Medical Rapid Response in Psychiatry: Reasons for Activation and Immediate Outcome.
Rapid response teams are used to improve the recognition of acute deteriorations in medical and surgical settings. They are activated by abnormal physiological parameters, symptoms or clinical concern, and are believed to decrease hospital mortality rates. We evaluated the reasons for activation and the outcome of rapid response interventions in a 222-bed psychiatric hospital in New York City using data obtained at the time of all activations from January through November, 2012. The primary outcome was the admission rate to a medical or surgical unit for each of the main reasons for activation. The 169 activations were initiated by nursing staff (78.7 %) and psychiatrists (13 %) for acute changes in condition (64.5 %), abnormal physiological parameters (27.2 %) and non-specified concern (8.3 %). The most common reasons for activation were chest pain (14.2 %), fluctuating level of consciousness (9.5 %), hypertension (9.5 %), syncope or fall (8.9 %), hypotension (8.3 %), dyspnea (7.7 %) and seizures (5.9 %). The rapid response team transferred 127 (75.2 %) patients to the Emergency Department and 46 (27.2 %) were admitted to a medical or surgical unit. The admission rates were statistically similar for acute changes in condition, abnormal physiological parameters, and clinicians' concern. In conclusion, a majority of rapid response activations in a self-standing psychiatric hospital were initiated by nursing staff for changes in condition, rather than for policy-specified abnormal physiological parameters. The findings suggest that a rapid response system may empower psychiatric nurses to use their clinical skills to identify patients requiring urgent transfer to a general hospital.


What is the potential of oligodendrocyte progenitor cells to successfully treat human spinal cord injury?
Spinal cord injury is a serious and debilitating condition, affecting millions of people worldwide. Long seen as a permanent injury, recent advances in stem cell research have brought closer the possibility of repairing the spinal cord. One such approach involves injecting oligodendrocyte progenitor cells, derived from human embryonic stem cells, into the injured spinal cord in the hope that they will initiate repair. A phase I clinical trial of this therapy was started in mid 2010 and is currently underway. The theory underlying this approach is that these myelinating progenitors will phenotypically replace myelin lost during injury whilst helping to promote a repair environment in the lesion. However, the importance of demyelination in the pathogenesis of human spinal cord injury is a contentious issue and a body of literature suggests that it is only a minor factor in the overall injury process. This review examines the validity of the theory underpinning the on-going clinical trial as well as analysing published data from animal models and finally discussing issues surrounding safety and purity in order to assess the potential of this approach to successfully treat acute human spinal cord injury.


Modulation of chemotactic and pro-inflammatory activities of endothelial progenitor cells by hepatocellular carcinoma.
Endothelial progenitor cells (EPCs) participate in the neovascularization processes in the development of hepatocellular carcinoma (HCC). We investigated whether interactions between EPCs and HCC cells affect chemotactic and pro-inflammatory activities of EPCs. Two distinct phenotypes of circulating EPCs, i.e., myeloid-derived EPCs (colony forming unit-endothelial cells, CFU-ECs) and outgrowth EPCs (endothelial-colony forming cells, ECFCs), were co-cultured with Huh7 and Hep3B cells by using transwell chamber and IBIDI(TM) Culture-Inserts and μ-slide plates. Transwell and horizontal migration/invasion assays and time-lapse microscopy were used to monitor and analyze the migration and invasion of EPCs induced by these HCC cells. A human cytokine antibody array was used to compare protein expression profiles in EPCs and HCC cells. Flow cytometry and electromobility shift analysis were used to detect nuclear factor-κB (NF-κB)-DNA binding activity and pro-inflammatory adhesion molecule expression in EPCs. Ectopic full-length CC chemokine receptor 6 (CCR6) plasmid was used to transfect into ECFCs to investigate the role of CCR6 in HCC-induced EPC migration and invasion. The results show that co-culture with Huh7 and Hep3B cells induces the expression of endothelial cell (EC) markers KDR, Flt1, CD31 and VE-cadherin in CFU-ECs, but down-regulates the expressions of CD31 and VE-cadherin in ECFCs. These HCC cells induce migration and invasion of CFU-ECs, but not ECFCs, and do not affect the cell cycle distribution in these EPCs. Cytokine protein array identifies macrophage inflammatory protein-3α (MIP-3α) produced by HCC cells as a critical factor responsible for the HCC-induced chemotaxis of CFU-ECs, which highly express the specific MIP-3α counterreceptor CCR6. Overexpressing CCR6 in ECFCs significantly increases their chemotaxis in response to HCC cells. Co-culturing EPCs with HCC cells results in decreases in NF-κB binding activity and hence intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin expressions in EPCs. Our results indicate that HCC cells exert differential effects on CFU-ECs and ECFCs, with increased chemotaxis for CFU-ECs, but not ECFCs. This HCC-induced chemotaxis of CFU-ECs is mediated by MIP-3α produced by HCC cells, which targets to CCR6 on CFU-ECs. Tumors may provide a humoral microenvironment to attenuate the pro-inflammatory activity of EPCs, which might be associated with the tumor escape mechanism.


