full-scale HSSFCW beds and fed with interstitial liquid pumped from two regions of planted and unplanted support media. Fourteen points were monitored along the system, covering carbon fractions, nitrogen and sulfate. The results indicate the method as a promising tool for investigations on CW support media, rhizosphere and open space for studies on CW modeling, respirometry, kinetic parameters, microbial communities, redox potential and plant influence on HSSFCW.


Modality-Invariant Image Classification Based on Modality Uniqueness and Dictionary Learning.
We present a unified framework for the image classification of image sets taken under varying modality conditions. Our method is motivated by a key observation that the image feature distribution is simultaneously influenced by the semantic-class and the modality category label, which limits the performance of conventional methods for that task. With this insight, we introduce modality uniqueness as a discriminative weight that divides each modality cluster from all other clusters. By leveraging the modality uniqueness, our framework is formulated as unsupervised modality clustering and classifier learning based on modality-invariant similarity kernel. Specifically, in the assignment step, each training image is first assigned to the most similar cluster according to its modality. In the update step, based on the current cluster hypothesis, the modality uniqueness and the sparse dictionary are updated. These two steps are formulated in an iterative manner. Based on the final clusters, a modality-invariant marginalized kernel is then computed, where the similarities between the reconstructed features of each modality are aggregated across all clusters. Our framework enables the reliable inference of semantic-class category for an image, even across large photometric variations. Experimental results show that our method outperforms conventional methods on various benchmarks, such as landmark identification under severely varying weather conditions, domain-adapting image classification, and RGB and near-infrared image classification.


Nucleation rate analysis of methane hydrate from molecular dynamics simulations.
Clathrate hydrates are solid crystalline structures most commonly formed from solutions that have nucleated to form a mixed solid composed of water and gas. Understanding the mechanism of clathrate hydrate nucleation is essential to grasp the fundamental chemistry of these complex structures and their applications. Molecular dynamics (MD) simulation is an ideal method to study nucleation at the molecular level because the size of the critical nucleus and formation rate occur on the nano scale. Various analysis methods for nucleation have been developed through MD to analyze nucleation. In particular, the mean first-passage time (MFPT) and survival probability (SP) methods have proven to be effective in procuring the nucleation rate and critical nucleus size for monatomic systems. This study assesses the MFPT and SP methods, previously used for monatomic systems, when applied to analyzing clathrate hydrate nucleation. Because clathrate hydrate nucleation is relatively difficult to observe in MD simulations (due to its high free energy barrier), these methods have yet to be applied to clathrate hydrate systems. In this study, we have analyzed the nucleation rate and critical nucleus size of methane hydrate using MFPT and SP methods from data generated by MD simulations at 255 K and 50 MPa. MFPT was modified for clathrate hydrate from the original version by adding the maximum likelihood estimate and growth effect term. The nucleation rates calculated by MFPT and SP methods are within 5%, and the critical nucleus size estimated by the MFPT method was 50% higher, than values obtained through other more rigorous but computationally expensive estimates. These methods can also be extended to the analysis of other clathrate hydrates.


