Seeing or doing? Influence of visual and motor familiarity in action observation.
The human brain contains specialized circuits for observing and understanding actions. Previous studies have not distinguished whether this "mirror system" uses specialized motor representations or general processes of visual inference and knowledge to understand observed actions. We report the first neuroimaging study to distinguish between these alternatives. Purely motoric influences on perception have been shown behaviorally, but their neural bases are unknown. We used fMRI to reveal the neural bases of motor influences on action observation. We controlled for visual and knowledge effects by studying expert dancers. Some ballet moves are performed by only one gender. However, male and female dancers train together and have equal visual familiarity with all moves. Male and female dancers viewed videos of gender-specific male and female ballet moves. We found greater premotor, parietal, and cerebellar activity when dancers viewed moves from their own motor repertoire, compared to opposite-gender moves that they frequently saw but did not perform. Our results show that mirror circuits have a purely motor response over and above visual representations of action. We understand actions not only by visual recognition, but also motorically. In addition, we confirm that the cerebellum is part of the action observation network.


Molecular analysis of the coiled body.
There is increasing interest in studying how specific metabolic activities within the nucleus are organised into functional domains. The best known example is the nucleolus where rRNA genes are transcribed and rRNA processed and assembled into ribosomal units. Other subnuclear domains have been known for many years through morphological studies but are only recently being analysed at the molecular level. Here we focus on an evolutionarily conserved nuclear domain, called the coiled body, which contains splicing snRNPs. We review recent literature on the coiled body and discuss a possible model for its biological function.


Potassium channel function in vascular disease.
Potassium ion (K(+)) channel activity is a major regulator of vascular muscle cell membrane potential (E(m)) and is therefore an important determinant of vascular tone. There is growing evidence that the function of several types of vascular K(+) channels is altered during major cardiovascular diseases, such as chronic hypertension, diabetes, and atherosclerosis. Vasoconstriction and the compromised ability of an artery to dilate are likely consequences of defective K(+) channel function in blood vessels during these disease states. In some instances, increased K(+) channel function may help to compensate for increased vascular tone. Endothelial cell dysfunction is commonly associated with cardiovascular disease, and altered activity of nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor could also contribute to changes in resting K(+) channel activity, E(m), and K(+) channel-mediated vasodilatation. Our current knowledge of the effects of disease on vascular K(+) channel function almost exclusively relies on interpretation of data obtained by using pharmacological modulators of K(+) channels. As further progress is made in the development of more selective drugs and through molecular approaches such as gene targeting technology in mice, specific K(+) channel abnormalities and their causes in particular diseases should be more readily identified, providing novel directions for vascular therapy.


Immunopathology of NZB/BL mice. VI. Virus separable from spleen and pathogenic for Swiss mice.
Hemolytic disease characterized by slight anemia, reticulocytosis, hemosiderosis, extramedullary hematopoiesis, and positive indirect antiglobulin (Coombs') tests and renal disease with proteinuria, hypoalbuminemia, and glomerular lesions were produced in Swiss mice by neonatal intraperitoneal inoculation of cell-free filtrates prepared from the spleens of old NZB/Bl mice. Lymphoid cell and plasma cell hyperplasia as well as hypergammaglobulinemia occurred in some of these inoculated mice. Type "C" murine oncogenic virus-like particles, indistinguishable from those previously described (1), were shown by electron microscopic study to be present in distinctive locations, notably in the basal foldings of convoluted tubules in the kidneys of a newborn NZB/Bl mouse, old NZB/Bl mice, a CBA x NZB F(1) hybrid mouse, and a Swiss mouse inoculated with NZB/Bl spleen cell-free filtrate. These observations point to two (perhaps related) circumstances which may be requisites for the pathogenic action of this newly discovered virus within and outside the strain NZB: infection of newborn, or infant, mice; persistent, possibly tolerant, infection of adult mice.


Hsp70 is present in human saliva.
There is increasing evidence that chaperones are also present outside the cell, exerting cytokine-like effects and influencing immune recognition. Hsp70 has been found to be present in human blood sera. Chaperonins Cpn10 and Cpn60 are present in pancreatic juice, but Hsp70 is not. These observations raise the possibility that molecular chaperones may be present in other secretory fluids, such as human saliva. Human whole saliva was collected from six participants under resting conditions and secretory stimulation. The samples were precleared by centrifugation and sterile filtered. Salivary volume, protein concentration and amylase activity were determined. For detection of Hsp70 saliva proteins were separated on a 12.5% SDS-PAGE. Semi-dry Western blot analysis was used with a primary antibody against the inducible form of Hsp70. Hsp70 bands were detected with a horseradish peroxidase-linked secondary antibody and ECL-Western blotting analysis. A single band was recognized around 70 kDa in the saliva of all the participants. There was a significant decrease of Hsp70, and a non-significant decrease of total protein concentration during stimulation, whereas the activity of salivary amylase increased significantly. Stimulation significantly increased the Hsp70, total protein and amylase outputs as well as the amylase/protein ratio, and decreased the Hsp70/amylase and Hsp70/protein ratios. Hsp70 is secreted to saliva, but unlike amylase is not transported by the exocytotic secretory mechanisms of acinar cells. Passive transport mechanisms of Hsp70 from blood serum or from salivary gland cells may be major routes of salivary Hsp70 secretion.


Components and characteristics of the dopamine reward utility signal.
Rewards are defined by their behavioral functions in learning (positive reinforcement), approach behavior, economic choices, and emotions. Dopamine neurons respond to rewards with two components, similar to higher order sensory and cognitive neurons. The initial, rapid, unselective dopamine detection component reports all salient environmental events irrespective of their reward association. It is highly sensitive to factors related to reward and thus detects a maximal number of potential rewards. It also senses aversive stimuli but reports their physical impact rather than their aversiveness. The second response component processes reward value accurately and starts early enough to prevent confusion with unrewarded stimuli and objects. It codes reward value as a numeric, quantitative utility prediction error, consistent with formal concepts of economic decision theory. Thus, the dopamine reward signal is fast, highly sensitive and appropriate for driving and updating economic decisions.


Use of intravenous magnesium sulfate for the treatment of severe acute asthma in children in emergency department.
Severe acute asthma is a medical emergency that must be quickly diagnosed and treated. Initial treatment includes a bronchodilator agent and systemic corticosteroids. In severe cases with poor response to the standard treatment, intravenous magnesium sulfate is a therapeutic option. This article aimed a literature review on the use of intravenous magnesium sulfate in the emergency room treatment of children with acute asthma. The treatment parameters of effectiveness, indication, dosage, adverse effects and contraindications were assessed. A narrative review of the literature based on a search of the Medline and Lilacs databases and the Cochrane Database of Systematic Reviews for articles published between 2000 and 2010 was conducted. The keywords used included the following: asthma, children, emergency and magnesium sulfate. Eight controlled clinical trials, three meta-analyses, one retrospective study, eight review articles and one cross-sectional study were included. A total of 21 articles were analyzed. Several authors reported that intravenous magnesium was effective in the treatment of acute asthma in children. Adverse effects were rare. The use of intravenous magnesium sulfate was indicated for patients with moderate to severe acute asthma not responding to initial treatment with a bronchodilator agent and systemic corticosteroids. Few contraindications were reported but included kidney failure and atrioventricular block. Reports of adverse drug interactions with magnesium were rare. Although reported as safe, intravenous magnesium is infrequently used in children with acute asthma. Most often it is used in severe, progressed cases to prevent respiratory failure and/or admission to the intensive care unit. Intravenous magnesium was concluded to be effective and safe in children with severe acute asthma, although its use in the emergency room is still limited.


Recommendations of the Neurolaryngology Study Group on laryngeal electromyography.
The Neurolaryngology Study Group convened a multidisciplinary panel of experts in neuromuscular physiology, electromyography, physical medicine and rehabilitation, neurology, and laryngology to meet with interested members from the American Academy of Otolaryngology Head and Neck Surgery, the Neurolaryngology Subcommittee and the Neurolaryngology Study Group to address the use of laryngeal electromyography (LEMG) for electrodiagnosis of laryngeal disorders. The panel addressed the use of LEMG for: 1) diagnosis of vocal fold paresis, 2) best practice application of equipment and techniques for LEMG, 3) estimation of time of injury and prediction of recovery of neural injuries, 4) diagnosis of neuromuscular diseases of the laryngeal muscles, and, 5) differentiation between central nervous system and behaviorally based laryngeal disorders. The panel also addressed establishing standardized techniques and methods for future assessment of LEMG sensitivity, specificity and reliability for identification, assessment and prognosis of neurolaryngeal disorders. Previously an evidence-based review of the clinical utility of LEMG published in 2004 only found evidence supported that LEMG was possibly useful for guiding injections of botulinum toxin into the laryngeal muscles. An updated traditional/narrative literature review and expert opinions were used to direct discussion and format conclusions. In current clinical practice, LEMG is a qualitative and not a quantitative examination. Specific recommendations were made to standardize electrode types, muscles to be sampled, sampling techniques, and reporting requirements. Prospective studies are needed to determine the clinical utility of LEMG. Use of the standardized methods and reporting will support future studies correlating electro-diagnostic findings with voice and upper airway function.


Sleep Disturbance Forecasts β-Amyloid Accumulation across Subsequent Years.
Experimental sleep-wake disruption in rodents and humans causally modulates β-amyloid (Aβ) dynamics (e.g., [1-3]). This leads to the hypothesis that, beyond cross-sectional associations, impaired sleep structure and physiology could represent prospective biomarkers of the speed with which Aβ accumulates over time. Here, we test the hypothesis that initial baseline measures of non-rapid eye movement (NREM) sleep slow-wave activity (SWA) and sleep quality (efficiency) provide future forecasting sensitivity to the rate of Aβ accumulation over subsequent years. A cohort of clinically normal older adults was assessed using objective sleep polysomnography in combination with longitudinal tracking of Aβ accumulation with [11C]PiB positron emission tomography (PET) imaging. Both the proportion of NREM SWA below 1 Hz and the measure of sleep efficiency predicted the speed (slope) of subsequent Aβ deposition over time, and these associations remained robust when taking into account additional cofactors of interest (e.g., age, sex, sleep apnea). Moreover, these measures were specific, such that no other macro- and microphysiological architecture metrics of sleep demonstrated such sensitivity. Our data support the proposal that objective sleep markers could be part of a set of biomarkers that statistically forecast the longitudinal trajectory of cortical Aβ deposition in the human brain. Sleep may therefore represent a potentially affordable, scalable, repeatable, and non-invasive tool for quantifying of Aβ pathological progression, prior to cognitive symptoms of Alzheimer's disease (AD).