Cost-effectiveness of prolonged exposure therapy versus pharmacotherapy and treatment choice in posttraumatic stress disorder (the Optimizing PTSD Treatment Trial): a doubly randomized preference trial.
Cost-effectiveness of treatment for posttraumatic stress disorder (PTSD) may depend on type of treatment (eg, pharmacotherapy vs psychotherapy) and patient choice of treatment. We examined the cost-effectiveness of treatment with prolonged exposure therapy versus pharmacotherapy with sertraline, overall treatment preference, preference for choosing prolonged exposure therapy, and preference for choosing pharmacotherapy with sertraline from the US societal perspective. Two hundred patients aged 18 to 65 years with PTSD diagnosis based on DSM-IV criteria enrolled in a doubly randomized preference trial. Patients were randomized to receive their treatment of choice (n = 97) or to be randomly assigned treatment (n = 103). In the choice arm, patients chose either prolonged exposure therapy (n = 61) or pharmacotherapy with sertraline (n = 36). In the no-choice arm, patients were randomized to either prolonged exposure therapy (n = 48) or pharmacotherapy with sertraline (n = 55). The total costs, including direct medical costs, direct nonmedical costs, and indirect costs, were estimated in 2012 US dollars; and total quality-adjusted life-year (QALY) was assessed using the EuroQoL Questionnaire-5 dimensions (EQ-5D) instrument in a 12-month period. This study was conducted from July 2004 to January 2009. Relative to pharmacotherapy with sertraline, prolonged exposure therapy was less costly (-$262; 95% CI, -$5,068 to $4,946) and produced more QALYs (0.056; 95% CI, 0.014 to 0.100) when treatment was assigned, with 93.2% probability of being cost-effective at $100,000/QALY. Independently, giving a choice of treatment also yielded lower cost (-$1,826; 95% CI, -$4,634 to $749) and more QALYs (0.010; 95% CI, -0.019 to 0.044) over no choice of treatment, with 87.0% probability of cost-effectiveness at $100,000/QALY. Giving PTSD patients a choice of treatment appears to be cost-effective. When choice is not possible, prolonged exposure therapy may provide a cost-effective option over pharmacotherapy with sertraline. ClinicalTrials.gov identifier: NCT00127673.


The Impact of Environmental Factors in Influencing Epigenetics Related to Oxidative States in the Cardiovascular System.
Oxidative states exert a significant influence on a wide range of biological and molecular processes and functions. When their balance is shifted towards enhanced amounts of free radicals, pathological phenomena can occur, as the generation of reactive oxygen species (ROS) in tissue microenvironment or in the systemic circulation can be detrimental. Epidemic chronic diseases of western societies, such as cardiovascular disease, obesity, and diabetes correlate with the imbalance of redox homeostasis. Current advances in our understanding of epigenetics have revealed a parallel scenario showing the influence of oxidative stress as a major regulator of epigenetic gene regulation via modification of DNA methylation, histones, and microRNAs. This has provided both the biological link and a potential molecular explanation between oxidative stress and cardiovascular/metabolic phenomena. Accordingly, in this review, we will provide current insights on the physiological and pathological impact of changes in oxidative states on cardiovascular disorders, by specifically focusing on the influence of epigenetic regulation. A special emphasis will highlight the effect on epigenetic regulation of human's current life habits, external and environmental factors, including food intake, tobacco, air pollution, and antioxidant-based approaches. Additionally, the strategy to quantify oxidative states in humans in order to determine which biological marker could best match a subject's profile will be discussed.


Exact off-resonance near fields of small-size extended hemielliptic 2-D lenses illuminated by plane waves.
The near fields of small-size extended hemielliptic lenses made of rexolite and isotropic quartz and illuminated by E- and H-polarized plane waves are studied. Variations in the focal domain size, shape, and location are reported versus the angle of incidence of the incoming wave. The problem is solved numerically in a two-dimensional formulation. The accuracy of results is guaranteed by using a highly efficient numerical algorithm based on the combination of the Muller boundary integral equations, the method of analytical regularization, and the trigonometric Galerkin discretization scheme. The analysis fully accounts for the finite size of the lens as well as its curvature and thus can be considered as a reference solution for other electromagnetic solvers. Moreover, the trusted description of the focusing ability of a finite-size hemielliptic lens can be useful in the design of antenna receivers.


