Cross-Sectional and Longitudinal Assessment of Retinal Sensitivity in Patients With Childhood-Onset Stargardt Disease.
We assess cross-sectional and longitudinal microperimetry and full-field static perimetry-derived retinal sensitivity with conventional and volumetric indices of retinal function in childhood-onset Stargardt disease (STGD1). Subjects with molecularly confirmed childhood-onset STGD1 underwent full-field static perimetry and/or microperimetry using custom designed grids. Mean sensitivity (MS) and total volume (VTOT) were computed for each microperimetry test. MS, VTOT, and central field volume (V30) were computed for each full-field static perimetry test. Subjects under 18 years old at baseline were classified as children and subjects 18 years or older as adults. A total of 43 children (mean age at baseline, 13.0 years; range, 8-17) and 13 adults (mean age at baseline, 23.1 years; range, 18-32) were included in the analysis. For full-field static perimetry and microperimetry for both subgroups, intraclass correlation coefficient results for MS and volumetric indices were good to excellent, indicating strong test-retest reliability. Interocular symmetry in terms of baseline measurements and the annual rate of progression was observed. A greater rate of progression was observed in childhood. To our knowledge, this is the first prospective study of retinal sensitivity in a large cohort of molecularly confirmed subjects with childhood-onset STGD1 demonstrating that children with STGD1 can reliably undertake detailed functional testing. Moreover, using custom designed grids and subsequent topographic analysis, volumetric indices of retinal function provide a reliable measure of retinal sensitivity. This study highlights the use of microperimetry and full-field static perimetry, as well as volumetric indices of retinal function, in monitoring disease progression.


Urinary excretion of leukotriene E4 and eosinophil protein X in children with atopic asthma.
Measurement of leukotriene E4 (LTE4) in urine is a noninvasive method for assessing changes in the rate of total body cysteinyl leukotriene production. Eosinophil protein X (EPX) has been used to assess eosinophil activity and monitor inflammation in bronchial asthma. The aim of the study was to look for differences in urinary LTE4 and EPX concentrations between children with stable atopic asthma and healthy controls and to compare asthmatic children with different disease severity. In addition the relationship was evaluated between urinary LTE4 and EPX levels and lung function. LTE4 was also measured (enzyme immunoassay) together with EPX (radioimmunoassay) in urine and lung function tests were carried out in children with mild asthma (steroid-naive) (n=49), moderate to severe asthma (using inhaled steroids) (n=31) and healthy control subjects (n=28). Urinary leukotriene E4 (LTE4) was significantly higher in children with asthma than in controls (median [25-75 percentile] 238.5 (126.5-375.7) SD 191.8 versus 189 (51-253.2) SD 131.7 pg.mg(-1) creatinine; p=0.021). Urinary EPX was also significantly increased in asthmatic children compared with controls (85.5 [64-131.5] SD 76.2 versus 48.5 [43.2-90] 112.1 microg x mmol(-1) creatinine; p=0.006). There were no differences in urinary LTE4 and EPX between the group of mild and the group of moderate to severe asthmatic children. There were significant associations between the urinary LTE4 and intrathoracic gas volume (ITGV), residual volume (RV), forced expiratory volume in one second (FEV1), forced expiratory capacity (FVC) and maximum expiratory flow rate at 25% of vital capacity (MEF25). Urinary EPX was only correlated with maximum expiratory flow rate at 75% of vital capacity (MEF75). Thus measurement of urinary LTE4 may predict the degree of airflow obstruction in asthmatic children. Urinary LTE4 and EPX are useful markers of airway inflammation and can be helpful in guiding asthma management. There was no correlation between LTE4 and EPX levels.


Physical activity of UK adults with chronic disease: cross-sectional analysis of accelerometer-measured physical activity in 96 706 UK Biobank participants.
Physical inactivity is associated with an increased risk of major chronic diseases, although uncertainty exists about which chronic diseases, themselves, might contribute to physical inactivity. The objective of this study was to compare the physical activity of those with chronic diseases to healthy individuals using an objective measure of physical activity. We conducted a cross-sectional analysis of data from 96 706 participants aged 40 years or older from the UK Biobank prospective cohort study (2006-10). Diagnoses were identified through ICD 9 and 10 coding within hospital admission records and a cancer registry linked to UK Biobank participants. We extracted summary physical activity information from participants who wore a wrist-worn triaxial accelerometer for 7 days. Statistical analyses included computation of adjusted geometric means and means using general linear models. Participants with chronic disease undertook 9% or 61 minutes (95% confidence interval: 57.8-64.8) less moderate activity and 11% or 3 minutes (95% confidence interval: 2.7-3.3) less vigorous activity per week than individuals without chronic disease. Participants in every chronic-disease subgroup undertook less physical activity than those without chronic disease. Sixty-seven diagnoses within these subgroups were associated with lower moderate activity. The cross-sectional association of physical activity with chronic disease is broad. Given the substantial health benefits of being physically active, clinicians and policymakers should be aware that their patients with any chronic disease are at greater health risk from other diseases than anticipated because of their physical inactivity.


Single dose phenobarbitone prevents convulsions in cerebral malaria.
48 patients over 6 years of age with strictly defined cerebral malaria were randomised to receive either a single intramuscular injection of phenobarbitone (3.5 mg/kg) or placebo in a double-blind, placebo-controlled study. Phenobarbitone significantly reduced the incidence of subsequent convulsions from 54% to 12.5%, without adverse effects. A single intramuscular injection of phenobarbitone is a simple, cheap, and effective method for prevention of convulsions in cerebral malaria.


SU-E-T-238: Annual QA of Proton Gantry with Robotic Table.
To perform the annual QA of proton gantry with a robotic table. A new proton gantry with robotic table has been commissioned and is being used in clinic for patient treatment. The gantry is equipped with a robotic table with 6-degrees of freedom and dual cardinal angle KV imagers for patient registration. The system allows direct movement from one beam location to another without additional image registration, which effectively reduces portal setup time and increases treatment efficiency. The annual QA has four main components: Beam parameter checks included proton depth dose, output, linearity, modulation factor, field size factor, effective source distance, compensator gap factor, and monitor unit comparison between model calibration and physical measurements for every energy. Mechanical checks included gantry and robotic table isocenter, gantry and robotic couch isocentricity, and mechanical movement of fully loaded couch and corresponding digital readout. Imaging system checks included proton, X-ray beam, laser and image receptor alignment, image quality of KV imagers, and image registration accuracy. The last were the system safety checks. Methods used to perform these checks, especially those pertaining to robotic positioner will be discussed. The new proton gantry and robotic table had the isocentric accuracy of about 1 mm. The accuracy of mechanical movements of the robotic table was within 1mm/0.5 degree in the clinical motion range. The accuracy of proton outputs determined by IAEA TRS 398 protocol was within +/-2% and the consistency of beam range for all clinical energies at cardinal gantry angles was within 1mm. The results of the gantry annual QA demonstrate that the machine satisfies the highest standards of quality assurance for proton radiation treatment. The annual QA verifies the proton output, robotic table movement accuracy, image registration and safety of the machine and thus increases our confidence level in the uncertainties of daily proton treatments.


Pregnancy in women with portal vein thrombosis: results of a multicentric European study on maternal and fetal management and outcome.
Women of childbearing age account for approximately 25% of patients with non-cirrhotic portal vein thrombosis (PVT). We aimed at assessing maternal and fetal outcome in pregnant women with known PVT. We performed a retrospective analysis of the files of women with chronic PVT in three European referral centers between 1986 and 2010. Forty-five pregnancies, 28 (62%) treated with low molecular weight heparin, occurred in 24 women. Nine (20%) were lost before gestation week 20. Preterm birth occurred in 38% of deliveries: there were 3 births at week 24-25, 7 at week 32-36, and 26 after week 37. A term birth with a healthy infant occurred in 58% of pregnancies. Cesarean section was used in 53% of deliveries. Two women developed HELLP syndrome. A favorable outcome happened in 64% of pregnancies. Pregnancies with an unfavorable outcome were associated with a higher platelet count at diagnosis. Bleeding from esophageal varices occurred in 3 patients during pregnancy, all without adequate primary prophylaxis. Genital or parietal bleeding occurred postpartum in 4 patients, only one being on anticoagulation therapy. Thrombotic events occurred in 2 patients, none related to lower limbs or mesenteric veins. There were no maternal deaths. In pregnant PVT patients treated with anticoagulation on an individual basis, the rate of miscarriage and preterm birth appears to be increased. However, fetal and maternal outcomes are favorable for most pregnancies reaching gestation week 20. High platelet counts appear to increase the risk for unfavorable outcome. Pregnancy should not be contraindicated in stable PVT patients.


Lateral geniculate body evoked potentials elicited by visual and electrical stimulation.
Blind individuals who have photoreceptor loss are known to perceive phosphenes with electrical stimulation of their remaining retinal ganglion cells. We proposed that implantable lateral geniculate body (LGB) stimulus electrode arrays could be used to generate phosphene vision. We attempted to refine the basic reference of the electrical evoked potentials (EEPs) elicited by microelectrical stimulations of the optic nerve, optic tract and LGB of a domestic pig, and then compared it to visual evoked potentials (VEPs) elicited by short-flash stimuli. For visual function measurement, VEPs in response to short-flash stimuli on the left eye of the domestic pig were assessed over the visual cortex at position Oz with the reference electrode at Fz. After anesthesia, linearly configured platinum wire electrodes were inserted into the optic nerve, optic track and LGB. To determine the optimal stimulus current, EEPs were recorded repeatedly with controlling the pulse and power. The threshold of current and charge density to elicit EEPs at 0.3 ms pulse duration was about ±10 µA. Our experimental results showed that visual cortex activity can be effectively evoked by stimulation of the optic nerve, optic tract and LGB using penetrating electrodes. The latency of P1 was more shortened as the electrical stimulation was closer to LGB. The EEPs of two-channel in the visual cortex demonstrated a similar pattern with stimulation of different spots of the stimulating electrodes. We found that the LGB-stimulated EEP pattern was very similar to the simultaneously generated VEP on the control side, although implicit time deferred. EEPs and VEPs derived from visual-system stimulation were compared. The LGB-stimulated EEP wave demonstrated a similar pattern to the VEP waveform except implicit time, indicating prosthetic-based electrical stimulation of the LGB could be utilized for the blind to perceive vision of phosphenes.


