Neurodevelopmental outcome in babies weighing less than 2001 g at birth.
From 1976 to 1980, 1034 infants with birth weights of 500-2000 g were cared for in the neonatal medical unit; 724 were discharged. Twenty (2.8%) subsequently died and 654 (90.3%) were followed up at a median age of 3 years 3 months. Fifty five (7.6%) survivors had major neurodevelopmental handicaps not attributable to congenital anomalies. Increasing prevalence of major handicap was found with decreasing birth weight and gestation. Children with birth weights of less than 1251 g had a higher incidence of all major disabilities. Handicapped children with a birth weight less than 1251 g were more likely to have blindness, deafness, multiple disabilities, and more severe cerebral palsy. There were 146 (20.2%) children with minor disabilities: neurological impairments (n = 11), borderline results on psychometric testing (n = 18), visual impairments (n = 52), hearing impairments (n = 40), and speech impairments (n = 71). Children weighing less than 1251 g at birth had a higher incidence of minor visual and hearing impairments. In 389 children the mean Griffiths quotient was 101.6 (SD 17.2) (range 50-147), and 158 children had a mean Wechsler preschool and primary intelligence quotient of 101.8 (13.2) (range 56-127): these quotients did not vary with birth weight or gestation but did vary with socioeconomic group, schooling, and family structure. During the study period an improving prognosis in terms of both survival and handicap was observed in children weighing less than 1251 g at birth.


Interspecies Dissemination of a Mobilizable Plasmid Harboring blaIMP-19 and the Possibility of Horizontal Gene Transfer in a Single Patient.
Carbapenemase-producing Gram-negative bacilli have been a global concern over the past 2 decades because these organisms can cause severe infections with high mortality rates. Carbapenemase genes are often carried by mobile genetic elements, and resistance plasmids can be transferred through conjugation. We conducted whole-genome sequencing (WGS) to demonstrate that the same plasmid harboring a metallo-β-lactamase gene was detected in two different species isolated from a single patient. Metallo-β-lactamase-producing Achromobacter xylosoxidans (KUN4507), non-metallo-β-lactamase-producing Klebsiella pneumoniae (KUN4843), and metallo-β-lactamase-producing K. pneumoniae (KUN5033) were sequentially isolated from a single patient and then analyzed in this study. Antimicrobial susceptibility testing, molecular typing (pulsed-field gel electrophoresis and multilocus sequence typing), and conjugation analyses were performed by conventional methods. Phylogenetic and molecular clock analysis of K. pneumoniae isolates were performed with WGS, and the nucleotide sequences of plasmids detected from these isolates were determined using WGS. Conventional molecular typing revealed that KUN4843 and KUN5033 were identical, whereas the phylogenetic tree analysis revealed a slight difference. These two isolates were separated from the most recent common ancestor 0.74 years before they were isolated. The same resistance plasmid harboring blaIMP-19 was detected in metallo-β-lactamase-producing A. xylosoxidans and K. pneumoniae Although this plasmid was not self-transferable, the conjugation of this plasmid from A. xylosoxidans to non-metallo-β-lactamase-producing K. pneumoniae was successfully performed. The susceptibility patterns for metallo-β-lactamase-producing K. pneumoniae and the transconjugant were similar. These findings supported the possibility of the horizontal transfer of plasmid-borne blaIMP-19 from A. xylosoxidans to K. pneumoniae in a single patient.


Discovery of novel heart rate-associated loci using the Exome Chip.
Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.


What have birth cohort studies asked about genetic, pre- and perinatal exposures and child and adolescent onset mental health outcomes? A systematic review.
Increased understanding of early neurobehavioural development is needed to prevent, identify, and treat childhood psychopathology most effectively at the earliest possible stage. Prospective birth cohorts can elucidate the association of genes, environment, and their interactions with neurobehavioural development. We conducted a systematic review of the birth cohort literature. On the basis of internet searches and 6,248 peer-reviewed references, 105 longitudinal epidemiological studies were identified. Twenty studies met inclusion criteria (prospectively recruited, population-based cohort studies, including at least one assessment before the end of the perinatal period and at least one assessment of behaviour, temperament/personality, neuropsychiatric or psychiatric status before 19 years of age), and their methodologies were reviewed in full. Whilst the birth cohort studies did examine some aspects of behaviour and neurodevelopment, observations in the early months and years were rare. Furthermore, aspects of sampling method, sample size, data collection, design, and breadth and depth of measurement in some studies made research questions about neurodevelopment difficult to answer. Existing birth cohort studies have yielded limited information on how pre- and perinatal factors and early neurodevelopment relate to child psychopathology. Further epidemiological research is required with a specific focus on early neurodevelopment. Studies are needed which include the measures of early childhood psychopathology and involve long-term follow-up.


Perioperative course of FXIII in children undergoing major surgery.
Acquired deficiency of FXIII because of perioperative hemodilution has been described several times in adults; however, data in children are scarce. We performed a prospective observational trial to evaluate the intraoperative course of FXIII in children undergoing elective major surgery. Blood samples were repeatedly taken from 46 children aged 0.3-16 years undergoing major surgery. Concentrations of FXIII and fibrinogen, thrombelastometry by ROTEM®, and cell count were assessed intraoperatively. A significant decrease in FXIII concentration (median 60%; IQR 49-69%) was already noted at beginning of surgical procedures, while most ROTEM® traces remain unchanged. FXIII levels further deteriorated intraoperatively to minimal levels of 33% (15-61%). Lowest intraoperative clot strength (ExTEM) was 44 mm (34-50 mm), and fibrinogen plasma levels decreased to minimal levels of 130 mg·dl(-1) (95-160 mg·dl(-1) ). In 43 of 46 children, transfusion therapy was necessary. Despite of transfusion of fresh frozen plasma (cumulative total dose 22 ml·kg(-1) [11-32 ml·kg(-1) ]) in 21 of 46 children, FXIII level remains low in all children till the end of surgery at levels of 39% (20-46%). Coagulation factor XIII decreased early during major surgery owing to hemodilution. Overall intraoperative FXIII levels remain low despite of transfusion of fresh frozen plasma.


High-Dose Chemotherapy with Stem Cell Rescue in Desmoplastic Small Round Cell Tumor: A Single-Institution Experience and Review of the Literature.
Desmoplastic small round cell tumor (DSRCT) is a rare cancer that predominantly affects males averaging 21 years of age at the time of diagnosis. We describe four cases from our institution and place them within the context of a comprehensive review of the literature. Study population included any patient who received treatment at Children's Hospital at Montefiore (CHAM) with histologic diagnosis of DSRCT. A search of the electronic databases PubMed, Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE for the terms "desmoplastic" AND "small" AND "round" AND "cell" AND "tumor" was performed. One CHAM patient died of disease at 39 months, one patient has relapsed disease at 40 months, and two patients have no evidence of disease at 60 and 91 months. In the literature review, the 3-year OS was 36% and 5-year OS was 13%. There was a statistically significant difference in OS between no transplant and SCT in remission (p=0.004); however, there was no difference between no transplant and SCT not in remission (p=0.23). Given the poor prognosis in DSRCT, this study supports further prospective research into the possible benefit of consolidation of autologous SCT in patients with DSRCT who are in remission, with the alternative inference that these patients in remission may fare well without SCT. Our retrospective review of the literature does not support SCT for patients who are not in remission.


Self-assembled orthoester cryptands: orthoester scope, post-functionalization, kinetic locking and tunable degradation kinetics.
Dynamic adaptability and biodegradability are key features of functional, 21st century host-guest systems. We have recently discovered a class of tripodal supramolecular hosts, in which two orthoesters act as constitutionally dynamic bridgeheads. Having previously demonstrated the adaptive nature of these hosts, we now report the synthesis and characterization - including eight solid state structures - of a diverse set of orthoester cages, which provides evidence for the broad scope of this new host class. With the same set of compounds, we demonstrated that the rates of orthoester exchange and hydrolysis can be tuned over a remarkably wide range, from rapid hydrolysis at pH 8 to nearly inert at pH 1, and that the Taft parameter of the orthoester substituent allows an adequate prediction of the reaction kinetics. Moreover, the synthesis of an alkyne-capped cryptand enabled the post-functionalization of orthoester cryptands by Sonogashira and CuAAC "click" reactions. The methylation of the resulting triazole furnished a cryptate that was kinetically inert towards orthoester exchange and hydrolysis at pH > 1, which is equivalent to the "turnoff" of constitutionally dynamic imines by means of reduction. These findings indicate that orthoester cages may be more broadly useful than anticipated, e.g. as drug delivery agents with precisely tunable biodegradability or, thanks to the kinetic locking strategy, as ion sensors.


Consecutive days of prolonged tennis match play: performance, physical, and perceptual responses in trained players.
To determine how consecutive days of prolonged tennis match play affect performance, physiological, and perceptual responses. Seven well-trained male tennis players completed 4-h tennis matches on 4 consecutive days. Pre- and postmatch measures involved tennis-specific (serve speed and accuracy), physical (20-m sprint, countermovement jump [CMJ], shoulder-rotation maximal voluntary contraction, isometric midthigh pull), perceptual (Training Distress Scale, soreness), and physiological (creatine kinase [CK]) responses. Activity profile was assessed by heart rate, 3D load (accumulated accelerations measured by triaxial accelerometers), and rating of perceived exertion (RPE). Statistical analysis compared within- and between-days values. Changes (± 90% confidence interval [CI]) ≥75% likely to exceed the smallest important effect size (0.2) were considered practically important. 3D load reduced on days 2 to 4 (mean effect size ± 90% CI -1.46 ± 0.40) and effective playing time reduced on days 3 to 4 (-0.37 ± 0.51) compared with day 1. RPE did not differ and total points played only declined on day 3 (-0.38 ± 1.02). Postmatch 20-m sprint (0.79 ± 0.77) and prematch CMJ (-0.43 ± 0.27) performance declined on days 2 to 4 compared with prematch day 1. Although serve velocity was maintained, compromised postmatch serve accuracy was evident compared with prematch day 1 (0.52 ± 0.58). CK increased each day, as did ratings of muscle soreness and fatigue. Players reduced external physical loads, through declines in movement, over 4 consecutive days of prolonged competitive tennis. This may be affected by tactical changes and pacing strategies. Alongside this, impairments in sprinting and jumping ability, perceptual and biochemical markers of muscle damage, and reduced mood states may be a function of neuromuscular and perceptual fatigue.