Effects of Environmental Manipulations and Treatment with Bupropion and Risperidone on Choice between Methamphetamine and Food in Rhesus Monkeys.
Preclinical and human laboratory choice procedures have been invaluable in improving our knowledge of the neurobiological mechanisms of drug reinforcement and in the drug development process for candidate medications to treat drug addiction. However, little is known about the neuropharmacological mechanisms of methamphetamine vs food choice. The aims of this study were to develop a methamphetamine vs food choice procedure and determine treatment effects with two clinically relevant compounds: the monoamine uptake inhibitor bupropion and the dopamine antagonist risperidone. Rhesus monkeys (n=6) responded under a concurrent schedule of food delivery (1-g pellets, fixed-ratio (FR) 100 schedule) and intravenous methamphetamine injections (0-0.32 mg/kg/injection, FR10 schedule) during 7-day bupropion (0.32-1.8 mg/kg/h) and risperidone (0.001-0.0056 mg/kg/h) treatment periods. For comparison, effects of removing food pellets or methamphetamine injections and FR response requirement manipulations were also examined. Under saline treatment conditions, food was preferred over no methamphetamine or small unit methamphetamine doses (0.01-0.032 mg/kg/injection). Larger methamphetamine doses resulted in greater methamphetamine preference and 0.32 mg/kg/injection methamphetamine maintained near exclusive preference. Removing food availability increased methamphetamine choice, whereas removing methamphetamine availability decreased methamphetamine choice. Methamphetamine choice was not significantly altered when the FR response requirements for food and drug were the same (FR100:FR100 or FR10:FR10). Risperidone treatment increased methamphetamine choice, whereas bupropion treatment did not alter methamphetamine choice up to doses that decreased rates of operant behavior. Overall, these negative results with bupropion and risperidone are concordant with previous human laboratory and clinical trials and support the potential validity of this preclinical methamphetamine vs food choice model.


Aperture averaging in multiple-input single-output free-space optical systems using partially coherent radial array beams.
Multiple-input single-output (MISO) techniques are employed in free-space optical (FSO) links to mitigate the degrading effects of atmospheric turbulence. In this paper, for the MISO FSO system, a partially coherent radial array and a finite-sized receiver aperture are used at the transmitter and the receiver, respectively. Using the extended Huygens-Fresnel principle, we formulate the average power and the power correlation at the finite-sized slow detector in weak atmospheric turbulence. System performance indicators such as the power scintillation index and the aperture averaging factor are determined. Effects of the source size, ring radius, receiver aperture radius, link distance, and structure constant and the degree of source coherence are analyzed on the performance of the MISO FSO system. In the limiting cases, the numerical results are found to be the same when compared to the existing coherent and partially coherent Gaussian beam scintillation indices.


Low-dose aspirin and omega-3 fatty acids improve uterine artery blood flow velocity in women with recurrent miscarriage due to impaired uterine perfusion.
To determine the effect of different therapeutic approaches on uterine artery blood flow in women with recurrent miscarriage (RM) and impaired uterine perfusion. Prospective, randomized study. Department of Obstetrics and Gynecology, University of Rome "Tor Vergata," Italy. Sixty women with unexplained RM and impaired uterine perfusion. Patients were randomly assigned to three different therapeutic regimens: 20 patients received a daily dose of 100 mg of aspirin (LDA); 20 patients were treated with omega-3 fatty acids (Omega(3)), 4 g daily; and 20 patients received LDA plus Omega(3). Doppler measurement of uterine artery pulsatility index (PI) was performed, in the midluteal phase of the cycle, before and after 2 months of therapy. All therapeutic regimens induced an improvement in uterine perfusion with a significant reduction of uterine artery PI values. LDA alone or in combination with Omega(3) was found to achieve the highest improvement of uterine blood flow. Omega-3 supplementation was less effective, as reflected by the lower PI values. LDA and Omega(3) are effective in improving uterine artery blood flow velocity in women with RM due to abnormal uterine perfusion. Further studies are needed to determine whether the improvement of uterine perfusion may lead to a better pregnancy outcome.


Dynamics of a network fluid within the liquid-gas coexistence region.
Low-density networks of molecules or colloids are formed at low temperatures when the interparticle interactions are valence limited. Prototypical examples are networks of patchy particles, where the limited valence results from highly directional pairwise interactions. We combine extensive Langevin simulations and Wertheim's theory of association to study these networks. We find a scale-free (relaxation) dynamics within the liquid-gas coexistence region, which differs from that usually observed for isotropic particles. While for isotropic particles the relaxation dynamics is driven by surface tension (coarsening), when the valence is limited, the slow relaxation proceeds through the formation of an intermediate non-equilibrium gel via a geometrical percolation transition in the Random Percolation universality class. We show that the slow dynamics is universal, being also observed outside the coexistence region at low temperatures in the single phase region.


Critical role of Spns2, a sphingosine-1-phosphate transporter, in lung cancer cell survival and migration.
The sphingosine-1-phosphate (S1P) transporter Spns2 regulates myocardial precursor migration in zebrafish and lymphocyte trafficking in mice. However, its function in cancer has not been investigated. We show here that ectopic Spns2 expression induced apoptosis and its knockdown enhanced cell migration in non-small cell lung cancer (NSCLC) cells. Metabolically, Spns2 expression increased the extracellular S1P level while its knockdown the intracellular. Pharmacological inhibition of S1P synthesis abolished the augmented cell migration mediated by Spns2 knockdown, indicating that intracellular S1P plays a key role in this process. Cell signaling studies indicated that Spns2 expression impaired GSK-3β and Stat3 mediated pro-survival pathways. Conversely, these pathways were activated by Spns2 knockdown, which explains the increased cell migration since they are also crucial for migration. Alterations of Spns2 were found to affect several enzymes involved in S1P metabolism, including sphingosine kinases, S1P phosphatases, and S1P lyase 1. Genetically, Spns2 mRNA level was found to be reduced in advanced lung cancer (LC) patients as quantified by using a small scale qPCR array. These data show for the first time that Spns2 plays key roles in regulating the cellular functions in NSCLC cells, and that its down-regulation is a potential risk factor for LC.


Allylmethylsulfide Down-Regulates X-Ray Irradiation-Induced Nuclear Factor-kappaB Signaling in C57/BL6 Mouse Kidney.
Allylmethylsulfide (AMS), a volatile organosulfur derivative from garlic, has been shown to have radioprotective effects in radiation-challenged cell and animal models, but the mechanism of radioprotection is not well understood. To determine the mechanism of radioprotection in an in vivo model, we first verified the antioxidant capacity of AMS using 2,2'-azobis(2-amidinopropane) dihydrochloride-induced human embryonic kidney 293T cells by measuring reactive oxygen species generation, reduced glutathione, protein tyrosine kinase/protein tyrosine phosphatase balance, and nuclear factor-kappaB (NF-kappaB) protein levels. We then investigated the protective effects of AMS (55 and 275 micromol/kg, intraperitoneal treatment) on 15 Gy X-ray-irradiated mouse kidney. The results showed that AMS decreased the free radical-induced lipid peroxidation in mice exposed to X-rays. Moreover, the antioxidative AMS suppressed the activation of NF-kappaB and its dependent genes such as vascular cell adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2 through inhibition of IkappaBalpha phosphorylation and activation of IkappaB kinase alpha/beta and mitogen-activated protein kinases (MAPKs). Based on these results, AMS may be a useful radioprotective agent by down-regulating the MAPKs and NF-kappaB signaling pathway that can be induced via X-ray irradiation.


An update of "Cost-effectiveness of rotavirus vaccination in the Netherlands: the results of a Consensus Rotavirus Vaccine model".
To update a cost-effectiveness analysis of rotavirus vaccination in the Netherlands previously published in 2011. The rotavirus burden of disease and the indirect protection of older children and young adults (herd protection) were updated. When updated data was used, routine infant rotavirus vaccination in the Netherlands would potentially become an even more cost-effective strategy than previously estimated with the incremental cost per QALY at only €3,000-4,000. Break-even total vaccination costs were indicated at €92-122, depending on the applied threshold. We concluded that the results on potentially favourable cost-effectiveness in the previous study remained valid, however, the new data suggested that previous results might represent an underestimation of the economic attractiveness of rotavirus vaccination.


Manganese uptake and distribution in the central nervous system (CNS).
Information about the nature of manganese (Mn)-binding ligands in plasma and serum, and its transport mechanism across the blood-brain barrier (BBB) is sparse. Most studies to date have focused on distribution, excretion, and accumulation of intravenous and intraperitoneal solutions of soluble divalent salts of Mn. Mn is transported in the blood primarily in the divalent oxidation state (Mn2+) and crosses the BBB via specific carriers at a rate far slower than in other tissues. Mn transport across the BBB occurs both in the 2+ and 3+ oxidation state. Within the CNS, Mn accumulates primarily within astrocytes, presumably because the astrocyte-specific enzyme, glutamine synthetase (GS), represents an important regulatory target of Mn. Compared to Mn2+, Mn3+ has a slower elimination rate and therefore, may have a greater tendency to accumulate in tissues. Furthermore, in view of the dependence of Mn accumulation within the CNS on iron (Fe) homeostasis, the oxidation state of Mn may represent a key determinant in the differential distribution, accumulation and secretion profiles of Mn, a fact that has received little attention in experimental biology toxicology. Accordingly, the distribution and membrane transport of Mn emphasizes the importance of: 1) the oxidation state of Mn, as it governs the affinity of Mn to endogenous ligands, and 2) the reaction of Mn3+ with transferrin, the plasma iron-carrying protein. This review will focus on transport kinetics of Mn across the BBB (both in the 2+ and 3+ oxidation state), the putative role of transferrin in the transport of Mn across the BBB, the transport of Mn by astrocytes, as well as the physiological significance of Mn to the function GS.


