Low dose extended exposure to saxitoxin and its potential neurodevelopmental effects: A review.
Saxitoxin (STX) and its analogs, the paralytic shellfish toxins (PSTs), are a group of potent neurotoxins well known for their role in acute paralytic poisoning by preventing the generation of action potentials in neuronal cells. They are found in both marine and freshwater environments globally and although acute exposure from the former has previously received more attention, low dose extended exposure from both sources is possible and to date has not been investigated. Given the known role of cellular electrical activity in neurodevelopment this pattern of exposure may be a significant public health concern. Additionally, the presence of PSTs is likely to be an ongoing and possibly increasing problem in the future. This review examines the neurodevelopmental toxicity of STX, the risk of extended or repeated exposure to doses with neurodevelopmental effects, the potential implications of this exposure and briefly, the steps taken and difficulties faced in preventing exposure.


Newly Developed TV-Based Cognitive Training Games Improve Car Driving Skills, Cognitive Functions, and Mood in Healthy Older Adults: Evidence From a Randomized Controlled Trial.
Background: Cognitive training in a laboratory improves car driving skills of older car drivers. However, it remains unclear whether other types of cognitive training at home have beneficial effects on driving skills. Using our developed cognitive training games that can be played on a television with a set-top box in a person's home, we investigated the effects of a 6-week cognitive training program on driving skills, which included on-road evaluation (primary outcome), and cognitive functions and emotional states (secondary outcome) in older people. Methods: In this double-blinded randomized control trial (RCT), 60 older licensed drivers were randomly assigned into one of the two groups: a cognitive training game for car driving (CTCD) group and an active control cognitive training game (ACT) group. Participants in the CTCD group played the CTCD (processing speed, dual attention, and speed prediction) for 20 min in five sessions per week for 6 weeks. Participants in the ACT group played the ACT (selecting the larger number; selecting a number from largest to smallest; play a game of rock, article, scissors) for 20 min in five sessions per week for 6 weeks. We measured driving skills, various cognitive functions, and emotional states before and after the 6-week intervention period. Results: Our main results showed that compared to the ACT group, the CTCD group demonstrated improved driving skills (adjusted p = 0.034). Moreover, the CTCD group demonstrated improved inhibition (stroop, adjusted p = 0.042: reverse Stroop, adjusted p = 0.043) and processing speed performance symbol search (SS), adjusted p = 0.049; digit symbol coding (adjusted p = 0.047), compared to the ACT group. The CTCD group scored higher on vigor-activity mood (adjusted p = 0.041) as measured using the Profile of Mood State. Discussion: This randomized controlled trial provides scientific evidence for the benefits of the 6-week CTCD program on driving skills and cognitive functions, such as processing speed, inhibition, and vigor-activity mood, in healthy older people. Our results suggest that cognitive training is useful to improve the driving skills of older adults. Trial registration: This trial was registered at The University Hospital Medical Information Network Clinical Trials Registry (UMIN 000029769). Registered 31 October 2017, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034010.


Preferential increases in nucleus accumbens dopamine after systemic cocaine administration are caused by unique characteristics of dopamine neurotransmission.
In vivo voltammetry was used to investigate the preferential increase of extracellular dopamine in the nucleus accumbens relative to the caudate-putamen after systemic cocaine administration. In the first part of this study, cocaine (40 mg/kg, i.p.) was compared with two other blockers of dopamine uptake, nomifensine (10 mg/kg, i.p.) and 3beta-(p-chlorophenyl)tropan-2beta-carboxylic acid p-isothiocyanatophenylmethyl ester hydrochloride (RTI-76; 100 nmol, i.c.v.), to assess whether the inhibitory mechanism of cocaine differed in the two regions. All three drugs robustly increased electrically evoked levels of dopamine, and cocaine elevated dopamine signals to a greater extent in the nucleus accumbens. However, kinetic analysis of the evoked dopamine signals indicated that cocaine and nomifensine increased the K(m) for dopamine uptake whereas the dominant effect of RTI-76 was a decrease in V(max). Under the present in vivo conditions, therefore, cocaine is a competitive inhibitor of dopamine uptake in both the nucleus accumbens and caudate-putamen. Whether the preferential effect of cocaine was mediated by regional differences in the presynaptic control of extracellular DA that are described by rates for DA uptake and release was examined next by a correlation analysis. The lower rates for dopamine release and uptake measured in the nucleus accumbens were found to underlie the preferential increase in extracellular dopamine after cocaine. This relationship explains the paradox that cocaine more effectively increases accumbal dopamine despite identical effects on the dopamine transporter in the two regions. The mechanism proposed for the preferential actions of cocaine may also mediate the differential effects of psychostimulant in extrastriatal regions and other uptake inhibitors in the striatum.


Detection of trace elements in nondegradable organic spent clay waste using optimized dual-pulsed laser induced breakdown spectrometer.
The detection of trace elements present in nondegradable organic spent clay waste has been carried out using an optimized dual-pulsed laser induced breakdown spectrometer. The two laser pulses at 1064 and 266 nm were collinearly collimated and focused on the sample surface in order to enhance the signal intensity. The atomic transition lines at 568.8 nm (Na-I), 504.2 nm (Pb-II), 405.8 nm (Pb -I), 443.56 nm (Ca-I), 469.41 nm (S-I), 520.8 nm (Cr-I), 643 nm (Cd-I), and 928.1 nm (Cl-I) were used as marker wavelengths, and the concentrations of 688, 300, 204, 460, and 2440 ppm of Pb, S, Cd, Cr, and Cl, respectively, were detected in the 5% spent clay in the binder. The limits of detection of Pb, S, Cd, Cr, and Cl were estimated to be 6.7, 17.2, 6.5, 5.1, and 14.8 ppm, respectively, from the calibration curve for each element. In order to confirm the reliability of our system, the concentrations of the reported elements detected using our system were compared to the ones obtained with inductively coupled plasma emission spectroscopy and found to be in good agreement.


Large-scale in silico modeling of metabolic interactions between cell types in the human brain.
Metabolic interactions between multiple cell types are difficult to model using existing approaches. Here we present a workflow that integrates gene expression data, proteomics data and literature-based manual curation to model human metabolism within and between different types of cells. Transport reactions are used to account for the transfer of metabolites between models of different cell types via the interstitial fluid. We apply the method to create models of brain energy metabolism that recapitulate metabolic interactions between astrocytes and various neuron types relevant to Alzheimer's disease. Analysis of the models identifies genes and pathways that may explain observed experimental phenomena, including the differential effects of the disease on cell types and regions of the brain. Constraint-based modeling can thus contribute to the study and analysis of multicellular metabolic processes in the human tissue microenvironment and provide detailed mechanistic insight into high-throughput data analysis.


P-doping mechanisms in catalyst-free gallium arsenide nanowires.
Doped catalyst-free GaAs nanowires have been grown by molecular beam epitaxy with the gallium-assisted method. The spatial dependence of the dopant concentration and resistivity have been measured by Raman spectroscopy and four point electrical measurements. Along with theoretical considerations, the doping mechanisms have been revealed. Two competing mechanisms have been revealed: dopant incorporation from the side facets and from the gallium droplet. In the latter incorporation path, doping compensation seems to play an important role in the effective dopant concentration. Hole concentrations of at least 2.4 x 10(18) cm(-3) have been achieved, which to our knowledge is the largest p doping range obtained up to date. This work opens the avenue for the use of doped GaAs nanowires in advanced applications and in mesoscopic physics experiments.


Use of proteinase K for RT-PCR of cytokine mRNA in formalin fixed tissue.
Fresh tissue from cases of sudden infant death syndrome is becoming increasingly scarce and therefore researchers interesting in studying the aetiology of this syndrome have had to resort to archival tissue, usually in the form of paraffin wax sections. A simple method for isolating mRNA from formalin fixed, paraffin wax embedded material of sufficient purity for reverse transcription (RT)-PCR is described. Proteinase K treatment of formalin fixed, wax embedded tissue followed by RNA STAT-60 extraction was successful in isolating mRNA suitable for RT-PCR. Interleukin (IL)-1alpha, IL-6 and tumour necrosis factor (TNF) transcripts were amplified successfully from heart, but not thyroid, kidney or liver tissue, of a patient who died following rejection of a transplanted heart, and IL-1alpha, but not IL-6 or TNF, transcripts from lung tissue of a six month old baby who died of viral pneumonia. Transcripts of a housekeeping gene were detected in all tissues. This method should be useful for examining gene expression in archival material.


Effect of the tumor vascular-damaging agent, ZD6126, on the radioresponse of U87 glioblastoma.
The effect of ZD6126 on tumor oxygen tension and tumor growth delay in combination with ionizing radiation was examined in the human U87 glioblastoma tumor model. Resistance to ZD6126 treatment was investigated with the nitric oxide synthase inhibitor, l-N(G)-nitroarginine methyl ester (hydrochloride; l-NAME/active form, l-NNA). U87 human xenografts were grown in athymic nude mice. ZD6126 was given with or without l-NNA. Tumor oxygen tension was measured using the Oxford Oxylite (Oxford, England) fiberoptic probe system. Tumor volume was determined by direct measurement with calipers and calculated by the formula [(smallest diameter(2) x widest diameter)/2]. Multiple doses of ZD6126 treatment (three doses) had a significant effect on tumor growth delay, reducing the average daily tumor growth rate from 29% to 16%. When given 1 hour before radiation, ZD6126 caused an acute increase in hypoxia in U87 tumors, and reduced tumor growth delay compared with that of radiation alone. The combination of ZD6126 given after radiation, either as a single dose or in multiple doses, had greater or similar antitumor activity compared with radiation alone. Twenty-four hours after administration, a single dose of ZD6126 induced little (10 +/- 8%) necrosis in U87 xenografts. l-NNA, when given in combination with ZD6126, significantly enhanced the effectiveness of ZD6126 in inducing tumor necrosis. Our observation that ZD6126-induced tumor hypoxia can decrease radiation response when ZD6126 is given prior to radiation indicates the importance of scheduling. Our findings suggest that the optimal therapeutic benefit of ZD6126 plus radiation in human glioblastoma may require multiple dosing in combination with a nitric oxide synthase inhibitor, to be scheduled following radiotherapy.