Investigating inflammation in depression in the chronically ill: Theoretical model and perspectives.
Inflammation is a risk factor for chronic physical illnesses. Evidence is building that inflammation is also a risk factor for mental illnesses making inflammation a common mechanism which could explain the high comorbidity between mental and physical illnesses. Based on a systematic search, a review on factors associated with inflammation in the depressed chronically ill has been conducted. Relevant articles have been selected according to the methodological considerations (scope, sample size, type of analysis and bias). Five categories of factors mediate the association between chronic physical and mental illnesses: (1) social-demographic factors, (2) social-economic background, (3) adverse health behaviours, (4) psychological stress and (5) genetics. Psychological therapies and medication also moderate this association. A theoretical model of the interplay between inflammation, depression and chronic physical illness is then presented. Inflammation contribute to both chronic physical and mental illnesses. These conclusions support future advances in clinical and research practice, as well as training and education.


Analytic Considerations in Applying a General Economic Evaluation Reference Case to Gene Therapy.
The concept of a reference case, first proposed by the US Panel on Cost-Effectiveness in Health and Medicine, has been used to specify the required methodological features of economic evaluations of healthcare interventions. In the case of gene therapy, there is a difference of opinion on whether a specific methodological reference case is required. The aim of this article was to provide a more detailed analysis of the characteristics of gene therapy and the extent to which these characteristics warrant modifications to the methods suggested in general reference cases for economic evaluation. We argue that a completely new reference case is not required, but propose a tailored checklist that can be used by analysts and decision makers to determine which aspects of economic evaluation should be considered further, given the unique nature of gene therapy.


Rechallenge with temozolomide in patients with recurrent gliomas.
Temozolomide (TMZ) is the standard of care for patients with newly diagnosed glioblastoma (GBM) as well as those with recurrent anaplastic glioma (AG) and GBM. It has become common practice to re-expose patients to TMZ who had been previously treated with TMZ, or to switch patients to alternative dosing regimens of TMZ when there are signs of relapse or progress on standard TMZ therapeutic regimens. To date, however, there is a scarcity of data on the efficacy of this therapeutic strategy, currently referred to as TMZ rechallenge. We have conducted a retrospective review of patients with recurrent glioma rechallenged with TMZ. Patients experiencing progressive disease (PD) during TMZ therapy who were rechallenged with alternative TMZ regimens and patients rechallenged after stable disease in a TMZ-free interval were evaluated separately. A total of 90 rechallenges were identified in 80 patients. The progression-free survival at 6 months (PFS-6) was 48% in patients with AG (12/25) and 27.7% in those with GBM (14/47). The PFS-6 was 16.7% in AG and 26.3% in GBM for patients switched during TMZ and 57.9 and 28.6% in patients rechallenged after a TMZ-free interval of at least 8 weeks. Relevant hematological toxicity (NCI-CTC grade 3-5) was observed in 22 of 90 rechallenges, and relevant non-hematological in ten of 90 rechallenges. Temozolomide was well tolerated and generated promising PFS-6 in patients who had previously failed TMZ, regardless if they progressed during TMZ treatment, or if they were rechallenged after a TMZ-free interval. These results suggest that the TMZ rechallenge strategy warrants further investigation in a prospective randomized trial.


Good, Bad, and Ugly Leadership Patterns: Implications for Followers' Work-Related and Context-Free Outcomes.
This research responds to calls for a more integrative approach to leadership theory by identifying subpopulations of followers who share a common set of perceptions with respect to their leader's behaviors. Six commonly researched styles were investigated: abusive supervision, transformational leadership (TFL), contingent reward (CR), passive and active management-by-exception (MBE-P and MBE-A, respectively), and laissez faire/avoidant (LF/A). Study hypotheses were tested with data from four independent samples of working adults, three from followers (N = 855) and a validation sample of leaders (N = 505). Using latent profile analysis, three pattern cohorts emerged across all four samples. One subpopulation of followers exhibited a constructive pattern with higher scores on TFL and CR relative to other styles. Two cohorts exhibited destructive patterns, one where the passive styles of MBE-A, MBE-P and LF/A were high relative to the other styles (passive) and one where the passive styles co-occurred with abusive supervision (passive-abusive). Drawing on conservation of resources theory, we confirmed differential associations with work-related (i.e., burnout, vigor, perceived organizational support and affective organizational commitment) and context-free (i.e., physical health and psychological well-being) outcomes. The passive-abusive pattern was devastating for physical health, yet passiveness without abuse was damaging for psychological well-being. Interestingly, we find a clear demarcation between passiveness as "benign neglect" and passiveness as an intentional and deliberate form of leadership aimed at disrupting or undermining followers-hence, the two faces of passiveness: "bad" and "ugly." We discuss the novel insights offered by a pattern (person)-oriented analytical strategy and the broader theoretical and practical implications for leadership research.


Delaying feedback compensates for impaired reinforcement learning in developmental dyslexia.
A theoretical framework suggests that developmental dyslexia is characterized by abnormalities in brain structures underlying the procedural learning and memory systems while the declarative learning and memory systems are presumed to remain intact or even enhanced (Procedural Deficit Hypothesis). This notion has been supported by a substantial body of research, which focused on each system independently. However, less attention has been paid to interactions between these memory systems which may provide insights as to learning situations and conditions in which learning in dyslexia can be improved. The current study was undertaken to examine these important but unresolved issues. To this end, probabilistic reinforcement learning and episodic memory tasks were examined in participants with dyslexia and neurotypicals simultaneously within a single task. Feedback timing presentation was manipulated, building on prior research indicating that delaying feedback timing shifts striatal-based probabilistic learning, to become more hippocampal-dependent. It was hypothesized that if the procedural learning and memory systems are impaired in dyslexia, performance will be impaired under conditions that encourage procedural memory engagement (immediate feedback trials) but not under conditions that promote declarative memory processing (long delayed feedback trials). It was also predicted that the ability to incidentally acquire episodic information would be preserved in dyslexia. The results supported these predictions. Participants with dyslexia were impaired in probabilistic learning of cue-outcome associations compared to neurotypicals in an immediate feedback condition, but not when feedback on choices was presented after a long delay. Furthermore, participants with dyslexia demonstrated similar performance to neurotypicals in a task requiring incidental episodic memory formation. These findings attest to a dissociation between procedural-based and declarative-based learning in developmental dyslexia within a single task, a finding that adds discriminative validity to the Procedural Deficit Hypothesis. Just as important, the present findings suggest that training conditions designed to shift the load from midbrain/striatal systems to declarative memory mechanisms have the potential to compensate for impaired learning in developmental dyslexia.


Nitric oxide and meiotic competence of porcine oocytes.
Reproductive biotechnology such as in vitro fertilization, the creation of transgenic animals or cloning by nuclear transfer depends on the use of fully grown, meiotically competent oocytes capable of completing meiotic maturation by reaching the stage of metaphase II. However, there exists only a limited quantity of these oocytes in the ovaries of females. In view of their limited number, growing oocytes without meiotic competence represent a possible source. The mechanisms controlling the acquisition of meiotic competence, however, are still not completely clear. A gas with a short half-life, nitric oxide (NO), produced by NO-synthase (NOS) enzyme can fulfill a regulatory role in this period. The objective of this study was to ascertain the role of NO in the growth phase of pig oocytes and its influence on the acquisition of meiotic competence with the help of NOS inhibitors, NO donors and their combinations. We demonstrated that the selective competitive iNOS inhibitor aminoguanidine and also the non-selective NOS inhibitor l-NAME block meiotic maturation of oocytes with partial or even full meiotic competence at the very beginning. NOS inhibitors influence even competent oocytes in the first stage of meiotic metaphase. However, blockage is less effective than at the beginning of meiotic maturation. The number of parthenogenetically activated competent oocytes greatly increased in a pure medium after inhibitor reversion. A large quantity of NO externally added to the in vitro cultivation environment disrupts the viability of oocytes. The effectiveness of the inhibitor can be reversed in oocytes by an NO donor in a very low concentration. However, the donor is not capable of pushing the oocytes farther than beyond the first stage of meiotic metaphase. The experiments confirmed the connection of NO with the growth period and the acquisition of meiotic competence. However, it is evident from the experiments that NO is not the only stimulus controlling the growth period.


Temporal shifts in the distribution of murine rodent body size classes at Liang Bua (Flores, Indonesia) reveal new insights into the paleoecology of Homo floresiensis and associated fauna.
Liang Bua, the type locality of Homo floresiensis, is a limestone cave located in the western part of the Indonesian island of Flores. The relatively continuous stratigraphic sequence of the site spans the past ∼190 kyr and contains ∼275,000 taxonomically identifiable vertebrate skeletal elements, ∼80% of which belong to murine rodent taxa (i.e., rats). Six described genera are present at Liang Bua (Papagomys, Spelaeomys, Hooijeromys, Komodomys, Paulamys, and Rattus), one of which, Hooijeromys, is newly recorded in the site deposits, being previously known only from Early to Middle Pleistocene sites in central Flores. Measurements of the proximal femur (n = 10,212) and distal humerus (n = 1186) indicate five murine body size classes ranging from small (mouse-sized) to giant (common rabbit-sized) are present. The proportions of these five classes across successive stratigraphic units reveal two major changes in murine body size distribution due to significant shifts in the abundances of more open habitat-adapted medium-sized murines versus more closed habitat-adapted smaller-sized ones. One of these changes suggests a modest increase in available open habitats occurred ∼3 ka, likely the result of anthropogenic changes to the landscape related to farming by modern human populations. The other and more significant change occurred ∼60 ka suggesting a rapid shift from more open habitats to more closed conditions at this time. The abrupt reduction of medium-sized murines, along with the disappearance of H. floresiensis, Stegodon florensis insularis (an extinct proboscidean), Varanus komodoensis (Komodo dragon), Leptoptilos robustus (giant marabou stork), and Trigonoceps sp. (vulture) at Liang Bua ∼60-50 ka, is likely the consequence of these animals preferring and tracking more open habitats to elsewhere on the island. If correct, then the precise timing and nature of the extinction of H. floresiensis and its contemporaries must await new discoveries at Liang Bua or other as yet unexcavated sites on Flores.