Biological invasions as disruptors of plant reproductive mutualisms.
Invasive alien species affect the composition and functioning of invaded ecosystems in many ways, altering ecological interactions that have arisen over evolutionary timescales. Specifically, disruptions to pollination and seed-dispersal mutualistic interactions are often documented, although the profound implications of such impacts are not widely recognized. Such disruptions can occur via the introduction of alien pollinators, seed dispersers, herbivores, predators or plants, and we define here the many potential outcomes of each situation. The frequency and circumstances under which each category of mechanisms operates are also poorly known. Most evidence is from population-level studies, and the implications for global biodiversity are difficult to predict. Further insights are needed on the degree of resilience in interaction networks, but the preliminary picture suggests that invasive species frequently cause profound disruptions to plant reproductive mutualisms.


Complementary and integrative medicine in the management of headache.
Headaches, including primary headaches such as migraine and tension-type headache, are a common clinical problem. Complementary and integrative medicine (CIM), formerly known as complementary and alternative medicine (CAM), uses evidence informed modalities to assist in the health and healing of patients. CIM commonly includes the use of nutrition, movement practices, manual therapy, traditional Chinese medicine, and mind-body strategies. This review summarizes the literature on the use of CIM for primary headache and is based on five meta-analyses, seven systematic reviews, and 34 randomized controlled trials (RCTs). The overall quality of the evidence for CIM in headache management is generally low and occasionally moderate. Available evidence suggests that traditional Chinese medicine including acupuncture, massage, yoga, biofeedback, and meditation have a positive effect on migraine and tension headaches. Spinal manipulation, chiropractic care, some supplements and botanicals, diet alteration, and hydrotherapy may also be beneficial in migraine headache. CIM has not been studied or it is not effective for cluster headache. Further research is needed to determine the most effective role for CIM in patients with headache.


Interaction of O2 diffusion and O2 metabolism in cat urinary bladder tissue.
We measured oxygen exchange across the inside surface of excised urinary bladders that were inflated with gas mixtures. By using a range of Po2 differences between the two sides of the tissue and relatively simple mathematical models, we could infer the exchanges across the outside surface and the total O2 economy of the tissue so that we could evaluate the interaction between diffusion and metabolic O2 consumption. The estimate of the Krogh diffusion constant or permeation coefficient with this preparation avoids errors due to O2 consumption and unstirred layers. At 37 degrees C, the value of bladder tissue O2 consumption was 4.4 times 10(-3) min-1 and the value of the Krogh constant for O2 was 2.22 times 10(-5)cm2min-1atm-1.


No association of two functional polymorphisms in human ALOX15 with myocardial infarction.
The 12/15-lipoxygenase plays a janus-role in inflammation with pro-inflammatory and anti-inflammatory effects in cell systems and even opposite effects on atherosclerosis in two different animal species. Screening of the human 15-lipoxygenase (ALOX15) gene detected a polymorphic C to T substitution at position c.-292, which led to three times higher ALOX15 activity in macrophages and showed a trend to be atheroprotective in a small case-control study for coronary artery disease (CAD). A second polymorphism at position c.1693C>T leading to an T560M exchange and an inactive enzyme was recently associated with increased CAD. We now investigated whether these polymorphisms or a certain haplotype of ALOX15 are associated with myocardial infarction (MI) in a case-control subset from the population-based MONIKA/KORA cohort S3. Six polymorphisms in ALOX15 were analyzed in 2629 participants to cover all major haplotypes with a frequency higher than 1% in the Caucasian population. None of the polymorphism was associated with MI but a rare ALOX15 haplotype showed a significant protective effect on the risk for MI (p=0.03). However, none of the polymorphisms or haplotypes was associated with CRP levels. These data suggest that ALOX15 may play a less prominent role during later stages of atherosclerosis involving atherothrombotic mechanisms than eventually during early plaque development.


Isoflavone exposure throughout suckling results in improved adult bone health in mice.
Exposure to isoflavones (ISO), abundant in soy protein infant formula, for the first 5 days of life results in higher bone mineral density (BMD), greater trabecular connectivity and higher peak load of lumbar vertebrae (LV) at adulthood. The effect of lengthening the duration of exposure to ISO on bone development has not been studied. This study determined if providing ISO for the first 21 days of life, which more closely mimics the duration that infants are fed soy protein formula, results in higher BMD, improved bone structure and greater strength in femurs and LV than a 5-day protocol. Female CD-1 mice were randomized to subcutaneous injections of ISO (7 mg/kg body weight/day) or corn oil from postnatal day 1 to 21. BMD, structure and strength were measured at the femur and LV at 4 months of age, representing young adulthood. At the LV, exposure to ISO resulted in higher (P < 0.05) BMD, trabecular connectivity and peak load compared with control (CON). Exposure to ISO also resulted in higher (P < 0.05) whole femur BMD, higher (P < 0.05) bone volume/total volume and lower (P < 0.05) trabecular separation at the femur neck, as well as greater (P < 0.05) peak load at femur midpoint and femur neck compared with the CON group. Exposure to ISO throughout suckling has favorable effects on LV outcomes, and, unlike previous studies using 5-day exposure to ISO, femur outcomes are also improved. Duration of exposure should be considered when using the CD-1 mouse to model the effect of early life exposure of infants to ISO.


Does marital status matter in an HIV hyperendemic country? Findings from the 2012 South African National HIV Prevalence, Incidence and Behaviour Survey.
South Africa has experienced declining marriage rates and the increasing practice of cohabitation without marriage. This study aims to improve the understanding of the relationship between marital status and HIV in South Africa, an HIV hyperendemic country, through an analysis of findings from the 2012 South African National HIV Prevalence, Incidence and Behaviour Survey. The nationally representative population-based cross-sectional survey collected data on HIV and socio-demographic and behavioural determinants in South Africa. This analysis considered respondents aged 16 years and older who consented to participate in the survey and provided dried blood spot specimens for HIV testing (N = 17,356). After controlling for age, race, having multiple sexual partners, condom use at last sex, urban/rural dwelling and level of household income, those who were married living with their spouse had significantly reduced odds of being HIV-positive compared to all other marital spouses groups. HIV incidence was 0.27% among respondents who were married living with their spouses; the highest HIV incidence was found in the cohabiting group (2.91%). Later marriage (after age 24) was associated with increased odds of HIV prevalence. Our analysis suggests an association between marital status and HIV prevalence and incidence in contemporary South Africa, where odds of being HIV-positive were found to be lower among married individuals who lived with their spouses compared to all other marital status groups. HIV prevention messages therefore need to be targeted to unmarried populations, especially cohabitating populations. As low socio-economic status, low social cohesion and the resulting destabilization of sexual relationships may explain the increased risk of HIV among unmarried populations, it is necessary to address structural issues including poverty that create an environment unfavourable to stable sexual relationships.


Biosurfactant mediated biosynthesis of selected metallic nanoparticles.
Developing a reliable experimental protocol for the synthesis of nanomaterials is one of the challenging topics in current nanotechnology particularly in the context of the recent drive to promote green technologies in their synthesis. The increasing need to develop clean, nontoxic and environmentally safe production processes for nanoparticles to reduce environmental impact, minimize waste and increase energy efficiency has become essential in this field. Consequently, recent studies on the use of microorganisms in the synthesis of selected nanoparticles are gaining increased interest as they represent an exciting area of research with considerable development potential. Microorganisms are known to be capable of synthesizing inorganic molecules that are deposited either intra- or extracellularly. This review presents a brief overview of current research on the use of biosurfactants in the biosynthesis of selected metallic nanoparticles and their potential importance.


Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management.
The Cardiovascular Autonomic Neuropathy (CAN) Subcommittee of the Toronto Consensus Panel on Diabetic Neuropathy worked to update CAN guidelines, with regard to epidemiology, clinical impact, diagnosis, usefulness of CAN testing, and management. CAN is the impairment of cardiovascular autonomic control in the setting of diabetes after exclusion of other causes. The prevalence of confirmed CAN is around 20%, and increases up to 65% with age and diabetes duration. Established risk factors for CAN are glycaemic control in type 1 and a combination of hypertension, dyslipidaemia, obesity, and glycaemic control in type 2 diabetes. CAN is a risk marker of mortality and cardiovascular morbidity, and possibly a progression promoter of diabetic nephropathy. Criteria for CAN diagnosis and staging are: (1) one abnormal cardiovagal test result identifies possible or early CAN; (2) at least two abnormal cardiovagal test results are required for definite or confirmed CAN; and (3) the presence of orthostatic hypotension in addition to abnormal heart rate test results identifies severe or advanced CAN. Progressive stages of CAN are associated with increasingly worse prognosis. CAN assessment is relevant in clinical practice for (1) diagnosis of CAN clinical forms, (2) detection and tailored treatment of CAN clinical correlates (e.g. tachycardia, orthostatic hypotension, non-dipping, QT interval prolongation), (3) risk stratification for diabetic complications and cardiovascular morbidity and mortality, and (4) modulation of targets of diabetes therapy. Evidence on the cost-effectiveness of CAN testing is lacking. Apart from the preventive role of intensive glycaemic control in type 1 diabetes, recommendations cannot be made for most therapeutic approaches to CAN.