Frequency and predictors of complications in neurological surgery: national trends from 2006 to 2011.
Surgical complications increase the cost of health care worldwide and directly contribute to patient morbidity and mortality. In an effort to mitigate morbidity and incentivize best practices, stakeholders such as health insurers and the US government are linking reimbursement to patient outcomes. In this study the authors analyzed a national database to determine basic metrics of how comorbidities specifically affect the subspecialty of neurosurgery. Data on 1,777,035 patients for the years 2006-2011 were acquired from the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database. Neurosurgical cases were extracted by querying the data for which the surgical specialty was listed as "neurological surgery." Univariate statistics were calculated using the chi-square test, and 95% confidence intervals were determined for the resultant risk ratios. A multivariate model was constructed using significant variables from the univariate analysis (p < 0.05) with binary logistic regression. Over 38,000 neurosurgical cases were analyzed, with complications occurring in 14.3%. Cranial cases were 2.6 times more likely to have complications than spine cases, and African Americans and Asians/Pacific Islanders were also at higher risk. The most frequent complications were bleeding requiring transfusion (4.5% of patients) and reoperation within 30 days of the initial operation (4.3% of patients), followed by failure to wean from mechanical ventilation postoperatively (2.5%). Significant predictors of complications included preoperative stroke, sepsis, blood transfusion, and chronic steroid use. Understanding the landscape of neurosurgical complications will allow better targeting of the most costly and harmful complications of preventive measures. Data from the ACS NSQIP database provide a starting point for developing paradigms of improved care of neurosurgical patients.


Continuous electroencephalography monitoring for early prediction of neurological outcome in postanoxic patients after cardiac arrest: a prospective cohort study.
To evaluate the value of continuous electroencephalography in early prognostication in patients treated with hypothermia after cardiac arrest. Prospective cohort study. Medical intensive care unit. Sixty patients admitted to the intensive care unit for therapeutic hypothermia after cardiac arrest. None. In all patients, continuous electroencephalogram and daily somatosensory evoked potentials were recorded during the first 5 days of admission or until intensive care unit discharge. Neurological outcomes were based on each patient's best achieved Cerebral Performance Category score within 6 months. Twenty-seven of 56 patients (48%) achieved good neurological outcome (Cerebral Performance Category score 1-2).At 12 hrs after resuscitation, 43% of the patients with good neurological outcome showed continuous, diffuse slow electroencephalogram rhythms, whereas this was never observed in patients with poor outcome.The sensitivity for predicting poor neurological outcome of low-voltage and isoelectric electroencephalogram patterns 24 hrs after resuscitation was 40% (95% confidence interval 19%-64%) with a 100% specificity (confidence interval 86%-100%), whereas the sensitivity and specificity of absent somatosensory evoked potential responses during the first 24 hrs were 24% (confidence interval 10%-44%) and 100% (confidence interval: 87%-100%), respectively. The negative predictive value for poor outcome of low-voltage and isoelectric electroencephalogram patterns was 68% (confidence interval 50%-81%) compared to 55% (confidence interval 40%-60%) for bilateral somatosensory evoked potential absence, both with a positive predictive value of 100% (confidence interval 63%-100% and 59%-100% respectively). Burst-suppression patterns after 24 hrs were also associated with poor neurological outcome, but not inevitably so. In patients treated with hypothermia, electroencephalogram monitoring during the first 24 hrs after resuscitation can contribute to the prediction of both good and poor neurological outcome. Continuous patterns within 12 hrs predicted good outcome. Isoelectric or low-voltage electroencephalograms after 24 hrs predicted poor outcome with a sensitivity almost two times larger than bilateral absent somatosensory evoked potential responses.


Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis.
Major depressive disorder is one of the most common mental disorders in children and adolescents. However, whether to use pharmacological interventions in this population and which drug should be preferred are still matters of controversy. Consequently, we aimed to compare and rank antidepressants and placebo for major depressive disorder in young people. We did a network meta-analysis to identify both direct and indirect evidence from relevant trials. We searched PubMed, the Cochrane Library, Web of Science, Embase, CINAHL, PsycINFO, LiLACS, regulatory agencies' websites, and international registers for published and unpublished, double-blind randomised controlled trials up to May 31, 2015, for the acute treatment of major depressive disorder in children and adolescents. We included trials of amitriptyline, citalopram, clomipramine, desipramine, duloxetine, escitalopram, fluoxetine, imipramine, mirtazapine, nefazodone, nortriptyline, paroxetine, sertraline, and venlafaxine. Trials recruiting participants with treatment-resistant depression, treatment duration of less than 4 weeks, or an overall sample size of less than ten patients were excluded. We extracted the relevant information from the published reports with a predefined data extraction sheet, and assessed the risk of bias with the Cochrane risk of bias tool. The primary outcomes were efficacy (change in depressive symptoms) and tolerability (discontinuations due to adverse events). We did pair-wise meta-analyses using the random-effects model and then did a random-effects network meta-analysis within a Bayesian framework. We assessed the quality of evidence contributing to each network estimate using the GRADE framework. This study is registered with PROSPERO, number CRD42015016023. We deemed 34 trials eligible, including 5260 participants and 14 antidepressant treatments. The quality of evidence was rated as very low in most comparisons. For efficacy, only fluoxetine was statistically significantly more effective than placebo (standardised mean difference -0·51, 95% credible interval [CrI] -0·99 to -0·03). In terms of tolerability, fluoxetine was also better than duloxetine (odds ratio [OR] 0·31, 95% CrI 0·13 to 0·95) and imipramine (0·23, 0·04 to 0·78). Patients given imipramine, venlafaxine, and duloxetine had more discontinuations due to adverse events than did those given placebo (5·49, 1·96 to 20·86; 3·19, 1·01 to 18·70; and 2·80, 1·20 to 9·42, respectively). In terms of heterogeneity, the global I(2) values were 33·21% for efficacy and 0% for tolerability. When considering the risk-benefit profile of antidepressants in the acute treatment of major depressive disorder, these drugs do not seem to offer a clear advantage for children and adolescents. Fluoxetine is probably the best option to consider when a pharmacological treatment is indicated. National Basic Research Program of China (973 Program).


Molecular identification and function of cis- and trans-acting determinants for petA transcript stability in Chlamydomonas reinhardtii chloroplasts.
In organelles, the posttranscriptional steps of gene expression are tightly controlled by nucleus-encoded factors, most often acting in a gene-specific manner. Despite the molecular identification of a growing number of factors, their mode of action remains largely unknown. In the green alga Chlamydomonas reinhardtii, expression of the chloroplast petA gene, which codes for cytochrome f, depends on two specific nucleus-encoded factors. MCA1 controls the accumulation of the transcript, while TCA1 is required for its translation. We report here the cloning of MCA1, the first pentatricopeptide repeat protein functionally identified in this organism. By chloroplast transformation with modified petA genes, we investigated the function of MCA1 in vivo. We demonstrate that MCA1 acts on the very first 21 nucleotides of the petA 5' untranslated region to protect the whole transcript from 5'-->3' degradation but does not process the 5' end of the petA mRNA. MCA1 and TCA1 recognize adjacent targets and probably interact together for efficient expression of petA mRNA. MCA1, although not strictly required for translation, shows features of a translational enhancer, presumably by assisting the binding of TCA1 to its own target. Conversely, TCA1 participates to the full stabilization of the transcript through its interaction with MCA1.


Chiropractic management of essential tremor and migraine: a case report.
The purpose of this case report is to describe the chiropractic management of a 39-year-old woman with essential tremors and migraine headaches. A 39-year-old woman presented with essential tremors and migraine headaches, which occurred 2 to 3 times per week. The essential tremor was diagnosed in 2000, and migraine headaches with aura were diagnosed when she was 10. Both diagnoses were made by her general medical practitioner. Previous treatments for migraine included propranolol, isometheptene, dichloralphenazone, acetaminophen, sumatriptan, and over-the-counter pain relievers. The patient received high-velocity, low-amplitude chiropractic spinal manipulation to her upper cervical spine using the Blair Upper Cervical chiropractic technique protocol. There was improvement in her tremors and migraine headaches following her initial chiropractic treatment, with a sustained improvement after 4 months of care. This case study demonstrated improvement in a woman with essential tremors and migraine headaches. This suggests the need for more research to examine how upper cervical specific chiropractic care may help mitigate tremors and migraine headaches.


Surgical anatomy of the pyramidal lobe and its significance in thyroid surgery.
The purpose of this prospective study was to highlight some new findings about anatomical and morphological variations of the thyroid pyramidal lobe and to emphasise the necessity and importance of exploration of the visceral compartment of the neck and resection of this structure in primary thyroid operations. We analysed 100 consecutive primary thyroid operations with additional pathological examination of the specimens. A pyramidal lobe was found in 61% of the cases. The lobe of Lalouette was found more often in women (61.96%) than in men (50%) and more often (67.3%) in patients less than 50 years old than in those older than 50 (54.2%). The lobe branched off more frequently from the midline (49.18%) than from other parts of the isthmus; its length ranged from 8 - 40 mm, with a median length of 20.13 mm. In diffuse thyroid diseases, the lobes were always pathologically involved and significantly longer. Since the pyramidal lobe is a normal component of the thyroid gland, of varying position and size, with pathological changes in benign and malignant diseases, it should always be examined during thyroid surgery and mandatorily removed in total and subtotal thyroidectomies.


Vesicoureteral Reflux in Kidney Transplantation.
Vesicoureteral reflux (VUR) is frequently found after transplantation, but its impact on graft function, urine tract infection, and graft loss remains uncertain. Therefore our objective was to evaluate the effects of VUR on the outcome of renal transplantation. We included 1008 adult renal transplant recipients of whom a 1-week posttransplant voiding cystourethrogram was available. Study end points included occurrence of bacteriuria, renal function, and graft survival. In total, 106 (10.5%) of 1008 graft recipients had a diagnosis of VUR on voiding cystography. The incidence of bacteriuria was comparable in the reflux and nonreflux group (17% vs 17.4%, P = .91). There was no significant difference in renal function at 3 months and 1 year in patients with and without VUR. One- and 5-year graft survival in patients with VUR was 85.8% and 82.1% compared to 87.3% and 83.0% in patients without VUR ( P = .68 and P = .80). Posttransplant VUR has no correlations with early bacteriuria, renal function, and graft survival.