Measurement of the intensity of cell surface antigen expression in B-cell chronic lymphocytic leukemia.
Immunophenotyping of peripheral blood lymphocytes from 95 patients with B-cell chronic lymphocytic leukemia (B-CLL) was performed to estimate surface membrane intensity of the HLA-DR, CD20, and light-chain antigens. Cases were classified as having weak, moderate, or strong intensity by a standard slide immunocytochemical method, and the fluorescence intensity (FI) was measured by flow cytometry in molecules of equivalent soluble fluorescence (MESF). Staining intensity was strongest for HLA-DR; with both methods, 94 cases were classified as strong. For CD20, 67% were weak, 27% moderate, and 6% strong; the mean MESF values were 31.7, 66.4, and 177.4 x 10(3), respectively (P < .001). Thirty-nine percent had weak surface light-chain staining, 50% moderate, and 11% strong; the mean MESF values were 4.9, 7.5, and 16 x 10(3), respectively (P = .005). These results indicate that the FI of cell surface antigens can be estimated and quantified by flow cytometry. Because of the wide overlap of FI values among the three groups, an exact correlation was not found between the two methods of classifying intensity of surface antigen expression. The usefulness of these quantitative measurements needs further analysis in clinical trials.


Costs and benefits of provocation in bacterial warfare.
Competition in animals involves a wide variety of aggressive behaviors. One of the most sophisticated strategies for a focal actor is to provoke a competitor into uncontrolled aggression toward other competitors. Like animals, bacteria rely on a broad spectrum of molecular weapons, some of which provoke potential rivals by triggering retaliation. While bacterial provocation is well documented, its potential adaptive value has received little attention. Here, we examine the costs and benefits of provocation using mathematical modeling and experiments with Escherichia coli strains encoding colicin toxins. We show that provocation is typically costly in one-to-one encounters because a provoking strain receives a strong reciprocal attack compared with nonprovoking strains. By contrast, provocation can be strongly beneficial in communities including more than two toxin-producing strains, especially when the provoker is shielded from, or resistant to, its opponents' toxins. In these scenarios, we demonstrate that the benefit of provocation derives from a "divide-and-conquer" effect by which aggression-provoking toxin producers force their competitors into increased reciprocal aggression, leading to their cross-elimination. Furthermore, we show that this effect can be mimicked by using antibiotics that promote warfare among strains in a bacterial community, highlighting the potential of provocation as an antimicrobial approach.


Characterization of binding properties of the myelin-associated glycoprotein to extracellular matrix constituents.
The myelin-associated glycoprotein (MAG) can be obtained from adult mouse brain from detergent-lysates of a crude membrane fraction as a 96-100 kd form (detergent solubilized MAG), and from 100,000 g supernatants of homogenates as a 90-96 kd form (soluble MAG). The soluble form distributes into the Triton X-114-poor aqueous phase, while detergent-solubilized MAG predominantly enters the Triton X-114-rich phase. Both molecular forms bind to heparin in hypo- and isotonic buffers. Soluble MAG binds to several collagens (type G, I, II, III, IV, V, VI, IX) with a kd of 5.7 X 10(-8) M for collagen type IX and 2.0 X 10(-7) for collagen type IV. Binding of 125I-labeled MAG to collagen G can be completely inhibited by unlabeled MAG and collagen G, but not by heat-denatured collagen. MAG does not bind to itself, laminin, fibronectin, or the neural cell adhesion molecules L1 and N-CAM. Binding of MAG to collagen G is most effectively blocked by a high molecular weight dextran sulfate, heparan sulfate and heparin, with chondroitin sulfate and a low molecular weight dextran sulfate being less potent blockers. These findings are in agreement with previous observations on the localization of MAG in basal lamina and interstitial collagens of the sciatic nerve in situ.


Climate change and broadacre livestock production across southern Australia. 1. Impacts of climate change on pasture and livestock productivity, and on sustainable levels of profitability.
Broadacre livestock production is a major but highly diverse component of agriculture in Australia that will be significantly exposed to predicted changes in climate over coming decades. We used the GRAZPLAN simulation models to assess the impacts of climate change under the SRES A2 scenario across southern Australia. Climate change impacts were examined across space (25 representative locations) and time (1970-99, 2030, 2050 and 2070 climate) for each of five livestock enterprises. Climate projection uncertainty was considered by analysing projections from four global circulation models (GCMs). Livestock production scenarios were compared at their profit-maximizing stocking rate, constrained to ensure that risks of soil erosion were acceptable. Impacts on net primary productivity (ANPP) varied widely between GCM projections; the average declines from historical climate were 9% in 2030, 7% in 2050 and 14% in 2070. Declines in ANPP were larger at lower-rainfall locations. Sensitivity of ANPP to changes in rainfall ranged from 0.4 to 1.7, to temperature increase from -0.15 to +0.07 °C(-1) and to CO2 increase from 0.11 to 0.32. At most locations the dry summer period lengthened, exacerbating the greater erosion risk due to lower ANPP. Transpiration efficiency of pastures increased by 6-25%, but the proportion of ANPP that could safely be consumed by livestock fell sharply so that operating profit (at constant prices) fell by an average of 27% in 2030, 32% in 2050 and 48% in 2070. This amplification of ANPP reductions into larger profitability declines is likely to generalize to other extensive livestock systems. Profit declines were most marked at drier locations, with operating losses expected at 9 of the 25 locations by 2070. Differences between livestock enterprises were smaller than differences between locations and dates. Future research into climate change impacts on Australian livestock production needs to emphasise the dry margin of the cereal-livestock zone.


Overcoming inefficient secretion of recombinant VEGF-C in baculovirus expression vector system by simple purification of the protein from cell lysate.
The first reports about successfully expressed recombinant proteins with the use of a baculovirus vector were published over 30years ago. Despite the long time of refining this expression system, early problems with the production of baculovirus-derived secretory proteins are still not satisfactorily solved. The high expression level driven by baculoviral promoters often does not result in the desired yield of secreted recombinant proteins, which frequently accumulate inside insect cells and are only partially processed. During our attempts to produce vascular endothelial growth factor C (VEGF-C) with the use of a baculovirus vector we also faced an inefficient secretion of the recombinant protein to culture medium. We were not able to improve the outcome and obtain an acceptable concentration of VEGF-C in the medium by changing the culture conditions or utilizing different signal peptides. However, as a significant amount of native VEGF-C was detected inside the baculovirus-infected cells, we developed a simple method to purify recombinant, glycosylated VEGF-C from a lysate of the cells. The presented results indicate that the lack of a secretory protein in the insect cell culture medium after baculovirus infection does not necessarily signify failure in the production of the protein. As demonstrated by us and contrary to generally accepted views, the lysate of baculovirus-infected cells may constitute a valuable source of the biologically active, secretory protein.


On the importance of initial conditions for excited-state dynamics.
Photodynamical simulations are increasingly used to explore photochemical mechanisms and interpret laser experiments. The vast majority of ab initio excited-state simulations are performed within semiclassical, trajectory-based approaches. Apart from underlying electronic-structure theory, the reliability of simulations is controlled by a selection of initial conditions for the classical trajectories. We discuss appropriate choices of initial conditions for simulations of different experimental arrangements: dynamics initiated by continuum-wave (CW) laser fields or triggered by ultrashort laser pulses. We introduce a new technique, CW-sampling, to treat the former case, based on the ideas of importance sampling, combined with the quantum thermostat approach based on the Generalized Langevin Equation (GLE) that allows for efficient sampling of both position and momentum space. The CW-sampling is particularly important for photodynamical processes initiated by absorption at the tail of the UV absorption spectrum. We also emphasize the importance of non-Condon effects for the dynamics. We demonstrate the performance of our approach on the photodissociation of the CF2Cl2 molecule (Freon CFC-12). A quantitative agreement with the experimental data is achieved with the use of empirical correlation energy correction (CEC) factor on top of FOMO-CASCI potential energy surfaces.


Defects in mitochondrial efficiency and H2O2 emissions in obese women are restored to a lean phenotype with aerobic exercise training.
The notion that mitochondria contribute to obesity-induced insulin resistance is highly debated. Therefore, we determined whether obese (BMI 33 kg/m(2)), insulin-resistant women with polycystic ovary syndrome had aberrant skeletal muscle mitochondrial physiology compared with lean, insulin-sensitive women (BMI 23 kg/m(2)). Maximal whole-body and mitochondrial oxygen consumption were not different between obese and lean women. However, obese women exhibited lower mitochondrial coupling and phosphorylation efficiency and elevated mitochondrial H2O2 (mtH2O2) emissions compared with lean women. We further evaluated the impact of 12 weeks of aerobic exercise on obesity-related impairments in insulin sensitivity and mitochondrial energetics in the fasted state and after a high-fat mixed meal. Exercise training reversed obesity-related mitochondrial derangements as evidenced by enhanced mitochondrial bioenergetics efficiency and decreased mtH2O2 production. A concomitant increase in catalase antioxidant activity and decreased DNA oxidative damage indicate improved cellular redox status and a potential mechanism contributing to improved insulin sensitivity. mtH2O2 emissions were refractory to a high-fat meal at baseline, but after exercise, mtH2O2 emissions increased after the meal, which resembles previous findings in lean individuals. We demonstrate that obese women exhibit impaired mitochondrial bioenergetics in the form of decreased efficiency and impaired mtH2O2 emissions, while exercise effectively restores mitochondrial physiology toward that of lean, insulin-sensitive individuals.


[Analysis of lipoprotein metabolism in alcoholics].
High density lipoprotein (HDL) is increased by exercise and drinking and is well known as a negative risk factor of coronary heart disease. We analyzed serum lipids of alcoholics from the view points of biochemical examination, remnant like particle (RLP) and particle size of lipoprotein for the purpose of estimated effect of serum lipids, especially HDL quality in alcoholics. Serum levels of total cholesterol, free glycerol, RLP-C and RLP-TG were significantly decreased after hospitalization. The condition of RLP-C/RLP-TG on admission revealed cholesterol-rich composition. In case of HDL-C, the longer period from last drinking to hospitalization affected its decrease. From analytical study of particle size of lipoprotein, quantities of HDL-C in very large size and large size were significantly decreased after hospitalization which means that HDL composition at hospitalization is cholesterol-rich. So, it is speculated that increased serum level of HDL in alcoholics may be caused by expanded cholesterol ester and its quality may be different from that of healthy people. In this meaning, the study of arteriosclerosis in alcoholics will be necessary in relation to high level of serum HDL-C.