Increased MKK4 abundance with replicative senescence is linked to the joint reduction of multiple microRNAs.
MKK4 (mitogen-activated protein kinase kinase 4) is a pivotal upstream activator of c-Jun N-terminal kinase and p38. Here, we report that the abundance of MKK4 increases in senescent human diploid fibroblasts through enhanced translation. We identified four microRNAs (miR-15b, miR-24, miR-25, and miR-141) that target the MKK4 messenger RNA (mRNA); the abundance of these microRNAs decreased during replicative senescence. Individually modulating the amount of each microRNA did not modify MKK4 abundance, but their concomitant overexpression decreased and their joint reduction increased MKK4 abundance. Reporter analyses indicated that these microRNAs acted through the MKK4 5' and 3' untranslated regions. Elevated MKK4 abundance inhibited cell proliferation and increased the phosphorylation and activity of p38 and PRAK (p38-regulated/activated protein kinase). Thus, multiple microRNAs acting on a single target, the MKK4 mRNA, collectively influence MKK4 abundance during replicative senescence.


A transgenic Cre mouse line for the study of cortical and hippocampal development.
Wnt signaling regulates cortical and hippocampal development. In a previous study we found that a particular Wnt receptor, Frizzled9 (Fzd9), was selectively expressed in both the developing and adult hippocampus. Taking advantage of the specificity of this promoter, we generated a transgenic cre mouse line using the putative control elements of the Fzd9 gene. In the Fzd9-cre mice, Cre is mainly detected in the developing cortex and hippocampus and is confined to the CA fields and dentate gyrus in adults. Furthermore, by crossing the Fzd9-cre mouse with the ROSA26 reporter line, we examined the activity of Cre and found that it has very high recombination efficiency. Thus, this mouse line will likely prove to be a useful tool for studying cortical and hippocampal development via activation or inactivation of interesting genes.


Tackling the re-emergence of wheat stem rust in Western Europe.
In our recent Communications Biology article, we reported the first occurrence of wheat stem rust in the UK in nearly six decades. An increased incidence of wheat stem rust in Western Europe, caused by the fungus Puccinia graminis f. sp. tritici, could signify the return of this formidable foe. As pathologists fight back against this devastating disease we outline the continuing research and strategies being employed to bridle its onslaught.


β-cell function in black South African women: exploratory associations with insulin clearance, visceral and ectopic fat.
The role of ectopic fat, insulin secretion and clearance in the preservation ofβ-cell function in black African women with obesity who typically present with hyperinsulinaemia is not clear. We aim to examine the associations between disposition index (DI, an estimate of β-cell function), insulin secretion and clearance and ectopic fat deposition. This is a cross-sectional study of 43 black South African women (age 20-35 years) with obesity (BMI 30-40 kg/m2) and without type 2 diabetes that measured the following: DI, insulin sensitivity (SI), acute insulin response (AIRg), insulin secretion rate (ISR), hepatic insulin extraction and peripheral insulin clearance (frequently sampled i.v. glucose tolerance test); pancreatic and hepatic fat, visceral adipose tissue (VAT) and abdominal s.c. adipose tissue (aSAT) volume (MRI), intra-myocellular (IMCL) and extra-myocellular fat content (EMCL) (magnetic resonance spectroscopy). DI correlated positively with peripheral insulin clearance (β 55.80, P = 0.002). Higher DI was associated with lower VAT, pancreatic fat and soleus fat, but VAT explained most of the variance in DI (32%). Additionally, higher first phase ISR (P = 0.033) and lower hepatic insulin extraction (P = 0.022) were associated with lower VAT, independent from SI, rather than with ectopic fat. In conclusion, peripheral insulin clearance emerged as an important correlate of DI. However, VAT was the main determinant of a lower DI above ectopic fat depots. Importantly, VAT, but not ectopic fat, is associated with both lower insulin secretion and higher hepatic insulin extraction. Prevention of VAT accumulation in young black African women should, therefore, be an important target for beta cell preservation.


Triple dissociation of attention and decision computations across prefrontal cortex.
Naturalistic decision-making typically involves sequential deployment of attention to choice alternatives to gather information before a decision is made. Attention filters how information enters decision circuits, thus implying that attentional control may shape how decision computations unfold. We recorded neuronal activity from three subregions of the prefrontal cortex (PFC) while monkeys performed an attention-guided decision-making task. From the first saccade to decision-relevant information, a triple dissociation of decision- and attention-related computations emerged in parallel across PFC subregions. During subsequent saccades, orbitofrontal cortex activity reflected the value comparison between currently and previously attended information. In contrast, the anterior cingulate cortex carried several signals reflecting belief updating in light of newly attended information, the integration of evidence to a decision bound and an emerging plan for what action to choose. Our findings show how anatomically dissociable PFC representations evolve during attention-guided information search, supporting computations critical for value-guided choice.


Attentional orientation induced by temporarily established self-referential cues.
Self-referential stimuli such as self-face surpass other-referential stimuli in capture of attention, which has been attributed to attractive perceptual features of self-referential stimuli. We investigated whether temporarily established self-referential stimuli are different from other-referential cues in guiding voluntary visual attention. Temporarily established self-referential or friend-referential shapes served as central cues in Posner's endogenous cueing task. We found that, relative to friend-referential cues, self-referential cues induced smaller cueing effect (i.e., the difference in reaction times to targets at cued and uncued locations) when the interstimulus interval was short but larger cueing effect when the interstimulus interval was long. Our findings suggest that temporarily established self-referential cues are more efficient to capture reflexive attention at the early stage of perceptual processing and to shift voluntary attention at the later stage of perceptual processing.


Data integration and visualization techniques for post-cytometric analysis of complex datasets.
The increasing number of measurable markers and the need to integrate flow cytometry datasets with data generated by other high throughput technologies, require the use of innovative tools, easy enough to be used by people with diverse levels of informatics skills. Flow cytometry analysis software has principally been designed for single sample analysis and it does not cover all the successive analysis steps such as integration with metadata and complex visualization. Here, we illustrated the use of data integration and visualization tools generally used in the business sector to analyze datasets generated by mass and flow cytometry. We selected a study that used mass cytometry to characterize immune cells in lung adenocarcinoma and a second study that used flow cytometry to characterize the expression signature of CD markers on human immune cells. These two examples showed the effectiveness of these tools in the analysis of cytometry data and the possibility to expand their use in any field of biology.


Effect of partial selfing and polygenic selection on establishment in a new habitat.
This article analyzes how partial selfing in a large source population influences its ability to colonize a new habitat via the introduction of a few founder individuals. Founders experience inbreeding depression due to partially recessive deleterious alleles as well as maladaptation to the new environment due to selection on a large number of additive loci. I first introduce a simplified version of the inbreeding history model to characterize mutation-selection balance in a large, partially selfing source population under selection involving multiple nonidentical loci. I then use individual-based simulations to study the eco-evolutionary dynamics of founders establishing in the new habitat under a model of hard selection. The study explores how selfing rate shapes establishment probabilities of founders via effects on both inbreeding depression and adaptability to the new environment, and also distinguishes the effects of selfing on the initial fitness of founders from its effects on the long-term adaptive response of the populations they found. A high rate of (but not complete) selfing is found to aid establishment over a wide range of parameters, even in the absence of mate limitation. The sensitivity of the results to assumptions about the nature of polygenic selection is discussed.


Photosynthesis, growth, and decay traits in Sphagnum - a multispecies comparison.
Peat mosses (Sphagnum) largely govern carbon sequestration in Northern Hemisphere peatlands. We investigated functional traits related to growth and decomposition in Sphagnum species. We tested the importance of environment and phylogeny in driving species traits and investigated trade-offs among them. We selected 15 globally important Sphagnum species, representing four sections (subgenera) and a range of peatland habitats. We measured rates of photosynthesis and decomposition in standard laboratory conditions as measures of innate growth and decay potential, and related this to realized growth, production, and decomposition in their natural habitats. In general, we found support for a trade-off between measures of growth and decomposition. However, the relationships are not strong, with r ranging between 0.24 and 0.45 for different measures of growth versus decomposition. Using photosynthetic rate to predict decomposition in standard conditions yielded R (2) = 0.20. Habitat and section (phylogeny) affected the traits and the trade-offs. In a wet year, species from sections Cuspidata and Sphagnum had the highest production, but in a dry year, differences among species, sections, and habitats evened out. Cuspidata species in general produced easily decomposable litter, but their decay in the field was hampered, probably due to near-surface anoxia in their wet habitats. In a principal components analysis, PCA, photosynthetic capacity, production, and laboratory decomposition acted in the same direction. The species were imperfectly clustered according to vegetation type and phylogeny, so that some species clustered with others in the same section, whereas others clustered more clearly with others from similar vegetation types. Our study includes a wider range of species and habitats than previous trait analyses in Sphagnum and shows that while the previously described growth-decay trade-off exists, it is far from perfect. We therefore suggest that our species-specific trait measures offer opportunities for improvements of peatland ecosystem models. Innate qualities measured in laboratory conditions translate differently to field responses. Most dramatically, fast-growing species could only realize their potential in a wet year. The same species decompose fast in laboratory, but their decomposition was more retarded in the field than that of other species. These relationships are crucial for understanding the long-term dynamics of peatland communities.


Genetic determinants of mortality. Can findings from genome-wide association studies explain variation in human mortality?
Twin studies have estimated the heritability of longevity to be approximately 20-30 %. Genome-wide association studies (GWAS) have revealed a large number of determinants of morbidity, but so far, no new polymorphisms have been discovered to be associated with longevity per se in GWAS. We aim to determine whether the genetic architecture of mortality can be explained by single nucleotide polymorphisms (SNPs) associated with common traits and diseases related to mortality. By extensive quality control of published GWAS we created a genetic score from 707 common SNPs associated with 125 diseases or risk factors related with overall mortality. We prospectively studied the association of the genetic score with: (1) time-to-death; (2) incidence of the first of nine major diseases (coronary heart disease, stroke, heart failure, diabetes, dementia, lung, breast, colon and prostate cancers) in two population-based cohorts of Dutch and Swedish individuals (N = 15,039; age range 47-99 years). During a median follow-up of 6.3 years (max 22.2 years), we observed 4,318 deaths and 2,132 incident disease events. The genetic score was significantly associated with time-to-death [hazard ratio (HR) per added risk allele = 1.003, P value = 0.006; HR 4th vs. 1st quartile = 1.103]. The association between the genetic score and incidence of major diseases was stronger (HR per added risk allele = 1.004, P value = 0.002; HR 4th vs. 1st quartile = 1.160). Associations were stronger for individuals dying at older ages. Our findings are compatible with the view of mortality as a complex and highly polygenetic trait, not easily explainable by common genetic variants related to diseases and physiological traits.