A Computational Model of Peripheral Photocoagulation for the Prevention of Progressive Diabetic Capillary Occlusion.
We developed a computational model of the propagation of retinal ischemia in diabetic retinopathy and analyzed the consequences of various patterns and sizes of burns in peripheral retinal photocoagulation. The model addresses retinal ischemia as a phenomenon of adverse local feedback in which once a capillary is occluded there is an elevated probability of occlusion of adjacent capillaries resulting in enlarging areas of retinal ischemia as is commonly seen clinically. Retinal burns of different sizes and patterns, treated as local oxygen sources, are predicted to have different effects on the propagation of retinal ischemia. The patterns of retinal burns are optimized with regard to minimization of the sum of the photocoagulated retina and computer predicted ischemic retina. Our simulations show that certain patterns of retinal burns are effective at preventing the spatial spread of ischemia by creating oxygenated boundaries across which the ischemia does not propagate. This model makes no statement about current PRP treatment of avascular peripheral retina and notes that the usual spot sizes used in PRP will not prevent ischemic propagation in still vascularized retinal areas. The model seems to show that a properly patterned laser treatment of still vascularized peripheral retina may be able to prevent or at least constrain the propagation of diabetic retinal ischemia in those retinal areas with intact capillaries.


Rationale for targeting BCL6 in MLL-rearranged acute lymphoblastic leukemia.
Chromosomal rearrangements of the mixed lineage leukemia (MLL) gene occur in ∼10% of B-cell acute lymphoblastic leukemia (B-ALL) and define a group of patients with dismal outcomes. Immunohistochemical staining of bone marrow biopsies from most of these patients revealed aberrant expression of BCL6, a transcription factor that promotes oncogenic B-cell transformation and drug resistance in B-ALL. Our genetic and ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) analyses showed that MLL-AF4 and MLL-ENL fusions directly bound to the BCL6 promoter and up-regulated BCL6 expression. While oncogenic MLL fusions strongly induced aberrant BCL6 expression in B-ALL cells, germline MLL was required to up-regulate Bcl6 in response to physiological stimuli during normal B-cell development. Inducible expression of Bcl6 increased MLL mRNA levels, which was reversed by genetic deletion and pharmacological inhibition of Bcl6, suggesting a positive feedback loop between MLL and BCL6. Highlighting the central role of BCL6 in MLL-rearranged B-ALL, conditional deletion and pharmacological inhibition of BCL6 compromised leukemogenesis in transplant recipient mice and restored sensitivity to vincristine chemotherapy in MLL-rearranged B-ALL patient samples. Oncogenic MLL fusions strongly induced transcriptional activation of the proapoptotic BH3-only molecule BIM, while BCL6 was required to curb MLL-induced expression of BIM. Notably, peptide (RI-BPI) and small molecule (FX1) BCL6 inhibitors derepressed BIM and synergized with the BH3-mimetic ABT-199 in eradicating MLL-rearranged B-ALL cells. These findings uncover MLL-dependent transcriptional activation of BCL6 as a previously unrecognized requirement of malignant transformation by oncogenic MLL fusions and identified BCL6 as a novel target for the treatment of MLL-rearranged B-ALL.


Missing data analysis using multiple imputation: getting to the heart of the matter.
Missing data are a pervasive problem in health investigations. We describe some background of missing data analysis and criticize ad hoc methods that are prone to serious problems. We then focus on multiple imputation, in which missing cases are first filled in by several sets of plausible values to create multiple completed datasets, then standard complete-data procedures are applied to each completed dataset, and finally the multiple sets of results are combined to yield a single inference. We introduce the basic concepts and general methodology and provide some guidance for application. For illustration, we use a study assessing the effect of cardiovascular diseases on hospice discussion for late stage lung cancer patients.


Gill morphometrics of the thresher sharks (Genus Alopias): Correlation of gill dimensions with aerobic demand and environmental oxygen.
Gill morphometrics of the three thresher shark species (genus Alopias) were determined to examine how metabolism and habitat correlate with respiratory specialization for increased gas exchange. Thresher sharks have large gill surface areas, short water-blood barrier distances, and thin lamellae. Their large gill areas are derived from long total filament lengths and large lamellae, a morphometric configuration documented for other active elasmobranchs (i.e., lamnid sharks, Lamnidae) that augments respiratory surface area while limiting increases in branchial resistance to ventilatory flow. The bigeye thresher, Alopias superciliosus, which can experience prolonged exposure to hypoxia during diel vertical migrations, has the largest gill surface area documented for any elasmobranch species studied to date. The pelagic thresher shark, A. pelagicus, a warm-water epi-pelagic species, has a gill surface area comparable to that of the common thresher shark, A. vulpinus, despite the latter's expected higher aerobic requirements associated with regional endothermy. In addition, A. vulpinus has a significantly longer water-blood barrier distance than A. pelagicus and A. superciliosus, which likely reflects its cold, well-oxygenated habitat relative to the two other Alopias species. In fast-swimming fishes (such as A. vulpinus and A. pelagicus) cranial streamlining may impose morphological constraints on gill size. However, such constraints may be relaxed in hypoxia-dwelling species (such as A. superciliosus) that are likely less dependent on streamlining and can therefore accommodate larger branchial chambers and gills.