Explicit Multielement Extension of the Spectral Neighbor Analysis Potential for Chemically Complex Systems.
A natural extension of the descriptors used in the Spectral Neighbor Analysis Potential (SNAP) method is derived to treat atomic interactions in chemically complex systems. Atomic environment descriptors within SNAP are obtained from a basis function expansion of the weighted density of neighboring atoms. This new formulation instead partitions the neighbor density into partial densities for each chemical element, thus leading to explicit multielement descriptors. For Nelem chemical elements, the number of descriptors increases as [Formula: see text], while the computational cost of the force calculation as implemented in LAMMPS is limited to [Formula: see text] and the favorable linear scaling in the number of atoms is retained. We demonstrate these chemically aware descriptors by producing an interatomic potential for indium phosphide capable of capturing high-energy defects that result from radiation damage cascades. This new explicit multielement SNAP method reproduces the relaxed defect formation energies with substantially greater accuracy than weighted-density SNAP, while retaining accurate representation of the bulk indium phosphide properties.


Insight Into the Posthospital Syndrome: A 3-Month Longitudinal Follow up on Geriatric Syndromes and Their Association With Functional Decline, Readmission, and Mortality.
Acute hospitalization may lead to posthospital syndrome, but no studies have investigated how this syndrome manifests and geriatric syndromes are often used as synonym. However, studies on longitudinal associations between syndromes and adverse outcomes are scarce. We aimed to analyze longitudinal associations between geriatric syndromes and functional decline (FD), readmission, and mortality. Prospective cohort study, including 401 acutely hospitalized patients (aged ≥ 70). We performed: (i) logistic regression analyses to assess associations between patterns of geriatric syndromes as they develop over time (between admission and 1 month postdischarge), and FD and readmission; (ii) generalized estimating equations to assess longitudinal associations between geriatric syndromes over five time points (admission, discharge, 1, 2, and 3 months postdischarge) and FD, mortality, and readmission at 3 months postdischarge. After syndrome absent, syndrome present at both admission and 1 month postdischarge was most prevalent. Persistent patterns of apathy (odds ratio [OR] = 4.35, 95% confidence interval [CI] = 1.54-12.30), pain (OR = 3.26, 95% CI = 1.21-8.8), malnutrition (OR = 3.4, 95% CI = 1.35-8.56), mobility impairment (OR = 6.65, 95% CI = 1.98-22.38), and fear of falling (OR = 3.17, 95% CI = 1.25-8.02) were associated with FD. Developing cognitive impairment (OR = 6.40, 95% CI = 1.52-26.84), fatigue (OR = 4.71, 95% CI = 1.03-21.60), and fall risk (OR = 4.30, 95% CI = 1.21-16.57) postdischarge, was associated with readmission; however, only 4%-6% developed these syndromes. Over the course of five time points, mobility impairment, apathy, and incontinence were longitudinally associated with FD; apathy, malnutrition, fatigue, and fall risk with mortality; malnutrition with readmission. Most geriatric syndromes are present at admission and patients are likely to retain them postdischarge. Several geriatric syndromes are longitudinally associated with mortality and, particularly, persistently present syndromes place persons are at risk of FD. Although few persons develop syndromes postdischarge, those developing cognitive impairment, fatigue, and fall risk were at increased readmission risk.


Brief hospitalization and pulse oximetry for predicting amoxicillin treatment failure in children with severe pneumonia.
In settings with limited assessment tools, we sought to determine whether early clinical signs and symptoms and blood oxygen saturation would predict amoxicillin treatment failure in children with severe pneumonia (as defined by the World Health Organization). Data were from a previously reported, multinational trial of orally administered amoxicillin versus injectable penicillin for the treatment of World Health Organization-defined severe pneumonia in children 3 to 59 months of age. We assessed all 857 participants assigned randomly to the experimental amoxicillin arm. Six multivariate logistic regression models were created and evaluated for their ability to predict failure after 48 hours of therapy. Regression models included vital signs, symptoms, and laboratory data collected at baseline and after 12 or 24 hours of observation. Oxygen saturation data were included in 3 models. Clinical treatment failure occurred for 18% of children. Younger age, increased initial respiratory rate, and baseline hypoxia predicted treatment failure in all models. Data available after 24 hours improved the ability to predict failure compared with data available at baseline or 12 hours. The inclusion of oximetry data improved the predictive ability at baseline, 12 hours, and 24 hours. The ability to predict failure after 12 hours of observation with oximetry data was similar to the predictive ability after 24 hours without pulse oximetry data. Assessment of clinical parameters at presentation and after 24 hours improved the ability to predict clinical failure of oral amoxicillin therapy, compared with assessment at presentation alone or at presentation and after only 12 hours, for children with World Health Organization-defined severe pneumonia.


Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts.
Abstract Aluminum (Al) is a ubiquitous substance encountered both naturally (as the third most abundant element) and intentionally (used in water, foods, pharmaceuticals, and vaccines); it is also present in ambient and occupational airborne particulates. Existing data underscore the importance of Al physical and chemical forms in relation to its uptake, accumulation, and systemic bioavailability. The present review represents a systematic examination of the peer-reviewed literature on the adverse health effects of Al materials published since a previous critical evaluation compiled by Krewski et al. (2007) . Challenges encountered in carrying out the present review reflected the experimental use of different physical and chemical Al forms, different routes of administration, and different target organs in relation to the magnitude, frequency, and duration of exposure. Wide variations in diet can result in Al intakes that are often higher than the World Health Organization provisional tolerable weekly intake (PTWI), which is based on studies with Al citrate. Comparing daily dietary Al exposures on the basis of "total Al"assumes that gastrointestinal bioavailability for all dietary Al forms is equivalent to that for Al citrate, an approach that requires validation. Current occupational exposure limits (OELs) for identical Al substances vary as much as 15-fold. The toxicity of different Al forms depends in large measure on their physical behavior and relative solubility in water. The toxicity of soluble Al forms depends upon the delivered dose of Al(+3) to target tissues. Trivalent Al reacts with water to produce bidentate superoxide coordination spheres [Al(O2)(H2O4)(+2) and Al(H2O)6 (+3)] that after complexation with O2(•-), generate Al superoxides [Al(O2(•))](H2O5)](+2). Semireduced AlO2(•) radicals deplete mitochondrial Fe and promote generation of H2O2, O2 (•-) and OH(•). Thus, it is the Al(+3)-induced formation of oxygen radicals that accounts for the oxidative damage that leads to intrinsic apoptosis. In contrast, the toxicity of the insoluble Al oxides depends primarily on their behavior as particulates. Aluminum has been held responsible for human morbidity and mortality, but there is no consistent and convincing evidence to associate the Al found in food and drinking water at the doses and chemical forms presently consumed by people living in North America and Western Europe with increased risk for Alzheimer's disease (AD). Neither is there clear evidence to show use of Al-containing underarm antiperspirants or cosmetics increases the risk of AD or breast cancer. Metallic Al, its oxides, and common Al salts have not been shown to be either genotoxic or carcinogenic. Aluminum exposures during neonatal and pediatric parenteral nutrition (PN) can impair bone mineralization and delay neurological development. Adverse effects to vaccines with Al adjuvants have occurred; however, recent controlled trials found that the immunologic response to certain vaccines with Al adjuvants was no greater, and in some cases less than, that after identical vaccination without Al adjuvants. The scientific literature on the adverse health effects of Al is extensive. Health risk assessments for Al must take into account individual co-factors (e.g., age, renal function, diet, gastric pH). Conclusions from the current review point to the need for refinement of the PTWI, reduction of Al contamination in PN solutions, justification for routine addition of Al to vaccines, and harmonization of OELs for Al substances.


Synthesis, in vitro formation, and behavioural effects of glutathione regioisomers of alpha-methyldopamine with relevance to MDA and MDMA (ecstasy).
Administration of 3,4-methylenedioxymethamphetamine (MDMA) or 3,4-methylenedioxyamphetamine (MDA) to rats produces serotonergic nerve terminal degeneration. However, they are not neurotoxic when injected directly into the brain, suggesting the requirement for peripheral metabolism of MDMA to a neurotoxic metabolite. Alpha-methyldopamine (alpha-MeDA) is a major metabolite of MDA. There are indications that a glutathione metabolite of alpha-MeDA and/or 3,4-dihydroxymethamphetamine may be responsible for the neurotoxicity and some of the behavioural effects produced by MDMA and/or MDA. The present study details the synthesis, purification and separation of the 5-(glutathion-S-yl)-alpha-MeDA and 6-(glutathion-S-yl)-alpha-MeDA regioisomers of alpha-MeDA. Incubation of MDA with human liver microsomes demonstrated that production of both glutathione adducts are related to cytochrome P450 2D6 isoform activity. Following intracerebroventricular administration (180 nmol) of either GSH adduct into Dark Agouti or Sprague-Dawley rats only 5-(glutathion-S-yl)-alpha-MeDA produced behavioural effects characterised by hyperactivity, teeth chattering, tremor/trembling, head weaving, splayed posture, clonus and wet dog shakes. Pre-treatment with a dopamine receptor antagonist (haloperidol, 0.25 mg/kg; i.p.) attenuated hyperactivity, teeth chattering, low posture and clonus and potentiated splayed postural effects. These results indicate that MDA can be converted into two glutathione regioisomers by human liver microsomes, but only the 5-(glutathion-S-yl)-alpha-MeDA adduct is behaviourally active in the rat.


myo-Inositol phosphorothioates, phosphatase-resistant analogues of myo-inositol phosphates. Synthesis of DL-myo-inositol 1,4-bisphosphate and DL-myo-inositol 1,4-bisphosphorothioate.
Syntheses of a metabolite of the second messenger myo-inositol 1,4,5-trisphosphate, myo-inositol 1,4-bisphosphate, and an analogue, the 1,4-bisphosphorothioate, are reported, by using phosphite chemistry on (+/-)-1,2:4,5-di-isopropylidene-myo-inositol. The synthesis of (+/-)-1,2:4,5-di-isopropylidene 3,6-bis[di-(2-cyanoethyl)]phosphite provides an intermediate that can be oxidized to either the corresponding bisphosphate or bisphosphorothioate. myo-Inositol phosphorothioates are proposed as novel analogues of myo-inositol phosphates; their resistance to phosphatase-catalysed breakdown is reported.