Rescue of human immunodeficiency virus type 1 matrix protein mutants by envelope glycoproteins with short cytoplasmic domains.
The matrix (MA) protein of human immunodeficiency virus type 1 (HIV-1) forms the outer protein shell directly underneath the lipid envelope of the virion. The MA protein has a key role in different aspects of virus assembly, including the incorporation of the HIV-1 Env protein complex, which contains a transmembrane glycoprotein with an unusually long cytoplasmic tail. In this study, we compared the abilities of HIV-1 MA mutants to incorporate Env protein complexes with long and short cytoplasmic tails. While the mutant particles failed to incorporate the authentic HIV-1 Env protein complex, they retained the ability to efficiently and functionally incorporate the amphotropic murine leukemia virus Env protein complex, which has a short cytoplasmic tail. Moreover, incorporation of the autologous Env protein complex could be restored by a second-site mutation that resulted in the truncation of the cytoplasmic tail of the HIV-1 transmembrane glycoprotein. Remarkably, the second-site mutation also restored the ability of MA mutants to replicate in MT-4 cells. These results imply that the long cytoplasmic tail of the transmembrane glycoprotein is responsible for the exclusion of the HIV-1 Env protein complex from MA mutant particles.


ChelomEx: Isotope-assisted discovery of metal chelates in complex media using high-resolution LC-MS.
Chelating agents can control the speciation and reactivity of trace metals in biological, environmental, and laboratory-derived media. A large number of trace metals (including Fe, Cu, Zn, Hg, and others) show characteristic isotopic fingerprints that can be exploited for the discovery of known and unknown organic metal complexes and related chelating ligands in very complex sample matrices using high-resolution liquid chromatography mass spectrometry (LC-MS). However, there is currently no free open-source software available for this purpose. We present a novel software tool, ChelomEx, which identifies isotope pattern-matched chromatographic features associated with metal complexes along with free ligands and other related adducts in high-resolution LC-MS data. High sensitivity and exclusion of false positives are achieved by evaluation of the chromatographic coherence of the isotope pattern within chromatographic features, which we demonstrate through the analysis of bacterial culture media. A built-in graphical user interface and compound library aid in identification and efficient evaluation of results. ChelomEx is implemented in MatLab. The source code, binaries for MS Windows and MAC OS X as well as test LC-MS data are available for download at SourceForge ( http://sourceforge.net/projects/chelomex ).


A new member of the hsp90 family of molecular chaperones interacts with the retinoblastoma protein during mitosis and after heat shock.
A gene encoding a new heat shock protein that may function as a molecular chaperone for the retinoblastoma protein (Rb) was characterized. The cDNA fragment was isolated by using the yeast two-hybrid system and Rb as bait. The open reading frame of the longest cDNA codes for a protein with substantial sequence homology to members of the hsp90 family. Antibodies prepared against fusions between glutathione S-transferase and portions of this new heat shock protein specifically recognized a 75-kDa cellular protein, hereafter designated hsp75, which is expressed ubiquitously and located in the cytoplasm. A unique LxCxE motif in hsp75, but not in other hsp90 family members, appears to be important for binding to the simian virus 40 T-antigen-binding domain of hypophosphorylated Rb, since a single mutation changing the cysteine to methionine abolishes the binding. In mammalian cells, Rb formed complexes with hsp75 under two special physiological conditions: (i) during M phase, when the envelope that separates the nuclear and cytoplasmic compartments broke down, and (ii) after heat shock, when hsp75 moved from its normal cytoplasmic location into the nucleus. In vitro, hsp75 had a biochemical activity to refold denatured Rb into its native conformation. Taken together, these results suggest that Rb may be a physiological substrate for the hsp75 chaperone molecule. The discovery of a heat shock protein that chaperones Rb identifies a mechanism, in addition to phosphorylation, by which Rb is regulated in response to progression of the cell cycle and to external stimuli.


A novel strategy for solving the stochastic point location problem using a hierarchical searching scheme.
Stochastic point location (SPL) deals with the problem of a learning mechanism (LM) determining the optimal point on the line when the only input it receives are stochastic signals about the direction in which it should move. One can differentiate the SPL from the traditional class of optimization problems by the fact that the former considers the case where the directional information, for example, as inferred from an Oracle (which possibly computes the derivatives), suffices to achieve the optimization-without actually explicitly computing any derivatives. The SPL can be described in terms of a LM (algorithm) attempting to locate a point on a line. The LM interacts with a random environment which essentially informs it, possibly erroneously, if the unknown parameter is on the left or the right of a given point. Given a current estimate of the optimal solution, all the reported solutions to this problem effectively move along the line to yield updated estimates which are in the neighborhood of the current solution(1) This paper proposes a dramatically distinct strategy, namely, that of partitioning the line in a hierarchical tree-like manner, and of moving to relatively distant points, as characterized by those along the path of the tree. We are thus attempting to merge the rich fields of stochastic optimization and data structures. Indeed, as in the original discretized solution to the SPL, in one sense, our solution utilizes the concept of discretization and operates a uni-dimensional controlled random walk (RW) in the discretized space, to locate the unknown parameter. However, by moving to nonneighbor points in the space, our newly proposed hierarchical stochastic searching on the line (HSSL) solution performs such a controlled RW on the discretized space structured on a superimposed binary tree. We demonstrate that the HSSL solution is orders of magnitude faster than the original SPL solution proposed by Oommen. By a rigorous analysis, the HSSL is shown to be optimal if the effectiveness (or credibility) of the environment, given by p , is greater than the golden ratio conjugate. The solution has been both analytically solved and simulated, and the results obtained are extremely fascinating, as this is the first reported use of time reversibility in the analysis of stochastic learning. The learning automata extensions of the scheme are currently being investigated. As we shall see later, hierarchical solutions have been proposed in the field of LA.


Extraordinary Survival Benefits of Severe and Critical Patients with COVID-19 by Immune Modulators: The Outcome of a Clinical Trial in Bangladesh.
Coronavirus disease (COVID)-19 has devasted the healthcare delivery system as well as social establishments of almost all countries of the world. However, vaccines for containing new cases of COVID-19 are yet to be realized. Also, presently available antiviral drugs and other standard of care (SOC) management strategies could not satisfactorily control COVID-19-related mortality, which has crossed the one million mark during the last 9 months. These facts present an emergent need for developing new, novel, and evolving therapeutic strategies for the management of COVID-19. This cohort study represents a clinical trial in real-life situations in Bangladesh where two immune modulators were applied in patients with severe and critical COVID-19 patients. A total of 199 confirmed patients of COVID-19 were enrolled in this study. All of them had severe and critical COVID-19 and they were hospitalized at the intensive care unit (ICU) of the Combined Military Hospital (CMH), Dhaka, Bangladesh. All patients were positive for SARS-CoV-2 by polymerase chain reaction (PCR) of the nasal swab and they were endowed with severe pneumonia, multiple organ dysfunctions, and coagulopathy. The median percentage of lung involvement was 65%. The mean oxygen saturation was 83%. The patients received two immune modulators (tocilizumab and bevacizumab) in different combinations to retrieve broader insights about the safety and efficacy of immune modulators in COVID-19 management. Out of the total 199 patients, 122 survived and 77 expired. A single dose of tocilizumab resulted in the survival of 71.5% (73 of 102 COVID-19 patients). On the other hand, a dramatic survival benefit was found in patients receiving bevacizumab (92%). The study indicates that active treatment should be started as early as possible for COVID-19 patients as moderate COVID-patients may progress to more severe illnesses with grave consequences. The safety of two immune modulators has been recorded in this cohort of severe and critical COVID-19 patients. In order to have a proper use of these immune modulators, there is a need to accomplish controlled, blinded, and large-scale prospective studies with at least two arms. Islam MA, Mazumder MA, Akhter N, et al. Extraordinary Survival Benefits of Severe and Critical Patients with COVID-19 by Immune Modulators: The Outcome of a Clinical Trial in Bangladesh. Euroasian J Hepato-Gastroenterol 2020;10(2):68-75.


Visceral adiposity and incident coronary heart disease in Japanese-American men. The 10-year follow-up results of the Seattle Japanese-American Community Diabetes Study.
To identify risk factors for incident coronary heart disease (CHD). A total of 175 Japanese-American men without CHD were followed for up to 10 years. Baseline variables were blood pressure, weight, BMI, fat areas by computed tomography, skinfold thicknesses, abdominal circumference, plasma insulin, C-peptide, cholesterol, LDL cholesterol, HDL cholesterol, HDL2 cholesterol, and HDL3 cholesterol, triglycerides, apoproteins A1 and B, and diagnosis of diabetes and hypertension. CHD was diagnosed by electrocardiogram and clinical events. Logistic regression was used to estimate odds ratio. There were 50 incident cases of CHD. Using univariate logistic regression analysis, significant risk factors were intra-abdominal fat (P = 0.0090), fasting glucose (P = 0.0002), 2-h glucose (P = 0.0008), fasting HDL cholesterol (P = 0.0086), fasting HDL2 cholesterol (P = 0.030), fasting HDL3 cholesterol (P = 0.018), fasting triglycerides (P = 0.013), systolic (P = 0.0007) and diastolic blood pressure (P = 0.0002), and presence of diabetes (P = 0.0023). Multiple logistic regression models adjusted for BMI and age showed that intra-abdominal fat accounted for the effects of HDL cholesterol or triglycerides. In a multiple logistic regression model that included intra-abdominal fat, all systolic blood pressure and fasting glucose were significant. Substituting diastolic blood pressure for systolic blood pressure and 2-h glucose or diabetes status for fasting glucose produced similar results. Visceral adiposity, blood pressure, and plasma glucose are important independent risk factors for incident CHD in this population of diabetic and nondiabetic Japanese-American men.


Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial.
The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis. The INBUILD trial was a randomised, double-blind, placebo-controlled, parallel group trial done at 153 sites in 15 countries. Participants had an investigator-diagnosed fibrosing ILD other than IPF, with chest imaging features of fibrosis of more than 10% extent on high resolution CT (HRCT), forced vital capacity (FVC) of 45% or more predicted, and diffusing capacity of the lung for carbon monoxide (DLco) of at least 30% and less than 80% predicted. Participants fulfilled protocol-defined criteria for ILD progression in the 24 months before screening, despite management considered appropriate in clinical practice for the individual ILD. Participants were randomly assigned 1:1 by means of a pseudo-random number generator to receive nintedanib 150 mg twice daily or placebo for at least 52 weeks. Participants, investigators, and other personnel involved in the trial and analysis were masked to treatment assignment until after database lock. In this subgroup analysis, we assessed the rate of decline in FVC (mL/year) over 52 weeks in patients who received at least one dose of nintedanib or placebo in five prespecified subgroups based on the ILD diagnoses documented by the investigators: hypersensitivity pneumonitis, autoimmune ILDs, idiopathic non-specific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs. The trial has been completed and is registered with ClinicalTrials.gov, number NCT02999178. Participants were recruited between Feb 23, 2017, and April 27, 2018. Of 663 participants who received at least one dose of nintedanib or placebo, 173 (26%) had chronic hypersensitivity pneumonitis, 170 (26%) an autoimmune ILD, 125 (19%) idiopathic non-specific interstitial pneumonia, 114 (17%) unclassifiable idiopathic interstitial pneumonia, and 81 (12%) other ILDs. The effect of nintedanib versus placebo on reducing the rate of FVC decline (mL/year) was consistent across the five subgroups by ILD diagnosis in the overall population (hypersensitivity pneumonitis 73·1 [95% CI -8·6 to 154·8]; autoimmune ILDs 104·0 [21·1 to 186·9]; idiopathic non-specific interstitial pneumonia 141·6 [46·0 to 237·2]; unclassifiable idiopathic interstitial pneumonia 68·3 [-31·4 to 168·1]; and other ILDs 197·1 [77·6 to 316·7]; p=0·41 for treatment by subgroup by time interaction). Adverse events reported in the subgroups were consistent with those reported in the overall population. The INBUILD trial was not designed or powered to provide evidence for a benefit of nintedanib in specific diagnostic subgroups. However, its results suggest that nintedanib reduces the rate of ILD progression, as measured by FVC decline, in patients who have a chronic fibrosing ILD and progressive phenotype, irrespective of the underlying ILD diagnosis. Boehringer Ingelheim.


Metabolic bone disease in chronic renal failure. II. Renal transplant patients.
Trabecular vertebral bone of renal transplant patients was quantitatively compared with bone from normal individuals and dialyzed and nondialyzed patienets with chronic renal failure reported in detail in an earlier study. Long- and short-term transplant patients have increased bone resorption and mineralization defects similar to renal osteodystrophy in dialyzed and nondialyzed patients. However, in transplant patients the magnitude of resorption is greater, and bone volume tends to decrease rather than increase. Resorptive activity in transplant patients is maximal during the first year after transplantation. Bone volume decreases continuously for at least 96 months after transplantation. Only decreased bone volume correlated with success or failure of the renal transplant. Morphologic findings in this study correlate with other clinical and morphologic data to suggest that reduction in bone volume in transplant patients results from a combination of persistent hyperparathyroidism and suppression of bone formation by steroid therapy.


Dual peptide-dendrimer conjugate inhibits acetylation of transforming growth factor β-induced protein and improves survival in sepsis.
Sepsis is a potentially fatal complication of infections and there are currently no effective therapeutic options for severe sepsis. In this study, we revealed the secretion mechanism of transforming growth factor β-induced protein (TGFBIp) that was recently identified as a therapeutic target for sepsis, and designed TGFBIp acetylation inhibitory peptide (TAIP) that suppresses acetylation of lysine 676 in TGFBIp. To improve bioavailability and biodegradation of the peptide, TAIP was conjugated to polyamidoamine (PAMAM) dendrimers. Additionally, the cell-penetrating peptide (CPP) was conjugated to the TAIP-modified PAMAM dendrimers for the intracellular delivery of TGFBIp. The resulting nanostructures, decorated with TAIP and CPP via poly(ethylene glycol) linkage, improved the mortality and organ damage in the septic mouse model and suppressed lipopolysaccharide-activated severe vascular inflammatory responses in endothelial cells. Thus, the dendrimer-based nanostructures for delivery of TAIP using CPP show great promise in practical applications in sepsis therapy.


Impedance control balances stability with metabolically costly muscle activation.
Humans are able to stabilize their movements in environments with unstable dynamics by selectively modifying arm impedance independently of force and torque. We further investigated adaptation to unstable dynamics to determine whether the CNS maintains a constant overall level of stability as the instability of the environmental dynamics is varied. Subjects performed reaching movements in unstable force fields of varying strength, generated by a robotic manipulator. Although the force fields disrupted the initial movements, subjects were able to adapt to the novel dynamics and learned to produce straight trajectories. After adaptation, the endpoint stiffness of the arm was measured at the midpoint of the movement. The stiffness had been selectively modified in the direction of the instability. The stiffness in the stable direction was relatively unchanged from that measured during movements in a null force field prior to exposure to the unstable force field. This impedance modification was achieved without changes in force and torque. The overall stiffness of the arm and environment in the direction of instability was adapted to the force field strength such that it remained equivalent to that of the null force field. This suggests that the CNS attempts both to maintain a minimum level of stability and minimize energy expenditure.


Neuropsychological assessment of fitness to drive following acquired cognitive impairment.
The study evaluated a neuropsychological assessment battery used to assess fitness to drive in cognitively impaired individuals and hypothesized that the battery would be associated with on-road outcome measures. A secondary aim was to explore the relationships between individual neuropsychological tests and driving performance. The study used a cross-sectional design in which a sample of individuals with various types of cognitive impairment completed the test battery and an on-road driving test. Performance on the test battery was compared to on-road driving performance in 104 individuals with acquired cognitive impairment. The battery had 73% sensitivity and 76% specificity in terms of agreement with the 'pass/fail' classification of the on-road driving test. Scores on the battery accounted for 18% of the variance in the total number of corrective interventions performed by a driving instructor during the on-road test. Most tests correlated significantly with driving test outcomes. While one test, the Rey Complex Figure Test, emerged as an independent predictor of driving performance in multiple regression analyses, the variance explained by this single test was small. The results provide support for the use of a battery approach to assess fitness to drive.


A bidirectional relationship between physical activity and executive function in older adults.
Physically active lifestyles contribute to better executive function. However, it is unclear whether high levels of executive function lead people to be more active. This study uses a large sample and multi-wave data to identify whether a reciprocal association exists between physical activity and executive function. Participants were 4555 older adults tracked across four waves of the English Longitudinal Study of Aging. In each wave executive function was assessed using a verbal fluency test and a letter cancelation task and participants reported their physical activity levels. Fixed effects regressions showed that changes in executive function corresponded with changes in physical activity. In longitudinal multilevel models low levels of physical activity led to subsequent declines in executive function. Importantly, poor executive function predicted reductions in physical activity over time. This association was found to be over 50% larger in magnitude than the contribution of physical activity to changes in executive function. This is the first study to identify evidence for a robust bidirectional link between executive function and physical activity in a large sample of older adults tracked over time.


Bayesian Data Selection.
Insights into complex, high-dimensional data can be obtained by discovering features of the data that match or do not match a model of interest. To formalize this task, we introduce the "data selection" problem: finding a lower-dimensional statistic-such as a subset of variables-that is well fit by a given parametric model of interest. A fully Bayesian approach to data selection would be to parametrically model the value of the statistic, nonparametrically model the remaining "background" components of the data, and perform standard Bayesian model selection for the choice of statistic. However, fitting a nonparametric model to high-dimensional data tends to be highly inefficient, statistically and computationally. We propose a novel score for performing data selection, the "Stein volume criterion (SVC)", that does not require fitting a nonparametric model. The SVC takes the form of a generalized marginal likelihood with a kernelized Stein discrepancy in place of the Kullback-Leibler divergence. We prove that the SVC is consistent for data selection, and establish consistency and asymptotic normality of the corresponding generalized posterior on parameters. We apply the SVC to the analysis of single-cell RNA sequencing data sets using probabilistic principal components analysis and a spin glass model of gene regulation.


Ty1 defect in proteolysis at high temperature.
Retrotransposition of the Ty1 element of Saccharomyces cerevisiae is temperature sensitive. Transposition activity of Ty1 is abolished at temperatures above 34 degrees C. In this report, we show that the major block to transposition at high temperature is the inhibition of processing of the Gag-Pol-p199 polyprotein and the concomitant reduction of reverse transcriptase (RT) activity. Expression of a Ty1 protease construct in Escherichia coli shows that protease enzymatic activity is inherently temperature sensitive. In yeast, Gag processing is only partially inhibited at high temperature, while cleavage of the Gag-Pol polyprotein is completely inhibited. Sites of proteolytic processing are differentially susceptible to cleavage during growth at high temperature. Overall levels of the Gag-Pol polyprotein are reduced at high temperature, although the efficiency of the requisite +1 frameshifting event appears to be increased. RT activity is inherently relatively temperature resistant, yet no cDNA is made at high temperature and the amount of RT activity is greatly reduced in virus-like particles formed at high temperature. Taken together, these results suggest that alterations in Ty1 proteins that occur at high temperature affect both protease activity and RT activity, such that Ty1 transposition is abolished.


Silicon-on-insulator spectrometers with integrated GaInAsSb photodiodes for wide-band spectroscopy from 1510 to 2300 nm.
We present a silicon-on-insulator (SOI) based spectrometer platform for a wide operational wavelength range. Both planar concave grating (PCG, also known as echelle grating) and arrayed waveguide grating (AWG) spectrometer designs are explored for operation in the short-wave infrared. In addition, a total of four planar concave gratings are designed to cover parts of the wavelength range from 1510 to 2300 nm. These passive wavelength demultiplexers are combined with GaInAsSb photodiodes. These photodiodes are heterogeneously integrated on SOI with benzocyclobutene (DVS-BCB) as an adhesive bonding layer. The uniformity of the photodiode characteristics and high processing yield, indicate a robust fabrication process. We demonstrate good performance of the miniature spectrometers over all operational wavelengths which paves the way to on-chip absorption spectroscopy in this wavelength range.