Effectiveness of a brief lay counsellor-delivered, problem-solving intervention for adolescent mental health problems in urban, low-income schools in India: a randomised controlled trial.
Mental health problems are a leading cause of disability in adolescents worldwide. Problem solving is a well-tested mental health intervention in many populations. We aimed to investigate the effectiveness of a brief, transdiagnostic problem-solving intervention for common adolescent mental health problems when delivered by non-specialist school counsellors in New Delhi, India. This randomised trial was done in six government-run schools (three all-boys schools, two all-girls schools, and one co-educational school) that serve low-income communities. We recruited participants from grades 9 to 12 (ages 12-20 years) by selecting students with persistently elevated mental health symptoms accompanied by distress or functional impairment. Clinical eligibility criteria were assessed by research assistants using the Hindi-language version of the Strengths and Difficulties Questionnaire (SDQ), with reference to locally validated borderline cutoff scores of 19 or greater for boys and 20 or greater for girls on the SDQ Total Difficulties scale, an abnormal score of 2 or more on the SDQ Impact scale, and persistence of more than 1 month on the SDQ Chronicity index. Participants were randomly allocated (1:1) to problem solving delivered through a brief (2-3 week) counsellor-led intervention with supporting printed materials (intervention group), or problem solving delivered via printed booklets alone (control group). Primary outcomes were adolescent-reported mental health symptoms (SDQ Total Difficulties scale) and idiographic psychosocial problems (Youth Top Problems [YTP]) at 6 weeks. Primary analyses were done on an intention-to-treat basis at the 6-week endpoint. The trial is registered with ClinicalTrials.gov, NCT03630471. Participants were enrolled between Aug 20, and Dec 4, 2018. 283 eligible adolescents were referred to the trial, and 251 (89%) of these were enrolled (mean age 15·61 years; 174 [69%] boys). 125 participants were allocated to each group (after accounting for one participant in the intervention group who withdrew consent after randomisation). Primary outcome data were available for 245 (98%) participants. At 6 weeks, the mean YTP scores were 3·52 (SD 2·66) in the intervention group and 4·60 (2·75) in the control group (adjusted mean difference -1·01, 95% CI -1·63 to -0·38; adjusted effect size 0·36, 95% CI 0·11 to 0·61; p=0·0015). The mean SDQ Total Difficulties scores were 17·48 (5·45) in the intervention group and 18·33 (5·45) in the control group (-0·86, -2·14 to 0·41; 0·16, -0·09 to 0·41; p=0·18). We observed no adverse events. A brief lay counsellor-delivered problem-solving intervention combined with printed booklets seemed to have a modest effect on psychosocial outcomes among adolescents with diverse mental health problems compared with problem-solving booklets alone. This counsellor-delivered intervention might be a suitable first-line intervention in a stepped care approach, which is being evaluated in ongoing studies. Wellcome Trust.


Validity and responsiveness of four measures of occupational sitting and standing.
Evidence on the detrimental health effects of prolonged sedentary behavior is accumulating. Interventions need to have a specific focus on sedentary behavior in order to generate clinically meaningful decreases in sedentary time. When evaluating such intervention, the question whether a participant improved or deteriorated their behavior is fundamental and instruments that are able to detect those changes are essential. Therefore, the aim of this study was to determine the criterion validity against activPAL and responsiveness to change of two activity monitors (ActiGraph and activPAL) and two questionnaires for the assessment of occupational sitting and standing time. 42 participants took part in the Stand@Work intervention trial. Six (T0) and two (T1) weeks before they received a sit-stand workstation and three weeks thereafter (T2), participants wore an ActiGraph and an activPAL activity monitor, and completed the Occupational Sitting and Physical Activity Questionnaire (OSPAQ) and the Workforce Sitting Questionnaire (WSQ). The activPAL was used as the criterion validity measure. The ActiGraph showed strong validity for occupational sedentary time at T0 and T1 (Spearman rho = 0.77 and 0.69), but its validity dropped substantially after introduction of the sit-stand workstation (rho = 0.19). Correlations between occupational light-intensity activity assessed by the ActiGraph and occupational standing time assessed by the activPAL varied between 0.25-0.63. The occupational sitting validity correlation of the OSPAQ and WSQ varied from 0.35-0.48 and 0.25-0.30, respectively, and between 0.16-0.68 for the OSPAQ for occupational standing time. The intervention-induced changes in occupational sitting and standing time were well detected by the activPAL, OSPAQ and WSQ (sitting only), but not by the ActiGraph, which had the lowest responsiveness to change. This study suggests that studies aimed at determining differences in occupational sitting and standing time should use activPAL-type inclinometers as a preferred type of objective measure. Simple questionnaires showed sufficient validity and are usable in addition to an objective measure or alone when objective monitoring is not possible. The hip-worn ActiGraph was unable to distinguish between occupational sitting and standing time, when using uniaxial data and traditional cut-points for sedentary time and light-intensity activity. The study was registered with the Australian New Zealand Clinical Trials Registry (No. ACTRN 12612000072819).


