A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease.
beta-Amyloid is a 39- to 43-amino-acid neurotoxic peptide that aggregates to form the core of Alzheimer disease-associated senile (amyloid) plaques. No satisfactory hypothesis has yet been proposed to explain the mechanism of beta-amyloid aggregation and toxicity. We present mass spectrometric and electron paramagnetic resonance spin trapping evidence that beta-amyloid, in aqueous solution, fragments and generates free radical peptides. beta-Amyloid fragments, at concentrations that previously have been shown to be neurotoxic to cultured neurons, can inactivate oxidation-sensitive glutamine synthetase and creatine kinase enzymes. Also, salicylate hydroxylation assays indicate that reactive oxygen species are generated by the beta-amyloid-(25-35) fragment during cell-free incubation. These results are formulated into a free radical-based unifying hypothesis for neurotoxicity of beta-amyloid and are discussed with reference to membrane molecular alterations in Alzheimer disease.


Enhanced HtrA2/Omi expression in oxidative injury to retinal pigment epithelial cells and murine models of neurodegeneration.
To investigate the role of HtrA2/Omi, a nuclear-encoded mitochondrial serine protease with a proapoptosis function, under H(2)O(2)-induced oxidative stress in human RPE, in the Ccl2(-)(/)(-)Cx3cr1(-)(/)(-) double-knockout (DKO) mouse retina, and the HtrA2/Omi-deficient mice. Oxidative stress was induced in ARPE-19 cells by 1 mM H(2)O(2) for 2 hours. HtrA2/Omi and caspase-3 expression was evaluated using RQ-PCR, immunohistochemistry, or Western blot. Cell viability was detected by MTT assay. HtrA2/Omi expression in the subcellular components and activated caspase-3 were measured. These processes were also evaluated in cells treated with UCF-101, an HtrA2/Omi inhibitor or in cells subjected to RNAi against HtrA2/Omi. Oxidative stress was assayed and compared in retinas of DKO and wild-type (WT) mice by determining serum NADPH oxidase subunits and nitrite levels. Transmission electron microscopy was used to view the retinal ultrastructure of the HtrA2/Omi-deficient mice. H(2)O(2)-induced oxidative damage resulted in HtrA2/Omi translocation from mitochondria to cytosol, leading to RPE cell apoptosis via a caspase-mediated pathway. Treatment of RPE cells with UCF-101 reduced the cytosolic translocation of HtrA2/Omi, attenuated caspase-3 activation, and decreased apoptosis. After specific HtrA2 downregulation, increased cell viability was measured in H(2)O(2)-treated ARPE-19 cells. Retina of DKO mice exhibit increased oxidative stress and upregulation of HtrA2/Omi. Fewer and abnormal mitochondria were found in HtrA2/Omi(-)(/)(-) photoreceptors and RPE. These findings suggest that HtrA2/Omi is related to RPE apoptosis due to oxidative stress, which may play an important role in the integrity of mitochondria and the pathogenesis of AMD.


Mouse teratocarcinoma cells resistant to aphidicolin and arabinofuranosyl cytosine: isolation and initial characterization.
With the long-range goals of elucidating the biochemical genetics and the phenotypic expression, both in vitro and in vivo, of mutator strains of mammalian cells, we have isolated and partially characterized a series of drug-resistant mutants from a subline a feeder-dependent parental mouse teratocarcinoma line (PSA-1) known to be capable of chimerizing host blastocysts via the injection of inner cell mass. Two series of stable mutants were isolated--one (Aphr) selected on the basis of resistance to aphidicolin (Aph), a specific inhibitor of DNA polymerase-alpha, and the other (AraCr) selected by resistance to arabinofuranosyl cytosine, an analogue of cytosine. Irrespective of the method of selection, most of the 32 mutants isolated were resistant to both agents, although to different degrees, and with variations in growth characteristics, deoxynucleoside sensitivities, and sensitivities to mutagens (5-bromodeoxyuridine, N-methyl-N'-nitro-N-nitrosoguanidine and ultraviolet light). A protocol of multi-step selection provided stable mutants highly resistant to aphidicolin and only mildly resistant to AraC, even in the absence of prior mutagenesis, and is thus recommended as an approach to the isolation of candidate mutator strains of multipotent teratocarcinomas.


Polarization mode dispersion measurement based on continuous polarization modulation.
A novel technique is proposed for measurement of the group delay (GD) and the differential group delay (DGD) of optical material, components, and fiber. This new method is based on continuous polarization modulation of the stimulus optical field as opposed to sequential polarization state switching used in the traditional phase shift method. A new complete derivation of the phase shift method, based on the modified Jones calculus of elementary matrices, is presented. The derivation reveals that the phase shift measurement actually depends on all eight elementary parameters that represent DGD and optical frequency derivatives of polarization-dependent loss (PDL). Thus, the new expression for the phase shift includes the combined effect of PDL and DGD. The proposed method is evaluated by measuring a section of polarization-maintaining fiber and a 50 km length of single-mode fiber over a wavelength range from 1530 to 1610 nm. Measurements of DGD in a long single-mode fiber are shown to be highly insensitive to environmentally induced GD drift.


Spine-specific skeletal related events and mortality in non-small cell lung cancer patients: a single-institution analysis.
The population prevalence of non-small cell lung cancer (NSCLC) continues to increase; however, data are limited regarding the incidence rate of skeletal related events (SREs) (i.e., surgery to the spinal column, radiation to the spinal column, radiofrequency ablation, kyphoplasty/vertebroplasty, spinal cord compression, or pathological vertebral body fractures) and their impact on overall mortality. In this study, the authors sought to estimate the incidence rates of SREs in NSCLC patients and to quantify their impact on overall mortality. This was a single-institution retrospective study of patients diagnosed with NSCLC between 2002 and 2014. The incidence rates for bone metastasis and subsequent SREs (per 1000 person-years) by time since lung cancer diagnosis were calculated and analyses were stratified separately for each histological type. Incidence rates for mortality at 1, 2, and 3 years from diagnosis stratified by the presence of SREs were also calculated. Kaplan-Meier survival curves were constructed to describe crude survival ratios in patients with spine metastasis and SREs and those with spine metastasis but without SREs. These curves were used to estimate the 1- and 2-year survival rates for each cohort. We identified 320 patients with incident NSCLC (median follow-up 9.5 months). The mean ± SD age was 60.65 ± 11.26 years; 94.48% of patients were smokers and 60.12% had a family history of cancer. The majority of first-time SREs were pathological vertebral body compression fractures (77.00%), followed by radiation (35%), surgery (14%), and spinal cord compression (13.04%). Mortality rates were highest in NSCLC patients with spine metastasis who had at least 1 SRE. Stratifying by histological subtype, the incidence rate of mortality in patients with SRE was highest in the large cell cohort, 7.42 per 1000 person-years (95% CI 3.09-17.84 per 1000 person-years); followed by the squamous cell cohort, 2.49 per 1000 person-years (95% CI 1.87-3.32 per 1000 person-years); and lowest in the adenocarcinoma cohort, 1.68 per 1000 person-years (95% CI 1.46-1.94 per 1000 person-years). Surgery for decompression of neural structures and stabilization of the spinal column was required in 6% of patients. SREs in NSCLC patients with bone metastasis are associated with an increased incidence rate of mortality.


Later circadian timing of food intake is associated with increased body fat.
Background: Weight gain and obesity have reached alarming levels. Eating at a later clock hour is a newly described risk factor for adverse metabolic health; yet, how eating at a later circadian time influences body composition is unknown. Using clock hour to document eating times may be misleading owing to individual differences in circadian timing relative to clock hour.Objective: This study examined the relations between the timing of food consumption relative to clock hour and endogenous circadian time, content of food intake, and body composition.Design: We enrolled 110 participants, aged 18-22 y, in a 30-d cross-sectional study to document sleep and circadian behaviors within their regular daily routines. We used a time-stamped-picture mobile phone application to record all food intake across 7 consecutive days during a participant's regular daily routines and assessed their body composition and timing of melatonin release during an in-laboratory assessment.Results: Nonlean individuals (high body fat) consumed most of their calories 1.1 h closer to melatonin onset, which heralds the beginning of the biological night, than did lean individuals (low body fat) (log-rank P = 0.009). In contrast, there were no differences between lean and nonlean individuals in the clock hour of food consumption (P = 0.72). Multiple regression analysis showed that the timing of food intake relative to melatonin onset was significantly associated with the percentage of body fat and body mass index (both P < 0.05) while controlling for sex, whereas no relations were found between the clock hour of food intake, caloric amount, meal macronutrient composition, activity or exercise level, or sleep duration and either of these body composition measures (all P > 0.72).Conclusions: These results provide evidence that the consumption of food during the circadian evening and/or night, independent of more traditional risk factors such as amount or content of food intake and activity level, plays an important role in body composition. This trial was registered at clinicaltrials.gov as NCT02846077.


A Global Meta-analysis of the Prevalence of HIV, Hepatitis C Virus, and Hepatitis B Virus Among People Who Inject Drugs-Do Gender-Based Differences Vary by Country-Level Indicators?
Women-specific factors exist that increases vulnerability to drug-related harms from injection drug use, including blood-borne viruses (BBVs), but gender-based differences in BBV prevalence have not been systematically examined. We conducted meta-analyses to estimate country, regional, and global prevalence of serologically confirmed human immunodeficiency virus (HIV), hepatitis C virus (HCV; based on detection of anti-HCV antibody), and hepatitis B virus (HBV; based on detection of HBV surface antigen) in people who inject drugs (PWID), by gender. Gender-based differences in the BBV prevalence (calculated as the risk among women relative to the risk among men) were regressed on country-level prevalence and inequality measures (Gender inequality index, Human development index, Gini coefficient, and high, low or middle income of the country). Gender-based differences varied by countries and regions. HIV prevalence was higher among women than men in sub-Saharan Africa (relative risk [RR], 2.8; 95% confidence interval [CI], 1.8-4.4) and South Asia (RR, 1.7; 95% CI, 1.1-2.7); anti-HCV was lower among women in the Middle East and North Africa (RR, 0.6; 95% CI, .5-.7) and East and Southeast Asia (RR, 0.8; 95% CI, .7-.9). Gender-based differences varied with country-levels of the BBV prevalence in the general population, human development, and income distribution. HIV was more prevalent in women who inject drugs as compared to their male counterparts in some countries, but there is variation between and within regions. In countries where women are at higher risks, there is a need to develop gender-sensitive harm-reduction services for the particularly marginalized population of women who inject drugs.