Are cadmium and other heavy metal compounds acting as endocrine disrupters?
Observations of specific interactions of the heavy metal cadmium with the estrogen receptor have spawned a series of studies to investigate the propensity of this and other heavy metals to act as estrogen mimicks. There is good evidence that Cd has the ability to produce estrogenic effects in rodents, including proliferation of the uterine and mammary tissues. These effects could be suppressed by cotreatment with specific estrogen receptor antagonists, suggesting mediation via the estrogen receptor. Epidemiological studies have provided some support for the idea that Cd poses cancer risks for hormone sensitive tissues, such as the breast and the endometrium. Strikingly, attempts to demonstrate estrogenic effects of Cd in in vitro assay systems have produced mixed results. Mitogenic effects on estrogen receptor-competent cells, activation of estrogen receptor-dependent gene transcription and signalling events associated with the estrogen receptor were observed in cellular models, but could not be reproduced by others. Despite these inconsistencies, the available evidence forces the conclusion that Cd and certain other heavy metals should be regarded as estrogen mimicks. In the context of deterministic risk assessment, this should lend further support for risk reduction measures by controlling exposure to Cd. However, data suitable for the quantitation of estrogenic risks, especially in comparison with the established health risks of Cd, are not yet available. It is recommended to close this knowledge gap with urgency.


Sedative activity of cannabis in relation to its delta'-trans-tetrahydrocannabinol and cannabidiol content.
1. The oral sedative potencies of cannabis herb, crude ethanolic and petroleum-ether fractions, were assayed against delta'-trans-tetrahydrocannabinol (THC) administered orally to mice, by measuring spontaneous motor activity over 30 min periods, at selected times, up to 6 h. 2. The THC contents of the extracts were determined chemically by gas-liquid chromatography analysis and the B/C ratio (biological activity divided by chemical activity) calculated for each. The B/C values for cannabis herb, which contained THC but no CBD, was 4.47 and for ethanolic and petroleum-ether extracts, 5.26 and 4.39, respectively. 3. The sedative potency expressed as SDA50, the dose required to give 50% effect over 6 h, was 1.06 (0.98 to 1.15) mg/kg for THC; 4.72 (4.22 to 5.27) mg/kg for cannabidiol and 1.26 (1.22 to 1.80) mg/kg for chlorpromazine. 4. An infusion of cannabis herb made with boiling water was shown to have sedative activity of very low potency. 5. When the cannabinoids were completely extracted from a sample of herb with petroleum-ether the aqueous and ethanolic extracts of the marc had some sedative activity; but the 70% ethanolic fraction had none. 6. The sedative activity of THC, cannabis herb and a water soluble fraction is blocked by aspirin, a cyclo-oxygenase inhibitor, and restored by prostaglandin E2 (PGE2). 7. The sedative effect of chlorpromazine is not blocked by aspirin.


Effects of single-dose dexmedetomidine on the quality of recovery after modified radical mastectomy: a randomised controlled trial.
Dexmedetomidine is a highly selective α2 agonist with analgesic, anxiolytic, and anti-inflammatory properties. We investigated the effect of a single dose of dexmedetomidine on patient-perceived quality of recovery and clinical recovery variables after modified radical mastectomy under general anesthesia in this randomized, double-blind, placebo-controlled study. After Institutional Review Board approval, ninety two female patients were randomly allocated to receive intravenously either saline (Group C, N.=46) or 0.5 μg/kg of dexmedetomidine (Group D, N.=46) five min before the end of surgery. The quality of recovery was assessed using a 40-item quality-of-recovery scoring system (QoR-40) preoperatively and 24 h after surgery. Pain intensity, rescue analgesics, and postoperative nausea and vomiting (PONV) were assessed at postanesthesia care unit (PACU), 1-6 h, and 6-24 h after surgery. Postoperative global QoR-40 scores were higher in Group D compared with Group C (181 [175-187] vs. 174 [154.5-181.5], P=0.004); postoperative QoR-40 scores were improved in the dimensions of emotional state, physical comfort, and psychological support. Total amount of tramadol during 24 h after surgery was significantly lower in Group D than in Group C (54 vs. 76 mg, P=0.006). The incidence of PONV was lower in Group D than in Group C in PACU (21% vs. 43%, P=0.026) and 6-24 h period after surgery (10% vs. 41%, P=0.012). Heart rate and mean blood pressure were significantly lower in Group D as compared with Group C at 5 min after administration of dexmedetomidine, 1 min after extubation, and 20 min after arrival in PACU. The use of a single dose dexmedetomidine improved the quality of recovery and reduced analgesic requirements and the incidence of PONV in the early postoperative period after modified radical mastectomy.


A high hypospadias rate in The Netherlands.
Reports on increasing hypospadias trends are based on birth defect registries, which are prone to inaccuracy. We assessed the prevalence of hypospadias precisely, by prospective examination of all newborns in Rotterdam over a 2-year period. A total of 7292 consecutive male births were examined for the presence of hypospadias, classified by severity. The frequency of hypospadias in newborn boys was 0.73% (53/7292). The rate among live births was 38 per 10 000, which is 6 times the previously reported rate for the Southwestern Netherlands (6.2) (P < 0.0001). This registry excludes glandular hypospadias. Without glandular cases, our rate is 26 per 10 000, which is still 4-fold higher (P < 0.0001). The ratio of minor to major hypospadias was 0.3. In 79% of cases, surgery was indicated. We found a 4-fold higher than expected hypospadias rate, which may be explained by case ascertainment differences. The proportion of major cases was higher than generally assumed. This study provides evidence for substantial geographical differences. Explanations for temporal and geographical differences need to be explored. To monitor hypospadias rates and trends accurately, complete case ascertainment, including standardized classification of severity, is warranted.


Elucidation of AMPA receptor-stargazin complexes by cryo-electron microscopy.
AMPA-subtype ionotropic glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and contribute to high cognitive processes such as learning and memory. In the brain, AMPAR trafficking, gating, and pharmacology is tightly controlled by transmembrane AMPAR regulatory proteins (TARPs). Here, we used cryo-electron microscopy to elucidate the structural basis of AMPAR regulation by one of these auxiliary proteins, TARP γ2, or stargazin (STZ). Our structures illuminate the variable interaction stoichiometry of the AMPAR-TARP complex, with one or two TARP molecules binding one tetrameric AMPAR. Analysis of the AMPAR-STZ binding interfaces suggests that electrostatic interactions between the extracellular domains of AMPAR and STZ play an important role in modulating AMPAR function through contact surfaces that are conserved across AMPARs and TARPs. We propose a model explaining how TARPs stabilize the activated state of AMPARs and how the interactions between AMPARs and their auxiliary proteins control fast excitatory synaptic transmission.


Automated localization of retinal features.
Retinal fundus images are widely used in the diagnosis and treatment of various eye diseases, such as diabetic retinopathy and glaucoma. A computer-aided retinal fundus image analysis could provide an immediate detection and characterization of retinal features prior to specialist inspection. This paper proposes an approach to automatically localize the main features in fundus images, such as blood vessels, optic disc, and fovea by exploiting the spatial and geometric relations that govern their distribution within the fundus image. The blood vessels are segmented by scale-space analysis. The average thickness of these blood vessels is then computed using the vessels centerlines and orientations from a Hessian matrix. The optic disc is localized using the circular Hough transform, the parabolic Hough transform fitting, and the localization of the fovea. The proposed method can be extended to establish a foveal coordinate system to facilitate grading lesions based on the spatial relationships between lesions and landmark features. The proposed method was evaluated on publicly available image databases, and the results have demonstrated a significant improvement over the current state-of-the-art methods.


Targeting of leukemia-initiating cells in acute promyelocytic leukemia.
Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) with peculiar molecular, phenotypic and clinical features and unique therapeutic response to specific treatments. The disease is characterized by a single, pathognomonic molecular event, consisting of the translocation t(15;17) which gives rise to the PML/retinoic acid receptor α (RARα) hybrid protein. The development of this leukemia is mainly related to the fusion oncoprotein PML/RARα, acting as an altered RAR mediating abnormal signalling and repression of myeloid differentiation, with consequent accumulation of undifferentiated promyelocytes. The prognosis of APL has dramatically been improved with the introduction in therapy of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). The main effect of these two drugs is linked to the targeting of either RAR moiety of the PML/RARα molecule and induction of cell differentiation (ATRA) or of the PML moiety of the fusion protein and induction of leukemic cell apoptosis, including leukemic progenitors (mostly induced by ATO). These two drugs exhibited excellent synergism and determine a very high rate of durable remissions in low/intermediate-risk APLs, when administered in the absence of any chemotherapeutic drug. The strong synergism and the marked clinical efficacy of these two agents when administered together seem to be related to their capacity to induce PML/RARα degradation and complete eradication of leukemia stem cells.


A comparison of community and physician explanatory models of AIDS in Mexico and the United States.
The goal of this research was to explore differences between lay and professional explanatory models both within and between two countries. We test which effect is stronger, country of residence or professional/lay status, in determining similarities and differences of explanatory models of AIDS. Interviews conducted in Guadalajara, Jalisco (Mexico) and the Edinburg-McAllen area of south Texas (United States) elicited explanatory models of AIDS. Two pairs of samples were interviewed: a physician and community sample in Mexico and a physician and community sample in the United States. Comparisons of the explanatory models indicated that there was a shared core model of AIDS across all four samples, but that physicians' models were more similar to those of lay people in their own communities than either was to samples across the border.


Dietary macronutrients and food consumption as determinants of long-term weight change in adult populations: a systematic literature review.
This systematic literature review examined the role of dietary macronutrient composition, food consumption and dietary patterns in predicting weight or waist circumference (WC) change, with and without prior weight reduction. The literature search covered year 2000 and onwards. Prospective cohort studies, case-control studies and interventions were included. The studies had adult (18-70 y), mostly Caucasian participants. Out of a total of 1,517 abstracts, 119 full papers were identified as potentially relevant. After a careful scrutiny, 50 papers were quality graded as A (highest), B or C. Forty-three papers with grading A or B were included in evidence grading, which was done separately for all exposure-outcome combinations. The grade of evidence was classified as convincing, probable, suggestive or no conclusion. We found probable evidence for high intake of dietary fibre and nuts predicting less weight gain, and for high intake of meat in predicting more weight gain. Suggestive evidence was found for a protective role against increasing weight from whole grains, cereal fibre, high-fat dairy products and high scores in an index describing a prudent dietary pattern. Likewise, there was suggestive evidence for both fibre and fruit intake in protection against larger increases in WC. Also suggestive evidence was found for high intake of refined grains, and sweets and desserts in predicting more weight gain, and for refined (white) bread and high energy density in predicting larger increases in WC. The results suggested that the proportion of macronutrients in the diet was not important in predicting changes in weight or WC. In contrast, plenty of fibre-rich foods and dairy products, and less refined grains, meat and sugar-rich foods and drinks were associated with less weight gain in prospective cohort studies. The results on the role of dietary macronutrient composition in prevention of weight regain (after prior weight loss) were inconclusive.