Naturally occurring B-cell responses to breast cancer.
As demonstrated by the effectiveness of trastuzumab, antibodies against breast cancer antigens are a potentially potent mechanism of tumor control. While trastuzumab is administered exogenously, its efficacy suggests that induction of very high titer antibody responses in vivo might also be therapeutic. Both naturally occurring and vaccine-induced antibody responses to some breast cancer antigens are associated with improved survival in some cases. However, the improvement in survival associated with antibody responses to breast cancer is modest, and tumor regression is not known to be associated with the natural antitumor antibody response, indicating a need for improved understanding of the natural antitumor antibody response. Naturally occurring B-cell responses in the form of serum antibody, tumor reactive lymph node B cells, and tumor-infiltrating B cells have been described, and a variety of breast tumor-associated antigens have been identified based on reactivity of patient antibodies. This review discusses current knowledge of humoral immunity to breast cancer with regard to specific antigens and the basis for their immunogenicity, and the contexts (tumor, lymph node, serum) in which responses are observed. With few exceptions, "tumor-associated antigens" identified with naturally occurring antibodies may be overexpressed on tumor but are in fact nonspecific autoantigens. This suggests that while overexpression or aberrant processing can increase immunogenicity in some cases, the immunogenicity of many or even most tumor-associated antigens is a function of expression in tumor or the result of ancillary tumor factors.


Effect of the 5-HT1A partial agonist buspirone on regional cerebral blood flow in man.
Repeated measurements of regional cerebral blood flow (rCBF) were made in normal volunteers before, and after, the administration of the 5-HT1A partial agonist, buspirone, or placebo. The difference in rCBF, before and after drug, (buspirone versus placebo) was used to identify brain areas affected by buspirone. Buspirone-induced changes in rCBF were studied under two behavioural conditions (5 word-list learning and 15 word-list learning). Compared to placebo, buspirone increased blood flow in the cuneus during both behavioural states. However, decreases in blood flow, centred in the left dorso-lateral prefrontal cortex and posterior cingulate cortex, were only observed under one of the two behavioural conditions. It is concluded that buspirone-induced alterations in regional cerebral blood flow are better understood, not in relation to the known distribution of monoamine neurotransmitter systems (particularly ascending 5-HT projections), but rather in relation to putative neuronal circuits possibly many synapses "downstream" of buspirone's pharmacological site of action.


Crystal structure of the Rous sarcoma virus intasome.
Integration of the reverse-transcribed viral DNA into the host genome is an essential step in the life cycle of retroviruses. Retrovirus integrase catalyses insertions of both ends of the linear viral DNA into a host chromosome. Integrase from HIV-1 and closely related retroviruses share the three-domain organization, consisting of a catalytic core domain flanked by amino- and carboxy-terminal domains essential for the concerted integration reaction. Although structures of the tetrameric integrase-DNA complexes have been reported for integrase from prototype foamy virus featuring an additional DNA-binding domain and longer interdomain linkers, the architecture of a canonical three-domain integrase bound to DNA remained elusive. Here we report a crystal structure of the three-domain integrase from Rous sarcoma virus in complex with viral and target DNAs. The structure shows an octameric assembly of integrase, in which a pair of integrase dimers engage viral DNA ends for catalysis while another pair of non-catalytic integrase dimers bridge between the two viral DNA molecules and help capture target DNA. The individual domains of the eight integrase molecules play varying roles to hold the complex together, making an extensive network of protein-DNA and protein-protein contacts that show both conserved and distinct features compared with those observed for prototype foamy virus integrase. Our work highlights the diversity of retrovirus intasome assembly and provides insights into the mechanisms of integration by HIV-1 and related retroviruses.