Liver injury caused by antibodies against dengue virus nonstructural protein 1 in a murine model.
Clinical manifestations of severe dengue diseases include thrombocytopenia, vascular leakage, and liver damage. Evidence shows that hepatic injury is involved in the pathogenesis of dengue infection; however, the mechanisms are not fully resolved. Our previous in vitro studies suggested a mechanism of molecular mimicry in which antibodies directed against dengue virus (DV) nonstructural protein 1 (NS1) cross-reacted with endothelial cells and caused inflammatory activation and apoptosis. In this study, the pathogenic effects of anti-DV NS1 antibodies were further examined in a murine model. We found, in liver sections, that anti-DV NS1 antibodies bound to naive mouse vessel endothelium and the binding activity was inhibited by preabsorption of antibodies with DV NS1. Active immunization with DV NS1 resulted in antibody deposition to liver vessel endothelium, and also apoptotic cell death of liver endothelium. Liver tissue damage was observed in DV NS1-immunized mice by histological examination. The serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were increased in mice either actively immunized with DV NS1 protein or passively immunized with antibodies obtained from DV NS1-immunized mice. Furthermore, histological examination revealed mononuclear phagocyte infiltration and cell apoptosis in mice passively immunized with antibodies obtained from mice immunized with DV NS1. Increased AST and ALT levels were observed in mice passively immunized with purified immunoglobulin G (IgG) from dengue patients compared with normal control human IgG-immunized mice. The increased AST and ALT levels were inhibited when dengue patient serum IgG was preabsorbed with DV NS1. In conclusion, active immunization with DV NS1 protein causes immune-mediated liver injury in mice. Passive immunization provides additional evidence that anti-DV NS1 antibodies may play a role in liver damage, which is a pathologic manifestation in dengue virus disease.


The Beck Depression Inventory requires modification in scoring before use in a haemodialysis population in the UK.
There are high rates of mental illness, especially depression in people with end-stage renal disease (ESRD) on haemodialysis (HD). Depression can be difficult to diagnose, as depression and the medical problem share many symptoms. It is essential that the diagnosis of a depressive illness be accurately made in order that subsequent psychiatric management can occur. This is the first study done in the UK which aims to validate a simple method for detecting depression, the Beck Depression Inventory (BDI), in people on HD against a structured psychiatric interview with a trained psychiatrist using the ICD-10 classification of depression. The BDI is validated in a normal population, but in patients with physical ill health there has been a difficulty in defining appropriate cut-off scores. Patients dialysing for over 3 months from a single HD unit were eligible for participation. Patients were excluded if a known psychiatric illness existed or if they were receiving medication for a psychiatric illness. Patients who had a recent major illness requiring hospitalisation were excluded. 57 consenting participants completed the self-reported BDI. Within the next week a psychiatrist carried out a clinical interview to diagnose depression, based on the ICD-10 classification of a depressive disorder. Patients were classified as not being depressed or having mild, moderate or severe depression according to their BDI score or the ICD-10 classification. The BDI gave more scores for depression and more severe scores than ICD-10. 30 cases had scores which agreed, 27 cases resulted in a higher BDI score than the ICD-10 classification, in no case was the ICD-10 classification more severe (Wilcoxon signed rank test p < 0.001). All 7 diagnosed as being depressed by clinical interview were also depressed by BDI, although in 2 cases the BDI worsened the depression score. Using the general population cut-off score, the BDI significantly overdiagnosed depression in this HD population. This study defines a BDI cut-off score which more reliably detects major depression in a HD population. Unrecognised depression remains high in those with no known psychiatric illness within the HD populations.


Calcium-binding parameter of Bacillus amyloliquefaciens alpha-amylase determined by inactivation kinetics.
The irreversible thermal inactivation and the thermodynamics of calcium ion binding of Bacillus amyloliquefaciens alpha-amylase in the absence of substrates were studied. The enzyme inactivation on heating was apparently followed by first-order kinetics. The enzyme was stabilized with an increased concentration of calcium ion and thus the inactivation was highly dependent on the state of calcium binding. The activation parameter for the inactivation suggests an unfolding of the enzyme protein upon heating. Values of both the activation enthalpy and entropy were increased with a higher calcium ion concentration. An inactivation kinetic model is based on the assumption of a two-stage unfolding transition in which the bivalent ion dissociation occurs in the first step followed by the secondary structural unfolding. This simple kinetic model provides both a qualitative and quantitative interpretation of calcium ion binding to the enzyme and its effect on the inactivation properties. The specific approximations of the kinetic model were strictly followed in the analysis to calculate the apparent inactivation rate at each calcium ion concentration in terms of the calcium-binding parameters. The enthalpy and entropy changes for the calcium ion binding were calculated to be -149 kJ/mol and -360 J.mol(-1).K(-1) respectively and these values suggest a strong enthalpic affinity for the bivalent ion binding to the enzyme protein. The thermodynamical interpretation attempts to provide clear relations between the terms of an apparent inactivation rate and the calcium binding.


Effects of Blood Pressure Lowering on Clinical Outcomes According to Baseline Blood Pressure and Cardiovascular Risk in Patients With Type 2 Diabetes Mellitus.
The optimal blood pressure (BP) goal in patients with diabetes mellitus remains controversial. We examined whether benefits and risks of intensified antihypertensive therapy in diabetes mellitus are influenced by either baseline BP or cardiovascular disease (CVD) risk. We studied 10 948 people with diabetes mellitus, at moderate-to-high risk, in the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation). Cox models were used to determine whether baseline BP category or CVD risk modified the outcomes of combination perindopril-indapamide treatment, compared with placebo. During 4.3 years of follow-up, treatment with perindopril-indapamide versus placebo reduced mortality and major vascular (macrovascular or microvascular) events. There was no evidence of differences in these effects, regardless of baseline systolic BP (evaluated down to <120 mm Hg; P for heterogeneity, 0.85), diastolic BP (evaluated down to <70 mm Hg; P=0.49), or whether 10-year CVD risk was ≥20% or <20% ( P=0.08). The effects of randomized treatment on discontinuation of treatment because of cough or hypotension/dizziness were also statistically consistent across subgroups defined by baseline BP and CVD risk (all P ≥0.08). Adults with diabetes mellitus appear to benefit from more intensive BP treatment even at levels of BP and CVD risk that some guidelines do not currently recommend for intervention. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00751972.


Functional connectivity and oscillatory neuronal activity in the resting human brain.
Perceptions, thoughts, emotions and actions emerge from interactions between neuronal assemblies distributed across the brain rather than from local computations in restricted brain areas. Indeed, the operation of every cognitive act requires the integration of distributed activity, as implemented through long-range neuronal communication via a network of structural connections. Functional interactions in the brain are very often studied in subjects at rest, since the resting state is a privileged condition in which brain activity is unbiased by any specific goal-directed task. Early resting state studies showed that electrophysiological oscillatory activity in specific frequency bands supports synchronization processes related to long-range neuronal communication. In turn, experimental evidence from neuroimaging studies revealed that the human brain is organized into multiple large-scale networks of regions showing correlated hemodynamic activity. Multimodal studies have begun to disclose relationships between functional connectivity, as revealed by hemodynamic signals, and underlying electrophysiological processes. Furthermore, functional connectivity studies directly based on electrophysiological signals have recently revealed fundamental information regarding long-range neuronal communication at behaviorally relevant time-scales. The integration of different lines of evidence from hemodynamic and electrophysiological studies suggests that rapid changes of synchronized oscillatory activity in distributed brain networks is relevant for the ongoing maintenance and modulation of the task representations that form the basis of our cognitive flexibility.


Packing density in holographic systems.
The holographic packing density is derived for any plane in a coherently illuminated optical system. The gain in packing density relative to the object plane is given. A two-lens optical system in which a condenser lens provides high packing densities and an imaging lens provides sufficient resolution is superior to a system in which a single lens performs both functions.


Thirty-day readmission risk after intracranial tumor resection surgeries in children.
The risk of readmission after brain tumor resection among pediatric patients has not been defined. The authors' objective was to evaluate the readmission rates and predictors of readmission after pediatric brain tumor resection. Nationwide Readmissions Database (NRD) data sets from 2010 to 2014 were searched for unplanned readmissions within 30 days of the discharge date after pediatric brain tumor resection. Patient demographic variables included sex, age, expected payment source (Medicaid or private insurance), and median annual household income. Readmission events for chemotherapy, radiation therapy, or further tumor resection were not included. Of 282 patients (12.7%) readmitted within 30 days of the index event, the median time to readmission was 10 days (IQR 5-19 days). The most common reason for readmission was hydrocephalus, which accounted for 19% of readmission events. Other CNS-related complications (24%), surgical site infections or septicemia (14%), seizures (7%), and hematological disorders (7%) accounted for other major readmission events. The median charge for readmission events was $35,431, and the median length of readmission stay was 4 days. In multivariate regression, factors associated with a significant increase in readmission risk included Medicaid as the primary payor, discharge from the index event with home health services, and fluid and electrolyte disorders during the index event. More than 10% of pediatric brain tumor patients have unplanned readmission events within 30 days of discharge after tumor resection. Medicaid patients and those with preoperative or early postoperative fluid and electrolyte disturbances may benefit from early or frequent outpatient visits after tumor resection.