[Results and complications of bicanalicular intubation in external dacryocystorhinostomy].
To analyze the success rate and complications in patients with lacrimal obstruction submitted to surgeries. The data of patients operated in the "Hospital do Servidor Público Estadual of São Paulo" were analyzed. The lacrimal intubation was performed with a silicone tube, removed after 8 weeks. Surgeries were considered successful in those cases where patients had no postoperative epiphora or ocular secretion, and with a good passage of fluid to the nose or oropharynx. The complications related to the silicone tube were grouped in a table. The patients were operated from April 2002 to July 2006 with an average follow-up period of three months. In a total of 65 eyes, success was obtained in 89.2% of the cases. Seven patients presented postoperative epiphora, and 5 of them were reoperated. In 7 eyes there was an extrusion of the silicone in less than 15 days from surgery, and in this group one patient needed a reoperation. Six eyes presented complications with the silicone: tube prolapse (4 cases), granuloma formation in the nasal cavity (1 case) and lacrimal puncta adhesion (1 case). This group of patients presented a high success rate with Ex-DCR surgery associated with lacrimal intubation. The intraoperative intubation with silicone tube is not free of complications.


Cell competition, apoptosis and tumour development.
The phenomenon of cell competition is an interactive process originally discovered in the imaginal discs of Drosophila; it is a developmental mechanism that identifies and eliminates cells that are weaker than their neighbours or have features that make them different or not well adapted to their surroundings. It appears to be an important homeostatic mechanism to contribute to the general fitness of developing tissues. Here we discuss some of the basic features of cell competition and then focus on results indicating that cell competition is responsible for the removal of malignant or aberrant cells that may appear during development, although in certain circumstances it can revert its role to promote tumour growth. We also consider several recent studies that indicate that cell competition also occurs in vertebrates where it performs similar functions.


Development of an intervention to improve mental health for obstetric fistula patients in Tanzania.
Obstetric fistula is a debilitating childbirth injury that has been associated with high rates of psychological distress. Global efforts have helped to link women to surgical repair, but thus far no evidence-based interventions exist to address the psychological needs of these women during the hospital stay. In this paper, we describe the development of a psychological intervention for women in Tanzania who are receiving surgical care for an obstetric fistula. The intervention was developed based on theories of cognitive behavioral therapy and coping models. Content and delivery were informed by qualitative data collection with a range of stakeholders including women with fistula, and input from a study advisory board. The resulting intervention was six individual sessions, delivered by a trained community health nurse. The session topics were (1) recounting the fistula story; (2) creating a new story about the fistula; (3) loss, grief and shame; (4) specific strategies for coping; (5) social relationships; and (6) planning for the future. A trial run of the intervention revealed that the intervention could be delivered with fidelity and was acceptable to patients. A future randomized control trial will evaluate the efficacy of this intervention to address the mental health symptoms of this population.


Symptomatic males and female carriers in a large Caucasian kindred with XIAP deficiency.
X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was originally described in male patients with X-linked lymphoproliferative syndrome type 2 (XLP2). Recent observations have highlighted a critical role of XIAP for the regulation of NOD2 signaling and are probably the molecular basis for increasingly recognized further immune dysregulatory symptoms of XIAP deficient patients, such as inflammatory bowel disease (IBD). We describe a large Caucasian family in which IBD and erythema nodosum (EN) also manifested in female carriers of XIAP mutations. Clinical data and laboratory findings including flow cytometric analysis of XIAP protein expression and sequencing of the BIRC4 gene. NOD2 signaling was investigated by determination of TNFα production in monocytes upon L18-MDP stimulation in vitro. The BIRC4 nonsense mutation p.P225SfsX226 was identified as the genetic cause of XIAP deficiency in our family. Surprisingly, clinical symptoms were not restricted to male patients, but also occurred in several female carriers. The most severely affected carrier demonstrated random X-inactivation, leading to a significant expression of mutated XIAP protein in monocytes, and consequently to impaired NOD2 responses in vitro. Our report provides further evidence that clinical symptoms of XIAP deficiency are not restricted to male patients. Random X-inactivation may be associated with EN and mild IBD also in female carriers of BIRC4 mutations. Analysis of the X-inactivation pattern reflected by XIAP protein expression can identify such carriers and the analysis of NOD2 signaling by flow cytometry can confirm the functional significance. XIAP expression patterns should be investigated in female patients with a family history of EN and/or IBD.


Profiling the genome-wide landscape of tandem repeat expansions.
Tandem repeat (TR) expansions have been implicated in dozens of genetic diseases, including Huntington's Disease, Fragile X Syndrome, and hereditary ataxias. Furthermore, TRs have recently been implicated in a range of complex traits, including gene expression and cancer risk. While the human genome harbors hundreds of thousands of TRs, analysis of TR expansions has been mainly limited to known pathogenic loci. A major challenge is that expanded repeats are beyond the read length of most next-generation sequencing (NGS) datasets and are not profiled by existing genome-wide tools. We present GangSTR, a novel algorithm for genome-wide genotyping of both short and expanded TRs. GangSTR extracts information from paired-end reads into a unified model to estimate maximum likelihood TR lengths. We validate GangSTR on real and simulated data and show that GangSTR outperforms alternative methods in both accuracy and speed. We apply GangSTR to a deeply sequenced trio to profile the landscape of TR expansions in a healthy family and validate novel expansions using orthogonal technologies. Our analysis reveals that healthy individuals harbor dozens of long TR alleles not captured by current genome-wide methods. GangSTR will likely enable discovery of novel disease-associated variants not currently accessible from NGS.


The geographic mosaic of sex and the Red Queen.
The maintenance of sexual reproduction in natural populations is a pressing question for evolutionary biologists. Under the "Red Queen" hypothesis, coevolving parasites reduce the reproductive advantage of asexual reproduction by adapting to infect clonal genotypes after they become locally common. In addition, the "geographic mosaic" theory of coevolution proposes that structured populations of interacting species can produce selection mosaics manifested as coevolutionary "hot spots" and "cold spots". Here, we tested whether a steep, habitat-specific cline in the frequency of sexual reproduction in a freshwater snail could be explained by the existence of hot spots and cold spots for coevolving parasites. We found that the shallow-water margins of lakes, where sexual reproduction is most common, are coevolutionary hot spots, and that deeper habitats are cold spots. These results are consistent with the geographic mosaic theory, in that the intensity of selection resulting from biological interactions can vary sharply in space. The results also support the Red Queen hypothesis, in that sex is associated with coevolutionary hot spots for virulent parasites.


[Treatment of intra-articular malunion of the distal radius of young active patients].
Management of malunion of the distal radius remains difficult. Planning of the correction of the articular displacement requires a comprehensive analysis by CT arthrography to analyze bone, cartilage and ligaments. Arthroscopy is a valuable tool in the context of joint trauma. In the absence of osteoarthritis, the correction can be carried out as early as possible in the weeks or months following the initial fracture. The use of locking plates allows early mobilization after surgery. This correction aims to prevent the development of secondary osteoarthritis.


Tailoring capture-recapture methods to estimate registry-based case counts based on error-prone diagnostic signals.
Surveillance research is of great importance for effective and efficient epidemiological monitoring of case counts and disease prevalence. Taking specific motivation from ongoing efforts to identify recurrent cases based on the Georgia Cancer Registry, we extend recently proposed "anchor stream" sampling design and estimation methodology. Our approach offers a more efficient and defensible alternative to traditional capture-recapture (CRC) methods by leveraging a relatively small random sample of participants whose recurrence status is obtained through a principled application of medical records abstraction. This sample is combined with one or more existing signaling data streams, which may yield data based on arbitrarily non-representative subsets of the full registry population. The key extension developed here accounts for the common problem of false positive or negative diagnostic signals from the existing data stream(s). In particular, we show that the design only requires documentation of positive signals in these non-anchor surveillance streams, and permits valid estimation of the true case count based on an estimable positive predictive value (PPV) parameter. We borrow ideas from the multiple imputation paradigm to provide accompanying standard errors, and develop an adapted Bayesian credible interval approach that yields favorable frequentist coverage properties. We demonstrate the benefits of the proposed methods through simulation studies, and provide a data example targeting estimation of the breast cancer recurrence case count among Metro Atlanta area patients from the Georgia Cancer Registry-based Cancer Recurrence Information and Surveillance Program (CRISP) database.


Epigenetic synergism between interleukin-4 and aryl-hydrocarbon receptor in human macrophages.
The aryl hydrocarbon receptor (AhR)-ligand axis is involved in immune regulation, but its molecular basis remains to be fully elucidated. Chemokine (C-C motif) ligand 1 (CCL1) is an important chemoattractant, but how CCL1 is regulated remains to be defined. The role of AhR in regulating CCL1 expression in two major subsets of macrophage was investigated. We used a human THP-1 cell line, monocytes, and mouse peritoneal macrophages to generate M(IFN-γ/LPS) and M(IL-4) subsets, and the AhR's ligand effect was determined by the use of a combination of chromatin immunoprecipitation, PCR, and ELISA. Upon exposure to a classical AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), selective induction of CCL1 was noted only in M(IL-4), not M(IFN-γ/LPS) cells in human but not murine macrophages. This selectivity was mediated by AhR's binding to the distal dioxin-responsive element (DRE) in the CCL1 promoter of the M(IL-4) subset, and a deletion mutant lacking the distal DRE sequence lost its activity. In contrast to the M(IFN-γ/LPS) cells, the distal DRE was devoid of tri-methylated histone 3 lysine 27 (H3K27) in M(IL-4) cells, and the addition of a H3K27 demethylase inhibitor blocked AhR-mediated CCL1 expression. Similar selectivity of CCL1 expression was also noted in monocyte-derived M(IL-4) subsets, and the level of AhR binding to distal DRE in monocytes was correlated with the levels of plasma interleukin-4 (IL-4) in 23 human subjects. These findings suggested the existence of a new regulatory epigenetic-based mechanism, wherein AhR in concert with IL-4 differentially regulated human, not murine, macrophage CCL1 response. Human CCL1 gene is selectively targeted by AhR in M(IL-4) macrophage. IL-4-induced epigenetic modification potentiates AhR-mediated CCL1 expression. This epigenetic control of CCL1 expression is not operative in murine macrophages.