Optimising pharmacotherapy for secondary prevention of non-invasively managed acute coronary syndrome.
About half of all patients who experience an acute coronary syndrome (ACS) in Australia have their conditions managed non-invasively - that is, they do not undergo coronary angiography and revascularisation in hospital. ACS patients whose conditions are managed non-invasively may not receive the same level of evidence-based care as those who receive coronary revascularisation. This article reviews the optimal pharmacological management of ACS managed non-invasively. There is strong evidence to support the prescription of dual antiplatelet therapy (DAPT; aspirin with a P2Y12 inhibitor). DAPT should continue for 12 months after an ACS, then aspirin should be continued indefinitely. Anticoagulation with warfarin or a novel oral anticoagulant may be needed if atrial fibrillation occurs; the combination with DAPT increases the risk of bleeding. Unless contraindicated, high-intensity statin therapy should be prescribed for all post-ACS patients irrespective of their cholesterol level. Non-statin lipid therapy has not been shown to improve outcomes. Use of β-adrenergic blockers is recommended in most guidelines, but the clinical trials to support this recommendation were performed more than 30 years ago, and routine long-term use may not be relevant to modern treatment, except when there is cardiac failure or left ventricular dysfunction. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are also widely recommended, but the evidence for benefit is stronger when there is left ventricular dysfunction. Calcium-channel blockers, nitrates, antiarrhythmic drugs, digoxin and diuretics do not improve outcomes in post-ACS patients.


PillCamColon2 after incomplete colonoscopy - A prospective multicenter study.
To evaluate the ability of PillCamColon2 to visualize colonic segments missed by incomplete optical colonoscopy (OC) and to assess the diagnostic yield. This prospective multicentre study included 81 patients from nine centres who underwent second-generation colon capsule endoscopy (CCE) following incomplete OC performed by an experienced gastroenterologist (> 1000 colonoscopies). Patients with stenosis were excluded. According to patient preferences, CCE was performed the following day (protocol A) after staying on clear liquids and 0.75 L Moviprep in the morning or within 30 d after new split-dose Moviprep (protocol B). Boosts consisted of 0.75 L and 0.25 L Moviprep, and phospho-soda was given as a rescue if the capsule was not excreted after seven hours. Seventy-four patients were analysed (51% of them in group A; 49% in group B). Bowel cleansing was adequate in 67% of cases, and CCE could visualize colonic segments missed by incomplete colonoscopy in 90% of patients under protocol A and 97% of patients under protocol B (P = 0.35, n.s.). Significant polyps including adenocarcinoma were detected in 24% of cases. Detection rates for all polyps and significant polyps per patient were similar in both protocols. Polyps were found predominantly in the right colon (86%) in segments that were not reached by OC. Extracolonic findings - such as reflux esophagitis, suspected Barrett esophagus, upper GI-bleeding, gastric polyps, gastric erosions and angiectasia - were detected in eight patients. PillCamColon2 capsule was retained in the ileum of one patient (1.4%) without symptoms and removed during an uneventful resection for unknown Crohn's disease that was diagnosed as the cause of anemia, which was the indication for colonoscopy. CCE was well tolerated. One patient suffered from self-limiting vomiting after consuming the phospho-soda. Second-generation CCE using a low-volume preparation is useful after incomplete OC, and it allows for the detection of additional relevant findings, but cleansing efficiency could be improved.


Hybrid Randomly Electrospun Poly(lactic-co-glycolic acid):Poly(ethylene oxide) (PLGA:PEO) Fibrous Scaffolds Enhancing Myoblast Differentiation and Alignment.
Cellular responses are regulated by their microenvironments, and engineered synthetic scaffolds can offer control over different microenvironment properties. This important relationship can be used as a tool to manipulate cell fate and cell responses for different biomedical applications. We show for the first time in this study how blending of poly(ethylene oxide) (PEO) to poly(lactic-co-glycolic acid) (PLGA) fibers to yield hybrid scaffolds changes the physical and mechanical properties of PLGA fibrous scaffolds and in turn affects cellular response. For this purpose we employed electrospinning to create fibrous scaffolds mimicking the basic structural properties of the native extracellular matrix. We introduced PEO to PLGA electrospun fibers by spinning a blend of PLGA:PEO polymer solutions in different ratios. PEO served as a sacrificial component within the fibers upon hydration, leading to pore formation in the fibers, fiber twisting, increased scaffold disintegration, and hydrophilicity, decreased Young's modulus, and significantly improved strain at break of initially electrospun scaffolds. We observed that the blended PLGA:PEO fibrous scaffolds supported myoblast adhesion and proliferation and resulted in increased myotube formation and self-alignment, when compared to PLGA-only scaffolds, even though the scaffolds were randomly oriented. The 50:50 PLGA:PEO blended scaffold showed the most promising results in terms of mechanical properties, myotube formation, and alignment, suggesting an optimal microenvironment for myoblast differentiation from the PLGA:PEO blends tested. The explored approach for tuning fiber properties can easily extend to other polymeric scaffolds and provides a valuable tool to engineer fibrillar microenvironments for several biomedical applications.


Diagnostic yield of capsule endoscopy in the setting of iron deficiency anemia without evidence of gastrointestinal bleeding.
The diagnostic yield of capsule endoscopy (CE) in the setting of iron deficiency anemia (IDA) without evidence of occult⁄overt bleeding has been questioned. Often, these patients have nongastrointestinal causes of iron deficiency but undergo CE to exclude a potential small bowel source. To assess the diagnostic yield of CE, the characteristics predicting positive results, the presumed etiology of IDA in negative⁄normal CE and patient management after CE. A retrospective review of 934 patients who underwent CE between December 2001 and February 2010 was conducted. All patients had undergone previous negative endoscopic examinations before CE. Patients with IDA but no evidence of overt⁄occult bleeding were separated into three categories based on CE findings: group A - positive; group B - negative⁄normal; and group C - incomplete⁄indeterminate. A total of 101 capsules in 97 patients were evaluated. Group A had 25 subjects with positive findings on CE, 18 of whom were managed supportively. Group B consisted of 69 subjects with negative⁄normal CE, 60 of whom were treated supportively. Group C consisted of three subjects with incomplete CE results. In patients with IDA without evidence of gastrointestinal bleeding, CE had a low diagnostic yield (25.7%), which increased to 45.5% after adjusting for low dietary iron intake and menorrhagia. However, CE did not alter management in most patients regardless of findings, and many of the lesions requiring intervention were within reach of standard endoscopes. No predictor of positive results was found. In this patient population, careful history taking and thorough endoscopy could improve CE utilization, although its value is still relatively limited.


Clusterin inhibition using OGX-011 synergistically enhances Hsp90 inhibitor activity by suppressing the heat shock response in castrate-resistant prostate cancer.
Small-molecule inhibitors of Hsp90 show promise in the treatment of castrate-resistant prostate cancer (CRPC); however, these inhibitors trigger a heat shock response that attenuates drug effectiveness. Attenuation is associated with increased expression of Hsp90, Hsp70, Hsp27, and clusterin (CLU) that mediate tumor cell survival and treatment resistance. We hypothesized that preventing CLU induction in this response would enhance Hsp90 inhibitor-induced CRPC cell death in vitro and in vivo. To test this hypothesis, we treated CRPC with the Hsp90 inhibitor PF-04929113 or 17-AAG in the absence or presence of OGX-011, an antisense drug that targets CLU. Treatment with either Hsp90 inhibitor alone increased nuclear translocation and transcriptional activity of the heat shock factor HSF-1, which stimulated dose- and time-dependent increases in HSP expression, especially CLU expression. Treatment-induced increases in CLU were blocked by OGX-011, which synergistically enhanced the activity of Hsp90 inhibition on CRPC cell growth and apoptosis. Accompanying these effects was a decrease in HSF-1 transcriptional activity as well as expression of HSPs, Akt, prostate-specific antigen, and androgen receptor. In vivo evaluation of the Hsp90 inhibitors with OGX-011 in xenograft models of human CRPC showed that OGX-011 markedly potentiated antitumor efficacy, leading to an 80% inhibition of tumor growth with prolonged survival compared with Hsp90 inhibitor monotherapy. Together, our findings indicate that Hsp90 inhibitor-induced activation of the heat shock response and CLU is attenuated by OGX-011, with synergistic effects on delaying CRPC progression.


The relationship of public support payments to substance abuse among homeless veterans with mental illness.
A suspicion that disability payments may exacerbate substance use among persons with chemical addictions recently led Congress to limit federal disability entitlements of applicants whose disability status is related to substance abuse, even if they have another serious mental disorder. This study empirically explored the relationship between receipt of disability payments and substance use among homeless mentally ill veterans. The study sample included 2,474 homeless veterans with a current diagnosis of schizophrenia and a substance abuse or dependence disorder who were assessed in a community outreach program sponsored by the Department of Veterans Affairs. After adjustment for other relevant factors, receipt of disability payments showed no significant relationship to the number of days of substance use a month, even among frequent users of alcohol and drugs. Findings about substance use among the homeless veterans with serious mental disorders in this study provide no support for the assertion that disability payments exacerbate substance use.