A GAL4-HP1 fusion protein targeted near heterochromatin promotes gene silencing.
We have constructed a new reporter transgene, Winkelried, equipped with a synthetic binding site for the yeast GAL4 transcriptional activator. The binding site is inserted between the white and lacZ reporter genes, and is flanked by FRT sequences. These elements allow excision of the GAL4 binding site by crossing the transgenic line with an FLP recombinase producing strain. We have generated by X-ray irradiation two independent chromosomal rearrangements, Heidi and Tell, relocating Winkelried next to pericentromeric heterochromatin. These rearrangements induce variegation of both white and lacZ. Variegation of Winkelried in the rearranged transgenic lines responds to the loss and excess of doses of the dominant suppressors of position-effect variegation (PEV) Su(var)3-7 and Su(var)2-5. Winkelried therefore constitutes a unique tool to test the effect on variegation in cis of any factor fused to the GAL4 DNA binding domain. Indeed, a chimeric protein, made of the DNA binding site of GAL4 and of HP1, the modifier of PEV encoded by Su(var)2-5, is shown to enhance variegation of Heidi and Tell. Excision of the binding sites for GAL4 in the variegating rearrangements Heidi and Tell abolishes the modifier effect of the GAL4-HP1 chimera. Therefore, in the Heidi and Tell rearrangements, enhancement of position-effect variegation depends strictly both on the concentration of GAL4-HP1 and on the presence of its binding site in the vicinity of the reporter genes.


Human and porcine Taenia solium infections in Mozambique: identifying research priorities.
The objective of this paper is to critically review and summarize available scientific and lay literature, and ongoing studies on human and porcine cysticercosis in Mozambique to identify knowledge gaps and direct immediate and long-term research efforts. Data on the spatial distribution and prevalence of the disease in human and swine populations are scarce and fragmented. Human serological studies have shown that 15-21% of apparently healthy adults were positive for cysticercosis antibodies or antigen, while in neuropsychiatric patients seroprevalence was as high as 51%. Slaughterhouse records indicate a countrywide occurrence of porcine cysticercosis, while studies have shown that 10-35% of pigs tested were seropositive for cysticercosis antibodies or antigen. Current research in Mozambique includes studies on the epidemiology, molecular biology, diagnosis and control of the disease. Future research efforts should be directed at better understanding the epidemiology of the disease in Mozambique, particularly risk factors for its occurrence and spread in human and swine populations, documenting the socio-economic impact of the disease, identifying critical control points and evaluating the feasibility and epidemiological impact of control measures and development of local level diagnostic tools for use in humans and swine.


A droplet-based microfluidic chip as a platform for leukemia cell lysate identification using surface-enhanced Raman scattering.
A new approach is presented for cell lysate identification which uses SERS-active silver nanoparticles and a droplet-based microfluidic chip. Eighty-nanoliter droplets are generated by injecting silver nanoparticles, KCl as aggregation agent, and cell lysate containing cell constituents, such as nucleic acids, carbohydrates, metabolites, and proteins into a continuous flow of mineral oil. This platform enables accurate mixing of small volumes inside the meandering channels of the quartz chip and allows acquisition of thousands of SERS spectra with 785 nm excitation at an integration time of 1 s. Preparation of three batches of three leukemia cell lines demonstrated the experimental reproducibility. The main advantage of a high number of reproducible spectra is to apply statistics for large sample populations with robust classification results. A support vector machine with leave-one-batch-out cross-validation classified SERS spectra with sensitivities, specificities, and accuracies better than 99% to differentiate Jurkat, THP-1, and MONO-MAC-6 leukemia cell lysates. This approach is compared with previous published reports about Raman spectroscopy for leukemia detection, and an outlook is given for transfer to single cells. A quartz chip was designed for SERS at 785 nm excitation. Principal component analysis of SERS spectra clearly separates cell lysates using variations in band intensity ratios.


Mutations altering synaptic connectivity between identified neurons in Drosophila.
By studying the effects of mutations on a simple circuit of identified neurons in Drosophila, we have found genes whose proper functioning is necessary to produce normal synaptic connections between the neurons. These neurons comprise the giant fiber (GF) system; the GFs are command neurons activated by a light-off stimulus and evoke a stereotyped pattern of activity in the thoracic muscles producing an escape jump. Each GF monosynaptically drives a motor neuron innervating the tergotrochanteral muscle (jump muscle, TTM). Each GF also disynaptically drives the motor neurons innervating the dorsal longitudinal flight muscle (DLM) via the peripherally synapsing interneuron (PSI) (King, D. G., and R. J. Wyman (1980) J. Neurocytol. 9: 753-770; M. A. Tanouye and R. J. Wyman (1980) J. Neurophysiol. 44: 405-421). A search was made for mutations affecting these identified synapses. Fifty thousand mutagenized flies were screened for nonjumping behavior to the light-off stimulus. Fifty-seven nonjumping mutant lines were established from individuals selected in the screen. Members of the lines were then tested for abnormal GF motor output to the TTM and DLM. From these lines, four X-linked mutations (representing three complementation groups) were isolated which affect the circuit. The mutations differentially disrupt specific synapses within the GF system. One mutation, bendless, disrupts synaptic transmission between the GF and the TTM motor neuron. Another, gfA, disrupts the synaptic connections of the PSI, and a third mutation, passover, disrupts transmission in both pathways.


Reconfigurable optical assembly of nanostructures.
Arrangements of nanostructures in well-defined patterns are the basis of photonic crystals, metamaterials and holograms. Furthermore, rewritable optical materials can be achieved by dynamically manipulating nanoassemblies. Here we demonstrate a mechanism to configure plasmonic nanoparticles (NPs) in polymer media using nanosecond laser pulses. The mechanism relies on optical forces produced by the interference of laser beams, which allow NPs to migrate to lower-energy configurations. The resulting NP arrangements are stable without any external energy source, but erasable and rewritable by additional recording pulses. We demonstrate reconfigurable optical elements including multilayer Bragg diffraction gratings, volumetric photonic crystals and lenses, as well as dynamic holograms of three-dimensional virtual objects. We aim to expand the applications of optical forces, which have been mostly restricted to optical tweezers. Holographic assemblies of nanoparticles will allow a new generation of programmable composites for tunable metamaterials, data storage devices, sensors and displays.


Cognitive outcomes of different surgical approaches in temporal lobe epilepsy.
Epilepsy surgery is a successful treatment option for pharmacoresistant focal symptomatic epilepsies. However, cognitive impairment is very common in epilepsy patients and may be negatively or positively affected by surgery. Amidst the long-standing discussion of whether a particular surgical approach for temporal lobe epilepsy patients may be superior with regards to seizure control, a recent meta-analysis indicated that this is the case for more extended resections. Larger temporal lobe resections, however, raise concerns that more unaffected and functional tissues may be involved, thus causing worse cognitive outcome. This review is based on published reports collected over a long period, with changing diagnostics and surgical methods, and focuses mainly on the experiences of one epilepsy centre. The review highlights the effects of standard versus selective surgery, the different surgical approaches in selective surgery, determinants other than surgery which may affect cognitive outcome, and the methodologically-important question of outcome assessment and how neuropsychological test selection may bias the result. Overall, from a neuropsychological point of view, individual and selective surgery is preferred in which the aim is to achieve seizure control with minimal effect on the functional integrity of tissues or fibre tracts. Cognition is important for the functions of everyday life and this should be kept in mind, irrespective of which kind of surgery is preferred.


Direct evidence for two distinct prosomatostatin converting enzymes. Detection using a rapid, sensitive, and specific assay for propeptide converting enzymes.
Many bioactive peptides are initially synthesized via larger precursors from which they are released by proteolytic cleavage at basic amino acids. Some precursors contain more than one final product peptide, multiple copies of a single peptide, or both. Different product peptides can be produced from a common precursor in different tissues. It is not currently known whether this cell-type specific production of bioactive peptides is mediated by different, specific propeptide converting enzymes (PCEs) or by a small number of similar PCEs. To resolve this issue for the conversion of prosomatostatin, the processing of prosomatostatin-I (aPSS-I) and prosomatostatin-II (aPSS-II) to either somatostatin-14 (SS-14) or somatostatin-28 (aSS-28), respectively, was examined in anglerfish islets. Two distinct forms of PSS PCE activity were detected using a rapid, sensitive, and specific assay. Examination of the specificity of these two enzyme activities showed that one proteolytic activity performs the aPSS-I to SS-14 conversion, while the other protease liberates aSS-28 from aPSS-II. The SS-14-generating PCE also cleaves aPSS-II to produce [Tyr7,Gly10]SS-14 (a tetra-decapeptide analog of SS-14) and converts proinsulin to insulin. The aSS-28-generating PCE does not process proinsulin. These results provide direct evidence that different, specific PCEs are required for liberation of SS-14 and aSS-28 from their precursors.


Developing a common framework for evaluating the implementation of genomic medicine interventions in clinical care: the IGNITE Network's Common Measures Working Group.
PurposeImplementation research provides a structure for evaluating the clinical integration of genomic medicine interventions. This paper describes the Implementing Genomics in Practice (IGNITE) Network's efforts to promote (i) a broader understanding of genomic medicine implementation research and (ii) the sharing of knowledge generated in the network.MethodsTo facilitate this goal, the IGNITE Network Common Measures Working Group (CMG) members adopted the Consolidated Framework for Implementation Research (CFIR) to guide its approach to identifying constructs and measures relevant to evaluating genomic medicine as a whole, standardizing data collection across projects, and combining data in a centralized resource for cross-network analyses.ResultsCMG identified 10 high-priority CFIR constructs as important for genomic medicine. Of those, eight did not have standardized measurement instruments. Therefore, we developed four survey tools to address this gap. In addition, we identified seven high-priority constructs related to patients, families, and communities that did not map to CFIR constructs. Both sets of constructs were combined to create a draft genomic medicine implementation model.ConclusionWe developed processes to identify constructs deemed valuable for genomic medicine implementation and codified them in a model. These resources are freely available to facilitate knowledge generation and sharing across the field.