ReadDB provides efficient storage for mapped short reads.
The advent of high-throughput sequencing has enabled sequencing based measurements of cellular function, with an individual measurement potentially consisting of more than 108 reads. While tools are available for aligning sets of reads to genomes and interpreting the results, fewer tools have been developed to address the storage and retrieval requirements of large collections of aligned datasets. We present ReadDB, a network accessible column store database system for aligned high-throughput read datasets. ReadDB stores collections of aligned read positions and provides a client interface to support visualization and analysis. ReadDB is implemented as a network server that responds to queries on genomic intervals in an experiment with either the set of contained reads or a histogram based interval summary. Tests on datasets ranging from 105 to 108 reads demonstrate that ReadDB performance is generally within a factor of two of local-storage based methods and often three to five times better than other network-based methods. ReadDB is a high-performance foundation for ChIP-Seq and RNA-Seq analysis. The client-server model provides convenient access to compute cluster nodes or desktop visualization software without requiring a shared network filesystem or large amounts of local storage. The client code provides a simple interface for fast data access to visualization or analysis. ReadDB provides a new way to store genome-aligned reads for use in applications where read sequence and alignment mismatches are not needed.


Anti-infective locks for treatment of central line-associated bloodstream infection: a systematic review and meta-analysis.
Central line-associated bloodstream infections (CLABSI) are associated with considerable morbidity, mortality and economic costs. In most cases, catheter removal is considered an essential component of managing CLABSI. However, in patients with poor access, catheter salvage may have to be attempted rather than removal and replacement of catheters. Anti-infective lock therapy (ALT) - instilling an antibiotic or antiseptic into the catheter lumen - is a novel way of treating CLABSI while attempting to salvage the catheter. However, data on the efficacy of ALT for catheter salvage is limited. In this systematic review, we critically review the evidence regarding the use of ALT for catheter salvage. We identified 8 studies including a total of 396 patients that compared ALT with systemic antibiotic therapy alone or an alternate method of catheter salvage (guidewire replacement). We found that the combination of systemic antibiotics and culture-guided lock therapy was superior to systemic antibiotics alone (OR: 0.20, 95% CI: 0.10-0.39), with 10% of locked patients requiring replacement compared to 33% of subjects without locks. There was a 20% relapse rate in the ALT group and a 30% relapse rate in the control group (OR: 0.43, 95% CI: 0.18-1.03). There was insufficient data on catheter exchange over a wire compared with ALT to permit conclusions. Our data support the use of ALT in conjunction with systemic antibiotics for catheter salvage. Large randomized controlled trials of ALT examining dose, dwell times and relapse rates stratified by infecting pathogen are needed.


Smad3 Signaling Promotes Fibrosis While Preserving Cardiac and Aortic Geometry in Obese Diabetic Mice.
Heart failure in diabetics is associated with cardiac hypertrophy, fibrosis and diastolic dysfunction. Activation of transforming growth factor-β/Smad3 signaling in the diabetic myocardium may mediate fibrosis and diastolic heart failure, while preserving matrix homeostasis. We hypothesized that Smad3 may play a key role in the pathogenesis of cardiovascular remodeling associated with diabetes mellitus and obesity. We generated leptin-resistant db/db Smad3 null mice and db/db Smad3+/- animals. Smad3 haploinsufficiency did not affect metabolic function in db/db mice, but protected from myocardial diastolic dysfunction, while causing left ventricular chamber dilation. Improved cardiac compliance and chamber dilation in db/db Smad3+/- animals were associated with decreased cardiomyocyte hypertrophy, reduced collagen deposition, and accentuated matrix metalloproteinase activity. Attenuation of hypertrophy and fibrosis in db/db Smad3+/- hearts was associated with reduced myocardial oxidative and nitrosative stress. db/db Smad3 null mice had reduced weight gain and decreased adiposity associated with attenuated insulin resistance, but also exhibited high early mortality, in part, because of spontaneous rupture of the ascending aorta. Ultrasound studies showed that both lean and obese Smad3 null animals had significant aortic dilation. Aortic dilation in db/db Smad3 null mice occurred despite reduced hypertension and was associated with perturbed matrix balance in the vascular wall. Smad3 mediates diabetic cardiac hypertrophy, fibrosis, and diastolic dysfunction, while preserving normal cardiac geometry and maintaining the integrity of the vascular wall.


Global regulation of gene expression in Escherichia coli.
Global transcription responses of Escherichia coli to various stimuli or genetic defects were studied by measuring mRNA levels in about 400 segments of the genome. Measuring mRNA levels was done by analyzing hybridization to DNA dot blots made with overlapping lambda clones spanning the genome of E. coli K-12. Conditions examined included isopropyl-beta-D-thiogalactopyranoside (IPTG) induction, heat shock, osmotic shock, starvation for various nutrients, entrance of cells into the stationary phase of growth, anaerobic growth in a tube, growth in the gnotobiotic mouse gut, and effects of pleiotropic mutations rpoH, himA, topA, and crp. Most mapped genes known to be regulated by a particular situation were successfully detected. In addition, many chromosomal regions containing no previously known regulated genes were discovered that responded to various stimuli. This new method for studying globally regulated genetic systems in E. coli combines detection, cloning, and physical mapping of a battery of coregulated genes in one step.


Return to Sport after Injury: A Web-Based Survey of Owners and Handlers of Agility Dogs.
Internet-based surveys of canine agility injury rates have been performed, but unlike with equine and human competition, there is a paucity of data on return to sport of agility dogs after orthopaedic injury. This study aimed to gather initial information on canine return to competition. Data were collected using an internet-based 18-question survey of 427 dogs from around the world (92.4% North America). Relationships between categorical variables and return to sport were assessed with descriptive statistics, a chi-squared or Fischer's exact test. Categorical variables included breed, sex, age, surgery, stifle versus shoulder surgery, stifle versus all other types of surgery and drop in competition class. Significance was set at p≤ 0.05. Of 427 completed surveys, age, sex and breed were not significantly associated with return to competition. Overall, 67.4% of dogs returned to competition post-orthopaedic injury, but jump height was lowered in 47% of cases. Dogs were returned to competition post-stifle surgery, but were the least likely of all injury types to return to competition (p = 0.044) and were more likely to compete at a lower class (p = 0.026). While over half of all dogs returned to competition, just under half of that group decreased jump class. Dogs that have undergone stifle surgery have the worst prognosis for return to agility and if they return, they are more likely to drop class.


Met 358 to Arg mutation of alpha 1-antitrypsin associated with protein C deficiency in a patient with mild bleeding tendency.
The molecular defect responsible for a dramatic prolongation of all standard clotting tests discovered in a 15-yr-old boy has been identified. Initial investigations revealed the presence of an activated Factor X (Factor Xa) and thrombin inhibitor which copurified with alpha 1-antitrypsin (alpha 1-AT), thereby suggesting the occurrence of an alpha 1-AT variant similar to alpha 1-AT Pittsburgh. This was confirmed by dot-blot analysis and direct sequencing after amplification by the polymerase chain reaction. A G to T transition at nucleotide 10038 results in the substitution of Met to an Arg, converting alpha 1-AT into an Arg-Ser protease inhibitor (serpin) that inhibited thrombin and Factor Xa more effectively than antithrombin III. Surprisingly, there was no bleeding history in the proband. The common mutation Z, which may explain a reduced expression of the allele bearing the Arg 358 Met mutation, was not observed in the propositus' DNA. To exclude the presence of another mutation, the coding regions and intron/exon junctions were sequenced. No other mutation was found. Recently, the patient experienced his first hemorrhagic episode at the age of 17. The level of the abnormal inhibitor had increased twofold 2 mo before. The large decrease in protein C concentration may account for the mild bleeding tendency in this case, despite the presence of the alpha 1-AT Pittsburgh mutation. An abnormal protein C pattern was observed in patient's plasma, suggesting that the circulating deficiency might be due to a deleterious effect of the abnormal inhibitor on both intracellular processing and catabolism of protein C.


CURRENT CONCEPTS OF MUSCLE AND TENDON ADAPTATION TO STRENGTH AND CONDITIONING.
Injuries to the muscle and/or associated tendon(s) are common clinical entities treated by sports physical therapists and other rehabilitation professionals. Therapeutic exercise is a primary treatment modality for muscle and/or tendon injuries; however, the therapeutic exercise strategies should not be applied in a "one-size-fits-all approach". To optimize an athlete's rehabilitation or performance, one must be able to construct resistance training programs accounting for the type of injury, the stage of healing, the functional and architectural requirements for the muscle and tendon, and the long-term goals for that patient. The purpose of this clinical commentary is to review the muscular and tendinous adaptations associated with strength training, link training adaptations and resistance training principles for the athlete recovering from an injury, and illustrate the application of evidence-based resistance training for patients with a tendinopathy. 5.