Integrative physiology of human adipose tissue.
Adipose tissue is now recognised as a highly active metabolic and endocrine organ. Great strides have been made in uncovering the multiple functions of the adipocyte in cellular and molecular detail, but it is essential to remember that adipose tissue normally operates as a structured whole. Its functions are regulated by multiple external influences such as autonomic nervous system activity, the rate of blood flow and the delivery of a complex mix of substrates and hormones in the plasma. Attempting to understand how all these factors converge and regulate adipose tissue function is a prime example of integrative physiology. Adipose tissue metabolism is extremely dynamic, and the supply of and removal of substrates in the blood is acutely regulated according to the nutritional state. Adipose tissue possesses the ability to a very large extent to modulate its own metabolic activities, including differentiation of new adipocytes and production of blood vessels as necessary to accommodate increasing fat stores. At the same time, adipocytes signal to other tissues to regulate their energy metabolism in accordance with the body's nutritional state. Ultimately adipocyte fat stores have to match the body's overall surplus or deficit of energy. This implies the existence of one (or more) signal(s) to the adipose tissue that reflects the body's energy status, and points once again to the need for an integrative view of adipose tissue function.


Multiple risk factor interventions for primary prevention of cardiovascular disease in low- and middle-income countries.
In many low- and middle-income countries (LMICs) morbidity and mortality associated with cardiovascular diseases (CVDs) have grown exponentially over recent years. It is estimated that about 80% of CVD deaths occur in LMICs. People in LMICs are more exposed to cardiovascular risk factors such as tobacco, and often do not have access to effective and equitable healthcare services (including early detection services). Evidence from high-income countries indicates that multiple risk factor intervention programmes do not result in reductions in CVD events. Given the increasing incidence of CVDs and lower CVD health awareness in LMICs it is possible that such programmes may have beneficial effects. To determine the effectiveness of multiple risk factor interventions (with or without pharmacological treatment) aimed at modifying major cardiovascular risk factors for the primary prevention of CVD in LMICs. We searched (from inception to 27 June 2014) the Cochrane Library (CENTRAL, HTA, DARE, EED), MEDLINE, EMBASE, Global Health and three other databases on 27 June 2014. We also searched two clinical trial registers and conducted reference checking to identify additional studies. We applied no language limits. We included randomised controlled trials (RCTs) of health promotion interventions to achieve behaviour change (i.e. smoking cessation, dietary advice, increasing activity levels) with or without pharmacological treatments, which aim to alter more than one cardiovascular risk factor (i.e. diet, reduce blood pressure, smoking, total blood cholesterol or increase physical activity) of at least six months duration of follow-up conducted in LMICs. Two authors independently assessed trial eligibility and risk of bias, and extracted data. We combined dichotomous data using risk ratios (RRs) and continuous data using mean differences (MDs), and presented all results with a 95% confidence interval (CI). The primary outcome was combined fatal and non-fatal cardiovascular disease events. Thirteen trials met the inclusion criteria and are included in the review. All studies had at least one domain with unclear risk of bias. Some studies were at high risk of bias for random sequence generation (two trials), allocation concealment (two trials), blinding of outcome assessors (one trial) and incomplete outcome data (one trial). Duration and content of multiple risk factor interventions varied across the trials. Two trials recruited healthy participants and the other 11 trials recruited people with varying risks of CVD, such as participants with known hypertension and type 2 diabetes. Only one study reported CVD outcomes and multiple risk factor interventions did not reduce the incidence of cardiovascular events (RR 0.57, 95% CI 0.11 to 3.07, 232 participants, low-quality evidence); the result is imprecise (a wide confidence interval and small sample size) and makes it difficult to draw a reliable conclusion. None of the included trials reported all-cause mortality. The pooled effect indicated a reduction in systolic blood pressure (MD -6.72 mmHg, 95% CI -9.82 to -3.61, I² = 91%, 4868 participants, low-quality evidence), diastolic blood pressure (MD -4.40 mmHg, 95% CI -6.47 to -2.34, I² = 92%, 4701 participants, low-quality evidence), body mass index (MD -0.76 kg/m², 95% CI -1.29 to -0.22, I² = 80%, 2984 participants, low-quality evidence) and waist circumference (MD -3.31, 95% CI -4.77 to -1.86, I² = 55%, 393 participants, moderate-quality evidence) in favour of multiple risk factor interventions, but there was substantial heterogeneity. There was insufficient evidence to determine the effect of these interventions on consumption of fruit or vegetables, smoking cessation, glycated haemoglobin, fasting blood sugar, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol and total cholesterol. None of the included trials reported on adverse events. Due to the limited evidence currently available, we can draw no conclusions as to the effectiveness of multiple risk factor interventions on combined CVD events and mortality. There is some evidence that multiple risk factor interventions may lower blood pressure levels, body mass index and waist circumference in populations in LMIC settings at high risk of hypertension and diabetes. There was considerable heterogeneity between the trials, the trials were small, and at some risk of bias. Larger studies with longer follow-up periods are required to confirm whether multiple risk factor interventions lead to reduced CVD events and mortality in LMIC settings.


A new approach in DCE MRI data analysis for differentiating benign and malignant breast lesions.
Dynamic contrast enhanced MRI (DCE MRI) is able to reflect changes in vascularity, vessel permeability and extracellular diffusion space of tissues. The goal of this study was to investigate the use of DCE MRI to differentiate benign and malignant breast lesions. From a database, five patients with malignant and five patients with benign lesions were randomly chosen. All patients underwent measurement in a 3T MR scanner using a breast coil. A series of T1-weighted MRI were performed using an intravenously delivered contrast agent. Then, 17 postcontrast sets were acquired within a timeframe of 13 seconds. All DCE MRI data were evaluated using the JIM image analysis package. We observed changes in signal intensity over the acquisition time - curves of dynamic contrast enhancement. We investigated parts of the curves with the largest increase in signal intensity during the timeframe. For further comparison, we used values of the highest signal intensity increases between the timeframes. Analysis of these results led to the proposal that the threshold between benign and malignant lesion had a relative value of 100. Furthermore, there was a significant difference between these two types of lesions.


Epidemiological determinants of the pattern and magnitude of the vCJD epidemic in Great Britain.
Understanding the epidemiology and aetiology of new-variant Creutzfeldt-Jakob (vCJD) disease in humans has become increasingly important given the scientific evidence linking it to bovine spongiform encephalopathy (BSE) in cattle and hence the wide exposure of the population of Great Britain (GB) to potentially infectious tissue. The recent analysis undertaken to determine the risk to the population from dorsal route ganglia illustrated the danger in presenting point estimates rather than ranges of scenarios in the face of uncertainty. We present a mathematical template that relates the past pattern of the BSE epidemic in cattle to the future course of any vCJD epidemic in humans, and use extensive scenario analysis to explore the wide range of possible outcomes given the uncertainty in epidemiological determinants. We demonstrate that the average number of humans infected by one infectious bovine and the incubation period distribution are the two epidemiological factors that have the greatest impact on epidemic size and duration. Using the time-series of the BSE epidemic and the cases seen to date, we show that the minimum length of the incubation period is approximately nine years, and that at least 20% of the cases diagnosed to date were exposed prior to 1986. We also demonstrate that the current age distribution of vCJD cases can only arise if younger people were either exposed to a greater extent, more susceptible to infection, or have shorter incubation periods. Extensive scenario analyses show that given the information currently available, the very high degree of uncertainty in the future size of the epidemic will remain for the next 3-5 years. Furthermore, we demonstrate that this uncertainty is unlikely to be reduced by mass screening for late-stage infection.


Perceptions among Dutch men who have sex with men and their willingness to use rectal microbicides and oral pre-exposure prophylaxis to reduce HIV risk--a preliminary study.
Oral pre-exposure prophylaxis (PrEP) with antiretroviral (ARV) tablets and topical PrEP or microbicides containing ARV drugs could help to reduce HIV incidence. These methods hold promise for men who have sex with men (MSM) who are at higher risk of acquiring HIV. This mixed-methods study in the Netherlands explored perceptions of MSM and their willingness to use oral PrEP and rectal microbicides (RM) if made available. Recruited through social media (Facebook and Twitter), 108 MSM completed online questionnaires. Seven of them consented to discuss the survey results in semi-structured interviews. Survey participants preferred a RM that could be applied before and after anal intercourse (60.8%) to daily oral PrEP (20.3%). This preference was based on anticipated user friendliness, hypothetically fewer expected adverse events, and perceptions that RM would be less likely to be confused with ARVs for treatment. Those who preferred oral PrEP had stronger beliefs in the effectiveness of pills, perceived its use as easy, and viewed not requiring sexual partner awareness as advantages. No predictive factors were found for the choice of one prevention method over the other. Although Dutch MSM perceive both oral and topical PrEP positively, many barriers exist to the introduction of these products in the Netherlands. These include lack of regulatory approval of oral PrEP, no proven efficacy as yet for RM, and strong HIV stigma within the MSM population. In-depth qualitative research is needed to further explore the perceptions of MSM to inform implementation of programmes should these HIV prevention methods become available.