Cardiac dose estimates from Danish and Swedish breast cancer radiotherapy during 1977-2001.
To estimate target and cardiac doses from breast cancer radiotherapy in Denmark and in the Stockholm and Umeå areas of Sweden during 1977-2001. Representative samples of irradiated women were identified from the databases of the Danish Breast Cancer Cooperative Group and the Swedish Nationwide Cancer Registry. Virtual simulation, computed tomography planning and manual planning were used to reconstruct radiotherapy regimens on a typical woman. Estimates of target dose and various measures of cardiac dose were derived from individual radiotherapy charts. Doses were estimated in 681 Danish and 130 Swedish women. Mean heart dose for individual women varied from 1.6 to 14.9 Gray in Denmark and from 1.2 to 22.1 Gray in Sweden. In Denmark, mean target doses averaged across women increased from 40.6 to 53.8 Gray during 1977-2001 but, despite this, mean heart dose averaged across women remained around 6 Gy for left-sided and 2-3 Gray for right-sided radiotherapy. In Sweden mean target dose averaged across women increased from 38.7 to 46.6 Gray during 1977-2001, while mean heart dose averaged across women decreased from 12.0 to 7.3 Gray for left-sided and from 3.6 to 3.2 Gray for right-sided radiotherapy. Temporal trends for mean biologically effective dose [BED] to the heart, mean dose to the left anterior descending coronary artery, the right coronary artery and the circumflex coronary artery were broadly similar. Cardiac doses in Denmark were low relative to those in Sweden. In both countries, target dose increased during 1977-2001. Despite this, cardiac doses remained constant in Denmark and decreased in Sweden.


Irrigated mountain meadow fertilizer application timing effects on overland flow water quality.
Nonpoint-source pollution from agricultural activities is currently the leading cause of degradation of waterways in the United States. Applying best management practices to flood-irrigated mountain meadows may improve agricultural runoff and return flow water quality. Prior research has focused on fertilizer use for increased hay yields, while few studies have investigated the environmental implications of this practice. We examined the effects of fertilizer application timing on overland flow water quality from an irrigated mountain meadow near Gunnison, Colorado. Application of 40 kg phosphorus (P) and 19 kg nitrogen (N) ha(-1) using monoammonium phosphate (11-52-0, N-P-K) fertilizer to plots in the fall significantly reduced concentrations of reactive P and ammonium N in irrigation overland flow compared with early or late spring fertilization. Reactive P loading was 9 to almost 16 times greater when fertilizer was applied in the early or late spring, respectively, compared with in the fall. Ammonium N followed a similar trend with early spring loading more than 18 times greater and late spring loading more than 34 times greater than loads from fall-fertilized plots. Losses of 45% of the applied P and more than 17% of the N were measured in runoff when fertilizer was applied in the late spring. These results, coupled with those from previous studies, suggest that mountain meadow hay producers should apply fertilizer in the fall, especially P-based fertilizers, to improve hay yields, avoid economic losses from loss of applied fertilizers, and reduce the potential for impacts to water quality.


Binding of ethanol on calcite: the role of the OH bond and its relevance to biomineralization.
The interaction of OH-containing compounds with calcite, CaCO(3), such as is required for the processes that control biomineralization, has been investigated in a low-water solution. We used ethanol (EtOH) as a simple, model, OH-containing organic compound, and observed the strength of its adsorption on calcite relative to OH from water and the consequences of the differences in interaction on crystal growth and dissolution. A combination of atomic force microscopy (AFM) and molecular dynamics (MD) simulations showed that EtOH attachment on calcite is stronger than HOH binding and that the first adsorbed layer of ethanol is highly ordered. The strong ordering of the ethanol molecules has important implications for mineral growth and dissolution because it produces a hydrophobic layer. Ethanol ordering is disturbed along steps and at defect sites, providing a bridge from the bulk solution to the surface. The strong influence of calcite in structuring ethanol extends further into the liquid than expected from electrical double-layer theory. This suggests that in fluids where water activity is low, such as in biological systems optimized for biomineralization, organic molecules can control ion transport to and from the mineral surface, confining it to specific locations, thus providing the organism with control for biomineral morphology.


Integrating technical and political views for a sustainable European Distributed Infrastructure on Population Health.
Non-Communicable diseases (NCD) are the main contributors to mortality and burden of disease. There is no infrastructure in Europe that could provide health information (HI) on Public Health monitoring and Health Systems Performance (HSP) for research and evidence-informed decision-making. Moreover, there was no EU and European Economic Area Member States (EU/EEA MSs) general consensus, on developing this initiative and guarantee its sustainability. The aim of this study is to analyze the integration of technical and political views made by the Joint Action on Health Information (InfAct; Information for Action) and the results obtained from those activities, in terms of advice and national and institutional support to develop an integrated and sustainable European Distributed Infrastructure on Population Health (DIPoH) for research and evidence-informed policy-making. InfAct established two main boards, the Technical Dialogues (TDs) and the Assembly of Members (AoM), to provide a platform for discussion with EU/EEA MSs to establish a sustainable infrastructure for HI: 1) The TDs were composed by national technical experts (NTE) with the aim to discuss and provide feedback about scientific aspects, feasibility and EU-added value of the infrastructure proposed by InfAct. 2) The AoM gathered country representatives from Ministries of Health and Research at the highest political level, with the aim of providing policy-oriented advice for the future political acceptance, support, implementation, and development of InfAct's outcomes including DIPoH. The documentation provided for the meetings consisted in Fact-Sheets, where the main results, new methods and proposals were clearly exposed for discussion and assessment; altogether with more extended information of the DIPoH. The documentation was provided to national representatives within one more before each TD and AoM meeting. The Agenda and methodological approaches for each TD and AoM meeting consisted in the presentations of the InfAct outcomes extending the information provided in the Fact-Sheets; followed by a non-structured interaction, exchange of information, discussion and suggestions by the MSs representatives. The outcomes of the non-structured discussions were collected in Minutes of the TD and AoM meetings, and the final version was obtained with the consensus of all participants. Additionally, structured letters of political support were provided to the AoM representatives, for them to consider providing their MS written support for DIPoH. NTE, within the TDs, considered that DIPoH was useful for technical mutual learning and cooperation among and within countries; although they considered that the technical feasibility to uptake InfAct deliverables at the national and EU level was complex. The AoM focused on political support, resources, and expected MSs returns. The AoM representatives agreed in the interest of setting up an integrated and sustainable HI infrastructure and they considered DIPoH to be well-articulated and defined; although, some of them, expressed some barriers for providing DIPoH political support. The AoM representatives stated that the AoM is the most suitable way to inform EU MSs/ACs about future advances of DIPoH. Both boards provided valuable feedback to develop this infrastructure. Eleven countries and sixteen institutions supported the proposal, either by letters of political support or by signing the Memorandum of Understandings (MoU) and three countries, additionally, provided expression of financial commitment, for DIPoH to be added to the ESFRI 2021 roadmap. TDs and AoM were key forums to develop, advise, advocate and provide support for a sustainable European research infrastructure for Population Health.


Sorting within the regulated secretory pathway occurs in the trans-Golgi network.
Bioactive peptides cleaved from the egg-laying hormone precursor in the bag cell neurons of Aplysia are sorted into distinct dense core vesicle classes (DCVs). Bag cell prohormone processing can be divided into two stages, an initial cleavage occurring in a late Golgi compartment, which is not blocked by monensin, and later cleavages that occur within DCVs and are blocked by monensin. Prohormone intermediates are sorted in the trans-Golgi network. The large soma-specific DCVs turn over, while the small DCVs are transported to processes for regulated release. Thus, protein trafficking differentially regulates the levels and localization of multiple biologically active peptides derived from a common prohormone.


Sequence heterogeneity in the 18S rRNA gene in Theileria equi from horses presented in Switzerland.
A reverse line blot (RLB) hybridization assay was adapted and applied for equine blood samples collected at the animal hospital of the University of Zurich to determine the presence of piroplasms in horses in Switzerland. A total of 100 equine blood samples were included in the study. The V4 hypervariable region of the 18S rRNA gene was amplified by polymerase chain reaction and analyzed using the RLB assay. Samples from seven horses hybridized to a Theileria/Babesia genus-specific and a Theileria genus-specific probe. Of these, two hybridized also to the Theileria equi-specific probe. The other five positive samples did not hybridize to any of the species-specific probes, suggesting the presence of unrecognized Theileria variants or genotypes. The 18S rRNA gene of the latter five samples were sequenced and found to be closely related to T. equi isolated from horses in Spain (AY534822) and China (KF559357) (≥98.4% identity). Four of the seven horses that tested positive had a documented travel history (France, Italy, and Spain) or lived abroad (Hungary). The present study adds new insight into the presence and sequence heterogeneity of T. equi in Switzerland. The results prompt that species-specific probes must be designed in regions of the gene unique to T. equi. Of note, none of the seven positive horses were suspected of having Theileria infection at the time of presentation to the clinic. Clinicians should be aware of the possibility of equine piroplasma infections outside of endemic areas and in horses without signs of piroplasmosis.


Optically driven full-angle sample rotation for tomographic imaging in digital holographic microscopy.
This study presents a novel tomographic imaging technique for living biomedical samples using an optically driven full-angle rotation scheme based on digital holographic microscopy, in which the three-dimensional refractive index distribution inside the sample can be measured and analyzed. To accomplish the full-angle sample rotation, two optical traps are driven by highly focused spots on the top and bottom of the sample. The rim image of the sample outside the focal depth at the different rotation angles and propagation distances can be corrected and compensated, respectively, via numerical focusing; therefore, tomographic imaging of the sample can be conducted. The proposed approach shows that an entire symmetric spectrum can be acquired for tomographic reconstruction without the missing apple core problem as in traditional sample-rotation schemes. The three-dimensional refractive index of living yeast in a fluid medium is measured and verified.


STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway.
Cytosolic double-stranded DNA (dsDNA) stimulates the production of type I interferon (IFN) through the endoplasmic reticulum (ER)-resident adaptor protein STING (stimulator of IFN genes), which activates the transcription factor interferon regulatory factor 3 (IRF3); however, how STING activates IRF3 is unclear. Here, we showed that STING stimulates phosphorylation of IRF3 by the kinase TBK1 (TANK-binding kinase 1) in an in vitro reconstitution system. With this system, we identified a carboxyl-terminal region of STING that was both necessary and sufficient to activate TBK1 and stimulate the phosphorylation of IRF3. We also found that STING interacted with both TBK1 and IRF3 and that mutations in STING that selectively disrupted its binding to IRF3 abrogated phosphorylation of IRF3 without impairing the activation of TBK1. These results suggest that STING functions as a scaffold protein to specify and promote the phosphorylation of IRF3 by TBK1. This scaffolding function of STING (and possibly of other adaptor proteins) may explain why IRF3 is activated in only a subset of signaling pathways that activate TBK1.