Crude phenolic extracts from extra virgin olive oil circumvent de novo breast cancer resistance to HER1/HER2-targeting drugs by inducing GADD45-sensed cellular stress, G2/M arrest and hyperacetylation of Histone H3.
Characterization of the molecular function of complex phenols naturally present in extra virgin olive oil (EVOO) against the HER2-gene amplified JIMT-1 cell line, a unique breast cancer model that inherently exhibits cross-resistance to multiple HER1/2-targeted drugs including trastuzumab, gefitinib, erlotinib and lapatinib, may underscore innovative cancer molecules with novel therapeutic targets because they should efficiently circumvent de novo resistance to HER1/2 inhibitors in order to elicit tumoricidal effects. We identified pivotal signaling pathways associated with the efficacy of crude phenolic extracts (PEs) obtained from 14 monovarietals of Spanish EVOOs. i) MTT-based cell viability and HPLC coupled to time-of-flight (TOF) mass spectrometry assays revealed that anti-cancer activity of EVOO PEs positively correlated with the phenolic index (i.e., total content of phenolics) and with a higher presence of the complex polyphenols secoiridoids instead of lignans. ii) Genome-wide analyses using 44 K Agilent's whole human arrays followed by Gene Set Enrichment Analysis (GSEA)-based screening of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database revealed a differential modulation of the JIMT-1 transcriptome at the level of the cell cycle and p53 pathways. EVOO PEs differentially impacted the expression status of stress-sensing, G2-M check-point-related GADD45 genes and of p53-related CDKN1A, CDKN1C and PMAIP-1 genes. iii) Cell cycle and fluorescence microscopy analyses confirmed that secoiridoid-rich EVOO PE inhibited mitosis to promote G2-M cell cycle arrest. This was accompanied with the appearance of diffuse, even DNA staining with γH2AX and pan-nuclear hyperacetylation of Histone H3 at Lysine 18. iv) Semi-quantitative Signaling Node Multi-Target ELISAs determined that secoiridoid-rich EVOO PE drastically activated the mitogen-activated protein kinases MEK1 and p38 MAPK, a GADD45-related kinase involved in Histone H3 acetylation. Secoiridoids, a family of complex polyphenols characteristic of Oleaceae plants, appear to permit histones to remain in hyperacetylated states and through the resulting alterations in gene regulation to reduce mitotic viability and metabolic competence of breast cancer cells inherently refractory to HER-targeting therapies ab initio. Oleaceae secoiridoids could provide a valuable phytochemical platform for the design of more pharmacologically active second-generation phytopharmaceutical anti-breast cancer molecules with a unique mode of action.


Optical authentication method using a three-dimensional phase object with various wavelength readouts.
An optical system for authentication using a 3D (3D) random phase object with various wavelength readouts is proposed. The 3D phase object without surface modulation is secure when the scattering is strong enough because it prevents from the interferometric measurement. The identification is implemented by the correlation between a measured speckle pattern of the 3D phase object and stored speckle patterns. For accurate identification, two speckle patterns of the 3D object obtained by illuminating two wavelengths are used. Experimental demonstrations and numerical evaluations of wavelength selectivity are presented.


Low free testosterone is an independent risk factor for Alzheimer's disease.
The purpose of this study was to assess pituitary gonadotropins and free testosterone levels in a larger cohort of men with Alzheimer's disease (AD, n=112) and age-matched controls (n=98) from the Oxford Project to Investigate Memory and Ageing (OPTIMA). We measured gonadotropins (follicle stimulating hormone, FSH, and luteinizing hormone, LH), sex hormone binding globulin (SHBG, which determines the amount of free testosterone) and total testosterone (TT) using enzyme immunoassays. AD cases had significantly higher LH and FSH and lower free testosterone levels. LH, FSH and SHBG all increased with age, while free testosterone decreased. Low free testosterone was an independent predictor for AD. Its variance was overall explained by high SHBG, low TT, high LH, an older age and low body mass index (BMI). In controls, low thyroid stimulating hormone levels were also associated with low free testosterone. Elderly AD cases had raised levels of gonadotropins. This response may be an attempt to normalize low free testosterone levels. In non-demented participants, subclinical hyperthyroid disease (a risk factor for AD) which can result in higher SHBG levels, was associated with low free testosterone. Lowering SHBG and/or screening for subclinical thyroid disease may prevent cognitive decline and/or wasting in men at risk for AD.


Auto-oscillations of skinned myocardium correlating with heartbeat.
Skinned myocardium (or myofibrils) exhibits auto-oscillations of sarcomere length and developed force called SPOC (SPontaneousOscillatoryContraction) under partial activation conditions. In SPOC, each sarcomere repeats the cycle of slow shortening and rapid lengthening, and the lengthening phase propagates sequentially to the adjacent sarcomeres in waves (SPOC wave). In this study, we analyzed the sarcomeric oscillation in SPOC in skinned myocardium of various animal species (rat, rabbit, dog, pig, and cow) with different heart rates. The period of oscillation, the sarcomere shortening velocity, and the velocity of SPOC wave, strongly correlated with the resting heart rate of the animal species. The shortening velocity in particular was proportional to the resting heart rate. We then examined the motile activity of each cardiac myosin by an in vitro motility assay. The sliding velocity of actin filaments, which is an index of the motile activity of myosin, also correlated with the resting heart rate but the relationship was not proportional. As a result, the ratio of sarcomere shortening velocity in SPOC to the sliding velocity of actin filaments was not constant but became higher with a higher heart rate. This suggests that the sarcomere shortening velocity in SPOC is modulated by some additional factors besides the motile activity of myosin, resulting in the proportional relationship between the shortening velocity of the sarcomere and the resting heart rate.


A review of the factors involved in older people's decision making with regard to influenza vaccination: a literature review.
The aim of this paper was to develop an understanding of the factors involved in older people's decision making with regard to influenza vaccination to inform strategies to improve vaccine uptake and reduce morbidity and mortality. Influenza is a major cause of morbidity and mortality world-wide. In the UK, it accounts for 3,000-6,000 deaths annually; 85% of these deaths are people aged 65 and over. Despite this, and the widespread and costly annual government campaigns, some older people at risk of influenza and the associated complications remain reluctant to take advantage of the offer of vaccination. A review of the English language literature referring to older people published between 1996 and 2005 was the method used. Inclusion and exclusion criteria were identified and applied. The majority of the literature was quantitative in nature, investigating personal characteristics thought to be predictors of uptake, such as age, sex, co-morbidity, educational level, income and area of residence. However, there was little discussion of the possible reasons for the significance of these factors and conflict between findings was often evident, particularly between studies employing different methodologies. Other factors identified were prior experience, concerns about the vaccine, perceived risk and advice and information. The wealth of demographic information available will be useful at a strategic level in targeting groups identified as being unlikely to accept vaccination. However, the promotion of person-centred ways of working that value the health beliefs, attitudes, perceptions and subjective experiences of older people is likely to be more successful during individual encounters designed to promote acceptance. Without more research in investigating these concepts, our understanding is inevitably limited.


The [NiFe]-Hydrogenase of Pyrococcus furiosus Exhibits a New Type of Oxygen Tolerance.
We report the first direct electrochemical characterization of the impact of oxygen on the hydrogen oxidation activity of an oxygen-tolerant, group 3, soluble [NiFe]-hydrogenase: hydrogenase I from Pyrococcus furiosus (PfSHI), which grows optimally near 100 °C. Chronoamperometric experiments were used to probe the sensitivity of PfSHI hydrogen oxidation activity to both brief and prolonged exposure to oxygen. For experiments between 15 and 80 °C, following short (<200 s) exposure to 14 μM O2 under oxidizing conditions, PfSHI always maintains some fraction of its initial hydrogen oxidation activity; i.e., it is oxygen-tolerant. Reactivation experiments show that two inactive states are formed by interaction with oxygen and both can be quickly (<150 s) reactivated. Analogous experiments, in which the interval of oxygen exposure is extended to 900 s, reveal that the response is highly temperature-dependent. At 25 °C, under sustained 1% O2/ 99% H2 exposure, the H2oxidation activity drops nearly to zero. However, at 80 °C, up to 32% of the enzyme's oxidation activity is retained. Reactivation of PfSHI following sustained exposure to oxygen occurs on a much longer time scale (tens of minutes), suggesting that a third inactive species predominates under these conditions. These results stand in contrast to the properties of oxygen-tolerant, group 1 [NiFe]-hydrogenases, which form a single state upon reaction with oxygen, and we propose that this new type of hydrogenase should be referred to as oxygen-resilient. Furthermore, PfSHI, like other group 3 [NiFe]-hydrogenases, does not possess the proximal [4Fe3S] cluster associated with the oxygen tolerance of some group 1 enzymes. Thus, a new mechanism is necessary to explain the observed oxygen tolerance in soluble, group 3 [NiFe]-hydrogenases, and we present a model integrating both electrochemical and spectroscopic results to define the relationships of these inactive states.


Potential mechanisms of postmenopausal endometriosis.
Endometriosis is a chronic gynaecological disorder, the cause of which remains a subject of controversy. Oestrogen dependence is considered central to development and progression, and endometriosis is widely viewed as a disease of the premenopausal years, which normally regresses during the menopause. Increasingly however, reports of cases of postmenopausal endometriosis challenge our current understanding of the pathophysiology and raise further questions concerning the processes involved. Exploring the limited evidence available on postmenopausal disease we attempt to draw comparisons with pre-menopausal endometriosis, and in doing so to propose mechanisms for postmenopausal disease that are compatible with our current general understanding of the condition.


Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy.
Bone morphogenic protein-7 (BMP-7), an essential developmental renal morphogen, is a secreted differentiation factor of the adult collecting duct. It activates receptors in the collecting duct, distal nephron, proximal tubule, and glomerulus. BMP-7 is therapeutic in tubulointerstitial nephritis raising the question of broader efficacy in chronic kidney disease (CKD). Diabetes was induced in 200 g rats by a single dose of streptozotocin. After 16 weeks, glomerular hypertrophy and proteinuria were established, and therapy with BMP-7 (10, 30, or 100 microg/kg intravenously twice a week), enalapril (20 mg/kg), or vehicle was begun and continued until 32 weeks. Kidney weight, glomerular filtration rate (GFR), urine albumin excretion, blood pressure, pathology, and BMP-7 expression were measured. Diabetic vehicle-treated rats developed renal insufficiency by 32 weeks (GFR, 0.34 +/- 0.02 mL/min/100 g body weight vs. 0.55 +/- 0.02 in normal). In the diabetic BMP-7 high-dose-treated rats, GFR was preserved (0.70 +/- 0.08, P < 0.01 vs. vehicle), and higher than diabetic enalapril-treated rats (0.58 +/- 0.06). Kidney weights of vehicle-treated animals were not affected, but were reduced in all of the treatment groups (P < 0.001). Proteinuria was reversed to normal by BMP-7 in a dose-dependent manner. The reduction in proteinuria by the intermediate dose of BMP-7 was similar to the effect of enalapril therapy. Glomerular area and interstitial volume were significantly decreased in the BMP-7 and enalapril-treated animals. Glomerular sclerosis was prevented by BMP-7 therapy more effectively than by enalapril. Enalapril controlled hypertension throughout the course of therapy while BMP-7 did not affect blood pressure until the final 4 weeks of therapy. Diabetic vehicle-treated rats lost BMP-7 expression in the kidney. BMP-7 and enalapril therapy restored BMP-7 expression at high levels. BMP-7 partially reversed diabetic-induced kidney hypertrophy, restoring GFR, urine albumin excretion, and glomerular histology toward normal. Restoration of BMP-7 expression was associated with a successful repair reaction and a reversal of the ill-fated injury response.