Expanded GAA repeats impair FXN gene expression and reposition the FXN locus to the nuclear lamina in single cells.
Abnormally expanded DNA repeats are associated with several neurodegenerative diseases. In Friedreich's ataxia (FRDA), expanded GAA repeats in intron 1 of the frataxin gene (FXN) reduce FXN mRNA levels in averaged cell samples through a poorly understood mechanism. By visualizing FXN expression and nuclear localization in single cells, we show that GAA-expanded repeats decrease the number of FXN mRNA molecules, slow transcription, and increase FXN localization at the nuclear lamina (NL). Restoring histone acetylation reverses NL positioning. Expanded GAA-FXN loci in FRDA patient cells show increased NL localization with increased silencing of alleles and reduced transcription from alleles positioned peripherally. We also demonstrate inefficiencies in transcription initiation and elongation from the expanded GAA-FXN locus at single-cell resolution. We suggest that repressive epigenetic modifications at the expanded GAA-FXN locus may lead to NL relocation, where further repression may occur.


Search for lead structures to develop new allosteric modulators of muscarinic receptors.
Various compounds are known to allosterically modulate the binding of ligands to muscarinic receptors. Most of these compounds have another predominant pharmacological action. Identification of the potent representatives should be useful for the development of allosteric modulators that are specific and highly active. For various reasons, a direct comparison of allosteric potencies on the basis of literature data is difficult. Therefore, a series of compounds was compared with regard to the allosteric delay of the dissociation of N-[3H]methylscopolamine from porcine heart M2 receptors under the following assay conditions: "Na,K,Pi buffer", 4 mM Na2HPO4, 1 mM KH2PO4, pH 7.4, 23 degrees C; "Mg,Tris,Cl,Pi buffer', 50 mM Tris-HCl, 3 mM MgHPO4,pH 7.3, 37 degrees C. Generally, the allosteric potency of the compounds was higher in the Na,K,Pi buffer, compared with the Mg,Tris,Cl,Pi buffer. However, the extent of the potency shift differed, ranging from approximately 2-fold for tacrine to approximately 100-fold for gallamine. The concentration retarding radioligand dissociation to half of the control rate (EC50) served as a measure of allosteric potency. Under both assay conditions, alcuronium was the most potent compound (EC50,Na,K,Pi = 4 nM and EC50,Mg,Tris,Cl,Pi = 55 nM), followed by alkane-bisammonium and bispyridinium compounds containing phthalimido moieties. Gallamine showed intermediate potency (EC50 values of 180 nM and 16,000 nM in Na,K,Pi buffer and Mg,Tris,Cl,Pi buffer, respectively). Obidoxime and hexamethonium, both known to antagonize allosteric actions, revealed submaximal efficacy and low potency (EC50,Na,K,Pi of approximately 100,000 nM). The relevance of these results, regarding the identification of lead structures for the development of new allosteric modulators, is discussed.


Molecular Organization of an Adsorbed Layer: A Zwitterionic, pH-Sensitive Surfactant at the Air/Water Interface.
Neutron and X-ray reflection measurements have been used to study the structure of the adsorbed layer of a chelating surfactant at the air/liquid interface. The chelating surfactant 2-dodecyldiethylenetriaminepentaacetic acid (C12-DTPA) has a large headgroup containing eight donor atoms that can participate in the coordination of metal ions. The donor atoms are also titrating, resulting in an amphoteric surfactant that can adopt a number of differently charged species depending on the pH. Very strong coordination complexes are formed with metal ions, where the metal ion can be considered as part of the surfactant structure, in contrast to monovalent cations that act as regular counterions to the negative net charge. Adsorption was investigated over a large concentration interval, from well below the critical micelle concentration (cmc) to five times the cmc. The most striking result is the maximum in the surface excess found around the cmc, which is consistent with previous indications from surface tension measurements. Adding divalent metal ions has a limited effect on the adsorption at the air/liquid interface. The reason is the coordination of the metal ion, resulting in compensating deprotonation of the complex. Small variations in the headgroup area of different metal complexes are found, correlating to the conditional stability constants. Adding sodium chloride has a significant effect on the adsorption behavior, and the results indicate that the protonation equilibrium is more important than the ionic strength effects. From combined fits of the neutron and X-ray data, a model that consists of a thick headgroup region and a relatively thin dehydrated tail region is found, and it indicates that the tails are not fully extended and that the limiting area per molecule is determined by the bulky headgroup.