Effectiveness of a rehabilitation dog in fostering gait retraining for adults with a recent stroke: a multiple single-case study.
Gait retraining approaches and walking aids currently used for patients with recent stoke present limitations regarding their utilization in clinical and real life settings. A rehabilitation facility implemented an innovative approach using a rehabilitation dog for gait retraining and as a walking aid. To explore the effectiveness of rehabilitation dog, both as a gait retraining approach and as a walking aid, to improve walking speed and gait pattern. Four participants, post recent stroke with hemiparesis, were recruited in a rehabilitation unit. A multiple single-case ABA design was used. The three-week training period focused on gait retraining using a rehabilitation dog. For each session, walking speed with the rehabilitation dog and the cane was documented. In each phase (ABA), the gait pattern was analyzed. Mean (SD) age of the participants was 58 (3.2) years old; time since stroke was 88 (61.41) days. For three participants, walking speed was significantly increased after retraining with the dog. The four participants showed improvement of their gait pattern across phases and walked significantly faster with the dog than with the cane. This pilot study suggests that a rehabilitation dog is an interesting gait retraining approach for a clinical setting and an effective walking aid following stroke.


Revisiting use of growth factors in myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematologic neoplasms characterized by morphologic dysplasia, aberrant hematopoiesis and peripheral blood refractory cytopenias. MDS is recognized to be associated with an increased risk of symptomatic anemia, infectious complications and bleeding diathesis, as well as a risk of progression to acute myeloid leukemia, particularly in patients with a high IPSS score. The advent of use of hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) and recombinant erythropoietin (EPO) has improved symptoms in MDS patients in addition to some data that suggest there might be an improvement in survival. G-CSF is an effective therapeutic option in MDS patients, and it should be considered for the management of refractory symptomatic cytopenias. G-CSF and EPO in combination can improve outcomes in appropriate MDS patients such as those with lower-risk MDS and refractory anemia with ring sideroblasts (RARS) . This article reviews use of growth factors for lower-risk MDS patients, and examines the data for G-CSF, EPO and thrombopietic growth factors (TPO) that are available or being developed as therapeutic modalities for this challenging disease.


Inducible gene and shRNA expression in resident hematopoietic stem cells in vivo.
Hematopoietic stem cells (HSC) are probably the best understood somatic stem cells and often serve as a paradigm for other stem cells. Nevertheless, most current techniques to genetically manipulate them in vivo are either constitutive and/or induced in settings of hematopoietic stress such as after irradiation. Here, we present a conditional expression system that allows for externally controllable transgenesis and knockdown in resident HSCs, based on a lentiviral vector containing a tet-O sequence and a transgenic mouse line expressing a doxycyclin-regulated tTR-KRAB repressor protein. HSCs harvested from tTR-KRAB mice are transduced with the lentiviral vector containing a cDNA (i.e., Green Fluorescent Protein (GFP)) and/or shRNA (i.e., p53) of interest and then transplanted into lethally irradiated recipients. While the vector is effectively repressed by tTR-KRAB during homing and engraftment, robust GFP/shp53 expression is induced on doxycyclin treatment in HSCs and their progeny. Doxycylin-controllable transcription is maintained on serial transplantation, indicating that repopulating HSCs are stably modified by this approach. In summary, this easy to implement conditional system provides inducible and reversible overexpression or knock down of genes in resident HSCs in vivo using a drug devoid of toxic or activating effects.


Evaluation of a software module for adaptive treatment planning and re-irradiation.
The aim of this work is to validate the Dynamic Planning Module in terms of usability and acceptance in the treatment planning workflow. The Dynamic Planning Module was used for decision making whether a plan adaptation was necessary within one course of radiation therapy. The Module was also used for patients scheduled for re-irradiation to estimate the dose in the pretreated region and calculate the accumulated dose to critical organs at risk. During one year, 370 patients were scheduled for plan adaptation or re-irradiation. All patient cases were classified according to their treated body region. For a sub-group of 20 patients treated with RT for lung cancer, the dosimetric effect of plan adaptation during the main treatment course was evaluated in detail. Changes in tumor volume, frequency of re-planning and the time interval between treatment start and plan adaptation were assessed. The Dynamic Planning Tool was used in 20% of treated patients per year for both approaches nearly equally (42% plan adaptation and 58% re-irradiation). Most cases were assessed for the thoracic body region (51%) followed by pelvis (21%) and head and neck cases (10%). The sub-group evaluation showed that unintended plan adaptation was performed in 38% of the scheduled cases. A median time span between first day of treatment and necessity of adaptation of 17 days (range 4-35 days) was observed. PTV changed by 12 ± 12% on average (maximum change 42%). PTV decreased in 18 of 20 cases due to tumor shrinkage and increased in 2 of 20 cases. Re-planning resulted in a reduction of the mean lung dose of the ipsilateral side in 15 of 20 cases. The experience of one year showed high acceptance of the Dynamic Planning Module in our department for both physicians and medical physicists. The re-planning can potentially reduce the accumulated dose to the organs at risk and ensure a better target volume coverage. In the re-irradiation situation, the Dynamic Planning Tool was used to consider the pretreatment dose, to adapt the actual treatment schema more specifically and to review the accumulated dose.


Spatiotemporal regulation of ERK2 by dual specificity phosphatases.
Although many stimuli activate extracellular signal-regulated kinases 1 and 2 (ERK1/2), the kinetics and compartmentalization of ERK1/2 signals are stimulus-dependent and dictate physiological consequences. ERKs can be inactivated by dual specificity phosphatases (DUSPs), notably the MAPK phosphatases (MKPs) and atypical DUSPs, that can both dephosphorylate and scaffold ERK1/2. Using a cell imaging model (based on knockdown of endogenous ERKs and add-back of wild-type or mutated ERK2-GFP reporters), we explored possible effects of DUSPs on responses to transient or sustained ERK2 activators (epidermal growth factor and phorbol 12,13-dibutyrate, respectively). For both stimuli, a D319N mutation (which impairs DUSP binding) increased ERK2 activity and reduced nuclear accumulation. These stimuli also increased mRNA levels for eight DUSPs. In a short inhibitory RNA screen, 12 of 16 DUSPs influenced ERK2 responses. These effects were evident among nuclear inducible MKP, cytoplasmic ERK MKP, JNK/p38 MKP, and atypical DUSP subtypes and, with the exception of the nuclear inducible MKPs, were paralleled by corresponding changes in Egr-1 luciferase activation. Simultaneous removal of all JNK/p38 MKPs or nuclear inducible MKPs revealed them as positive and negative regulators of ERK2 signaling, respectively. The effects of JNK/p38 MKP short inhibitory RNAs were not dependent on protein neosynthesis but were reversed in the presence of JNK and p38 kinase inhibitors, indicating DUSP-mediated cross-talk between MAPK pathways. Overall, our data reveal that a large number of DUSPs influence ERK2 signaling. Together with the known tissue-specific expression of DUSPs and the importance of ERK1/2 in cell regulation, our data support the potential value of DUSPs as targets for drug therapy.


Amorfrutins Are Natural PPARγ Agonists with Potent Anti-inflammatory Properties.
Amorfrutins are isoprenoid-substituted benzoic acid derivatives, which were found in Amorpha fruticosa L. (bastard indigo) and in Glycyrrhiza foetida Desf. (licorice). Recently, amorfrutins were shown to be selective activators of the nuclear receptor PPARγ. Here, we investigated the effects and PPARγ-based mechanisms of reducing inflammation in colon cells by treatment with amorfrutins. In TNF-α-stimulated colon cells amorfrutin A (1) reduced significantly the expression and secretion of several inflammation mediators, in part due to interaction with PPARγ. These results support the hypothesis that amorfrutins may have the potential to treat inflammation disorders such as chronic inflammatory bowel diseases.


Material efficiency: providing material services with less material production.
Material efficiency, as discussed in this Meeting Issue, entails the pursuit of the technical strategies, business models, consumer preferences and policy instruments that would lead to a substantial reduction in the production of high-volume energy-intensive materials required to deliver human well-being. This paper, which introduces a Discussion Meeting Issue on the topic of material efficiency, aims to give an overview of current thinking on the topic, spanning environmental, engineering, economics, sociology and policy issues. The motivations for material efficiency include reducing energy demand, reducing the emissions and other environmental impacts of industry, and increasing national resource security. There are many technical strategies that might bring it about, and these could mainly be implemented today if preferred by customers or producers. However, current economic structures favour the substitution of material for labour, and consumer preferences for material consumption appear to continue even beyond the point at which increased consumption provides any increase in well-being. Therefore, policy will be required to stimulate material efficiency. A theoretically ideal policy measure, such as a carbon price, would internalize the externality of emissions associated with material production, and thus motivate change directly. However, implementation of such a measure has proved elusive, and instead the adjustment of existing government purchasing policies or existing regulations-- for instance to do with building design, planning or vehicle standards--is likely to have a more immediate effect.


Prioritizing the school environment in school violence prevention efforts.
Numerous studies have demonstrated an association between characteristics of the school environment and the likelihood of school violence. However, little is known about the relative importance of various characteristics of the school environment or their differential impact on multiple violence outcomes. Primarily African-American students (n = 27) from Baltimore City high schools participated in concept mapping sessions, which produced interpretable maps of the school environment's contribution to school violence. Participants generated statements about their school environment's influence on school violence and, with the assistance of quantitative methods, grouped these statements according to their similarity. Participants provided information about the importance of each of these statements for the initiation, cessation, and severity of the violence that occurs at school. More than half of the 132 statements generated by students were rated as school environment characteristics highly important for the initiation, cessation, and/or severity of school violence. Participants identified students' own actions, expectations for disruptive behavior, and the environment outside the school as the characteristics most important for the initiation and increased severity of violence that occurs in school. Participants had a more difficult time identifying school environment characteristics important for the cessation of school violence. This study provides support from students for the role of the school environment in school violence prevention, particularly in preventing the initiation and reducing the severity of school violence. Schools can utilize the information presented in this article to begin discussions with students and staff about prioritizing school environment changes to reduce school violence.