Enantioselective Total Synthesis of Berkeleyone A and Preaustinoids.
Herein we report the first enantioselective total synthesis of 3,5-dimethylorsellinic acid-derived meroterpenoids (-)-berkeleyone A and its five congeners ((-)-preaustinoids A, A1, B, B1, and B2) in 12-15 steps, starting from commercially available 2,4,6-trihydroxybenzoic acid hydrate. Based upon the recognition of latent symmetry within D-ring, our convergent synthesis features two critical reactions: 1) a symmetry-breaking, diastereoselective dearomative alkylation to assemble the entire carbon core, and 2) a Sc(OTf)3 -mediated sequential Krapcho dealkoxycarbonylation/carbonyl α-tert-alkylation to forge the intricate bicyclo[3.3.1]nonane framework. We also conducted our preliminary biomimetic investigations and uncovered a series of rearrangements (α-ketol, α-hydroxyl-β-diketone, etc.) responsible for the biomimetic diversification of (-)-berkeleyone A into its five preaustinoid congeners.


Trends in bioanalytical methods for the determination and quantification of club drugs: 2000-2010.
The term 'club drug' can be loosely defined as any substance used to enhance social settings. Such drugs are commonly found at raves or similar all-night dance parties and include methamphetamine, 3,4-methylenedioxymethamphetamine, gamma-hydroxybutyrate (GHB), ketamine (KET), and flunitrazepam (FLU). These drugs have potentially dangerous side effects including hallucinations, paranoia, amnesia and hyperthermia. In addition, GHB, KET and FLU are considered predatory drugs due to their roles in drug-facilitated sexual assault. Forensic and regulatory agencies routinely have the need for determination and accurate quantification of these drugs in biological fluids, especially in cases of mortality or criminal investigations. This review presents the chromatographic and spectroscopic methods published for such analyses over the last decade, including sample preparation techniques and validation data.


Gender differences in the surgical management of lumbar degenerative disease: a scoping review.
Despite efforts toward achieving gender equality in clinical trial enrollment, females are often underrepresented, and gender-specific data analysis is often unavailable. Identifying and reducing gender bias in medical decision-making and outcome reporting may facilitate equitable healthcare delivery. Gender disparity in the utilization of surgical therapy has been exemplified in the orthopedic literature through studies of total joint arthroplasty. A paucity of literature is available to guide the management of lumbar degenerative disease, which stratifies on the basis of demographic factors. The objective of this study was to systematically map and synthesize the adult surgical literature regarding gender differences in pre- and postoperative patient-reported clinical assessment scores for patients with lumbar degenerative disease (disc degeneration, disc herniation, spondylolisthesis, and spinal canal stenosis). A systematic scoping review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. MEDLINE, Embase, and the Cochrane Registry of Controlled Trials were searched from inception to September 2018. Study characteristics including patient demographics, diagnoses, procedures, and pre- and postoperative clinical assessment scores (pain, disability, and health-related quality of life [HRQoL]) were collected. Thirty articles were identified, accounting for 32,951 patients. Six studies accounted for 84% of patients; 5 of the 6 studies were published by European groups. The most common lumbar degenerative conditions were disc herniation (59.0%), disc degeneration (20.3%), and spinal canal stenosis (15.9%). The majority of studies reported worse preoperative pain (93.3%), disability (81.3%), and HRQoL (75%) among females. The remainder reported equivalent preoperative scores between males and females. The majority of studies (63.3%) did not report preoperative duration of symptoms, and this represents a limitation of the data. Eighty percent of studies found that females had worse absolute postoperative scores in at least one outcome category (pain, disability, or HRQoL). The remainder reported equivalent absolute postoperative scores between males and females. Seventy-three percent of studies reported either an equivalent or greater interval change for females. Female patients undergoing surgery for lumbar degenerative disease (disc degeneration, disc herniation, spondylolisthesis, and spinal canal stenosis) have worse absolute preoperative pain, disability, and HRQoL. Following surgery, females have worse absolute pain, disability, and HRQoL, but demonstrate an equal or greater interval change compared to males. Further studies should examine gender differences in preoperative workup and clinical course.


Parents' attitudes towards hepatitis B vaccination for their children. A survey comparing paper and web questionnaires, Sweden 2005.
The World Health Organisation, WHO, recommends that most countries should vaccinate all children against hepatitis B. Sweden has chosen not to do so, but the issue is reassessed regularly. The objective of this survey was to assess knowledge and attitudes towards hepatitis B vaccine for children among parents living in Sweden, and to compare distribution of responses and response rate between parents answering a postal questionnaire and those responding via the Internet. A population-based cross-sectional survey, where the sampling frame consisted of all parents to a child born 2002 living in Sweden. Two independent samples of 1001 parents in each sample were drawn. All parents were contacted by postal mail. The parents in the first sample were invited to participate by answering a paper questionnaire. The parents in the second sample were given an individual user name along with a password, and asked to log on to the Internet to answer an identical electronic questionnaire. A total of 1229 questionnaires were analysed. The overall response rate for paper questionnaires was 55%, and 15% for the web version. Knowledge of the disease hepatitis B was overall high (90%). A higher degree of knowledge was seen among parents with education beyond high school (p = 0.001). This group of parents also had a higher tendency to reply via the Internet (p = 0.001). The willingness to accept hepatitis B vaccine for their child was correlated to the acceptance of the present childhood vaccination programme (p = 0.001). The results reveal a high level of knowledge of the disease and a positive attitude to having their children vaccinated. This study also displays that the conventional postal method of surveying still delivers a higher response rate than a web-based survey.


A comprehensive assessment of geographic variation in heat tolerance and hardening capacity in populations of Drosophila melanogaster from eastern Australia.
We examined latitudinal variation in adult and larval heat tolerance in Drosophila melanogaster from eastern Australia. Adults were assessed using static and ramping assays. Basal and hardened static heat knockdown time showed significant linear clines; heat tolerance increased towards the tropics, particularly for hardened flies, suggesting that tropical populations have a greater hardening response. A similar pattern was evident for ramping heat knockdown time at 0.06°C min(-1) increase. There was no cline for ramping heat knockdown temperature (CT(max) ) at 0.1°C min(-1) increase. Acute (static) heat knockdown temperature increased towards temperate latitudes, probably reflecting a greater capacity of temperate flies to withstand sudden temperature increases during summer in temperate Australia. Larval viability showed a quadratic association with latitude under heat stress. Thus, patterns of heat resistance depend on assay methods. Genetic correlations in thermotolerance across life stages and evolutionary potential for critical thermal limits should be the focus of future studies.


Effects of hip flexor training on sprint, shuttle run, and vertical jump performance.
Although hip flexion is integral in sports, hip flexion exercises are seldom emphasized in strength and conditioning for sports performance. This study aimed to determine whether a hip flexor resistance-training program could improve performance on a variety of tasks. Thirteen men and 11 women completed an 8-week hip flexion resistance-training program. Eleven men and 13 women served as controls. Isometric hip flexion strength, 40-yd dash time and the time for the first 10-yds, 4 x 5.8-m shuttle run time, and vertical jump height were evaluated at the beginning and end of the training and control period. Improvements were observed in the training group but not in the control group. Individuals in the training group improved hip flexion strength by 12.2% and decreased their 40-yd and shuttle run times by 3.8% and 9.0%, respectively. An increase in hip flexion strength can help to improve sprint and agility performance for physically active, untrained individuals.


Spatiotemporal recruitment of human DNA polymerase delta to sites of UV damage.
Human DNA polymerase δ (Pol δ) is involved in various DNA damage responses in addition to its central role in DNA replication. The Pol δ4 holoenzyme consists of four subunits, p125, p50, p68 and p12. It has been established that the p12 subunit is rapidly degraded in response to DNA damage by UV leading to the in vivo conversion of Pol δ4 to Pol δ3, a trimeric form lacking the p12 subunit. We provide the first analysis of the time-dependent recruitment of the individual Pol δ subunits to sites of DNA damage produced by UV irradiation through 5 μm polycarbonate filters by immunofluorescence microscopy and laser scanning cytometry (LSC). Quantitative analysis demonstrates that the recruitments of the three large subunits was near complete by 2 h and did not change significantly up to 4 h after UV exposure. However, the recruitment of p12 was incomplete even at 4 h, with about 70% of the Pol δ lacking the p12 subunit. ChIP analysis of Pol δ after global UV irradiation further demonstrates that only p125, p50 and p68 were present. Thus, Pol δ3 is the predominant form of Pol δ at sites of UV damage as a result of p12 degradation. Using LSC, we have further confirmed that Pol δ was recruited to CPD damage sites in all phases of the cell cycle. Collectively, our results show that Pol δ at the DNA damage site is the Pol δ trimer lacking p12 regardless of the cell cycle phase.


Above-threshold ionization by few-cycle phase jump pulses.
We theoretically investigate the above-threshold ionization of hydrogen atoms driven by few-cycle phase jump laser pulses. By numerically solving the three-dimensional time-dependent Schrödinger equation, we demonstrate that the phase jump plays an important role in the ionization process. The cutoff of the photoelectron energy spectrum can extend to a range of very high energy, and the yield of the photoelectrons can be dramatically enhanced by choosing proper phase jump times. Both the classical simulations and Fourier transform method are used to understand the spectra features found in our investigation.


The long-lasting legacy of reproduction: lifetime reproductive success shapes expected genetic contributions of humans after 10 generations.
An individual's lifetime reproductive success (LRS) measures its realized genetic contributions to the next generation, but how well does it predict this over longer periods? Here we use human genealogical data to estimate expected individual genetic contributions (IGC) and quantify the degree to which LRS, relative to other fitness proxies, predicts IGC over longer periods. This allows an identification of the life-history stages that are most important in shaping variation in IGC. We use historical genealogical data from two non-isolated local populations in Switzerland to estimate the stabilized IGC for 2230 individuals approximately 10 generations after they were born. We find that LRS explains 30% less variation in IGC than the best predictor of IGC, the number of grandoffspring. However, albeit less precise than the number of grandoffspring, we show that LRS does provide an unbiased prediction of IGC. Furthermore, it predicts IGC better than lifespan, and accounting for offspring survival to adulthood does not improve the explanatory power. Overall, our findings demonstrate the value of human genealogical data to evolutionary biology and suggest that reproduction-more than lifespan or offspring survival-impacts the long-term genetic contributions of historic humans, even in a population with appreciable migration.