Experience with hemihyperplasia and Beckwith-Wiedemann syndrome surveillance protocol.
Beckwith-Wiedemann syndrome (BWS) and isolated hemihyperplasia (IHH) are two well known overgrowth conditions that are associated with cancer predisposition. Multiple surveillance protocols have been proposed to detect the most commonly reported tumor types Wilms tumor and hepatoblastoma. We reviewed the history of our patients who were part of this monitoring protocol. Information from 63 cases was collected retrospectively while another 63 control samples for AFP measurement were obtained prospectively. Twenty-five (40%) patients had an ultrasound abnormality, the most frequent being nephromegaly/size discrepancy. Two patients had well documented cases of tumors/tumor precursor (2/63:3.2%) detected by ultrasound images. Three hundred thirty-six separate AFP values were available with values above 50,000 ng/ml seen in three patients older than 2 months, one with hepatoblastoma and two other with hemangiomas/hemangioendotheliomas. There was no clear difference in the range of AFP values between previously reported controls, our own normal population and affected patients. In conclusion, ultrasound surveillance detected renal and liver pathology including benign and malignant lesions. The known variability of AFP in normal neonates and patients with BWS makes interpretation difficult in early infancy. Very high AFP values did seem to be correlated with risk for identifiable liver lesions. Determination of the natural changes in AFP levels over time will allow more appropriate comparison.


Response of grasshoppers (Orthoptera: Acrididae) to livestock grazing in southeastern Arizona: differences between seasons and subfamilies.
Grasshopper densities were compared between grazed and ungrazed semidesert grassland sites in southeastern Arizona. Bouteloua-dominated perennial grass cover was about 1.5 times greater on the livestock exclosure. Grasshoppers were 3.7 times more abundant on the protected area in the summers of 1983 and 1984, when dominant species were grass-feeding members of the subfamily Gomphocerinae. In fall 1984, grasshoppers were 3.8 times more common on the grazed site, when dominants were mainly herb-feeders in the subfamily Melanoplinae. These results indicate important seasonal and taxonomic differences in the responses of grasshoppers to the activities of vertebrate grazers.


GpIIb/IIIa+ subpopulation of rat megakaryocyte progenitor cells exhibits high responsiveness to human thrombopoietin.
The recently cloned factor thrombopoietin (TPO) has been shown to exhibit megakaryocyte colony-stimulating activity in vitro. In this investigation, to further evaluate the action of TPO on megakaryocyte progenitor cells (colony-forming units-megakaryocyte [CFU-MK]), GpIIb/IIIa+ and GpIIb/IIIa- populations of CFU-MK were prepared from rat bone marrow cells based on their reactivity with P55 antibody, a monoclonal antibody against rat GpIIb/IIIa, and their responsiveness to recombinant human TPO (rhTPO) and recombinant rat interleukin-3 (rrIL-3) was examined using a megakaryocyte colony-forming assay (Meg-CSA). rhTPO supported only megakaryocyte colony growth from both fractions in a dose-dependent fashion. The mean colony size observed with the GpIIb/IIIa+ population was smaller than that seen with the GpIIb/IIIa- population. With the optimal concentration of either rhTPO or rrIL-3, similar numbers of megakaryocyte colonies were formed from the GpIIb/IIIa+ population previously shown to be highly enriched for CFU-MK. In contrast, the maximum number of megakaryocyte colonies from the GpIIb/IIIa- population stimulated by rhTPO was only 24.2% of that achieved with rrIL-3. Morphologic analysis of rhTPO-promoted megakaryocyte colonies from the GpIIb/IIIa+ population showed that the average colony size was smaller but that the mean diameter of individual megakaryocytes was larger than in megakaryocyte colonies promoted with rrIL-3. rhTPO plus rrIL-3, each at suboptimal concentrations, had an additive effect on proliferation of CFU-MK in the GpIIb/IIIa+ fraction, whereas rhTPO plus murine IL-6 or murine granulocyte-macrophage colony-stimulating factor (mG-M-CSF) modestly but significantly reduced megakaryocyte colony growth. These results indicate that TPO preferentially acts on GpIIb/IIIa+ late CFU-MK with lower proliferative capacity and interacts with some other cytokines in CFU-MK development.


Ultrapulsed fractional CO2 laser for the treatment of post-traumatic and pathological scars.
Scar management is a long-term process. A variety of modalities have been employed and, depending on scar type, treatment may be invasive and/or conservative. The purpose of this study was to evaluate a new CO2 laser resurfacing for post-traumatic and pathological scars and to compare this device with classic dermabrasion. The new fractionated ultrapulsed CO2 laser (Ultrapulse Encore, Lumenis Ltd., Santa Clara, CA) is equipped with two types of scanners: the first, ActiveFX, is non-sequential while the second, DeepFX, is sequential and produces microspot. From September 2008 to November 2008, a study on 60 patients was performed. The patients (average age 47.3 years) enrolled in this study had severely scarred skin and were divided into two groups of 30 people. All patients were Caucasian with skin type II or III. Each scar was photographed and scored by the authors using the Manchester Scar Scale (MSS). Follow-up ranged from 12-15 months. Sixty patients were analyzed in two homogeneous groups. Significant improvement in skin tone, texture and appearance of skin was noted in all patients treated with CO2 laser, lower improvement resulted with dermabrasion. Both subjects and investigators noted similar aesthetic improvement. No major complications were found for both groups and minor complications included transient erythema and edema. Fractional ultrapulsed CO2 laser resurfacing has proven to be both safe and effective. The efficacy and favorable side effects profile for this technology, with low incidence of pigmentary changes, make it a viable alternative for the treatment of moderate-to-severe scars.


The Prevalence and Management of Dehydration amongst Neonatal Admissions to General Paediatric Wards in Kenya-A Clinical Audit.
An audit of randomly selected case records of 810 patients admitted to 13 hospitals between December 2015 and November 2016 was done. Prevalence of dehydration was 19.7% (2293 of 11 636) [95% CI: 17.1-22.6%], range across hospitals was 9.4% to 27.0%. Most cases with dehydration were clinically diagnosed (82 of 153; 53.6%), followed by excessive weight loss (54 of 153; 35.3%) and abnormal urea/electrolytes/creatinine (23 of 153; 15.0%). Documentation of fluids prescribed was poor but, where data were available, Ringers lactate (30 of 153; 19.6%) and 10% dextrose (18 of 153; 11.8%) were mostly used. Only 17 of 153 (11.1%) children had bolus fluid prescription, and Ringer's lactate was most commonly used for bolus at a median volume per kilogram body weight of 20 ml/kg (interquartile range, 12-30 ml/kg). Neonatal dehydration is common, but current documentation may underestimate the burden. Heterogeneity in practice likely reflects the absence of guidelines that in turn reflects a lack of research informing practical treatment guidelines.


Ocular disorders in renal transplant patients.
This cross-sectional study was performed to determine ocular findings in renal transplant recipients and to correlate them with certain clinical characteristics related to transplantation. The study was performed on 150 patients who had received a renal transplant at least three months earlier and had serum creatinine levels < 3 mg/dL. All patients underwent a complete ophthalmologic examination. Clinical variables studied related to the transplant included cause of renal failure, duration of hemodialysis prior to transplantation and immunosuppressive regimen. Overall, 91 male and 59 female subjects with a mean age of 39.9 +/- 17.7 years were included. At least one ocular abnormality could be detected in 89.3% including impaired visual acuity < or = 20/25 (48.6%), conjunctival degeneration in the palpebral fissure (36.6%), posterior sub-capsular cataracts (24%), pinguecula (17.3%), retinal pigment epitheliopathy (14%), arteriovenous crossing changes (8.6%), proliferative diabetic retinopathy (6%), central serous chorioretinopathy and retinal vein occlusions (each in 3.3%), and non-proliferative diabetic retinopathy, optic nerve atrophy and diabetic macular edema (each in 2.7%). Abnormal ocular findings were not correlated with the underlying renal disorder or use of cyclosporine and prednisolone; however, they were positively correlated with transplant duration, pre-transplant dialysis duration and usage of azathioprine or mycophenolate mofetil. Our study suggests that ocular disorders are frequent among renal transplant patients especially with older transplants and those with a longer period of pre-transplant hemodialysis.


Streamlined downstream process for efficient and sustainable (Fab')2 antivenom preparation.
Antivenoms are the only validated treatment against snakebite envenoming. Numerous drawbacks pertaining to their availability, safety and efficacy are becoming increasingly evident due to low sustainability of current productions. Technological innovation of procedures generating therapeutics of higher purity and better physicochemical characteristics at acceptable cost is necessary. The objective was to develop at laboratory scale a compact, feasible and economically viable platform for preparation of equine F(ab')2 antivenom against Vipera ammodytes ammodytes venom and to support it with efficiency data, to enable estimation of the process cost-effectiveness. The principle of simultaneous caprylic acid precipitation and pepsin digestion has been implemented into plasma downstream processing. Balance between incomplete IgG breakdown, F(ab')2 over-digestion and loss of the active drug's protective efficacy was achieved by adjusting pepsin to a 1:30 substrate ratio (w/w) and setting pH at 3.2. Precipitation and digestion co-performance required 2 h-long incubation at 21 °C. Final polishing was accomplished by a combination of diafiltration and flow-through chromatography. In vivo neutralization potency of the F(ab')2 product against the venom's lethal toxicity was determined. Only three consecutive steps, performed under finely tuned conditions, were sufficient for preservation of the highest process recovery with the overall yield of 74%, comparing favorably to others. At the same time, regulatory requirements were met. Final product was aggregate- and pepsin-free. Its composition profile was analyzed by mass spectrometry as a quality control check. Impurities, present in minor traces, were identified mostly as IgG/IgM fragments, contributing to active drug. Specific activity of the F(ab')2 preparation with respect to the plasma was increased 3.9-fold. A highly streamlined mode for production of equine F(ab')2 antivenom was engineered. In addition to preservation of the highest process yield and fulfillment of the regulatory demands, performance simplicity and rapidity in the laboratory setting were demonstrated. Suitability for large-scale manufacturing appears promising.