Toxic indole alkaloids avrainvillamide and stephacidin B produced by a biocide tolerant indoor mold Aspergillus westerdijkiae.
Toxic Aspergillus westerdijkiae were present in house dust and indoor air fall-out from a residence and a kindergarten where the occupants suffered from building related ill health. The A. westerdijkiae isolates produced indole alkaloids avrainvillamide (445 Da) and its dimer stephacidin B (890 Da). It grew and sporulated in presence of high concentrations of boron or polyguanidine (PHMB, PHMG) based antimicrobial biocides used to remediate mold infested buildings. The boar sperm cells were used as sensor cells to purify toxins from HPLC fractions of the fungal biomass. Submicromolar concentrations (EC50 0.3-0.4 μM) blocked boar spermatozoan motility and killed porcine kidney tubular epithelial cells (PK-15). Plate grown hyphal mass of the A. westerdijkiae isolates contained 300-750 ng of avrainvillamide and 30-300 ng of stephacidin B per mg (wet weight). The toxins induced rapid (30 min) loss of boar sperm motility, followed (24 h) by loss of mitochondrial membrane potential (ΔΨm). Apoptotic cell death was observed in PK-15 cell monolayers, prior to cessation of glucose uptake or loss of ΔΨm. Avrainvillamide and stephacidin B were 100-fold more potent towards the porcine cells than the mycotoxins stephacidin A, ochratoxin A, sterigmatocystin and citrinin. The high toxicity of stephacidin B indicates a role of nitrone group in the mechanism of toxicity. Avrainvillamide and stephacidin B represent a new class of toxins with possible a threat to human health in buildings. Furthermore, the use of biocides highly enhanced the growth of toxigenic A. westerdijkiae.


Does more mean less? The value of information for conservation planning under sea level rise.
Many studies have explored the benefits of adopting more sophisticated modelling techniques or spatial data in terms of our ability to accurately predict ecosystem responses to global change. However, we currently know little about whether the improved predictions will actually lead to better conservation outcomes once the costs of gaining improved models or data are accounted for. This severely limits our ability to make strategic decisions for adaptation to global pressures, particularly in landscapes subject to dynamic change such as the coastal zone. In such landscapes, the global phenomenon of sea level rise is a critical consideration for preserving biodiversity. Here, we address this issue in the context of making decisions about where to locate a reserve system to preserve coastal biodiversity with a limited budget. Specifically, we determined the cost-effectiveness of investing in high-resolution elevation data and process-based models for predicting wetland shifts in a coastal region of South East Queensland, Australia. We evaluated the resulting priority areas for reserve selection to quantify the cost-effectiveness of investment in better quantifying biological and physical processes. We show that, in this case, it is considerably more cost effective to use a process-based model and high-resolution elevation data, even if this requires a substantial proportion of the project budget to be expended (up to 99% in one instance). The less accurate model and data set failed to identify areas of high conservation value, reducing the cost-effectiveness of the resultant conservation plan. This suggests that when developing conservation plans in areas where sea level rise threatens biodiversity, investing in high-resolution elevation data and process-based models to predict shifts in coastal ecosystems may be highly cost effective. A future research priority is to determine how this cost-effectiveness varies among different regions across the globe.


A PARALYTIC DISEASE OF GUINEA PIGS DUE TO THE TUBERCLE BACILLUS.
The experimental data collected during this study of a transmissible type of paralysis developing in tuberculous guinea pigs indicate the condition to be a true tuberculous meningitis. We have been able to rule out the possibility that it is due to a non-tuberculous infection of the central nervous system caused by Roemer's virus, or by an atypical herpes virus, or by some bacterium other than the tubercle bacillus. Roemer's virus and herpes could be eliminated from consideration when Berkefeld N filtrates of infectious brain emulsions proved incapable of reproducing the disease. Furthermore, rabbits could be infected as they cannot with Roemer's virus, and the disease elicited in rabbits bears no semblance to herpes encephalitis. No organism other than the tubercle bacillus could be obtained on culturing brain or brain emulsions from experimental cases, and no others were seen in examining fresh smear preparations from the central nervous system. In a modified Noguchi medium a tubercle bacillus possessing atypical staining properties was obtained. This organism was capable of producing the typical paralytic disease when injected intracerebrally into guinea pigs, and also generalized tuberculosis in animals inoculated subcutaneously with it. Typical tuberde bacilli were readily demonstrable in sections of the meninges from animals with the disease, and culture of pieces of brain on Dorset's egg medium usually yielded a growth of tubercle bacilli. Only in the first of the experimental passages, on the other hand, was it possible to demonstrate acid-fast organisms in fresh smear preparations from the central nervous system. This fact and the attributes of the atypically staining organisms encountered in the cultures in Noguchi media will be considered more fully in a subsequent publication. In view of the much discussed question of the filtrability of the tubercle bacillus our observations concerning the failure of this organism to pass a Berkefeld N filter are of interest. No animal in our series inoculated intracerebrally with brain emulsion from either a "spontaneous" or experimental case of tuberculous meningitis failed to develop meningitis, and that rather acutely, while no animal in our series injected with a Berkefeld filtrate of brain emulsion has developed tuberculous meningitis or any other form of tuberculosis. In connection with this observation it must be recalled that the organism was atypical in respect to its staining qualities at least.


Enhanced endoplasmic reticulum and mitochondrial stress in abdominal aortic aneurysm.
Abdominal aortic aneurysm (AAA) is a degenerative vascular disease with a complex aetiology that remains to be fully elucidated. Clinical management of AAA is limited to surgical repair, while an effective pharmacotherapy is still awaited. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction have been involved in the pathogenesis of cardiovascular diseases (CVDs), although their contribution to AAA development is uncertain. Therefore, we aimed to determine their implication in AAA and investigated the profile of oxysterols in plasma, specifically 7-ketocholesterol (7-KC), as an ER stress inducer.In the present study, we determined aortic ER stress activation in a large cohort of AAA patients compared with healthy donors. Higher gene expression of activating transcription factor (ATF) 6 (ATF6), IRE-1, X-binding protein 1 (XBP-1), C/EBP-homologous protein (CHOP), CRELD2 and suppressor/enhancer of Lin-12-like (SEL1L) and greater protein levels of active ATF6, active XBP1 and of the pro-apoptotic protein CHOP were detected in human aneurysmatic samples. This was accompanied by an exacerbated apoptosis, higher reactive oxygen species (ROS) production and by a reduction in mitochondrial biogenesis in the vascular wall of AAA. The quantification of oxysterols, performed by liquid chromatography-(atmospheric pressure chemical ionization (APCI))-mass spectrometry, showed that levels of 7-KC were significantly higher while those of 7α-hydroxycholesterol (HC), 24-HC and 27-HC were lower in AAA patients compared with healthy donors. Interestingly, the levels of 7-KC correlate with the expression of ER stress markers.Our results evidence an induction of ER stress in the vascular wall of AAA patients associated with an increase in circulating 7-KC levels and a reduction in mitochondrial biogenesis suggesting their implication in the pathophysiology of this disease.


Association of Systemic Inflammation With Retinal Vascular Caliber in Patients With AIDS.
To evaluate relationships among retinal vascular caliber and biomarkers of systemic inflammation in patients with AIDS. A total of 454 participants with AIDS had retinal vascular caliber (central retinal artery equivalent and central retinal vein equivalent) determined from enrollment retinal photographs by reading center graders masked to clinical and biomarker information. Cryopreserved plasma specimens were assayed for inflammatory biomarkers, including C-reactive protein (CRP), IL-6, interferon-γ inducible protein (IP)-10, kynurenine/tryptophan (KT) ratio, and intestinal fatty acid binding protein (I-FABP). In the simple linear regression of retinal vascular caliber on plasma biomarkers, elevated CRP, IL-6, and IP-10 were associated with retinal venular dilation, and elevated KT ratio with retinal arteriolar narrowing. In the multiple linear regression, including baseline characteristics and plasma biomarkers, AMD was associated with dilation of retinal arterioles (mean difference: 9.1 μm; 95% confidence interval [CI] 5.2, 12.9; P < 0.001) and venules (mean difference, 10.9 μm; 95% CI, 5.3, 16.6; P < 0.001), as was black race (P < 0.001). Hyperlipidemia was associated with retinal venular narrowing (mean difference, -7.5 μm; 95% CI, -13.7, -1.2; P = 0.02); cardiovascular disease with arteriolar narrowing (mean difference, -5.2 μm; 95% CI, -10.3, -0.1; P = 0.05); age with arteriolar narrowing (slope, -0.26 μm/year; 95% CI, -0.46, -0.06; P = 0.009); and IL-6 with venular dilation (slope, 5.3 μm/standard deviation log10[plasma IL-6 concentration]; 95% CI, 2.7, 8.0; P < 0.001). These data suggest that retinal vascular caliber is associated with age, race, AMD, hyperlipidemia, cardiovascular disease, and selected biomarkers of systemic inflammation.


Brain PET imaging optimization with time of flight and point spread function modelling.
To assess the influence of reconstruction algorithms and parameters on the PET image quality of brain phantoms in order to optimize reconstruction for clinical PET brain studies in a new generation PET/CT. The 3D Hoffman phantom that simulates (18)F-fluorodeoxyglucose (FDG) distribution was imaged in a Siemens Biograph mCT TrueV PET/CT with Time of Flight (TOF) and Point Spread Function (PSF) modelling. Contrast-to-Noise Ratio (CNR), contrast and noise were studied for different reconstruction models: OSEM, OSEM + TOF, OSEM + PSF and OSEM + PSF + TOF. The 2D multi-compartment Hoffman phantom was filled to simulate 4 different tracers' spatial distribution: FDG, (11)C-flumazenil (FMZ), (11)C-Methionine (MET) and 6-(18)F-fluoro-l-dopa (FDOPA). The best algorithm for each tracer was selected by visual inspection. The maximization of CNR determined the optimal parameters for each reconstruction. In the 3D Hoffman phantom, both noise and contrast increased with increasing number of iterations and decreased with increasing FWHM. OSEM + PSF + TOF reconstruction was generally superior to other reconstruction models. Visual analysis of the 2D Hoffman brain phantom suggested that OSEM + PSF + TOF is the optimum algorithm for tracers with focal uptake, such as MET or FDOPA, and OSEM + TOF for tracers with diffuse cortical uptake (i.e. FDG and FMZ). Optimization of CNR demonstrated that OSEM + TOF reconstruction must be performed with 2 iterations and a filter FWHM of 3 mm, and OSEM + PSF + TOF reconstruction with 4 iterations and 1 mm FWHM filter. Optimization of reconstruction algorithm and parameters has been performed to take particular advantage of the last generation PET scanner, recommending specific settings for different brain PET radiotracers.