Recurrence risk and prognostic parameters in stage I rectal cancers.
The standard therapy for stage I rectum cancer is surgical resection. Currently, there is no strong evidence to suggest that any type of adjuvant therapy is beneficial. The risks of local relapse and distant metastasis are higher in rectal tumors. Therefore, while there is no clearly defined absolute indication for adjuvant therapy in lymph node negative colon cancers, rectum tumors that are T3N0 and higher require adjuvant treatment. Due to the more aggressive nature of rectal cancers, we explored the clinical and pathologic factors that could predict the risk of relapse in Stage I (T1-T2) disease and whether there was any progression-free survival benefit to adjuvant therapy. This multicenter study was carried out by the Anatolian Society of Medical Oncology. A total of 178 patients with rectal cancers who underwent curative surgery between January 1994 and August 2012 in 13 centers were included in the study. Patient demographics, including survival data and tumor characteristics were obtained from medical charts. The median age was 58 years (range 26-85 years). Most tumors were well or moderately differentiated. For adjuvant treatment, 13 patients (7.3%) received radiotherapy alone, 12 patients (6.7%) received chemotherapy alone and 15 patients (8.4%) were given chemoradiotherapy. Median follow up was 29 months (3-225 months). Some 42 patients (23.6%) had relapse during follow up; 30 with local recurrence (71.4%) whereas 12 (28.6%) were distant metastases. Among the patients, 5-year DFS was 64% and OS was 82%. Mucinous histology and receiving adjuvant therapy were found to have statistically insignificant correlations with relapse and survival. In our retrospective analysis, approximately one quarter of patients exhibited either local or systemic relapse. The rates of relapse were slightly higher in the patients who had no adjuvant therapy. There may thus be a role for adjuvant therapy in high-risk stage I rectal tumors.


Protracted Developmental Trajectory of Shape Processing along the Two Visual Pathways.
Studies of the emergence of shape representations in childhood have focused primarily on the ventral visual pathway. Importantly, however, there is increasing evidence that, in adults, the dorsal pathway also represents shape-based information. These dorsal representations follow a gradient with more posterior regions being more shape-sensitive than anterior regions and with representational similarity in some posterior regions that is equivalent to that observed in some ventral regions. To explore the emergence and nature of dorsal shape representations in development, we acquired both fMRI BOLD signals and behavioral data in children (aged 8-10 years) using a parametric image scrambling paradigm. Children exhibited adult-like large-scale organization of shape processing along both ventral and dorsal pathways. Also, as in adults, the activation profiles of children's posterior dorsal and ventral regions were correlated with recognition performance, reflecting a possible contribution of these signals to perception. There were age-related changes, however, with children being more affected by the distortion of shape information than adults, both behaviorally and neurally. These findings reveal that shape-processing mechanisms along both dorsal and ventral pathways are subject to a protracted developmental trajectory.


Evaluating assembly and variant calling software for strain-resolved analysis of large DNA viruses.
Infection with human cytomegalovirus (HCMV) can cause severe complications in immunocompromised individuals and congenitally infected children. Characterizing heterogeneous viral populations and their evolution by high-throughput sequencing of clinical specimens requires the accurate assembly of individual strains or sequence variants and suitable variant calling methods. However, the performance of most methods has not been assessed for populations composed of low divergent viral strains with large genomes, such as HCMV. In an extensive benchmarking study, we evaluated 15 assemblers and 6 variant callers on 10 lab-generated benchmark data sets created with two different library preparation protocols, to identify best practices and challenges for analyzing such data. Most assemblers, especially metaSPAdes and IVA, performed well across a range of metrics in recovering abundant strains. However, only one, Savage, recovered low abundant strains and in a highly fragmented manner. Two variant callers, LoFreq and VarScan2, excelled across all strain abundances. Both shared a large fraction of false positive variant calls, which were strongly enriched in T to G changes in a 'G.G' context. The magnitude of this context-dependent systematic error is linked to the experimental protocol. We provide all benchmarking data, results and the entire benchmarking workflow named QuasiModo, Quasispecies Metric determination on omics, under the GNU General Public License v3.0 (https://github.com/hzi-bifo/Quasimodo), to enable full reproducibility and further benchmarking on these and other data.


Bis(pentafluorophenyl)phenothiazylborane - an intramolecular frustrated Lewis pair catalyst for stannane dehydrocoupling.
We synthesized a novel Lewis acidic aminoborane containing a phenothiazyl substituent and demonstrated its potential to catalytically promote the dehydrocoupling of tin hydrides. The observed reactivity would imply a homolytic frustrated Lewis pair type mechanism, however computational analysis suggests a heterolytic mechanism for this reaction. This result represents one of the first frustrated Lewis pair systems to dehydrocouple stannanes in a heterolytic fashion.


Climate change, food, water and population health in China.
Anthropogenic climate change appears to be increasing the frequency, duration and intensity of extreme weather events. Such events have already had substantial impacts on socioeconomic development and population health. Climate change's most profound impacts are likely to be on food, health systems and water. This paper explores how climate change will affect food, human health and water in China. Projections indicate that the overall effects of climate change, land conversion and reduced water availability could reduce Chinese food production substantially - although uncertainty is inevitable in such projections. Climate change will probably have substantial impacts on water resources - e.g. changes in rainfall patterns and increases in the frequencies of droughts and floods in some areas of China. Such impacts would undoubtedly threaten population health and well-being in many communities. In the short-term, population health in China is likely to be adversely affected by increases in air temperatures and pollution. In the medium to long term, however, the indirect impacts of climate change - e.g. changes in the availability of food, shelter and water, decreased mental health and well-being and changes in the distribution and seasonality of infectious diseases - are likely to grow in importance. The potentially catastrophic consequences of climate change can only be avoided if all countries work together towards a substantial reduction in the emission of so-called greenhouse gases and a substantial increase in the global population's resilience to the risks of climate variability and change.


Avocado-Soybean Unsaponifiables: A Panoply of Potentialities to Be Exploited.
Avocado and soybean unsaponifiables (ASU) constitute vegetable extracts made from fruits and seeds of avocado and soybean oil. Characterized by its potent anti-inflammatory effects, this ASU mixture is recommended to act as an adjuvant treatment for osteoarthritic pain and slow-acting symptomatic treatment of hip and knee osteoarthritis; autoimmune diseases; diffuse scleroderma and scleroderma-like states (e.g., morphea, sclerodactyly, scleroderma in bands). Besides, it was reported that it can improve the mood and quality of life of postmenopausal women in reducing menopause-related symptoms. This article aims to summarize the studies on biological effects of the avocado-soybean unsaponifiable, its chemical composition, pharmacotherapy as well as applications in auto-immune, osteoarticular and menopausal disorders. Finally, we will also discuss on its safety, toxicological and regulatory practices.


The chronic effect of pulsed 1800 MHz electromagnetic radiation on amino acid neurotransmitters in three different areas of juvenile and young adult rat brain.
The extensive use of mobile phones worldwide has raised increasing concerns about the effects of electromagnetic radiation (EMR) on the brain due to the proximity of the mobile phone to the head and the appearance of several adverse neurological effects after mobile phone use. It has been hypothesized that the EMR-induced neurological effects may be mediated by amino acid neurotransmitters. Thus, the present study investigated the effect of EMR (frequency 1800 MHz, specific absorption rate 0.843 W/kg, power density 0.02 mW/cm2, modulated at 217 Hz) on the concentrations of amino acid neurotransmitters (glutamic acid, aspartic acid, gamma aminobutyric acid, glycine, taurine, and the amide glutamine) in the hippocampus, striatum, and hypothalamus of juvenile and young adult rats. The juvenile and young adult animals were each divided into two groups: control rats and rats exposed to EMR 1 h daily for 1, 2, and 4 months. A subgroup of rats were exposed daily to EMR for 4 months and then left without exposure for 1 month to study the recovery from EMR exposure. Amino acid neurotransmitters were measured in the hippocampus, striatum, and hypothalamus using high-performance liquid chromatography. Exposure to EMR induced significant changes in amino acid neurotransmitters in the studied brain areas of juvenile and young adult rats, being more prominent in juvenile animals. It could be concluded that the alterations in amino acid neurotransmitters induced by EMR exposure of juvenile and young adult rats may underlie many of the neurological effects reported after EMR exposure including cognitive and memory impairment and sleep disorders. Some of these effects may persist for some time after stopping exposure.


Developmental deficiency of the cholinergic system in congenitally hyperammonemic spf mice: effect of acetyl-L-carnitine.
The sparse-fur (spf) mutant mouse has an X-linked deficiency of hepatic ornithine transcarbamylase (OTC) and develops hyperammonemia in the postnatal period similar to that seen in human patients. We studied the effect of congenital hyperammonemia on the development of cerebral cholinergic parameters such as choline acetyltransferase (ChAT), acetylcholinesterase (AChE) and high-affinity choline uptake (HACU) in spf mice. The serum ammonia levels of spf mutant mice were significantly elevated after weaning compared with control animals. ChAT activity levels started decreasing in mutant spf mice from the age of 30 days (i.e., immediately after weaning); it reached significantly lower levels in the adult animals. HACU was consistently lower (P < .01) in spf/Y mice compared with controls up to the adult stage. However, there were no marked changes in the activity of AChE between control and hyperammonemic spf mice. The levels of beta-NGF, which is essential for cholinergic differentiation and function, were significantly lower in different brain regions of adult mutant mice compared with normal controls. A treatment of spf/spf breeding females with acetyl-L-carnitine, at a dose of 1.5 mM in drinking water, starting from day 1 of conception, resulted in a significant restoration of ChAT activity levels in some brain regions of the spf/Y offspring. The beta-NGF levels were also significantly elevated after supplementation with ALCAR in mutant mice compared with untreated mutant mice. These data are suggestive of a neurotrophic property of ALCAR during cholinergic deficiency caused by congenital hyperammonemia.