The significance of radiolucent zones surrounding pedicle screws. Definition of screw loosening in spinal instrumentation.
We examined the radiographs from a prospective clinical study of fixation by pedicle screws and those from an experimental study in a sheep model. In the clinical study, instruments were removed from 21 patients after implantation for 11 to 16 months and the extraction torques of the screws were recorded. A structured protocol was used for the radiological examinations. In the experimental study, loaded pedicle screw instrumentations were implanted in the sheep for six or 12 weeks. After radiological examination the pull-out resistance and the histological characteristics were studied. In the clinical study, all screws with radiolucent zones had a significantly reduced mean extraction torque compared with screws without radiolucent zones (16 +/- 10 Ncm v 403 +/- 220 Ncm; p < 0.0001). In the experimental study the mean maximum pull-out resistance for the screws with radiolucent zones was significantly lower than for those with no radiolucency (243 +/- 156 N v2214 +/- 578 N; p = 0.0006) and the mean bone-to-screw contact was reduced for screws with zones compared with those without zones (8 +/- 9% v 55 +/- 29%; p = 0.0002). Our findings showed that all screws with radiolucent zones had low extraction torques or low pull-out resistance. A radiolucent zone is a good indicator of loosening of a pedicle screw.


Thermodynamically neutral Kubas-type hydrogen storage using amorphous Cr(III) alkyl hydride gels.
In this paper we present amorphous chromium(III) hydride gels that show promise as reversible room temperature hydrogen storage materials with potential for exploitation in mobile applications. The material uses hydride ligands as a light weight structural feature to link chromium(III) metal centres together which act as binding sites for further dihydrogen molecules via the Kubas interaction, the mode of hydrogen binding confirmed by high pressure Raman spectroscopy. The best material possesses a reversible gravimetric storage of 5.08 wt% at 160 bar and 25 °C while the volumetric density of 78 kgH2 m(-3) compares favourably to the DOE ultimate system goal of 70 kg m(-3). The enthalpy of hydrogen adsorption is +0.37 kJ mol(-1) H2 as measured directly at 40 °C using an isothermal calorimeter coupled directly to a Sieverts gas sorption apparatus. These data support a mechanism confirmed by computations in which the deformation enthalpy required to open up binding sites is almost exactly equal and opposite to the enthalpy of hydrogen binding to the Kubas sites, and suggests that this material can be used in on-board applications without a heat management system.


Reference moist smokeless tobacco-induced apoptosis in human monocytes/macrophages cell line MM6.
Moist smokeless tobacco use is associated with various types of oral injury, including leukoplakia and dipper's pouch, although the mechanism by which the injury is caused still remains unclear. One possible mechanism is that moist smokeless tobacco affects the inflammatory response. For example, a study by Johnson et al. demonstrated a reduction in the volume density of macrophages and increased inflammation and redness at the smokeless tobacco placement site when compared to non-placement site. The current study investigated the direct effect of reference moist smokeless tobacco extract (STE) exposure on the viability of MM6 monocyte/macrophage cell line. The exposure of MM6 cells to various concentrations of STE, led to a significant and dose-related decrease in cell viability. Furthermore, STE exposure resulted in an increase in Annexin V/PI positive cells, an increase in TUNEL-positive cells, and cleaved PARP staining all of which were inhibited by pre-incubation with a pan-caspase inhibitor, suggesting that the observed STE toxicity was due to the induction of apoptosis. Next, the role of various moist smokeless tobacco-derived components in STE-induced apoptosis of MM6 cells was investigated. Our findings suggest that STE-induced osmotic stress, but not exposure to nicotine, plays an important role in STE-induced apoptosis of MM6 cells. Together, these data show for the first time that STE exposure leads to the induction of apoptosis in human monocyte/macrophage cells, which appears to be induced in part, by reference STE-mediated osmotic stress.


Herbivory strongly influences among-population variation in reproductive output of Lythrum salicaria in its native range.
Herbivory can negatively affect several components of plant reproduction. Yet, because of a lack of experimental studies involving multiple populations, the extent to which differences in herbivory contribute to among-population variation in plant reproductive success is poorly known. We experimentally determined the effects of insect herbivory on reproductive output in nine natural populations of the perennial herb Lythrum salicaria along a disturbance gradient in an archipelago in northern Sweden, and we quantified among-population differentiation in resistance to herbivory in a common-garden experiment in the same area. The intensity of leaf herbivory varied >500-fold and mean female reproductive success >400-fold among the study populations. The intensity of herbivory was lowest in populations subject to strong disturbance from ice and wave action. Experimental removal of insect herbivores showed that the effect of herbivory on female reproductive success was correlated with the intensity of herbivory and that differences in insect herbivory could explain much of the among-population variation in the proportion of plants flowering and seed production. Population differentiation in resistance to herbivory was limited. The results demonstrate that the intensity of herbivory is a major determinant of flowering and seed output in L. salicaria, but that differences in herbivory are not associated with differences in plant resistance at the spatial scale examined. They further suggest that the physical disturbance regime may strongly influence the performance and abundance of perennial herbs and patterns of selection not only because of its effect on interspecific competition, but also because of effects on interactions with specialized herbivores.


Is mean platelet volume associated with the angiographic severity of coronary artery disease?
Platelet activation and aggregation play key roles both in the pathogenesis of atherosclerosis and in the developmentof acute thrombotic events. Platelet volume is a marker of platelet activation and function, and is measured usingmean platelet volume (MPV). To determine the relationship between MPV and angiographic Gensini and SYNTAX scores, which give information about the severity and complexity of coronary artery disease (CAD). This study included 435 consecutive patients undergoing elective coronary angiography. The complete blood countand biochemical examination of blood were obtained after 12 h of fasting. The independent association between MPV andthe severity of CAD was statistically evaluated using PASW Statistics 18 for Windows. Mean age of the study population was 58.4 ± 9.3 years, of whom 196 were female (45.1%) and 239 male (54.9%). Of the patients, 63.2% had CAD, 31.7% had diabetes mellitus, 61.8% had hypertension, 56.6% had hyperlipidaemia, and 38.6% were smokers. Mean Gensini score was 20.7 ± 31.1. According to Gensini scores, 160 of the patients (36.8%) hadnormal coronary arteries (Gensini score: 0), 134 of the patients (30.8%) had minimal CAD (Gensini score: 1-19), and 141 ofthem (32.4%) had severe CAD (Gensini score ≥ 20). Mean MPV values were 8.4 ± 1.0 fL in the group that had no CAD,8.7 ± 1.0 fL in the group with minimal CAD, and 9.3 ± 1.5 fL in the group with severe CAD. According to Spearman correlationanalysis, the positive relationship found between MPV and Gensini score was statistically significant (p < 0.001,r = 0.290). Likewise, SYNTAX score was also associated with MPV (p < 0.001, r = 0.504). We determined a positive correlation between MPV and Gensini and SYNTAX scores. Therefore, this simple haematology test can be used in determining cardiovascular disease burden besides other risk factors during routine clinical practice. For further information about this topic, large-scale studies are needed.


A mechanism for the coordination of proliferation and differentiation by spatial regulation of Fus2p in budding yeast.
Yeast cells induce the genes required for mating prior to the completion of mitosis. To ensure proper cell cycle progression prior to mating differentiation, a key cytoplasmic regulator of cell fusion, Fus2p, is sequestered in the nucleus by cyclin-dependent kinase (Cdk). In response to pheromone signaling, the mitogen-activated protein kinase Fus3p phosphorylates Ser 84 in Fus2p to drive nuclear export. We found that Fus3p becomes active and phosphorylates S84 as early as S phase, raising the question of how Cdk prevents inappropriate activation of Fus2p. Countering Fus3p, Cdk and a p21-activated kinase, Cla4p, maintain Fus2p's nuclear localization by phosphorylating Ser 67, which drives nuclear import and inhibits nuclear export. When Cdk and Cla4p activities drop after cell division, Fus3p promotes Fus2p export both via S84 phosphorylation and by down-regulating S67 phosphorylation. Thus, potential premature activation of Fus2p in mitosis is prevented by cell cycle-dependent phosphorylation that overrides the mating pheromone-induced phosphorylation that drives nuclear export.


Importance of the GluN2B carboxy-terminal domain for enhancement of social memories.
The N-methyl-D-aspartate (NMDA) receptor is known to be necessary for many forms of learning and memory, including social recognition memory. Additionally, the GluN2 subunits are known to modulate multiple forms of memory, with a high GluN2A:GluN2B ratio leading to impairments in long-term memory, while a low GluN2A:GluN2B ratio enhances some forms of long-term memory. Here, we investigate the molecular motif responsible for the differences in social recognition memory and olfactory memory in the forebrain-specific transgenic GluN2A overexpression mice and the forebrain-specific transgenic GluN2B overexpression mice by using two transgenic mouse lines that overexpress chimeric GluN2 subunits. The transgenic chimeric GluN2 subunit mice were tested for their ability to learn and remember fruit scents, male juveniles of the same strain, females of the same strain, male juveniles of another strain, and rodents of another species. The data presented here demonstrate that the GluN2B carboxy-terminal domain is necessary for enhanced social recognition memory in GluN2B transgenic overexpression mice. Furthermore, the GluN2A carboxy-terminal domain is responsible for the impaired long-term olfactory and social memory observed in the GluN2A overexpression mice.


SUMOylation silences heterodimeric TASK potassium channels containing K2P1 subunits in cerebellar granule neurons.
The standing outward K(+) current (IKso) governs the response of cerebellar granule neurons to natural and medicinal stimuli including volatile anesthetics. We showed that SUMOylation silenced half of IKso at the surface of cerebellar granule neurons because the underlying channels were heterodimeric assemblies of K2P1, a subunit subject to SUMOylation, and the TASK (two-P domain, acid-sensitive K(+)) channel subunits K2P3 or K2P9. The heterodimeric channels comprised the acid-sensitive portion of IKso and mediated its response to halothane. We anticipate that SUMOylation also influences sensation and homeostatic mechanisms in mammals through TASK channels formed with K2P1.