Serum metabolic profile in multiple sclerosis patients.
Multiple sclerosis (MS) is a progressive demyelinating process considered as an autoimmune disease, although the causes of this pathology have not been yet fully established. Similarly to other neurodegenerations, MS is characterized by a series of biochemical changes affecting to different extent neuronal functions; great attention has been given to oxidative/nitrosative stress and to alterations in mitochondrial functions. According to previous data, MS patients show significant changes in the circulating concentrations of different metabolites, although it is still unclear whether uric acid undergoes to decrease, increase, or no change under this pathological condition. In this study, we report the serum metabolic profile in terms of purines, pyrimidines, creatinine, malondialdehyde, ascorbic acid, nitrite, and nitrate in a group of 170 MS patients. The results show increase in circulating uric acid and other oxypurines (hypoxanthine and xanthine), as well as in uridine and β-pseudouridine. The concomitant increase in circulating creatinine, malondialdehyde, nitrite, and nitrate, and decrease in ascorbic acid, demonstrates that MS induces alteration in energy metabolism and in oxidants/antioxidants balance that can be monitored in serum of MS patients.


Dietary fiber and lipoprotein metabolism in the genetically obese Zucker rat.
The present investigation was designed to examine the influence of dietary fibers with differing soluble fiber compositions upon the metabolism of lipids in a hyperlipemic animal model, the Zucker fatty rat. The response to fiber was examined using a diet supplemented with cellulose, oat bran, or pectin which have a soluble/insoluble fiber ratio of 0:100, 33:66, and 100:0, respectively. These fibers provided 10% of the total diet weight; the control diet contained no fiber. A rapid increase in plasma triglyceride concentration was observed in all animals given fiber-supplemented diets in correlation with the increased carbohydrate content of the defined diets relative to the prestudy diets. This increase in plasma triglyceride was due to increased production of triglycerides with no change in the rates of clearance. The plasma total cholesterol levels were relatively constant on all diets. However, after 7 weeks on the pectin-supplemented diet, rats showed a 39% elevation in HDL and a 44% reduction in LDL concentration. This diet also resulted in reduced weight gain, in spite of a caloric intake equivalent to the control diets. Our data suggest that the ability of dietary fiber to alter plasma lipoproteins might be predictable from the soluble fiber composition or the pectin content of a given dietary fiber in this model of genetic endogenous hyperlipemia.


Efficacy of dental unit waterlines disinfectants on a polymicrobial biofilm.
Due to their high surface-volume ratio, their laminar flow and frequent stagnation periods, dental unit waterlines (DUWL) foster the attachment of microorganisms and the development of biofilm, resulting in the continuous contamination of the outlet water from dental units; this contamination may be responsible for a potential risk of infection due to the exposure of patients and medical staff to droplet inhalation or splashed water. In this study, the anti-biofilm activity of three disinfectants recommended by dental unit manufacturers -Calbenium(©), Oxygenal 6(©) and Sterispray(©) - was evaluated. A dynamic model simulating DUWL conditions was developed and polymicrobial biofilms containing bacteria (Pseudomonas aeruginosa), fungi (Candida albicans) and Free Living Amoeba (FLA: Vermamoeba vermiformis) were allowed to form. The ability of disinfectants to reduce biofilm formation or to eradicate an already formed biofilm was evaluated. Results showed the various effects of the tested disinfectants according to their composition, concentration and the targeted species. V. vermiformis was resistant to disinfectants, regardless of the tested concentrations and the concentrations recommended by manufacturers were not the most appropriate. Results also showed that Calbenium(©) was the most effective disinfectant to reduce already formed biofilms; its maximum efficiency was observed from 0.5% on both P. aeruginosa and C. albicans compared to 2 and 3% respectively for Sterispray(©). The maximum efficiency of Oxygenal(©) was observed from 3% on P. aeruginosa but Oxygenal(©) was unable to totally eliminate C. albicans in the tested conditions, contrary to other disinfectants. Calbenium(©) was able to prevent biofilm formation efficiently even if it displayed no prophylactic activity against V. vermiformis. Overall, the FLA survival may contribute to maintaining other species. Finally the tested disinfectants were partially active against sessile microorganisms and more suitable concentrations could be used to increase their efficacy. Their use in a prophylactic rather than curative way should be recommended.


Cardiac abnormalities after aneurysmal subarachnoid hemorrhage: effects of β-blockers and angiotensin-converting enzyme inhibitors.
Cardiac abnormalities attributed to adrenergic surge are common after aneurysmal subarachnoid hemorrhage. Prescribed medications that block adrenergic stimulation may suppress the onset of cardiopulmonary compromise in patients after aneurysmal subarachnoid hemorrhage. To compare the incidence of early cardiac complications between patients who reported prescribed use of β-blockers and/or angiotensin-converting enzyme inhibitors before aneurysmal subarachnoid hemorrhage and patients who did not. A retrospective review of 254 adult patients after acute aneurysmal subarachnoid hemorrhage who were enrolled in an existing R01 study. Demographic data and history were obtained from patients'/proxies' reports and charts. Cardiac enzyme levels, 12-lead electrocardiograms, and chest radiographs were obtained on admission. Holter monitoring and echocardiograms were completed as a part of the R01 study. Patients reporting prescribed use of angiotensin-converting enzyme inhibitors or β-blockers before aneurysmal subarachnoid hemorrhage had more ventricular and supraventricular ectopy on a Holter report than did patients who did not (P < .05). When age, race, sex, and injury (Fisher grade) were controlled for, patients reporting use of β-blockers were 8 times more likely than others to have occasional to frequent ventricular ectopy (P = .02). No concrete evidence was found that exposure to adrenergic blockade before aneurysmal subarachnoid hemorrhage provides protection from neurocardiac injury.


Impairment of thymocyte function via induction of apoptosis by areca nut extract.
Areca quid (AQ) chewing is a popular oral habit, especially in Southeast Asia cultures, in which children may be engaged in the addictive habit early in their lives. Extracts of areca nuts, the main component of AQ, have been shown to affect the functionality of T-cells. However, the potential influence of ANE on the development of T-cells is unknown. This study, therefore, investigated the impact of areca nut extracts (ANE) on thymocytes and the potential mechanisms of action. Mice administered intraperitoneally with ANE at 1, 5, or 25 mg/kg daily for 5 days showed significant dose-dependent reductions in thymocyte viability. A marked decrease in the total number of thymocytes and the proportion of thymic CD4(+)CD8(+) cells was observed in the 25 mg ANE/kg-treated mice, whereas the proportion of CD4 and CD8 single positive and CD4(-)CD8(-) cells was significantly increased. Further examination on the functionality of thymocytes showed that ANE suppress IL-2 production both ex vivo and in vitro. These results suggest that ANE may attenuate the development and functionality of thymic T-cells. ANE also directly induced apoptosis in thymic T-cells through activation of casapase-3 and apoptosis inducing factor (AIF). Collectively, the data suggested that the thymus is a sensitive target to ANE. Early exposure to ANE may interfere with the development and functionality of thymic T-cells.


Glatiramer Acetate Enhances Myeloid-Derived Suppressor Cell Function via Recognition of Paired Ig-like Receptor B.
Glatiramer acetate (GA; Copaxone) is a copolymer therapeutic that is approved by the Food and Drug Administration for the relapsing-remitting form of multiple sclerosis. Despite an unclear mechanism of action, studies have shown that GA promotes protective Th2 immunity and stimulates release of cytokines that suppress autoimmunity. In this study, we demonstrate that GA interacts with murine paired Ig-like receptor B (PIR-B) on myeloid-derived suppressor cells and suppresses the STAT1/NF-κB pathways while promoting IL-10/TGF-β cytokine release. In inflammatory bowel disease models, GA enhanced myeloid-derived suppressor cell-dependent CD4+ regulatory T cell generation while reducing proinflammatory cytokine secretion. Human monocyte-derived macrophages responded to GA by reducing TNF-α production and promoting CD163 expression typical of alternative maturation despite the presence of GM-CSF. Furthermore, GA competitively interacts with leukocyte Ig-like receptors B (LILRBs), the human orthologs of PIR-B. Because GA limited proinflammatory activation of myeloid cells, therapeutics that target LILRBs represent novel treatment modalities for autoimmune indications.


Bioinorganic modeling chemistry of carbon monoxide dehydrogenases: description of model complexes, current status and possible future scopes.
Carbon monoxide dehydrogenases (CODHs) use CO as their sole source of carbon and energy and are found in both aerobic and anaerobic carboxidotrophic bacteria. Reversible transformation of CO to CO2 is catalyzed by a bimetallic [Mo-(μ2-S)-Cu] system in aerobic and by a highly asymmetric [Ni-Fe-S] cluster in anaerobic CODH active sites. The CODH activity in the microorganisms effects the removal of almost 10(8) tons of CO annually from the lower atmosphere and earth and thus help to maintain a sub-toxic concentration of CO. Despite an appreciable amount of work, the mechanism of CODH activity is not clearly understood yet. Moreover, biomimetic chemistry directed towards the active sites of CODHs faces several synthetic challenges. The synthetic problems associated with the modeling chemistry and strategies adopted to overcome those problems are discussed along with their limitations. A critical analysis of the exciting results delineating the present status of CODH modeling chemistry and its future prospects are presented.


Barriers to guideline adherence. Based on a presentation by Michael Cabana, MD.
Successful implementation of the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI) should improve quality of care by decreasing inappropriate variation and by disseminating new advances to everyday practice. A key component of this process is physician adherence to JNC-VI guidelines. However several reports in the literature show a discrepancy between hypertension guidelines and actual practice. The factors that influence physician behavior change and optimal use of practice guidelines are poorly understood. A combined model that uses the Awareness-to-Adherence Model and Social Cognitive Theory identifies five sequential steps that lead to adherence to a guideline--awareness, agreement, self-efficacy, outcome expectancy, and presence of a cueing mechanism. Barriers to implementation may occur at any of these steps and can be identified with this model. Programs can then be designed to overcome specific barriers. By conceptualizing the underlying issues in physician adherence, the combined model should be useful to guideline developers, practice directors, and health services researchers.