Pns12 protein of Rice dwarf virus is essential for formation of viroplasms and nucleation of viral-assembly complexes.
Cytoplasmic inclusion bodies, known as viroplasms or viral factories, are assumed to be the sites of replication of members of the family Reoviridae. Immunocytochemical and biochemical analyses were carried out to characterize the poorly understood viroplasms of the phytoreovirus Rice dwarf virus (RDV). Within 6 h of inoculation of cells, viroplasms, namely discrete cytoplasmic inclusions, were formed that contained the non-structural proteins Pns6, Pns11 and Pns12 of RDV, which appeared to be the constituents of the inclusions. Formation of similar inclusions in non-host insect cells upon expression of Pns12 in a baculovirus system and the association of molecules of Pns12 in vitro suggested that the inclusions observed in RDV-infected cells were composed basically of Pns12. Core proteins P1, P3, P5 and P7 and core virus particles were identified in the interior region of the inclusions. In contrast, accumulation of the outer capsid proteins P2, P8 and P9 and of intact virus particles was evident in the peripheral regions of the inclusions. These observations suggest that core particles were constructed inside the inclusions, whereas outer capsid proteins were assembled at the periphery of the inclusions. Viral inclusions were shown to be the sites of viral RNA synthesis by labelling infected cells with 5-bromouridine 5'-triphosphate. The number of viroplasms decreased with time post-inoculation as their sizes increased, suggesting that inclusions might fuse with one another during the virus-propagation process. Our results are consistent with a model, proposed for vertebrate reoviruses, in which viroplasms play a pivotal role in virus assembly.


Diffraction effects in optical microelectromechanical system Michelson interferometers.
We study the effect of diffraction on the performance of microelectromechanical system Michelson interferometers. By using a simple Gaussian model, we calculate the degradation of the interferometer visibility due to the diffraction effect. We then use this model to estimate the optimum detector diameter to maximize the fringe visibility at the interferometer output and study its effect on the resolution of Fourier transform spectrometers based on Michelson interferometers.


Escherichia coli ST410 among humans and the environment in Southeast Asia.
Escherichia coli ST410 (Ec-ST410) is an emerging, multidrug-resistant clone. Recent investigations of its global epidemiology and evolution have been based almost exclusively on isolates from Europe and North America. It is unclear whether Southeast Asian-origin Ec-ST410 (SEA-Ec-ST410) belong to these same clones or represent regionally disseminated variants. Antimicrobial resistance mechanisms among SEA-Ec-ST410 were characterised, and whether they belonged to regional variants was investigated by contextualising them within a global collection. Seven Ec-ST410 were identified among a recent collection of expanded-spectrum cephalosporin-resistant E. coli recovered from 91 healthy women (stool) and 26 infected patients (blood and urine) living in Phnom Penh, Cambodia. Nine additional Ec-ST410 genomes were identified from Thailand (n = 7) and Vietnam (n = 2) through EnteroBase and PubMed searches. The assembled genomes were characterised and a SNP-based phylogenetic tree was created comparing these 16 SEA-Ec-ST410 with a previously published Ec-ST410 collection, primarily sourced from Europe (97/128) and North America (24/128). SEA-Ec-ST410 belonged to several distinct branches within previously described clonal clades. SEA-Ec-ST410 within the B3/H24Rx sublineage encoded blaCTX-M-55 (8/12) and F18:A-:B1 plasmid replicons (6/12), neither of which were detected among other Ec-ST410 belonging to this clade. Three of four SEA-Ec-ST410 within the B4/H24RxC sublineage lacked both blaOXA-181 and an IncX3 plasmid replicon that were harboured by 97% and 100% of all other Ec-ST410 in this sublineage (n = 64), respectively. In conclusion, Ec-ST410 are present in Southeast Asia following multiple introductions. The unique pattern of antimicrobial resistance elements harboured by SEA-Ec-ST410 suggests independent circulation in the region.


EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials.
Epidemiologic and case-control data suggest that increased dietary intake of omega-3 long-chain polyunsaturated fatty acids (omega3 LC-PUFAs) may be of benefit in depression. However, the results of randomized controlled trials are mixed and controversy exists as to whether either eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) or both are responsible for the reported benefits. The aim of the current study was to provide an updated meta-analysis of all double-blind, placebo-controlled, randomized controlled trials examining the effect of omega3 LC-PUFA supplementation in which depressive symptoms were a reported outcome. The study also aimed to specifically test the differential effectiveness of EPA versus DHA through meta-regression and subgroup analyses. Studies were selected using the PubMed database on the basis of the following criteria: (1) randomized design; (2) placebo controlled; (3) use of an omega3 LC-PUFA preparation containing DHA, EPA, or both where the relative amounts of each fatty acid could be quantified; and (4) reporting sufficient statistics on scores of a recognizable measure of depressive symptoms. Two hundred forty-one studies were identified, of which 28 met the above inclusion criteria and were therefore included in the subsequent meta-analysis. Using a random effects model, overall standardized mean depression scores were reduced in response to omega3 LC-PUFA supplementation as compared with placebo (standardized mean difference = -0.291, 95% CI = -0.463 to -0.120, z = -3.327, p = 0.001). However, significant heterogeneity and evidence of publication bias were present. Meta-regression studies showed a significant effect of higher levels of baseline depression and lower supplement DHAEPA ratio on therapeutic efficacy. Subgroup analyses showed significant effects for: (1) diagnostic category (bipolar disorder and major depression showing significant improvement with omega3 LC-PUFA supplementation versus mild-to-moderate depression, chronic fatigue and non-clinical populations not showing significant improvement); (2) therapeutic as opposed to preventive intervention; (3) adjunctive treatment as opposed to monotherapy; and (4) supplement type. Symptoms of depression were not significantly reduced in 3 studies using pure DHA (standardized mean difference 0.001, 95% CI -0.330 to 0.332, z = 0.004, p = 0.997) or in 4 studies using supplements containing greater than 50% DHA (standardized mean difference = 0.141, 95% CI = -0.195 to 0.477, z = 0.821, p = 0.417). In contrast, symptoms of depression were significantly reduced in 13 studies using supplements containing greater than 50% EPA (standardized mean difference = -0.446, 95% CI = -0.753 to -0.138, z = -2.843, p = 0.005) and in 8 studies using pure ethyl-EPA (standardized mean difference = -0.396, 95% CI = -0.650 to -0.141, z = -3.051, p = 0.002). However, further meta-regression studies showed significant inverse associations between efficacy and study methodological quality, study sample size, and duration, thus limiting the confidence of these findings. The current meta-analysis provides evidence that EPA may be more efficacious than DHA in treating depression. However, owing to the identified limitations of the included studies, larger, well-designed, randomized controlled trials of sufficient duration are needed to confirm these findings.


Warfarin and acetaminophen interaction: a summary of the evidence and biologic plausibility.
Ms TS is a 66-year-old woman who receives warfarin for prevention of systemic embolization in the setting of hypertension, diabetes, and atrial fibrillation. She had a transient ischemic attack about 4 years ago when she was receiving aspirin. Her INR control was excellent; however, over the past few months it has become erratic, and her average dose required to maintain an INR of 2.0 to 3.0 appears to have decreased. She has had back pain over this same period and has been taking acetaminophen at doses at large as 650 mg four times daily, with her dose varying based on her symptoms. You recall a potential interaction and wonder if (1) her acetaminophen use is contributing to her loss of INR control, and (2) does this interaction place her at increased risk of warfarin-related complications?


Patient involvement in healthcare is associated with higher rates of surveillance for hepatocellular carcinoma.
Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrhosis, but earlier studies suggest that it is used less than one-third of the time. Patient factors associated with surveillance rates are incompletely understood. The aims of our study were to determine HCC surveillance rates in a tertiary-care center and to identify patient predictors of receiving surveillance. Patients with Child A or B cirrhosis seen in the University of Michigan liver clinics between October 2008 and March 2009 were enrolled to complete a self-administered survey. Surveillance rates and clinical data were extracted from the patient electronic medical record. Of the 160 patients enrolled, 74.4% had HCC surveillance performed in the past year. On multivariate analysis, predictors of receiving surveillance included male sex (odds ratio 7.1, 95% confidence interval, 1.2-43.2) and patient involvement in their care (odds ratio 3.4, 95% confidence interval, 1.5-7.9). Patients expressed high levels of concern regarding HCC, desired more information from their physicians, and wanted to be more involved in their care. HCC surveillance rates in a tertiary-care center were significantly higher than earlier reported rates. Direct patient involvement in decisions regarding HCC surveillance may help to improve surveillance rates.


Rapid evolution of distinct Helicobacter pylori subpopulations in the Americas.
For the last 500 years, the Americas have been a melting pot both for genetically diverse humans and for the pathogenic and commensal organisms associated with them. One such organism is the stomach-dwelling bacterium Helicobacter pylori, which is highly prevalent in Latin America where it is a major current public health challenge because of its strong association with gastric cancer. By analyzing the genome sequence of H. pylori isolated in North, Central and South America, we found evidence for admixture between H. pylori of European and African origin throughout the Americas, without substantial input from pre-Columbian (hspAmerind) bacteria. In the US, strains of African and European origin have remained genetically distinct, while in Colombia and Nicaragua, bottlenecks and rampant genetic exchange amongst isolates have led to the formation of national gene pools. We found three outer membrane proteins with atypical levels of Asian ancestry in American strains, as well as alleles that were nearly fixed specifically in South American isolates, suggesting a role for the ethnic makeup of hosts in the colonization of incoming strains. Our results show that new H. pylori subpopulations can rapidly arise, spread and adapt during times of demographic flux, and suggest that differences in transmission ecology between high and low prevalence areas may substantially affect the composition of bacterial populations.