Epstein-Barr virus-derived plasmids replicate only once per cell cycle and are not amplified after entry into cells.
Some possible ways in which replication of plasmids containing the Epstein-Barr virus (EBV) plasmid maintenance origin, oriP, might be controlled were investigated. Virtually all plasmid molecules were found to replicate no more than once per cell cycle, whether replication was observed after stable introduction of the plasmids into cells by drug selection or during the first few cell divisions after introducing the DNA into cells. The presence in the cells of excess amounts of EBNA1, the only viral protein needed for oriP function, did not increase the number of oriP-replicated plasmids maintained by cells under selection. In the cell lines studied, EBNA1 and oriP seem to lack the capacity to override the cellular controls that limit DNA replication to one initiation event per DNA molecule per S phase. The multicopy status of EBV-derived, selectable plasmids appears to result from the initial uptake by cells of large numbers of plasmid molecules, the efficient maintenance of these plasmids, and the pressure of genetic selection against plasmid loss. Other unknown controls must be responsible for the amplification of EBV genomes soon after latent infection of cells.


Phase II trial of zanolimumab (HuMax-CD4) in relapsed or refractory non-cutaneous peripheral T cell lymphoma.
The efficacy and safety of zanolimumab (HuMax-CD4) in patients with relapsed or refractory peripheral T Cell lymphoma (PTCL) was evaluated. Twenty-one adult patients with relapsed or refractory CD4(+) PTCL of non-cutaneous type (angioimmunoblastic T cell lymphoma (AITL) n = 9, PTCL-not otherwise specified (NOS) n = 7, anaplastic large cell lymphoma (ALCL) n = 4 and enteropathy type T cell lymphoma n = 1) were treated in a single-arm multi-centre study, with weekly intravenous infusions of zanolimumab 980 mg for 12 weeks. Median age was 69 years (range 26-85). Seventeen of the patients had advanced stage disease (Ann Arbor stages III-IV). Objective tumour responses were obtained in 24% of the patients with two complete responses unconfirmed (CRu) and three partial responses (PR). One of the CRus lasted more than 252 d. Responses were obtained in different PTCL entities: AITL (n = 3), ALCL (n = 1) and PTCL-NOS (n = 1). In general, the trial drug was well tolerated with no major toxicity. Zanolimumab at a dose of 980 mg weekly demonstrated clinical activity and an acceptable safety profile in this poor-prognosis patient population, suggesting that the potential benefit combining zanolimumab with standard chemotherapy in the treatment of PTCL should be investigated.


Tumor-associated antigens identified early in mouse mammary tumor development can be effective vaccine targets.
Breast cancer vaccines composed of antigens identified by serological analysis of cDNA expression libraries (SEREX) induce antigen specific immune responses in patients but have had disappointing clinical benefits. While many attempts to modify the adjuvants and vaccine method have been tried, one issue not addressed was whether the SEREX tumor-associated antigens identified from late stages of disease were ideal targets. We questioned in the transgenic TgMMTV-neu mouse model whether the antigen repertoire is distinct between early and late stage breast cancer and whether the antigens identified via SEREX from transgenic mice with early or late stage tumors would elicit differential anti-tumor effects to address this question. Three early stage antigens, Pdhx, Stk39, and Otud6B, were identified from a SEREX screen of mice prior to development of palpable lesions. Formulated into a vaccine, each early antigen inhibited tumor growth (p < 0.0001). The antigens identified from mice with late stage tumors (Swap70, Gsn, and Arhgef2) were unable to inhibit tumor growth when used as vaccines (for example Gsn p = 0.26). Each of the three early stage antigens were essential for tumor survival in syngeneic mouse tumor cells and in human breast cancer cell lines across breast cancer subtypes. Silencing protein expression of the early antigens increased apoptosis (p < 0.0001 for all antigens in mouse and p < 0.05 for all antigens in human triple negative breast cancer) and decreased survival (p < 0.0001 for all antigens in mouse and human triple negative and HER2 positive breast cancer). Overexpression of the early stage antigens in women with breast cancer predicted worse prognosis (p = 0.03) while overexpression of late stage antigens did not impact prognosis (p = 0.09). These data suggest that antigens expressed earlier in breast tumor development and functionally relevant to breast tumor growth may be more effective targets for therapeutic breast cancer vaccines than antigens identified in later disease.


Immediate or early skin-to-skin contact after a Caesarean section: a review of the literature.
The World Health Organization and the United Nations International Children's Emergency Fund recommends that mothers and newborns have skin-to-skin contact immediately after a vaginal birth, and as soon as the mother is alert and responsive after a Caesarean section. Skin-to-skin contact can be defined as placing a naked infant onto the bare chest of the mother. Caesarean birth is known to reduce initiation of breastfeeding, increase the length of time before the first breastfeed, reduce the incidence of exclusive breastfeeding, significantly delay the onset of lactation and increase the likelihood of supplementation. The aim of this review is to evaluate evidence on the facilitation of immediate (within minutes) or early (within 1 h) skin-to-skin contact following Caesarean section for healthy mothers and their healthy term newborns, and identify facilitators, barriers and associated maternal and newborn outcomes. A range of electronic databases were searched for papers reporting research findings published in English between January 2003 and October 2013. Seven papers met the criteria. This review has provided some evidence that with appropriate collaboration skin-to-skin contact during Caesarean surgery can be implemented. Further evidence was provided, albeit limited, that immediate or early skin-to-skin contact after a Caesarean section may increase breastfeeding initiation, decrease time to the first breastfeed, reduce formula supplementation in hospital, increase bonding and maternal satisfaction, maintain the temperature of newborns and reduce newborn stress.


Ramucirumab, a fully human mAb to the transmembrane signaling tyrosine kinase VEGFR-2 for the potential treatment of cancer.
Angiogenesis is essential for tumor growth, invasion and metastasis, and is mediated, at least in part, by a large family of VEGF ligands and receptors. Ramucirumab, which is being developed by ImClone Systems Inc, is a fully human mAb that binds human VEGFR-2, thus blocking VEGF binding and inhibiting angiogenesis. Proof-of-concept preclinical studies with the mouse mAb DC-101 supported this hypothesis, and ramucirumab inhibited cell proliferation in vitro, as well as tumor progression in mouse xenograft models of human cancer. Ramucirumab was well tolerated on weekly and fortnightly schedules in phase I clinical trials in patients with advanced cancers; mechanism-related DLTs were hypertension and deep venous thrombosis. Stable disease was also observed in several patients treated on either schedule, and several patients on the weekly schedule exhibited partial responses. At the time of publication, ramucirumab was undergoing assessment in phase II trials as a monotherapy in hepatocellular, renal cell and ovarian carcinomas. Ramucirumab was also in phase II trials in combination with dacarbazine in melanoma, with mitoxantrone/prednisone in prostate cancer, with carboplatin/paclitaxel in NSCLC and with oxaliplatin/folinic acid/5-fluorouracil in colorectal cancer. A phase III trial in combination with docetaxel in breast cancer was also ongoing. Pending results from these trials, ramucirumab may be a useful addition to current antiangiogenic therapies. The results are awaited with interest.


Architectural Dynamics of CaMKII-Actin Networks.
Calcium-calmodulin-dependent kinase II (CaMKII) has an important role in dendritic spine remodeling upon synaptic stimulation. Using fluorescence video microscopy and image analysis, we investigated the architectural dynamics of rhodamine-phalloidin stabilized filamentous actin (F-actin) networks cross-linked by CaMKII. We used automated image analysis to identify F-actin bundles and crossover junctions and developed a dimensionless metric to characterize network architecture. Similar networks were formed by three different CaMKII species with a 10-fold length difference in the linker region between the kinase domain and holoenzyme hub, implying linker length is not a primary determinant of F-actin cross-linking. Electron micrographs showed that at physiological molar ratios, single CaMKII holoenzymes cross-linked multiple F-actin filaments at random, whereas at higher CaMKII/F-actin ratios, filaments bundled. Light microscopy established that the random network architecture resisted macromolecular crowding with polyethylene glycol and blocked ATP-powered compaction by myosin-II miniature filaments. Importantly, the networks disassembled after the addition of calcium-calmodulin and were then spaced within 3 min into compacted foci by myosin motors or more slowly (30 min) aggregated by crowding. Single-molecule total internal reflection fluorescence microscopy showed CaMKII dissociation from surface-immobilized globular actin exhibited a monoexponential dwell-time distribution, whereas CaMKII bound to F-actin networks had a long-lived fraction, trapped at crossover junctions. Release of CaMKII from F-actin, triggered by calcium-calmodulin, was too rapid to measure with flow-cell exchange (<20 s). The residual bound fraction was reduced substantially upon addition of an N-methyl-D-aspartate receptor peptide analog but not ATP. These results provide mechanistic insights to CaMKII-actin interactions at the collective network and single-molecule level. Our findings argue that CaMKII-actin networks in dendritic spines maintain spine size against physical stress. Upon synaptic stimulation, CaMKII is disengaged by calcium-calmodulin, triggering network disassembly, expansion, and subsequent compaction by myosin motors with kinetics compatible with the times recorded for the poststimulus changes in spine volume.


Discontinuing Psychotropic Drugs from Participants in Randomized Controlled Trials: A Systematic Review.
Methods and justifications for discontinuing psychotropic drugs in randomized controlled trials (RCTs), and RCTs' acknowledgement of possible withdrawal symptoms following discontinuation, have not been examined systematically, which this review aims to do. Study Eligibility, Data Extraction, and Synthesis: Publications in MEDLINE, EMBASE, and PsycINFO (2000-2017) randomly assigning participants diagnosed with mental disorders to discontinue antipsychotic, antidepressant, anticonvulsant, antimanic, mood-stabilizing, benzodiazepine, or stimulant drugs. Authors independently extracted data, devised a typology of trials, and assessed trials' recognition of with-drawal symptoms. Eighty RCTs (70% with industry participation) discontinued drugs from 5,757 participants to investigate relapse prevention (44%), successful dis-continuation (26%), architecture of withdrawal (14%), and practicality of discontinuation (10%). RCTs of stimulants, antidepressants, and antipsychotics mostly aimed to reach conclusions about relapse prevention by testing abrupt or rapid discontinuations; RCTs of benzodiazepines mostly aimed to reduce drug use by testing longer-lasting, supportive discontinuations. In 67% of RCTs, no justification was given for the specific discontinuation strategy, which lasted under 2 weeks in 60% of RCTs. Possible withdrawal confounding of trial outcomes was addressed in 14% of eligible RCTs. Only the published literature was searched. RCTs use drug discontinuation to study several key issues in psychopharmacology but infrequently justify how they implement it or acknowledge that possible withdrawal symptoms may threaten internal validity. Reappraising the use of drug discontinuation and the recognition of withdrawal symptoms in RCTs is required.