Lymphatic anatomy of the inguinal region in aid of vascularized lymph node flap harvesting.
Vascularized lymph node transfer (VLNT) has shown promise as a treatment for breast cancer-related lymphedema, a common and debilitating condition among breast cancer survivors. In VLNT, the most popular lymph node flap donor site is the inguinal region; however, concerns about the possibility of iatrogenic lymphedema hamper the widespread adoption of VLNT. A better understanding of the anatomy of the lymphatic system in the inguinal region is essential to preserving lymph drainage in the leg and avoiding iatrogenic lymphedema. Five human cadaver hind-quarter specimens were used for this study. First, the specimens were scanned with indocyanine green fluorescence lymphography to map the lymphatic vessels. A dual injection technique using different radiocontrast media was then applied to delineate arteries and lymphatic vessels on radiographs. Finally, radiological analysis and meticulous dissection were used to investigate relationships between the arteries and lymphatic vessels. By chasing the lymphatic vessels retrogradely from their corresponding lymph nodes, we were able to divide the superficial inguinal lymph nodes into three subgroups: the abdominal, medial thigh, and lateral thigh nodes. We found no connections between the superficial and deep lymphatic system in the inguinal region. The dominant lymph nodes draining the leg were in the lower part of the inguinal triangle, and their efferent lymphatic vessels ran medial to the common femoral artery. Preserving the sentinel nodes of the lower leg in the medial thigh and their efferent lymphatic vessels is crucial to avoid iatrogenic lymphedema in limbs with donor sites for VLNT.


PKBγ/AKT3 loss-of-function causes learning and memory deficits and deregulation of AKT/mTORC2 signaling: Relevance for schizophrenia.
Psychiatric genetic studies have identified genome-wide significant loci for schizophrenia. The AKT3/1q44 locus is a principal risk region and gene-network analyses identify AKT3 polymorphisms as a constituent of several neurobiological pathways relevant to psychiatric risk; the neurobiological mechanisms remain unknown. AKT3 shows prenatal enrichment during human neocortical development and recurrent copy number variations involving the 1q43-44 locus are associated with cortical malformations and intellectual disability, implicating an essential role in early brain development. Here, we investigated the role of AKT3 as it relates to aspects of learning and memory and behavioral function, relevant to schizophrenia and cognitive disability, utilizing a novel murine model of Akt3 genetic deficiency. Akt3 heterozygous (Akt3-/+) or null mice (Akt3-/-) were assessed in a comprehensive test battery. Brain biochemical studies were conducted to assess the impact of Akt3 deficiency on cortical Akt/mTOR signaling. Akt3-/+ and Akt3-/- mice exhibited selective deficits of temporal order discrimination and spatial memory, tasks critically dependent on intact prefrontal-hippocampal circuitry, but showed normal prepulse inhibition, fear conditioned learning, memory for novel objects and social function. Akt3 loss-of-function, reduced brain size and dramatically impaired cortical Akt Ser473 activation in an allele-dose dependent manner. Such changes were observed in the absence of altered Akt1 or Akt2 protein expression. Concomitant reduction of the mTORC2 complex proteins, Rictor and Sin1 identifies a potential mechanism. Our findings provide novel insight into the neurodevelopmental role of Akt3, identify a non-redundant role for Akt3 in the development of prefrontal cortical-mediated cognitive function and show that Akt3 is potentially the dominant regulator of AKT/mTOR signaling in brain.


Protease production by Pseudomonas aeruginosa isolates from patients with cystic fibrosis.
The temporal appearance of extracellular proteases produced by Pseudomonas aeruginosa was analyzed by pH 9 and pH 4 polyacrylamide gel electrophoresis (PAGE) and sodium dodecyl sulfate-PAGE. Ammonium sulfate precipitates of culture supernatants from various stages of growth revealed a time-dependent increase in number and amount of proteolytically active proteins. One mucoid P. aeruginosa clinical isolate and its derived nonmucoid variant, as well as two other nonmucoid variant P. aeruginosa strains (all from cystic fibrosis patients), showed similar production of five differently migrating proteases (P1 to P5, numbered according to increasing net negative charge) in pH 9 PAGE and one protease in pH 4 PAGE. P2, P3, and P5 increased to maximum concentrations at 24 to 48 h, decreasing thereafter, whereas P4 continued increasing even at 83 h, and P1 fluctuated. P3 was identified as an elastase. P2 was possibly composed of polypeptide chains bridged by disulfide bonds, since without reduction it migrated in sodium dodecyl sulfate-PAGE as a single protein, and with reduction it migrated as three protein bands. Two-dimensional PAGE revealed multiple molecular weight species within protease-positive bands in pH 9 gel strips. Isoelectric focusing gave a pattern of protein separation that correlated with two-dimensional PAGE analysis. Thus, greater heterogeneity of active proteases than previously reported has been demonstrated in all P. aeruginosa clinical isolates studied by sensitive two-dimensional PAGE analysis.


Amphotericin B and terbinafine but not the azoles prolong survival in Galleria mellonella larvae infected with Madurella mycetomatis.
Mycetoma is a tropical neglected disease characterized by large subcutaneous lesions in which the causative organisms reside in the form of grains. The most common causative agent is Madurella mycetomatis. Antifungal therapy often fails due to these grains, but to identify novel treatment options has been difficult since grains do not form in vitro. We recently used Galleria mellonella larvae to develop an in vivo grain model. In the current study, we set out to determine the therapeutic efficacy of commonly used antifungal agents in this larval model. Pharmacokinetics of ketoconazole, itraconazole, voriconazole, posaconazole, amphotericin B, and terbinafine were determined in the hemolymph of G. mellonella larvae. Antifungal therapy was given either therapeutically or prophylactic on three consecutive days in therapeutically equivalent dosages. Survival was monitored for 10 days and colony-forming units (cfu) and melanization were determined on day 3. Measurable concentrations of antifungal agents were found in the hemolymph of the larvae. None of the azole antifungal agents prolonged survival when given therapeutically or prophylactically. Amphotericin B and terbinafine did prolong survival, even at concentrations below the minimal inhibitory concentration of M. mycetomatis. The cfu and melanization did not differ between any of the treated groups and phosphate-buffered saline (PBS) treated groups. Grains were still present in surviving larvae but appeared to be encapsulated. This study demonstrated for the first time a comparison between the efficacy of different antifungal agents toward grains of M. mycetomatis. It appeared that amphotericin B and terbinafine were able to prolong larval survival.


Prediction of cardiovascular risk factors from retinal fundus photographs via deep learning.
Traditionally, medical discoveries are made by observing associations, making hypotheses from them and then designing and running experiments to test the hypotheses. However, with medical images, observing and quantifying associations can often be difficult because of the wide variety of features, patterns, colours, values and shapes that are present in real data. Here, we show that deep learning can extract new knowledge from retinal fundus images. Using deep-learning models trained on data from 284,335 patients and validated on two independent datasets of 12,026 and 999 patients, we predicted cardiovascular risk factors not previously thought to be present or quantifiable in retinal images, such as age (mean absolute error within 3.26 years), gender (area under the receiver operating characteristic curve (AUC) = 0.97), smoking status (AUC = 0.71), systolic blood pressure (mean absolute error within 11.23 mmHg) and major adverse cardiac events (AUC = 0.70). We also show that the trained deep-learning models used anatomical features, such as the optic disc or blood vessels, to generate each prediction.


Population genetic structure in Indian Austroasiatic speakers: the role of landscape barriers and sex-specific admixture.
The geographic origin and time of dispersal of Austroasiatic (AA) speakers, presently settled in south and southeast Asia, remains disputed. Two rival hypotheses, both assuming a demic component to the language dispersal, have been proposed. The first of these places the origin of Austroasiatic speakers in southeast Asia with a later dispersal to south Asia during the Neolithic, whereas the second hypothesis advocates pre-Neolithic origins and dispersal of this language family from south Asia. To test the two alternative models, this study combines the analysis of uniparentally inherited markers with 610,000 common single nucleotide polymorphism loci from the nuclear genome. Indian AA speakers have high frequencies of Y chromosome haplogroup O2a; our results show that this haplogroup has significantly higher diversity and coalescent time (17-28 thousand years ago) in southeast Asia, strongly supporting the first of the two hypotheses. Nevertheless, the results of principal component and "structure-like" analyses on autosomal loci also show that the population history of AA speakers in India is more complex, being characterized by two ancestral components-one represented in the pattern of Y chromosomal and EDAR results and the other by mitochondrial DNA diversity and genomic structure. We propose that AA speakers in India today are derived from dispersal from southeast Asia, followed by extensive sex-specific admixture with local Indian populations.


Preventing fatal destruction: inhibitors of the anaphase-promoting complex in meiosis.
The anaphase-promoting complex/cyclosome (APC/C) is a multi-subunit ubiquitin-ligase whose major functions in the cell cycle are the initiation of sister chromatid separation and the inactivation of cyclin-dependent kinases. This complex is also essential for meiosis, a specialized form of the cell cycle characterized by two consecutive rounds of chromosome segregation. To ensure a proper meiotic cell cycle, the activity of APC/C needs to be tightly controlled. It is now evident that inhibitors of APC/C play pivotal roles to avert its untimely activation. During prophase I, this ubiquitin-ligase must be kept inactive to prevent precocious sister chromatid separation. Studies in yeast showed that this inhibition is mediated by a specific subunit of the complex. Accurate chromosome segregation in meiosis I depends on spindle checkpoint proteins such as Mad2 which delay APC/C activation in response to an erroneous spindle attachment of chromosomes. Additional APC/C antagonists are known to block complete cyclin destruction between meiosis I and II, thereby ensuring that cyclin dependent kinases remain active and that DNA replication does not occur. Inhibitors of APC/C also mediate the cytostatic factor induced metaphase II arrest of oocytes. This review highlights the current knowledge about the role and relevance of these diverse regulators of the meiotic APC/C.