Liquefaction of Biopolymers: Solvent-free Liquids and Liquid Crystals from Nucleic Acids and Proteins.
Biomacromolecules, such as nucleic acids, proteins, and virus particles, are persistent molecular entities with dimensions that exceed the range of their intermolecular forces hence undergoing degradation by thermally induced bond-scission upon heating. Consequently, for this type of molecule, the absence of a liquid phase can be regarded as a general phenomenon. However, certain advantageous properties usually associated with the liquid state of matter, such as processability, flowability, or molecular mobility, are highly sought-after features for biomacromolecules in a solvent-free environment. Here, we provide an overview over the design principles and synthetic pathways to obtain solvent-free liquids of biomacromolecular architectures approaching the topic from our own perspective of research. We will highlight the milestones in synthesis, including a recently developed general surfactant complexation method applicable to a large variety of biomacromolecules as well as other synthetic principles granting access to electrostatically complexed proteins and DNA. These synthetic pathways retain the function and structure of the biomacromolecules even under extreme, nonphysiological conditions at high temperatures in water-free melts challenging the existing paradigm on the role of hydration in structural biology. Under these conditions, the resulting complexes reveal their true potential for previously unthinkable applications. Moreover, these protocols open a pathway toward the assembly of anisotropic architectures, enabling the formation of solvent-free biomacromolecular thermotropic liquid crystals. These ordered biomaterials exhibit vastly different mechanical properties when compared to the individual building blocks. Beyond the preparative aspects, we will shine light on the unique potential applications and technologies resulting from solvent-free biomacromolecular fluids: From charge transport in dehydrated liquids to DNA electrochromism to biocatalysis in the absence of a protein hydration shell. Moreover, solvent-free biological liquids containing viruses can be used as novel storage and process media serving as a formulation technology for the delivery of highly concentrated bioactive compounds. We are confident that this new class of hybrid biomaterials will fuel further studies and applications of biomacromolecules beyond water and other solvents and in a much broader context than just the traditional physiological conditions.


Sm1, a proteinaceous elicitor secreted by the biocontrol fungus Trichoderma virens induces plant defense responses and systemic resistance.
The soilborne filamentous fungus Trichoderma virens is a biocontrol agent with a well-known ability to produce antibiotics, parasitize pathogenic fungi, and induce systemic resistance in plants. Even though a plant-mediated response has been confirmed as a component of bioprotection by Trichoderma spp., the molecular mechanisms involved remain largely unknown. Here, we report the identification, purification, and characterization of an elicitor secreted by T. virens, a small protein designated Sm1 (small protein 1). Sm1 lacks toxic activity against plants and microbes. Instead, native, purified Sm1 triggers production of reactive oxygen species in monocot and dicot seedlings, rice, and cotton, and induces the expression of defense-related genes both locally and systemically in cotton. Gene expression analysis revealed that SM1 is expressed throughout fungal development under different nutrient conditions and in the presence of a host plant. Using an axenic hydroponic system, we show that SM1 expression and secretion of the protein is significantly higher in the presence of the plant. Pretreatment of cotton cotyledons with Sm1 provided high levels of protection to the foliar pathogen Colletotrichum sp. These results indicate that Sm1 is involved in the induction of resistance by Trichoderma spp. through the activation of plant defense mechanisms.


Multiscale Currents Observed by MMS in the Flow Braking Region.
We present characteristics of current layers in the off-equatorial near-Earth plasma sheet boundary observed with high time-resolution measurements from the Magnetospheric Multiscale mission during an intense substorm associated with multiple dipolarizations. The four Magnetospheric Multiscale spacecraft, separated by distances of about 50 km, were located in the southern hemisphere in the dusk portion of a substorm current wedge. They observed fast flow disturbances (up to about 500 km/s), most intense in the dawn-dusk direction. Field-aligned currents were observed initially within the expanding plasma sheet, where the flow and field disturbances showed the distinct pattern expected in the braking region of localized flows. Subsequently, intense thin field-aligned current layers were detected at the inner boundary of equatorward moving flux tubes together with Earthward streaming hot ions. Intense Hall current layers were found adjacent to the field-aligned currents. In particular, we found a Hall current structure in the vicinity of the Earthward streaming ion jet that consisted of mixed ion components, that is, hot unmagnetized ions, cold E × B drifting ions, and magnetized electrons. Our observations show that both the near-Earth plasma jet diversion and the thin Hall current layers formed around the reconnection jet boundary are the sites where diversion of the perpendicular currents take place that contribute to the observed field-aligned current pattern as predicted by simulations of reconnection jets. Hence, multiscale structure of flow braking is preserved in the field-aligned currents in the off-equatorial plasma sheet and is also translated to ionosphere to become a part of the substorm field-aligned current system.


Short-term outcomes of the surgical management of acquired rectourethral fistulas: does technique matter?
Acquired rectourethral fistulas are uncommon and challenging to repair. Most arise as a complication of prostate cancer treatment. Several procedures have been described to repair rectourethral fistulas with varying outcomes. We review the etiology, management, and outcomes of patients with rectourethral fistulas at our institution. A retrospective review of patients undergoing repair of rectourethral fistulas was undertaken. Data were collected on patient demographics, fistula etiology, operative procedure, fecal and urinary diversion, and clinical outcome. Patients with urinary and/or fecal diversion underwent radiographic evaluation to confirm closure of the fistula prior to reversal of the diversion. Fistula repair was performed on 22 patients from 1999 to 2009. All the patients were male of an average age of 69 years (range: 39-82 years). All patients, except one, had prostate cancer. Fistula formation was associated with radiotherapy in 54.4% of patients, brachytherapy in 36.4% of patients, and with external beam radiation therapy in 18.2% of patients. Other causes included prostatectomy (seven patients, 31.8%), cryotherapy (two patients, 9.1%), and perianal abscess (one patient, 4.5%). Procedures performed for fistula repair included transanal repair (eleven patients, 50%), transperineal repair (five patients, 22.7%), transabdominal repair (three patients, 13.6%), and York-Mason repair (three patients, 13.6%). Fourteen patients (63.6%) had urinary diversion. Fecal diversion was performed in 16 (72.7%) patients. Five (22.7%) patients had had previous attempts at fistula repair. Of the 22 patients treated, repair was successful in 20 patients (91%). The average follow-up time was 6 months (range: 3-13 months). The success rate of treatment of rectourethral fistulas is high, regardless of the procedure type. Patients with previous repair attempts tend to have less favorable outcomes. With high success rates, less invasive procedures should be attempted first.


Towards real-time photon Monte Carlo dose calculation in the cloud.
Near real-time application of Monte Carlo (MC) dose calculation in clinic and research is hindered by the long computational runtimes of established software. Currently, fast MC software solutions are available utilising accelerators such as graphical processing units (GPUs) or clusters based on central processing units (CPUs). Both platforms are expensive in terms of purchase costs and maintenance and, in case of the GPU, provide only limited scalability. In this work we propose a cloud-based MC solution, which offers high scalability of accurate photon dose calculations. The MC simulations run on a private virtual supercomputer that is formed in the cloud. Computational resources can be provisioned dynamically at low cost without upfront investment in expensive hardware. A client-server software solution has been developed which controls the simulations and transports data to and from the cloud efficiently and securely. The client application integrates seamlessly into a treatment planning system. It runs the MC simulation workflow automatically and securely exchanges simulation data with the server side application that controls the virtual supercomputer. Advanced encryption standards were used to add an additional security layer, which encrypts and decrypts patient data on-the-fly at the processor register level. We could show that our cloud-based MC framework enables near real-time dose computation. It delivers excellent linear scaling for high-resolution datasets with absolute runtimes of 1.1 seconds to 10.9 seconds for simulating a clinical prostate and liver case up to 1% statistical uncertainty. The computation runtimes include the transportation of data to and from the cloud as well as process scheduling and synchronisation overhead. Cloud-based MC simulations offer a fast, affordable and easily accessible alternative for near real-time accurate dose calculations to currently used GPU or cluster solutions.


Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer.
Molecularly targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR signalling undermines therapeutic efficacy and promotes progression to lethal castration-resistant prostate cancer (CRPC), even when patients are treated with potent second-generation AR-targeted therapies abiraterone and enzalutamide. Here we define diverse AR genomic structural rearrangements (AR-GSRs) as a class of molecular alterations occurring in one third of CRPC-stage tumours. AR-GSRs occur in the context of copy-neutral and amplified AR and display heterogeneity in breakpoint location, rearrangement class and sub-clonal enrichment in tumours within and between patients. Despite this heterogeneity, one common outcome in tumours with high sub-clonal enrichment of AR-GSRs is outlier expression of diverse AR variant species lacking the ligand-binding domain and possessing ligand-independent transcriptional activity. Collectively, these findings reveal AR-GSRs as important drivers of persistent AR signalling in CRPC.


Hydration in older adults: the contribution of bioelectrical impedance analysis.
The sensory and gastrointestinal changes that occur with ageing affect older adults' food and liquid intake. Any decreased liquid intake increases the risk for dehydration. This increased dehydration risk is compounded in older adults with dysphagia. The availability of a non-invasive and easily administered way to document hydration levels in older adults is critical, particularly for adults in residential care. This pilot study investigated the contribution of bioelectrical impedance analysis to measure hydration in 19 older women in residential care: 13 who viewed themselves as healthy and six with dysphagia. Mann-Whitney U analyses documented no significant between-group differences for Total Body Water (TBW), Fat Free Mass (FFM), Fat Mass (FM), and percentage Body Fat (%BF). However, when compared to previously published data for age-matched women, the TBW and FFM values of the two participant groups were notably less, and FM and %BF values were notably greater than expected. If results are confirmed through continued investigation, such findings may suggest that long-term care facilities are unique environments in which all older residents can be considered at-risk for dehydration and support the use of BIA as a non-invasive tool to assess and monitor their hydration status.