CB1 cannabinoid receptors mediate anxiolytic effects: convergent genetic and pharmacological evidence with CB1-specific agents.
Cannabinoids are known to modulate GABAergic and glutamatergic transmission in cortical areas, the former via CB1 and the latter via a novel receptor. Pharmacological data demonstrate that several widely used cannabinoid ligands bind to both receptors, which may explain the inconsistencies in their behavioural effects. Earlier we showed that the cannabinoid antagonist SR-141716A affected behaviour in both CB1 knockout and wild-type animals, and its effect (anxiolysis) was different from that of CB1 gene disruption (anxiogenesis). In the present experiments, we studied the effects of the CB1 antagonist AM-251, and the cannabinoid agonist WIN-55,212-2 in wild-type as well as in CB1 knockout mice. CB1 knockout mice showed higher scores of anxiety-like behaviour than the wild-type animals in the elevated plus-maze. Selective blockade of CB1 receptors by AM-251 (0.3, 1 and 3 mg/kg) increased anxiety-like behaviour dose-dependently in the wild-type mice but had no effect in the knockouts. In wild types, the cannabinoid agonist WIN-55,212-2 (1 and 3 mg/kg) caused a decrease in anxiety-like behaviour, which was abolished by the CB1-selective antagonist AM-251 (3 mg/kg). The same agonist did not change plus-maze behaviour in CB1 knockout animals. These data demonstrate at the behavioural level that AM-251 and, at low concentrations, WIN-55,212-2, are selective ligands of the CB1 cannabinoid receptor in mice. Our studies on the behavioural effects of the cannabinoid antagonist SR-141716A and the CB1 antagonist AM-251 show that the CB1 and the novel cannabinoid receptor mediate anxiolytic and anxiogenic effects, respectively. This suggests that agonists of the former, or antagonists of the latter, are promising new compounds in the pharmacotherapy of anxiety.


Year-round monitoring reveals prevalence of fatal bird-window collisions at the Virginia Tech Corporate Research Center.
Collisions with glass are a serious threat to avian life and are estimated to kill hundreds of millions of birds per year in the United States. We monitored 22 buildings at the Virginia Tech Corporate Research Center (VTCRC) in Blacksburg, Virginia, for collision fatalities from October 2013 through May 2015 and explored possible effects exerted by glass area and surrounding land cover on avian mortality. We documented 240 individuals representing 55 identifiable species that died due to collisions with windows at the VTCRC. The relative risk of fatal collisions at all buildings over the study period were estimated using a Bayesian hierarchical zero-inflated Poisson model adjusting for percentage of tree and lawn cover within 50 m of buildings, as well as for glass area. We found significant relationships between fatalities and surrounding lawn area (relative risk: 0.96, 95% credible interval: 0.93, 0.98) as well as glass area on buildings (RR: 1.30, 95% CI [1.05-1.65]). The model also found a moderately significant relationship between fatal collisions and the percent land cover of ornamental trees surrounding buildings (RR = 1.02, 95% CI [1.00-1.05]). Every building surveyed had at least one recorded collision death. Our findings indicate that birds collide with VTCRC windows during the summer breeding season in addition to spring and fall migration. The Ruby-throated Hummingbird (Archilochus colubris) was the most common window collision species and accounted for 10% of deaths. Though research has identified various correlates with fatal bird-window collisions, such studies rarely culminate in mitigation. We hope our study brings attention, and ultimately action, to address this significant threat to birds at the VTCRC and elsewhere.


Quantum quenches in the Dicke model: statistics of the work done and of other observables.
We study the statistics of the work done in a zero temperature quench of the coupling constant in the Dicke model describing the interaction between an ensemble of two level systems and a single bosonic mode. When either the final or the initial coupling constants approach the critical coupling lambdac that separates the normal and superradiant phases of the system, the probability distribution of the work done displays singular behavior. The average work tends to diverge as the initial coupling parameter is brought closer to the critical value lambdac. In contrast, for quenches ending close to criticality, the distribution of work has finite moments but displays a sequence of edge singularities. This contrasting behavior is related to the difference between the processes of compression and expansion of a particle subject to a sudden change in its confining potential. We confirm this by studying in detail the time-dependent statistics of other observables, such as the quadratures of the photons and the total occupation of the bosonic modes.


Hydralazine for essential hypertension.
Hypertension is associated with an increased risk of stroke, myocardial infarction and congestive heart failure. Hydralazine is a direct-acting vasodilator which has been used for the treatment of hypertension since the 1950's. Although it has largely been replaced by newer antihypertensive drugs with more acceptable tolerability profiles, hydralazine is still widely used in developing countries due to its lower cost. A review of its relative effectiveness compared to placebo on surrogate and clinical outcomes is justified. To quantify the effect of hydralazine compared to placebo in randomized controlled trials (RCTs) on all cause mortality, cardiovascular mortality, serious adverse events, myocardial infarctions, strokes, withdrawals due to adverse effects and blood pressure in patients with primary hypertension. We searched the following databases: Cochrane Central Register of Controlled Trials (to Second Quarter 2009), MEDLINE (2005-June 2009), International Pharmaceutical Abstracts (1970-June 2009) and EMBASE (2007-June 2009). Bibliographic citations from retrieved studies were also reviewed. No language restrictions were applied. We selected RCTs studying the effect of oral hydralazine compared to oral placebo in patients with primary hypertension. We excluded studies of patients with secondary hypertension or gestational hypertension. Two reviewers independently extracted data and assessed trial quality using the risk of bias tool. Data synthesis and analysis was performed using RevMan 5. The search strategy did not yield any randomized controlled trials comparing hydralazine to placebo for inclusion in this review. There is insufficient evidence to conclude on the effects of hydralazine versus placebo on mortality, morbidity, withdrawals due to adverse effects, serious adverse events, or systolic and diastolic blood pressure. Some of the adverse effects related to hydralazine that have been reported in the literature include reflex tachycardia, hemolytic anemia, vasculitis, glomerulonephritis, and a lupus-like syndrome. Hydralazine may reduce blood pressure when compared to placebo in patients with primary hypertension, however this data is based on before and after studies, not RCTs. Furthermore, its effect on clinical outcomes remains uncertain.


Silibinin, a plant extract with antioxidant and membrane stabilizing properties, protects exocrine pancreas from cyclosporin A toxicity.
Silymarin can be extracted from the milk thistle, and silibinin is the main component of the plant extract. Possibly due to their antioxidant and membrane-stabilizing properties, the compounds have been shown to protect different organs and cells against a number of insults. Thus liver, kidney, erythrocytes and platelets have been protected from the toxic effects of ethanol, carbon tetrachloride, cold ischemia and drugs, respectively. The effect of silibinin on endocrine and exocrine pancreas, however, has not been studied. We therefore investigated whether silibinin treatment attenuates cyclosporin A (CiA) toxicity on rat endocrine and exocrine pancreas. Groups of 15 male Wistar rats were treated for 8 days with CiA and/or silibinin. On day 9, endocrine and exocrine pancreatic functions were tested in vitro. At the end of the treatment period, blood glucose levels in vivo were significantly higher in rats treated with CiA while silibinin did not affect glucose levels. In vitro, insulin secretion was inhibited after treatment with silibinin, but amylase secretion was not affected. After treatment with CiA both insulin and amylase secretion were reduced. Silibinin and CiA had an additive inhibitory effect on insulin secretion, but silibinin attenuated CiA-induced inhibition of amylase secretion. Despite CiA treatment, amylase secretion was in fact restored to normal with the highest dose of silibinin. Thus silibinin inhibits glucose-stimulated insulin release in vitro, while not affecting blood glucose concentration in vivo. This combination of effects could be useful in the treatment of non-insulin-dependent diabetes mellitus. Furthermore, silibinin protects the exocrine pancreas from CiA toxicity. As this inhibitory effect is probably unspecific, silibinin may also protect the exocrine pancreas against other insult principles, such as alcohol.


Selectivity shift from paraffins to α-olefins in low temperature Fischer-Tropsch synthesis in the presence of carboxylic acids.
A shift of selectivity to long chain α-olefins has been observed during Fischer-Tropsch synthesis over Co catalysts in the presence of carboxylic acids. The total selectivity to α-olefins of 39% was obtained in the presence of acids. The effect has been ascribed to intermediate formation of esters which hinder secondary olefin hydrogenation.


Admission cardiotocography: Its role in predicting foetal outcome in high-risk obstetric patients.
Routine and continuous electronic monitoring of foetal heart rate (FHR) in labour has become an established obstetric practice in high-risk pregnancies in industrialised countries. However, the same may not be possible in non-industrialised countries where antenatal care is inadequate with a large number of high-risk pregnancies being delivered in crowded settings and inadequate health care provider to patient ratios. The objective of this study was to evaluate the predictive value of the admission cardiotocogram (CTG) in detecting foetal hypoxia at the time of admission in labour and to correlate the results of the admission CTG with the perinatal outcome in high-risk obstetric cases. This was a prospective observational study conducted in the labour and maternity ward of a hospital in Gangtok, India, during the period 2008 to 2010. The study included high-risk pregnant women, admitted via the emergency or outpatient department with a period of gestation ≥36 weeks, in first stage of labour with foetus in the cephalic presentation. All women were subjected to an admission CTG, which included a 20 minute recording of FHR and uterine contractions. One hundred and sixty patients were recruited. The majority of women were primigravida in the 21-30 years age group. About 42% patients were postdated pregnancy followed by pregnancy-induced hypertension (PIH) (15.6%) and premature rupture of membranes (PROM) (11.3%) as the major risk factors. The admission CTG were 'reactive' in 77%, 'equivocal' in 14.4% and 'ominous' in 8.7% women. Incidence of foetal distress, moderate-thick meconium stained liquor and neonatal intensive care unit (NICU) admission was significantly more frequent among patients with ominous test results compared with equivocal or reactive test results on admission. Incidence of vaginal delivery was more common when the test was reactive. The admission CTG appears to be a simple non-invasive test that can serve as a screening tool in 'triaging' foetuses of high-risk obstetric patients in non-industrialised countries with a heavy workload and limited resources.