The ERN1 transcription factor gene is a target of the CCaMK/CYCLOPS complex and controls rhizobial infection in Lotus japonicus.
Bacterial accommodation inside living plant cells is restricted to the nitrogen-fixing root nodule symbiosis. In many legumes, bacterial uptake is mediated via tubular structures called infection threads (ITs). To identify plant genes required for successful symbiotic infection, we screened an ethyl methanesulfonate mutagenized population of Lotus japonicus for mutants defective in IT formation and cloned the responsible gene, ERN1, encoding an AP2/ERF transcription factor. We performed phenotypic analysis of two independent L. japonicus mutant alleles and investigated the regulation of ERN1 via transactivation and DNA-protein interaction assays. In ern1 mutant roots, nodule primordia formed, but most remained uninfected and bacterial entry via ITs into the root epidermis was abolished. Infected cortical nodule cells contained bacteroids, but transcellular ITs were rarely observed. A subset exhibited localized cell wall degradation and loss of cell integrity associated with bacteroid spread into neighbouring cells and the apoplast. Functional promoter studies revealed that CYCLOPS binds in a sequence-specific manner to a motif within the ERN1 promoter and in combination with CCaMK positively regulates ERN1 transcription. We conclude that the activation of ERN1 by CCaMK/CYCLOPS complex is an important step controlling IT-mediated bacterial progression into plant cells.


Using plant-soil feedbacks to predict plant biomass in diverse communities.
It has become clear that plants can create soils that affect subsequent plant growth. However, because plant-soil feedbacks (PSFs) are typically measured in monoculture experiments, it remains unclear to what extent PSFs affect plant growth in communities. Here we used data from a factorial PSF experiment to predict the biomass of 12 species grown in 162 plant community combinations. Five different plant growth models were parameterized with either monoculture biomass data (Null) or with PSF data (PSF) and model predictions were compared to plant growth observed in communities. For each of the five models, PSF model predictions were closer to observed species biomass in communities than Null model predictions. PSFs, which were associated with a 28% difference in plant biomass across soil types, explained 10% more variance than Null models. Results provided strong support for a small role for PSFs in predicting plant growth in communities and suggest several reasons that PSFs, as traditionally measured in monoculture experiments, may overestimate PSF effects in communities. First, monoculture data used in Null models inherently includes "self " PSF effects. Second, PSFs must be large relative to differences in intrinsic growth rates among species to change competitive outcomes. Third, PSFs must vary among species to change species relative abundances.


Scaffold-based three-dimensional human fibroblast culture provides a structural matrix that supports angiogenesis in infarcted heart tissue.
We have developed techniques to implant angiogenic patches onto the epicardium over regions of infarcted cardiac tissue to stimulate revascularization of the damaged tissue. These experiments used a scaffold-based 3D human dermal fibroblast culture (3DFC) as an epicardial patch. The 3DFC contains viable cells that secrete angiogenic growth factors and has previously been shown to stimulate angiogenic activity. The hypothesis tested was that a viable 3DFC cardiac patch would stimulate an angiogenic response within an area of infarcted cardiac tissue. A coronary occlusion of a branch of the left anterior descending coronary artery was performed by thermal ligation in severe combined immunodeficient mice. 3DFCs with or without viable cells were sized to the damaged area, implanted in replicate mice onto the epicardium at the site of tissue injury, and compared with animals that received infarct surgery but no implant. Fourteen and 30 days after surgery, hearts were exposed and photographed, and tissue samples were prepared for histology and cytochemistry. Fourteen and 30 days after surgery, the damaged myocardium receiving viable 3DFC exhibited a significantly greater angiogenic response (including arterioles, venules, and capillaries) than nonviable and untreated control groups. In this animal model, viable 3DFC stimulates angiogenesis within a region of cardiac infarction and can augment a repair response in damaged tissue. Therefore, a potential use for 3DFC is the repair of myocardial tissue damaged by infarction.


Does renin determine the blood pressure response to calcium entry blockers?
Male Wistar rats with one-kidney, one clip renal hypertension were maintained on either a regular or a low salt diet for 3 weeks after clipping. At that time mean blood pressure in the unanesthetized rats was equally elevated in sodium-depleted (n = 17) and in sodium-replete rats (n = 19), but plasma renin activity was significantly higher in the former (p less than 0.05). Infusion of the calcium entry blocker verapamil at a rate of 0.05 mg/kg/minute decreased blood pressure within 60 minutes to a similar extent in rats kept on a salt-deficient diet and in rats fed a regular salt diet. In all rats taken as a group, there was a close, direct correlation (r = 0.87, p less than 0.001) between the magnitude of the blood pressure response to verapamil and the pretreatment blood pressure levels. Verapamil markedly accelerated heart rate and stimulated renin release in all rats. In additional groups of sodium-depleted (n = 8) and sodium-replete renal hypertensive rats (n = 7), nifedipine administration (4 micrograms/kg/min i.v.) within a 45-minute observation period caused a blood pressure fall (p less than 0.001) and heart rate acceleration (p less than 0.001) that were comparable in both groups. These findings suggest that in the rat with renal hypertension the short-term blood pressure response to the calcium antagonists verapamil and nifedipine is not influenced by the state of sodium balance and plasma renin activity. In this experimental model of hypertension, the magnitude of the blood pressure lowering effect of calcium entry blockers appears to be proportional to pretreatment blood pressure levels.


Does socioeconomic status account for racial and ethnic disparities in childhood cancer survival?
For many childhood cancers, survival is lower among non-Hispanic blacks and Hispanics in comparison with non-Hispanic whites, and this may be attributed to underlying socioeconomic factors. However, prior childhood cancer survival studies have not formally tested for mediation by socioeconomic status (SES). This study applied mediation methods to quantify the role of SES in racial/ethnic differences in childhood cancer survival. This study used population-based cancer survival data from the Surveillance, Epidemiology, and End Results 18 database for black, white, and Hispanic children who had been diagnosed at the ages of 0 to 19 years in 2000-2011 (n = 31,866). Black-white and Hispanic-white mortality hazard ratios and 95% confidence intervals, adjusted for age, sex, and stage at diagnosis, were estimated. The inverse odds weighting method was used to test for mediation by SES, which was measured with a validated census-tract composite index. Whites had a significant survival advantage over blacks and Hispanics for several childhood cancers. SES significantly mediated the race/ethnicity-survival association for acute lymphoblastic leukemia, acute myeloid leukemia, neuroblastoma, and non-Hodgkin lymphoma; SES reduced the original association between race/ethnicity and survival by 44%, 28%, 49%, and 34%, respectively, for blacks versus whites and by 31%, 73%, 48%, and 28%, respectively, for Hispanics versus whites ((log hazard ratio total effect - log hazard ratio direct effect)/log hazard ratio total effect). SES significantly mediates racial/ethnic childhood cancer survival disparities for several cancers. However, the proportion of the total race/ethnicity-survival association explained by SES varies between black-white and Hispanic-white comparisons for some cancers, and this suggests that mediation by other factors differs across groups.


Aptamer evolution for array-based diagnostics.
Closed loop aptameric directed evolution, (CLADE) is a technique enabling simultaneous discovery, evolution, and optimization of aptamers. It was previously demonstrated using a fluorescent protein, and here we extend its applicability with the generation of surface-bound aptamers for targets containing no natural fluorescence. Starting from a random population, in four generations CLADE produced a new aptamer to thrombin with high specificity and affinity. The best aptameric sequence was void of the set of four guanine repeats typifying thrombin aptamers and, thus, highlights the benefits of evolution performed in an environment closely mimicking the final diagnostic application.


GIANT API: an application programming interface for functional genomics.
GIANT API provides biomedical researchers programmatic access to tissue-specific and global networks in humans and model organisms, and associated tools, which includes functional re-prioritization of existing genome-wide association study (GWAS) data. Using tissue-specific interaction networks, researchers are able to predict relationships between genes specific to a tissue or cell lineage, identify the changing roles of genes across tissues and uncover disease-gene associations. Additionally, GIANT API enables computational tools like NetWAS, which leverages tissue-specific networks for re-prioritization of GWAS results. The web services covered by the API include 144 tissue-specific functional gene networks in human, global functional networks for human and six common model organisms and the NetWAS method. GIANT API conforms to the REST architecture, which makes it stateless, cacheable and highly scalable. It can be used by a diverse range of clients including web browsers, command terminals, programming languages and standalone apps for data analysis and visualization. The API is freely available for use at http://giant-api.princeton.edu.


Chemolithotrophic primary production in a subglacial ecosystem.
Glacial comminution of bedrock generates fresh mineral surfaces capable of sustaining chemotrophic microbial communities under the dark conditions that pervade subglacial habitats. Geochemical and isotopic evidence suggests that pyrite oxidation is a dominant weathering process generating protons that drive mineral dissolution in many subglacial systems. Here, we provide evidence correlating pyrite oxidation with chemosynthetic primary productivity and carbonate dissolution in subglacial sediments sampled from Robertson Glacier (RG), Alberta, Canada. Quantification and sequencing of ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) transcripts suggest that populations closely affiliated with Sideroxydans lithotrophicus, an iron sulfide-oxidizing autotrophic bacterium, are abundant constituents of microbial communities at RG. Microcosm experiments indicate sulfate production during biological assimilation of radiolabeled bicarbonate. Geochemical analyses of subglacial meltwater indicate that increases in sulfate levels are associated with increased calcite and dolomite dissolution. Collectively, these data suggest a role for biological pyrite oxidation in driving primary productivity and mineral dissolution in a subglacial environment and provide the first rate estimate for bicarbonate assimilation in these ecosystems. Evidence for lithotrophic primary production in this contemporary subglacial environment provides a plausible mechanism to explain how subglacial communities could be sustained in near-isolation from the atmosphere during glacial-interglacial cycles.


Grasping visual illusions: consistent data and no dissociation.
The finding that the Ebbinghaus/Titchener illusion deceives perception but not grasping is usually seen as strong evidence for Goodale and Milner's (1992) notion of two parallel visual systems, one being conscious and deceived by the illusion (vision-for-perception) and the other being unconscious and not deceived (vision-for-action). However, this finding is controversial and led to studies with seemingly contradictory results. We argue that these results are not as contradictory as it might seem. Instead, studies consistently show similar effects of the illusion on grasping. The perceptual effects are strongly dependent on the specific perceptual measure employed. If, however, some methodological precautions are used, then these diverse perceptual results can be reconciled and point to a single internal size estimate that is used for perception and for grasping. This suggests that the Ebbinghaus illusion deceives a common representation of object size that is used by perception and action.