Gas-phase organics in environmental tobacco smoke. 1. Effects of smoking rate, ventilation, and furnishing level on emission factors.
We measured the emissions of 26 gas-phase organic compounds in environmental tobacco smoke (ETS) using a model room that simulates realistic conditions in residences and offices. Exposure-relevant emission factors (EREFs), which include the effects of sorption and re-emission over a 24-h period, were calculated by mass balance from measured compound concentrations and chamber ventilation rates in a 50-m3 room constructed and furnished with typical materials. Experiments were conducted at three smoking rates (5, 10, and 20 cigarettes day(-1)), three ventilation rates (0.3, 0.6, and 2 h(-1)), and three furnishing levels (wallboard with aluminum flooring, wallboard with carpet, and full furnishings). Smoking rate did not affect EREFs, suggesting that sorption was linearly related to gas-phase concentration. Furnishing level and ventilation rate in the model room had little effect on EREFs of several ETS compounds including 1,3-butadiene, acrolein, acrylonitrile, benzene, toluene, and styrene. However, sorptive losses at low ventilation with full furnishings reduced EREFs for the ETS tracers nicotine and 3-ethenylpyridine by as much as 90 and 65% as compared to high ventilation, wallboard/aluminum experiments. Likewise, sorptive losses were 40-70% for phenol, cresols, naphthalene, and methylnaphthalenes. Sorption persisted for many compounds; for example, almost all of the sorbed nicotine and most of the sorbed cresol remained sorbed 3 days after smoking. EREFs can be used in models and with ETS tracer-based methods to refine and improve estimates of exposures to ETS constituents.


The effect of time delay to surgical debridement of open tibia shaft fractures on infection rate.
Historical practices have advocated emergent operative debridement for all open fractures. To date only studies in guinea pigs have demonstrated decreased infection with surgical intervention within 6 hours of injury. Recent studies have questioned this practice in humans. The purpose of this study was to determine if there was an increased infection rate based on time delay from presentation to initial operative debridement. A retrospective chart review was done from 1998 to 2004 to identify patients who presented to our level 1 trauma center with open tibia shaft fractures and had at least 2 years of follow-up. Two hundred fifteen open tibia shaft fractures in 206 patients were included in this study. A time delay of 0 to 6 hours revealed a 10.8% (7/65) infection rate, of 6 to 12 hours a 9.5% (9/95) infection rate, of 12 to 24 hours a 5.6% (2/36) infection rate, and no infections in a delay >24 hours (N=19). Using the Mantel-Haenszel chi-square test, P=.12; Fisher exact test P value was .53. Combining time intervals to 0 to 12 hours and >12 hours returned 10% (16/160) and 3.6% (2/55) infection rates, respectively. Fisher exact test P value was .17. Statistical analysis failed to show significant differences among the various time interval groups. Based on current evidence, we recommend that in the absence of gross contamination, early informal irrigation should be done on an urgent basis along with initiation of intravenous antibiotics, while a formal debridement combined with fixation, if indicated, can be done later in a timely manner.


Cancer, signal transduction and nanotechnology.
Understanding the mechanisms underlying different cellular signaling pathways implicated in the pathogenesis of cancer are leading to the identification of novel drug targets as well as novel drug candidates. Multiple targeted therapeutics that modulate aberrant molecular pathways have already reached the clinic. However, targeted therapeutics can exert mechanism-driven side effects as a result of the implication of the molecular target in normal physiological functions besides tumorigenesis. We hypothesize that targeted therapeutics can be optimized by merging them with nanotechnology, which offers the potential for preferential targeting to the tumor, resulting in increased intratumoral concentrations of the active agent with reduced distribution to other parts of the body. This review will address some of the emerging concepts that integrate these two disciplines to engineer novel nanovectors that target different signaling pathways.