Muscle Activity During Unilateral vs. Bilateral Battle Rope Exercises.
High training intensity is important for efficient strength gains. Although battle rope training is metabolically demanding, no studies have quantified intensity of muscle activity during this type of training. This study analyzes muscle activity during unilateral alternating waves vs. bilateral waves of battle rope training. Twenty-one volunteers participated in a repeated-measures study on 2 different occasions. Surface electromyographic signals were recorded from the anterior deltoid (AD), external oblique (OBLIQ), lumbar erector spinae (LUMB), and gluteus medius (GM) during bilateral waves and unilateral waves and were normalized to the maximum voluntary isometric contraction (MVIC). Results showed that muscle activity ranged from 51%MVIC to 73%MVIC for AD, OBLIQ, and LUMB, whereas GM muscle activity was only 14-18%MVIC. OBLIQ activation was significantly greater (20%MVIC; p = 0.02) with the unilateral waves compared with the bilateral waves, whereas LUMB signal was significantly higher (16%MVIC; p = 0.001) with the bilateral waves compared with the unilateral waves. In conclusion, both wave movements can be used to provide moderate to high levels of muscle activity in the AD, OBLIQ, and LUMB. Fitness practitioners aiming for higher OBLIQ activity should perform unilateral waves, whereas the bilateral variation of the movement can be used for higher LUMB activity.


The epidemiology of Japanese encephalitis on Taiwan during 1966-1997.
Japanese encephalitis (JE) is an endemic disease in Taiwan. A mass vaccination program of children against JE was first implemented in 1968. Along with general improvements in various aspects of living conditions over the years, the program has brought JE well under control. The main characteristics of JE epidemiology in Taiwan in the past 3 decades are as follows. The transmission mode remains unchanged-that is, the amplification stage of the virus in pigs is followed by a human epidemic each year. The frequency of JE incidence has dropped significantly. The incidence rate of confirmed cases was 2.05 per 100,000 in 1967, the highest in record, and merely 0.03 per 100,000 in 1997. Confirmed cases occur sporadically all over the island. The peak of the epidemic season has shifted from August in the 1960s to June since the 1980s. The age distribution of confirmed cases has shifted gradually from mainly children to adults. Vaccine efficacy for those having received more than 2 doses of the vaccine is estimated to be about 85%.


An miR-502-binding site single-nucleotide polymorphism in the 3'-untranslated region of the SET8 gene is associated with early age of breast cancer onset.
MicroRNAs regulate gene expression by binding to the 3'-untranslated region (UTR) of target genes. Single-nucleotide polymorphisms of critical genes may affect their regulation by microRNAs. We have identified a single-nucleotide polymorphism within the miR-502 seed binding region in the 3'-UTR of the SET8 gene. SET8 methylates TP53 and regulates genome stability. We investigated the role of this SET8 single-nucleotide polymorphism and in concert with the TP53 codon 72 single-nucleotide polymorphism in the propensity for onset of breast cancer. We measured the SET8 single-nucleotide polymorphisms in a case-control study on 1,110 breast cancer cases and 1,097 controls. The SET8 CC and TP53 GG genotypes were independently associated with an earlier age of breast cancer onset in an allele-dose-dependent manner (for SET8, 52.2 years for TT, 51.4 for TC, and 49.5 for CC; and for TP53, 53.1 years for CC, 51.5 for GC, 50.7 for GG). Individuals with combined SET8 CC and TP53 GG genotypes developed cancer at a median age of 47.7 years as compared with 54.6 years for individuals with combined SET8 TT and TP53 CC genotypes. In the 51 breast cancer tissue samples tested, the SET8 CC genotype was associated with reduced SET8, but not miR-502, transcript levels. These data suggest that the miR-502-binding site single-nucleotide polymorphism in the 3'-UTR of SET8 modulates SET8 expression and contributes to the early development of breast cancer, either independently or together with the TP53 codon 72 single-nucleotide polymorphism. Larger studies with multiethnic groups are warranted to validate our findings.