Major vault protein regulates cell growth/survival signaling through oxidative modifications.
Major vault protein forms a hollow, barrel-like structure in the cell called the vault, whose functions and regulation are not well understood. The present study reports that major vault protein regulates growth/survival signaling in human airway smooth muscle cells through oxidative modifications. The promotion of protein S-glutathionylation by asthma mediators such as interleukin-22 and platelet-derived growth factor or by knocking down glutaredoxin-1 or thioredoxin activated cell growth signaling. Mass spectrometry identified that major vault protein is glutathionylated. Major vault protein knockdown enhanced cell death and inhibited STAT3 and Akt signaling. We identified a protein partner of major vault protein that is regulated by glutaredoxin-1, namely myosin-9, which was found to serve as a cell death factor. Knocking down myosin-9 or promoting protein S-glutathionylation by knocking down glutaredoxin-1 inhibited the death of airway smooth muscle cells by heating to simulate bronchial thermoplasty, a clinically successful procedure for the treatment of severe asthma. These results establish a novel signaling pathway in which ligand/receptor-mediated oxidation promotes the S-glutathionylation of major vault protein, which in turn binds to myosin-9 to suppress the heating-induced death of airway smooth muscle cells.


Diabetes empowerment and needs for self-management support among people with type 2 diabetes in a rural inland community in northern Sweden.
Self-management among people with T2D includes being responsible for attaining a blood sugar level within the normal range, eating healthy food, exercising and following prescriptions for medication, something that may need support. In rural areas, access to health care may be limited, and support from family members becomes important. The aim of this study was to describe perceptions and associations of diabetes empowerment, self-management ability and needs of self-management support among people with T2D in a northern rural community of Sweden. People with T2D (n = 159) living a rural municipality in northern Sweden answered the SWE-DES-23 questionnaire and additional questions concerning self-management and needs for self-management support. A higher diabetes empowerment was associated with longer diabetes duration and support from healthcare professionals and relatives. Women rated a need for self-management support significantly higher than men did. Nonretired persons rated a significantly higher need for self-management support and a lower perception of support from healthcare professionals compared to retired persons. Cohabitant persons had a significantly higher perception of support from relatives and also estimated a higher need for relatives' involvement in clinical visits compared to persons living alone. Both the newly diagnosed and also those people with a diabetes duration of 10-15 years rated a higher need for group support. Higher self-awareness and readiness to change were apparent among people with short and long diabetes duration. Furthermore, self-management ability, support from healthcare professionals and from relatives and lastly diabetes duration was associated with diabetes empowerment. Not only people newly diagnosed with T2D should be offered patient-centred group support, strengthening patient empowerment. For future, family-focused care and education and training in person-centred care among diabetes specialist nurses is recommended.


Testing the hypothesis of a recombinant origin of human immunodeficiency virus type 1 subtype E.
The human immunodeficiency virus type 1 (HIV-1) epidemic in Southeast Asia has been largely due to the emergence of clade E (HIV-1E). It has been suggested that HIV-1E is derived from a recombinant lineage of subtype A (HIV-1A) and subtype E, with multiple breakpoints along the E genome. We obtained complete genome sequences of clade E viruses from Thailand (93TH057 and 93TH065) and from the Central African Republic (90CF11697 and 90CF4071), increasing the total number of HIV-1E complete genome sequences available to seven. Phylogenetic analysis of complete genomes showed that subtypes A and E are themselves monophyletic, although together they also form a larger monophyletic group. The apparent phylogenetic incongruence at different regions of the genome that was previously taken as evidence of recombination is shown to be not statistically significant. Furthermore, simulations indicate that bootscanning and pairwise distance results, previously used as evidence for recombination, can be misleading, particularly when there are differences in substitution or evolutionary rates across the genomes of different subtypes. Taken jointly, our analyses suggest that there is inadequate support for the hypothesis that subtype E variants are derived from a recombinant lineage. In contrast, many other HIV strains claimed to have a recombinant origin, including viruses for which only a single parental strain was employed for analysis, do indeed satisfy the statistical criteria we propose. Thus, while intersubtype recombinant HIV strains are indeed circulating, the criteria for assigning a recombinant origin to viral structures should include statistical testing of alternative hypotheses to avoid inappropriate assignments that would obscure the true evolutionary properties of these viruses.


GRADE guidelines: 12. Preparing summary of findings tables-binary outcomes.
Summary of Findings (SoF) tables present, for each of the seven (or fewer) most important outcomes, the following: the number of studies and number of participants; the confidence in effect estimates (quality of evidence); and the best estimates of relative and absolute effects. Potentially challenging choices in preparing SoF table include using direct evidence (which may have very few events) or indirect evidence (from a surrogate) as the best evidence for a treatment effect. If a surrogate is chosen, it must be labeled as substituting for the corresponding patient-important outcome. Another such choice is presenting evidence from low-quality randomized trials or high-quality observational studies. When in doubt, a reasonable approach is to present both sets of evidence; if the two bodies of evidence have similar quality but discrepant results, one would rate down further for inconsistency. For binary outcomes, relative risks (RRs) are the preferred measure of relative effect and, in most instances, are applied to the baseline or control group risks to generate absolute risks. Ideally, the baseline risks come from observational studies including representative patients and identifying easily measured prognostic factors that define groups at differing risk. In the absence of such studies, relevant randomized trials provide estimates of baseline risk. When confidence intervals (CIs) around the relative effect include no difference, one may simply state in the absolute risk column that results fail to show a difference, omit the point estimate and report only the CIs, or add a comment emphasizing the uncertainty associated with the point estimate.


Teaching while learning while practicing: reframing faculty development for the patient-centered medical home.
Soaring costs of health care, patients living longer with chronic illnesses, and continued attrition of interest in primary care contribute to the urgency of developing an improved model of health care delivery. Out of this need, the concept of the team-based, patient-centered medical home (PCMH) has developed. Amidst implementation in academic settings, clinical teachers face complex challenges not previously encountered: teaching while simultaneously learning about the PCMH model, redesigning clinical delivery systems while simultaneously delivering care within them, and working more closely in expanded interprofessional teams.To address these challenges, the authors reviewed three existing faculty development models and recommended four important adaptations for preparing clinical teachers for their roles as system change agents and facilitators of learning in these new settings. First, many faculty find themselves in the awkward position of teaching concepts they have yet to master themselves. Professional development programs must recognize that, at least initially, health professions learners and faculty will be learning system redesign content and skills together while practicing in the evolving workplace. Second, all care delivery team members influence learning in the workplace. Thus, the definition of faculty must expand to include nurses, pharmacists, social workers, medical assistants, patients, and others. These team members will need to accept their roles as educators. Third, learning to deliver health care in teams will require support of both interprofessional collaboration and intraprofessional identity development. Fourth, learning to manage change and uncertainty should be part of the core content of any faculty development program within the PCMH.


Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology.
To date, there is no validated fluid biomarker for tau pathology in Alzheimer's disease, with contradictory results from studies evaluating the correlation between phosphorylated tau in CSF with tau PET imaging. Tau protein is subjected to proteolytic processing into fragments before being secreted to the CSF. A recent study suggested that tau cleavage after amino acid 368 by asparagine endopeptidase (AEP) is upregulated in Alzheimer's disease. We used immunoprecipitation followed by mass spectrometric analyses to evaluate the presence of tau368 species in CSF. A novel Simoa® assay for quantification of tau368 in CSF was developed, while total tau (t-tau) was measured by ELISA and the presence of tau368 in tangles was evaluated using immunohistochemistry. The diagnostic utility of tau368 was first evaluated in a pilot study (Alzheimer's disease = 20, control = 20), then in a second cohort where the IWG-2 biomarker criteria were applied (Alzheimer's disease = 37, control = 45), and finally in a third cohort where the correlation with 18F-GTP1 tau PET was evaluated (Alzheimer's disease = 38, control = 11). The tau368/t-tau ratio was significantly decreased in Alzheimer's disease (P < 0.001) in all cohorts. Immunohistochemical staining demonstrated that tau fragments ending at 368 are present in tangles. There was a strong negative correlation between the CSF tau368/t-tau ratio and 18F-GTP1 retention. Our data suggest that tau368 is a tangle-enriched fragment and that the CSF ratio tau368/t-tau reflects tangle pathology. This novel tau biomarker could be used to improve diagnosis of Alzheimer's disease and to facilitate the development of drug candidates targeting tau pathology. Furthermore, future longitudinal studies will increase our understanding of tau pathophysiology in Alzheimer's disease and other tauopathies.


Montreal Cognitive Assessment: One Cutoff Never Fits All.
The objective of this study is to examine the discrepancy between single versus age and education corrected cutoff scores in classifying performance on the Montreal Cognitive Assessment (MoCA) in patients with stroke or transient ischemic attack. MoCA norms were collected from 794 functionally independent and stroke- and dementia-free persons aged ≥65 years. magnetic resonance imaging was used to exclude healthy controls with significant brain pathology and medial temporal lobe atrophy. Cutoff scores at 16th, 7th, and 2nd percentiles by age and education were derived for the MoCA and MoCA 5-minute Protocol. MoCA performance in 919 patients with stroke or transient ischemic attack was classified using the single and norm-derived cutoff scores. The norms for the Hong Kong version of the MoCA total and domain scores and the total score of the MoCA 5-minute protocol are described. Only 65.1% and 25.7% healthy controls and 45.2% and 19.0% patients scored above the conventional cutoff scores of 21/22 and 25/26 on the MoCA. Using classification with norm-derived cutoff scores as reference, locally derived cutoff score of 21/22 yielded a classification discrepancy of ≤42.4%. Discrepancy increased with higher age and lower education level, with the majority being false positives by single cutoffs. With the 25/26 cutoff of the original MoCA, discrepancy further increased to ≤74.3%. Conventional single cutoff scores are associated with substantially high rates of misclassification especially in older and less-educated patients with stroke. These results caution against the use of one-size-fits-all cutoffs on the MoCA.