A spatial frequency spectral peakedness model predicts discrimination performance of regularity in dot patterns.
Subjective assessments of spatial regularity are common in everyday life and also in science, for example in developmental biology. It has recently been shown that regularity is an adaptable visual dimension. It was proposed that regularity is coded via the peakedness of the distribution of neural responses across receptive field size. Here, we test this proposal for jittered square lattices of dots. We examine whether discriminability correlates with a simple peakedness measure across different presentation conditions (dot number, size, and average spacing). Using a filter-rectify-filter model, we determined responses across scale. Consistently, two peaks are present: a lower frequency peak corresponding to the dot spacing of the regular pattern and a higher frequency peak corresponding to the pattern element (dot). We define the "peakedness" of a particular presentation condition as the relative heights of these two peaks for a perfectly regular pattern constructed using the corresponding dot size, number and spacing. We conducted two psychophysical experiments in which observers judged relative regularity in a 2-alternative forced-choice task. In the first experiment we used a single reference pattern of intermediate regularity and, in the second, Thurstonian scaling of patterns covering the entire range of regularity. In both experiments discriminability was highly correlated with peakedness for a wide range of presentation conditions. This supports the hypothesis that regularity is coded via peakedness of the distribution of responses across scale.


Defining success for translational research organizations.
Translational research organizations (TROs) seek to enhance the clinical impact of scientific discoveries and play a multifaceted role characterized by multidisciplinary collaboration, outreach initiatives, and the provision of shared resources and facilities. Given this complexity, TROs require a flexible framework for performance assessment that tracks their progress, incentivizes fruitful activities, and aligns individuals throughout the organization. We suggest a framework that assesses TRO performance along seven main dimensions-funding, talent, creation, validation, dissemination, external uptake, and collaboration-and we encourage individual organizations to develop additional metrics as needed.


Laboratory Diagnosis of COVID-19: Current Issues and Challenges.
The COVID-19 outbreak has had a major impact on clinical microbiology laboratories in the past several months. This commentary covers current issues and challenges for the laboratory diagnosis of infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the preanalytical stage, collecting the proper respiratory tract specimen at the right time from the right anatomic site is essential for a prompt and accurate molecular diagnosis of COVID-19. Appropriate measures are required to keep laboratory staff safe while producing reliable test results. In the analytic stage, real-time reverse transcription-PCR (RT-PCR) assays remain the molecular test of choice for the etiologic diagnosis of SARS-CoV-2 infection while antibody-based techniques are being introduced as supplemental tools. In the postanalytical stage, testing results should be carefully interpreted using both molecular and serological findings. Finally, random-access, integrated devices available at the point of care with scalable capacities will facilitate the rapid and accurate diagnosis and monitoring of SARS-CoV-2 infections and greatly assist in the control of this outbreak.


Ipilimumab in the real world: the UK expanded access programme experience in previously treated advanced melanoma patients.
Before licensing, ipilimumab was first made available to previously treated advanced melanoma patients through an expanded access programme (EAP) across Europe. We interrogated data from UK EAP patients to inform future clinical practice. Clinicians registered in the UK EAP provided anonymized patient data using a prespecified variable fields datasheet. Data collected were baseline patient characteristics, treatment delivered, toxicity, response, progression-free survival and overall survival (OS). Data were received for 193 previously treated metastatic melanoma patients, whose primary sites were cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At baseline, 88% of patients had a performance status (PS) of 0-1 and 20% had brain metastases. Of the patients, 53% received all four planned cycles of ipilimumab; the most common reason for stopping early was disease progression, including death from melanoma. Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median progression-free survival and OS were 2.8 and 6.1 months, respectively; the 1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was significantly lower for patients with poorer PS (P<0.0001), low albumin concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline. These baseline characteristics are negative predictors of benefit from ipilimumab and should be taken into consideration before prescription.


Human Oral Buccal Microbiomes Are Associated with Farmworker Status and Azinphos-Methyl Agricultural Pesticide Exposure.
In a longitudinal agricultural community cohort sampling of 65 adult farmworkers and 52 adult nonfarmworkers, we investigated agricultural pesticide exposure-associated changes in the oral buccal microbiota. We found a seasonally persistent association between the detected blood concentration of the insecticide azinphos-methyl and the taxonomic composition of the buccal swab oral microbiome. Blood and buccal samples were collected concurrently from individual subjects in two seasons, spring/summer 2005 and winter 2006. Mass spectrometry quantified blood concentrations of the organophosphate insecticide azinphos-methyl. Buccal oral microbiome samples were 16S rRNA gene DNA sequenced, assigned to the bacterial taxonomy, and analyzed after "centered-log-ratio" transformation to handle the compositional nature of the proportional abundances of bacteria per sample. Nonparametric analysis of the transformed microbiome data for individuals with and without azinphos-methyl blood detection showed significant perturbations in seven common bacterial taxa (>0.5% of sample mean read depth), including significant reductions in members of the common oral bacterial genus Streptococcus Diversity in centered-log-ratio composition between individuals' microbiomes was also investigated using principal-component analysis (PCA) to reveal two primary PCA clusters of microbiome types. The spring/summer "exposed" microbiome cluster with significantly less bacterial diversity was enriched for farmworkers and contained 27 of the 30 individuals who also had azinphos-methyl agricultural pesticide exposure detected in the blood. In this study, we show in human subjects that organophosphate pesticide exposure is associated with large-scale significant alterations of the oral buccal microbiota composition, with extinctions of whole taxa suggested in some individuals. The persistence of this association from the spring/summer to the winter also suggests that long-lasting effects on the commensal microbiota have occurred. The important health-related outcomes of these agricultural community individuals' pesticide-associated microbiome perturbations are not understood at this time. Future investigations should index medical and dental records for common and chronic diseases that may be interactively caused by this association between pesticide exposure and microbiome alteration.


Robotic Roux-en-Y duodenojejunostomy for superior mesenteric artery syndrome: operative technique.
Superior mesenteric artery (SMA) syndrome, also known as Wilkie's syndrome, is a rare condition characterized by vascular compression of the duodenum that leads to intestinal obstruction. While there have been a few recent case reports of laparoscopic duodenojejunostomy performed as an option for surgical treatment, the role of the da Vinci(®) robot in superior mesenteric syndrome has been underestimated. The authors report a robotic Roux-en-Y duodenojejunostomy for the treatment of SMA syndrome. A 39-year-old man with a history of Amyotrophic lateral sclerosis presented with an upper gastrointestinal obstruction with distended abdomen. A computed tomography scan showed a transition in the third portion of the duodenum where the SMA vessels crossed over, with a decompressed jejunum. He was identified as a candidate for a duodenojejunostomy. The da Vinci Surgical System was used to mobilize the colon and duodenum, and a Roux-en-Y duodenojejunostomy was performed with hand-sewn anastomosis. There were no intraoperative complications. The blood loss was minimal and operative time was 120 minutes. The postoperative course was uneventful with resolution of intestinal obstruction. Robotic Roux-en-Y duodenojejunostomy as a surgical option for treatment of SMA syndrome is safe, feasible, and a valid alternative to open surgery with the added benefits of a minimally invasive approach.


Magnetic resonance elastography with guided pressure waves.
Magnetic resonance elastography aims to non-invasively and remotely characterize the mechanical properties of living tissues. To quantitatively and regionally map the shear viscoelastic moduli in vivo, the technique must achieve proper mechanical excitation throughout the targeted tissues. Although it is straightforward, ante manibus, in close organs such as the liver or the breast, which practitioners clinically palpate already, it is somewhat fortunately highly challenging to trick the natural protective barriers of remote organs such as the brain. So far, mechanical waves have been induced in the latter by shaking the surrounding cranial bones. Here, the skull was circumvented by guiding pressure waves inside the subject's buccal cavity so mechanical waves could propagate from within through the brainstem up to the brain. Repeatable, reproducible and robust displacement fields were recorded in phantoms and in vivo by magnetic resonance elastography with guided pressure waves such that quantitative mechanical outcomes were extracted in the human brain.


The clinical meaningfulness of ADAS-Cog changes in Alzheimer's disease patients treated with donepezil in an open-label trial.
In 6-month anti-dementia drug trials, a 4-point change in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is held to be clinically important. We examined how this change compared with measures of clinical meaningfulness. This is a secondary analysis of a 12 month open-label study of 100 patients (71 women) diagnosed with mild to moderate AD treated with 5-10 mg of donepezil daily. We studied the observed case, 6-month change from baseline on the ADAS-Cog, the Clinician's Interview Based Impression of Change-Plus Caregiver Input (CIBIC-Plus), patient-Goal Attainment Scaling (PGAS) and clinician-GAS (CGAS). At 6 months, donepezil-treated patients (n = 95) were more likely to show no change (+/- 3 points) on the ADAS-Cog (56%) than to improve (20%) or decline (24%) by 4-points. ADAS-Cog change scores were little correlated with other measures: from -0.09 for PGAS to 0.27 for the CIBIC-Plus. While patients who improved on the ADAS-Cog were less likely to decline on the clinical measures (26%), 43% of patients who declined on the ADAS-Cog improved on at least two of the clinical measures. The ADAS-Cog did not capture all clinically important effects. In general, ADAS-Cog improvement indicates clinical improvement, whereas many people with ADAS-Cog decline do not show clinical decline. The open-label design of this study does not allow us to know whether this is a treatment effect, which requires further investigation.


Stretched exponentials and tensionless glass in the plaquette Ising model.
Using Monte Carlo simulations, we show that the autocorrelation function C(t) in the d = 3 Ising model with a plaquette interaction has a stretched-exponential decay in a supercooled liquid phase. Such a decay characterizes also some ground-state probability distributions obtained from the numerically exact counting of up to 10(450) configurations. A related model with a strongly degenerate ground state but lacking glassy features does not exhibit such a decay. Although the stretched exponential decay of C(t) in the three-dimensional supercooled liquid is inconsistent with the droplet model, its modification that considers tensionless droplets might explain such a decay. An indication that tensionless droplets might play some role comes from the analysis of low-temperature domains that compose the glassy state. It shows that the energy of a domain of size l scales as l(1.15), hence these domains are indeed tensionless.