Neoplastic-Stromal Cell Cross-talk Regulates Matrisome Expression in Pancreatic Cancer.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly desmoplastic reaction, warranting intense cancer-stroma communication. In this study, we interrogated the contribution of the BET family of chromatin adaptors to the cross-talk between PDAC cells and the tumor stroma. Short-term treatment of orthotopic xenograft tumors with CPI203, a small-molecule inhibitor of BET proteins, resulted in broad changes in the expression of genes encoding components of the extracellular matrix (matrisome) in both cancer and stromal cells. Remarkably, more than half of matrisome genes were expressed by cancer cells. In vitro cocultures of PDAC cells and cancer-associated fibroblasts (CAF) demonstrated that matrisome expression was regulated by BET-dependent cancer-CAF cross-talk. Disrupting this cross-talk in vivo resulted in diminished growth of orthotopic patient-derived xenograft tumors, reduced proliferation of cancer cells, and changes in collagen structure consistent with that of patients who experienced better survival. Examination of matrisome gene expression in publicly available data sets of 573 PDAC tumors identified a 65-gene signature that was able to distinguish long- and short-term PDAC survivors. Importantly, the expression of genes predictive of short-term survival was diminished in the cancer cells of orthotopic xenograft tumors of mice treated with CPI203. Taken together, these results demonstrate that inhibiting the activity BET proteins results in transcriptional and structural differences in the matrisome are associated with better patient survival. IMPLICATIONS: These studies highlight the biological relevance of the matrisome program in PDAC and suggest targeting of epigenetically driven tumor-stroma cross-talk as a potential therapeutic avenue.


Plasmodium falciparum field isolates from areas of repeated emergence of drug resistant malaria show no evidence of hypermutator phenotype.
Multiple transcontinental waves of drug resistance in Plasmodium falciparum have originated in Southeast Asia before spreading westward, first into the rest of Asia and then to sub-Saharan Africa. In vitro studies have suggested that hypermutator P. falciparum parasites may exist in Southeast Asia and that an increased rate of acquisition of new mutations in these parasites may explain the repeated emergence of drug resistance in Southeast Asia. This study is the first to test the hypermutator hypothesis using field isolates. Using genome-wide SNP data from human P. falciparum infections in Southeast Asia and West Africa and a test for relative rate differences we found no evidence of increased relative substitution rates in P. falciparum isolates from Southeast Asia. Instead, we found significantly increased substitution rates in Mali and Bangladesh populations relative to those in populations from Southeast Asia. Additionally we found no association between increased relative substitution rates and parasite clearance following treatment with artemisinin derivatives.


Public attitudes and perceptions about health-related research.
Health-related research in the United States is funded by US citizens, either as taxpayers or as consumers. Public support is critical to the success of the research enterprise, and it is essential for stakeholders in research to pay attention to the public's views about the investment level in research and the nature of its conduct, as well as to understand the public's level of awareness and opinions about research to improve health. This article reviews key results from surveys concerning public attitudes and perceptions toward health-related research. Collectively, these data demonstrate that Americans rate research as a high national priority, and they strongly support greater investment by public and private funders.


Activation of anterior insula during self-reflection.
Functional neuroimaging studies have suggested activation of midline frontoparietal brain regions to be at the core of self-related processes. However, although some studies reported involvement of the insula, little attention has been paid to this region as forming part of the "self"-network. Using functional magnetic resonance imaging (fMRI), we aimed at replicating and extending previous studies by scanning subjects whilst reflecting upon their own personal qualities as compared to those of an acquaintance. A third condition with statements about general knowledge was used to control for attention, semantic processing and decision making processes. The results showed a significant effect of task in brain activity, consistent with previous findings, by which both person conditions recruited a common set of medial prefrontal and posterior regions, yet significant differences between self and other were found in the medial prefrontal cortex (MPFC) and the anterior cingulate cortex (ACC). Notably, significant neural activation in the left anterior insula was observed as uniquely associated with self-reflection. The results provide further evidence for the specific recruitment of anterior MPFC and ACC regions for self-related processing, and highlight a role for the insula in self-reflection. As the insula is closely connected with ascending internal body signals, this may indicate that the accumulation of changes in affective states that might be implied in self-processing may contribute to our sense of self.


Recognition and management of autonomic dysreflexia in patients with a spinal cord injury.
Autonomic dysreflexia is a potentially life-threatening condition that affects patients with a spinal cord injury at the level of T6 or above. It is characterised by uncontrolled elevation of systolic blood pressure of more than 20mmHg, which may occur alongside bradycardia. This article explains the pathophysiology of autonomic dysreflexia, alongside its causes, signs and symptoms. It also details the pharmacological and non-pharmacological management interventions that should be promptly initiated in patients who present to the emergency department with autonomic dysreflexia, to alleviate their symptoms and prevent further complications.


First Report of Powdery Mildew Caused by Erysiphe cruciferarum on Garden Cress in Korea.
Garden cress (Lepidium sativum L.), belonging to the family Brassicaceae, is an edible herb with peppery flavor and aroma (2). This plant was recently introduced and is cultivated as an edible green under organic farming in Korea. In September 2012, seedlings showing typical symptoms of powdery mildew were found in greenhouses in Pyeongchang County, Korea. Symptoms first appeared as thin white colonies, which progressed to abundant growth on the leaves and stems. Infected herbs were unmarketable mainly due to signs of senescence and withering of leaves and mostly abandoned without becoming harvested. Two samples of diseased leaves were deposited in the Korea University Herbarium (KUS Accession Nos. F27137 and F27150). Appressoria on the mycelium were well-developed, lobed, and solitary or in opposite pairs. Conidiophores were unbranched, cylindrical, 88 to 120 × 8.5 to 10 μm, and composed of 3 to 4 cells. Foot-cells of conidiophores were straight to sub-straight, cylindric, 22 to 42 μm long, and generally equal to or shorter than the upper cells. Singly produced conidia were oblong to cylindrical or oval, 34 to 52 × 14 to 18 μm with a length/width ratio of 2.2 to 3.3, with angular/rectangular wrinkling of outer walls, and no distinct fibrosin bodies. Germ tubes were produced on the perihilar position of conidia. No chasmothecia were found. These structures are typical of the powdery mildew Pseudoidium anamorph of the genus Erysiphe. The specific measurements match with those of E. cruciferarum Opiz ex L. Junell as previously described (1). To confirm the identification, the complete internal transcribed spacer (ITS) region of rDNA from KUS-F27150 was amplified with primers ITS5 and P3 and directly sequenced (4). The resulting 554-bp sequence was deposited in GenBank (Accession No. KC414675). The amplified ITS sequence shared >99% similarity with the sequences of E. cruciferarum on several brassicaceous hosts (EU140958, FJ548627, and GU721075). Pathogenicity was confirmed through inoculation by gently dusting conidia onto leaves of five healthy potted garden cress plants. Five non-inoculated plants served as controls. Inoculated plants were isolated from non-inoculated plants in separate rooms in a greenhouse at 18 to 24°C. Inoculated plants developed signs and symptoms after 8 days, whereas the control plants remained symptomless. The fungus present on the inoculated plants was morphologically identical to that originally observed on diseased plants, fulfilling Koch's postulates. Previously, the disease was reported in several European countries and southeastern Asia (Lebanon, Israel, Iran, Iraq, India, and China) (3). To our knowledge, this is the first report of powdery mildew caused by E. cruciferarum on garden cress in Korea. Since garden cress production was only recently started on a commercial scale in Korea, powdery mildew infections pose a serious threat to the production of this herb, especially in organic farming where chemical control options are limited. References: (1) U. Braun and R. T. A. Cook. Taxonomic Manual of the Erysiphales (Powdery Mildews), CBS Biodiversity Series No.11. CBS, Utrecht, 2012. (2) S. Choudhary et al. Indian J. Agric. Sci. 80:752, 2010. (3) D. F. Farr and A. Y. Rossman. Fungal Databases, Syst. Mycol. Microbiol. Lab., Online publication. ARS, USDA. Retrieved December 2, 2012. (4) S. Takamatsu et al. Mycol. Res. 113:117, 2009.


Proliferative Fasciitis/Myositis Involving the Facial Muscles Including the Masseter Muscle: A Rare Cause of Trismus.
BACKGROUND Proliferative fasciitis/myositis is a benign disease that can be treated conservatively. However, some patients are mistakenly treated surgically because of a misdiagnosis of the condition as a malignant tumor. CASE REPORT A 50-year-old Japanese man developed swelling in his left cheek 12 days before admission; he developed a fever and trismus 3 days later. He was admitted to our hospital because of worsening of his condition despite treatment with sitafloxacin for 5 days and needle-aspiration drainage. On admission, he had a fever of 38.1°C, swelling in his left cheek spreading to the lower jaw, and several dental caries. Although ceftriaxone and clindamycin were administered for 7 days because an odontogenic infection was suspected, his condition did not improve. T2-weighted magnetic resonance imaging of the facial muscles on Day 5 of hospitalization showed swelling and high-intensity signals in the left masseter, temporalis, and pterygoid muscles. Macroscopic findings from a biopsy of the left temporalis muscle performed on Day 17 showed white and thickened fascia. Histopathological examination revealed fibrous hyperplasia of the fascia, increased fibrous connective tissue between muscle fibers, and infiltration of inflammatory cells, providing not a definite but a compatible diagnosis of proliferative fasciitis/myositis. Beginning on Day 18, the patient's fever lessened with gradual improvement of his facial swelling and trismus. CONCLUSIONS It is imperative to include proliferative fasciitis/myositis as a possible diagnosis when patients present with facial swelling and trismus of unknown cause.