A Versatile Isobaric Tag Enables Proteome Quantification in Data-Dependent and Data-Independent Acquisition Modes.
Quantifying proteins based on peptide-coupled reporter ions is a multiplexed quantitative strategy in proteomics that alleviates the problem of ratio distortion caused by peptide cofragmentation, as commonly observed in other reporter-ion-based approaches, such as TMT and iTRAQ. Data-independent acquisition (DIA) is an attractive alternative to data-dependent acquisition (DDA) due to its better reproducibility. While multiplexed labeling is widely used in DDA, it is rarely used in DIA, presumably because current approaches lead to more complex MS2 spectra, severe ratio distortion, or to a reduction in quantification accuracy and precision. Herein, we present a versatile acetyl-alanine-glycine (Ac-AG) tag that conceals quantitative information in isobarically labeled peptides and reveals it upon tandem MS in the form of peptide-coupled reporter ions. Since the peptide-coupled reporter ion is precursor-specific while fragment ions of the peptide backbone originating from different labeling channels are identical, the Ac-AG tag is compatible with both DDA and DIA. By isolating the monoisotopic peak of the precursor ion in DDA, intensities of the peptide-coupled reporter ions represent the relative ratios between constituent samples, whereas in DIA, the ratio can be inferred after deconvoluting the peptide-coupled reporter ion isotopes. The proteome quantification capability of the Ac-AG tag was demonstrated by triplex labeling of a yeast proteome spiked with bovine serum albumin (BSA) over a 10-fold dynamic range. Within this complex proteomics background, BSA spiked at 1:5:10 ratios was detected at ratios of 1.00:4.87:10.13 in DDA and 1.16:5.20:9.64 in DIA.


Factors related to cardiovascular disease risk reduction in midlife and older women: a qualitative study.
Cardiovascular disease (CVD) is the leading cause of death for women in the United States. A healthy diet and appropriate physical activity can help reduce the risk for CVD. However, many women do not follow recommendations for these behaviors. In this study, we used qualitative methods to better understand knowledge and awareness about CVD in women, perceived threat of CVD, barriers to heart-healthy eating and physical activity, and intervention strategies for behavior change. We conducted four focus groups with 38 white women aged 40 years or older in Kansas and Arkansas. We also interviewed 25 Cooperative State Research, Education, and Extension Service agents in those states. Environmental audits of grocery stores and the physical environment were done in three communities. Most women were aware of the modifiable risk factors for CVD. Although they realized they were susceptible, they thought CVD was something they could overcome. Common barriers to achieving a heart-healthy diet included time and concern about wasting food. Most women had positive attitudes toward physical activity and reported exercising in the past, but found it difficult to resume when their routine was disrupted. The environmental audits suggested that there are opportunities to be physically active and that with the exception of fresh fish in Kansas, healthful foods are readily available in local food stores. Interventions to change behavior should be hands-on, have a goal-setting component, and include opportunities for social interaction. It is especially important to offer interventions as awareness increases and women seek opportunities to build skills to change behavior.


Lateral retinacular release as a function of femoral component rotation in total knee arthroplasty.
A consensus exists in the orthopaedic community that proper rotational placement of components may reduce the need for lateral release. This study compares the rates and results of lateral release before and after femoral component placement was defined by the transepicondylar axis (TEA). Between 1990 and 1991, 104 primary total knee arthroplasties (TKA) were reviewed during which equal amounts of bone from the posterior femoral condyles were removed. In this group, the lateral release incidence was 24% for varus deformities and 33% for valgus deformities. When the femoral component was externally rotated approximating the TEA, a review of 246 primary TKAs performed between 1998 and 1999 showed lateral release rates of 7% in varus deformities and 29% in valgus deformities. This study documents the statistically significant decline in the lateral release rate with external rotation of the femoral component during TKA in varus deformities (P<.0001), and a decreasing trend in valgus knees (P =.09).


Social anxiety and self-impression: cognitive preparation enhances the beneficial effects of video feedback following a stressful social task.
Negative and distorted images of the observable self are important in the development and maintenance of social phobia. Previous research has shown that video feedback has potential to correct the distorted self-perception [Rapee, R. M. & Hayman, K. (1996). The effects of video feedback on the self-evaluation of performance in socially anxious subjects. Behaviour Research and Therapy, 34, 315-322]. The present experiment investigated whether the construction of a self-image prior to viewing the video may enhance the therapeutic effects of video feedback. High and low socially anxious individuals gave a speech and then viewed the video of their performance. Half of the sample were given cognitive preparation prior to viewing the video. Cognitive preparation involved asking participants to (1) predict in detail what they will see in the video, (2) form an image of themselves giving the speech and (3) watch the video as though they were watching a stranger. Participants who received cognitive preparation prior to the video feedback made higher ratings of their overall performance and of specific aspects of their performance compared to those who were not given cognitive preparation and compared to the same ratings made prior to the video feedback. These results suggest that the therapeutic effects of video feedback can be enhanced by careful cognitive preparation which maximises the perceived discrepancy between self and video images.


Chemical composition and molecular structure of polysaccharide-protein biopolymer from Durio zibethinus seed: extraction and purification process.
The biological functions of natural biopolymers from plant sources depend on their chemical composition and molecular structure. In addition, the extraction and further processing conditions significantly influence the chemical and molecular structure of the plant biopolymer. The main objective of the present study was to characterize the chemical and molecular structure of a natural biopolymer from Durio zibethinus seed. A size-exclusion chromatography coupled to multi angle laser light-scattering (SEC-MALS) was applied to analyze the molecular weight (Mw), number average molecular weight (Mn), and polydispersity index (Mw/Mn). The most abundant monosaccharide in the carbohydrate composition of durian seed gum were galactose (48.6-59.9%), glucose (37.1-45.1%), arabinose (0.58-3.41%), and xylose (0.3-3.21%). The predominant fatty acid of the lipid fraction from the durian seed gum were palmitic acid (C16:0), palmitoleic acid (C16:1), stearic acid (C18:0), oleic acid (C18:1), linoleic acid (C18:2), and linolenic acid (C18:2). The most abundant amino acids of durian seed gum were: leucine (30.9-37.3%), lysine (6.04-8.36%), aspartic acid (6.10-7.19%), glycine (6.07-7.42%), alanine (5.24-6.14%), glutamic acid (5.57-7.09%), valine (4.5-5.50%), proline (3.87-4.81%), serine (4.39-5.18%), threonine (3.44-6.50%), isoleucine (3.30-4.07%), and phenylalanine (3.11-9.04%). The presence of essential amino acids in the chemical structure of durian seed gum reinforces its nutritional value.


Intravenous Levetiracetam for Treatment of Seizures in Term and Preterm Neonates.
Seizures are the most frequent neurological disturbance in the neonatal period, and there are no evidence-based guidelines for the treatment of neonatal seizures. Here we report a study on the use of levetiracetam as second-line therapy in the treatment of seizures in term and preterm neonates. The aim of this study was to assess the efficacy and safety of levetiracetam for seizures of term and preterm neonates. We retrospectively analyzed data of the patients who had seizures and who were treated with levetiracetam as an add-on therapy to phenobarbital during the neonatal period. The Statistical Package for the Social Sciences (SPSS) software, version 15.0 (SPSS, Chicago, Illinois), was used for statistical analysis. Continuous variables were expressed as mean values and standard deviations. Thirty-six patients (8 term and 28 preterm) received levetiracetam. Mean dose of levetiracetam was 31.67 ± 14.83mg/kg/day. Twenty-five of the patients (69.4%) were seizure free with levetiracetam treatment. Electroencephalography recordings improved in 28 (77.8%) of the patients after levetiracetam. No severe adverse effects were observed. Our data suggest that levetiracetam may be a safe and effective treatment for neonatal seizures, which are unresponsive to phenobarbital.


Effectiveness of the Valsalva Manoeuvre for reversion of supraventricular tachycardia.
People with the cardiac arrhythmia supraventricular tachycardia (SVT) frequently present to clinicians in the prehospital and emergency medicine settings. Restoring sinus rhythm by terminating the SVT involves increasing the refractoriness of atrioventricular nodal tissue within the myocardium by means of vagal manoeuvres, pharmacological agents, or electrical cardioversion. A commonly used first-line technique to restore the normal sinus rhythm (reversion) is the Valsalva Manoeuvre (VM). This is a non-invasive means of increasing myocardial refractoriness by increasing intrathoracic pressure for a brief period, thus stimulating baroreceptor activity in the aortic arch and carotid bodies, resulting in increased parasympathetic (vagus nerve) tone. To assess the evidence of effectiveness of the VM in terminating SVT. We updated the electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 7); MEDLINE Ovid (1946 to August week 3, 2014); EMBASE Classic and EMBASE Ovid (1947 to 27 August 2014); Web of Science (1970 to 27 August 2014); and BIOSIS Previews (1969 to 22 August 2014). We also checked trials registries, the Index to Theses, and the bibliographies of all relevant publications identified by these strategies. We included all randomised controlled trials (RCTs) that examined the effectiveness of VM in terminating SVT. Two review authors independently extracted the data using a standardised form. We assessed each trial for internal validity, resolving any differences by discussion. We then extracted and entered data into Review Manager 5. In this update, we did not identify any new RCT studies for inclusion. We identified two RCT studies as ongoing that we are likely to include in future updates. Accordingly, our results are unchanged and include three RCTs with a total of 316 participants. All three studies compared the effectiveness of VM in reverting SVT with that of other vagal manoeuvres in a cross-over design. Two studies induced SVT within a controlled laboratory environment. Participants had ceased all medications prior to engaging in these studies. The third study reported on people presenting to a hospital emergency department with an episode of SVT. These participants were not controlled for medications or other factors prior to intervention.The two laboratory studies demonstrated reversion rates of 45.9% and 54.3%, whilst the clinical study demonstrated reversion success of 19.4%. This discrepancy may be due to methodological differences between studies, the effect of induced SVT versus spontaneous episodic SVT, and participant factors such as medications and comorbidities. We were unable to assess any of these factors, or adverse effects, further, since they were either not described in enough detail or not reported at all.Statistical pooling was not possible due to heterogeneity between the included studies. We did not find sufficient evidence to support or refute the effectiveness of VM for termination of SVT. Further research is needed, and this research should include a standardised approach to performance technique and methodology.