Relateralizing hypnosis: or, have we been barking up the wrong hemisphere?
Research and theory over the past couple decades have suggested that the right cerebral hemisphere might be the focus of brain activity during hypnosis. Recent evidence from electrodermal responding, visual event-related potentials, and Stroop interference, however, can make a case for a role of the left hemisphere in some hypnotic phenomena. Although hemispheric activation on hypnotic challenge may depend in large part on the kind of task the challenge might involve, several general aspects of hypnosis might be more appropriately seen as left-rather than right-hemisphere brain functions. Among these are concentrated attentional focus and the role of language in the establishment of hypnotic reality. A left-hemisphere theory of hypnosis is discussed in light of recent findings and theories about a left-hemisphere basis for synthetic or generational capabilities (Corballis, 1991) and a neuro-evolutionary model of a left-hemisphere dopaminergic activation system for the implementation of predetermined motor programs (Tucker & Williamson, 1984).


Reorientation of aquaculture production systems can reduce environmental impacts and improve nutrition security in Bangladesh.
Aquatic foods are a critical source of human nutrition in many developing countries. As a result, declines in wild-caught fish landings threaten nutritionally vulnerable populations. Aquaculture presents an opportunity to meet local demand, but it also places pressure on natural resource inputs and causes a range of environmental impacts. Here, we examine whether current aquaculture systems in Bangladesh can be reoriented to address prevailing nutritional deficiencies while minimizing these environmental impacts. Current fish farming practices, even when optimized, cannot fully supply the same essential micronutrient densities of zinc, iron and calcium as wild-caught fish. However, when the proportion of highly nutrient-dense small indigenous fish species (SIS) was increased to at least 30% of the total output in any of the 14 aquaculture production systems analysed, these systems were able to meet or surpass the nutrient densities of average wild-capture fisheries. Extensive aquaculture systems that co-produce fish and rice had the lowest environmental burdens in six out of seven metrics examined when the composition of all aquaculture systems was modified to include 50% SIS. Nutrition-sensitive aquaculture that provides greater human health benefits and minimizes environmental impacts is a key societal challenge that requires targeted interventions and supportive policies.


Mouse HSF1 disruption perturbs redox state and increases mitochondrial oxidative stress in kidney.
Increased synthesis of heat shock proteins (Hsps), mainly regulated by heat shock factor 1 (Hsf1), protects the heart against oxidative stress under pathophysiological conditions such as ischemia/reperfusion. To investigate whether Hsps might exert a similar protective effect under physiological conditions in the kidney, we first evaluated the HSF1-dependent expression of several Hsps, including Hsp25, alphaB-crystallin (alphaBC), Hsp70, and Hsp90. Unlike either alphaBC or Hsp70, protein expression of Hsp25 and Hsp90 was decreased 26% and 50%, respectively, in Hsf1 knockout compared with the wild-type mice. The effects of Hsp down-regulation on renal cellular redox status are presently unknown. Indeed, HSF1 deficiency caused a 37% decrease in renal cellular GSH/GSSG ratio, a marker of redox status, and a 40% increase in the rate of mitochondrial superoxide generation in Hsf1 knockout compared with wild-type mice. HSF1 disruption also increased mitochondrial permeability transition pore opening and induced greater mitochondrial membrane potential change (48% increase versus wild type). Thus, the present study demonstrates that Hsf1-dependent transcription of selective Hsps is required for normal renal homeostasis, which protects renal cells against oxidative stress under physiological conditions. The source of mitochondrial superoxide generation is discussed.


Protein arrays as tools for serum autoantibody marker discovery in cancer.
Protein array technology has begun to play a significant role in the study of protein-protein interactions and in the identification of antigenic targets of serum autoantibodies in a variety of autoimmune disorders. More recently, this technology has been applied to the identification of autoantibody signatures in cancer. The identification of tumour-associated antigens (TAAs) recognised by the patient's immune response represents an exciting approach to identify novel diagnostic cancer biomarkers and may contribute towards a better understanding of the molecular mechanisms involved. Circulating autoantibodies have not only been used to identify TAAs as diagnostic/prognostic markers and potential therapeutic targets, they also represent excellent biomarkers for the early detection of tumours and potential markers for monitoring the efficacy of treatment. Protein array technology offers the ability to screen the humoral immune response in cancer against thousands of proteins in a high throughput technique, thus readily identifying new panels of TAAs. Such an approach should not only aid in improved diagnostics, but has already contributed to the identification of complex autoantibody signatures that may represent disease subgroups, early diagnostics and facilitated the analysis of vaccine trials.


Tuberculous mediastinal lymphadenopathy in an adult.
We describe a patient who presented to us with fever, decreased appetite, weight loss and dry cough for 1 month with no abnormalities on examination. A chest radiograph showed a mediastinal shadow. CT of the chest revealed multiple mediastinal lymph nodes. Bronchoalveolar lavage was negative for acid-fast bacilli and cytological examination did not show malignant cells. Serum ACE levels were high (93 U/L). Bone marrow aspiration and biopsy did not reveal any pathology. Mediastinoscopy-guided mediastinal lymph node biopsy showed features of granulomatous lymphadenitis. This case report summarises an unusual presentation of tuberculosis in an adult.


Global gene expression profiles in skeletal muscle of monozygotic female twins discordant for hormone replacement therapy.
Aging is accompanied by inexorable loss of muscle tissue. One of the underlying causes for this is the massive change in the hormonal milieu of the body. The role of a female sex steroid - estrogen - in these processes is frequently neglected, although the rapid decline in its production coincides with a steep deterioration in muscle performance. We recruited 54- to 62-year-old monozygotic female twin pairs discordant for postmenopausal hormone replacement therapy (HRT, n=11 pairs; HRT use 7.3 ± 3.7 years) from the Finnish Twin Cohort to investigate the association of long-term, estrogen-based HRT with skeletal muscle transcriptome. Pathway analysis of muscle transcript profiles revealed significant HRT-induced up-regulation of a biological process related to regulation of cell structure and down-regulation of processes concerning, for example, cell-matrix interactions, energy metabolism and utilization of nutrients (false discovery rate < 0.15). Lending clinical relevance to the findings, these processes explained a significant fraction of the differences observed in relative proportion of muscle within thigh and in muscle performance (R(2) =0.180-0.257, P=0.001-0.023). Although energy metabolism was affected through down-regulation of the transcripts related to succinate dehydrogenase complex in mitochondria, no differences were observed in mtDNA copy number or oxidative capacity per muscle cross section. In conclusion, long-term use of HRT was associated with subtle, but significant, differences in muscle transcript profiles. The better muscle composition and performance among the HRT users appeared to be orchestrated by improved regulatory actions on cytoskeleton, preservation of muscle quality via regulation of intramuscular extracellular matrix and a switch from glucose-oriented metabolism to utilization of fatty acids.


Performance of an optimum receiver designed for pattern recognition with nonoverlapping target and scene noise.
The design of an optimum receiver for pattern recognition is based on multiple-alternative hypothesis testing with unknown parameters for detecting and locating a noisy target or a noise-free target in scene noise that is spatially nonoverlapping with this target. The optimum receiver designed for a noise-free target has the interesting property of detecting, without error, a noise-free target that has unknown illumination by using operations that are independent of the scene-noise statistics. We investigate the performance of the optimum receiver designed for nonoverlapping target and scene noise in terms of rotation and scale sensitivity of the input targets and discrimination against similar objects. Because it is not possible in practical systems to have a completely noise-free target, we examine how the performance of the optimum receiver designed for a noise-free target is affected when there is some overlapping noise on the target. The application of the optimum receiver to binary character recognition is described. Computer simulation results are provided.


Cigarette smoke oxidation of human plasma constituents.
In vitro exposure of fresh human plasma to cigarette smoke (CS) was used as a model for reactions that could be occurring in CS-exposed respiratory tract lining fluids (RTLFs) and lung parenchyma. The central focus of this model was to characterize the consumption of endogenous plasma antioxidants in relationship to the appearance of oxidized proteins and lipids as a consequence of exposure to CS, or to aldehydes present in CS. The amelioration of CS-induced protein and lipid oxidation in plasma by the addition of selective exogenous antioxidants was also assessed. We found that: (i) exposure of human plasma to gas phase CS causes both lipid peroxidation and protein oxidation, and endogenous ascorbic acid protects against lipid, but not protein, oxidation; (ii) whole CS causes protein oxidation, but does not induce lipid peroxidation; (iii) addition to plasma of aldehydes known to be present in CS causes protein damage, but does not induce either lipid peroxidation or oxidation of ascorbic acid; and (iv) exogenously added dihydrolipoic acid (DHLA) preserves ascorbic acid levels in plasma exposed to the gas phase of CS, and protects, to some extent, against lipid peroxidation; DHLA also protects against protein oxidation, whereas added glutathione (GSH) only protects against protein, but not lipid, oxidation.


Effect of types and anatomic arrangement of painful stimuli on conditioned pain modulation.
Reduced pain perception during painful stimulation to another body region (ie, conditioned pain modulation [CPM]) is considered important for pain modulation and development of pain disorders. The various methods used to study CPM limit comparison of findings. We investigated the influence of key methodologic variations on CPM and the properties of CPM when the back is used for the test stimulus or the conditioning stimulus (CS). Two different test stimuli (pressure pain threshold and pain response to suprathreshold heat [Pain-45, ie, pain rated at 45 on a 0-100 numeric rating scale]) were assessed before and during application of a noxious or non-noxious (sham) CS. Eight blocks of trials varied the anatomic location (back and forearms) and arrangement (body side) of the stimuli. Pressure pain threshold (as the test stimulus) increased during application of noxious, but not non-noxious, CS when stimuli were applied to opposite body sides or heterotopic sites on one body side. Inconsistent with pain-induced CPM, Pain-45 decreased during both noxious and non-noxious CS. These findings indicate that 1) pressure pain threshold can be more confidently interpreted with respect to CPM evoked by a painful stimulus than Pain-45, 2) the back and forearm are equally effective as sites for stimuli, and 3) stimuli arrangement does not influence CPM, except for identical anatomic regions on the same body side. This study indicates that pressure pain threshold as the test stimulus provides a more valid measure of pain-induced CPM than pain response to a suprathreshold heat stimulus. Induction and magnitude of CPM is independent of stimuli arrangement, as long as ipsilateral homotopic sites are avoided. These findings clarify methods to study CPM.