Soil and forest structure predicts large-scale patterns of occurrence and local abundance of a widespread Amazonian frog.
The distribution of biodiversity within the Amazon basin is often structured by sharp environmental boundaries, such as large rivers. The Amazon region is also characterized by subtle environmental clines, but how they might affect the distributions and abundance of organisms has so far received less attention. Here, we test whether soil and forest characteristics are associated with the occurrence and relative abundance of the forest-floor dwelling Aromobatid frog, Allobates femoralis. We applied a structured sampling regime along an 880 km long transect through forest of different density. High detection probabilities were estimated for A. femoralis in each of the sampling modules. Using generalized linear mixed-effects models and simple linear regressions that take detectability into account, we show that A. femoralis is more abundant in open forests than in dense forests. The presence and relative abundance of A. femoralis is also positively associated with clay-rich soils, which are poorly drained and therefore likely support the standing water bodies required for reproduction. Taken together, we demonstrate that relatively easy-to-measure environmental features can explain the distribution and abundance of a widespread species at different spatial scales. Such proxies are of clear value to ecologists and conservation managers working in large inaccessible areas such as the Amazon basin.


Inflammasome Regulates Hematopoiesis through Cleavage of the Master Erythroid Transcription Factor GATA1.
Chronic inflammatory diseases are associated with altered hematopoiesis that could result in neutrophilia and anemia. Here we report that genetic or chemical manipulation of different inflammasome components altered the differentiation of hematopoietic stem and progenitor cells (HSPC) in zebrafish. Although the inflammasome was dispensable for the emergence of HSPC, it was intrinsically required for their myeloid differentiation. In addition, Gata1 transcript and protein amounts increased in inflammasome-deficient larvae, enforcing erythropoiesis and inhibiting myelopoiesis. This mechanism is evolutionarily conserved, since pharmacological inhibition of the inflammasome altered erythroid differentiation of human erythroleukemic K562 cells. In addition, caspase-1 inhibition rapidly upregulated GATA1 protein in mouse HSPC promoting their erythroid differentiation. Importantly, pharmacological inhibition of the inflammasome rescued zebrafish disease models of neutrophilic inflammation and anemia. These results indicate that the inflammasome plays a major role in the pathogenesis of neutrophilia and anemia of chronic diseases and reveal druggable targets for therapeutic interventions.


Pilot study to explore effects of low-fat, flaxseed-supplemented diet on proliferation of benign prostatic epithelium and prostate-specific antigen.
Dietary factors may influence the prostate and have an impact on prostatic growth and disease. A small number of studies have suggested that flaxseed-supplemented, fat-restricted diets may thwart prostate cancer growth in both animals and humans. Unknown, however, is the potential effect of such a diet on benign prostatic epithelium. We undertook a pilot study to explore whether a flaxseed-supplemented, fat-restricted diet affects the proliferation rates in benign epithelium. We also explored the effects on circulating levels of prostate-specific antigen (PSA), total testosterone, and cholesterol. Fifteen men who were scheduled to undergo repeat prostate biopsy were instructed to follow a low-fat (less than 20% kcal), flaxseed-supplemented (30 g/day) diet and were provided with a supply of flaxseed to last throughout the 6-month intervention period. The PSA, total testosterone, and cholesterol levels were determined at baseline and at 6 months of follow-up. Reports from the original and repeat biopsies were compared, and proliferation (MIB-1) rates were quantified in the benign prostatic epithelium. Statistically significant decreases in PSA (8.47 +/- 3.82 to 5.72 +/- 3.16 ng/mL; P = 0.0002) and cholesterol (241.1 +/- 30.8 to 213.3 +/- 51.2 mg/dL; P = 0.012) were observed. No statistically significant change was seen in total testosterone (434.5 +/- 143.6 to 428.3 +/- 92.5 ng/dL). Although 6-month repeat biopsies were not performed in 2 cases because of PSA normalization, of the 13 men who underwent repeat biopsy, the proliferation rates in the benign epithelium decreased significantly from 0.022 +/- 0.027 at baseline to 0.007 +/- 0.014 at 6 months of follow-up (P = 0.0168). These pilot data suggest that a flaxseed-supplemented, fat-restricted diet may affect the biology of the prostate and associated biomarkers. A randomized controlled trial is needed to determine whether flaxseed supplementation, a low-fat diet, or a combination of the two regimens may be of use in controlling overall prostatic growth.


Pipeline Endovascular Device vs Stent-Assisted Coiling in Small Unruptured Aneurysms: A Cost-Effectiveness Analysis.
Both stent-assisted coiling (SAC) and flow diversion with the Pipeline Embolization device (PED; Medtronic Inc) have been shown to be safe and clinically effective for treatment of small (<10 mm) unruptured aneurysms. However, the economic impact of these different techniques has not been established. To analyze the cost-effectiveness between stent-assisted coiling and flow diversion using PED, including procedural costs, long-term outcomes, and aneurysm recurrence. A decision-analytical study was performed with Markov modeling methods to simulate patients undergoing SAC or PED for treatment for unruptured aneurysms of sizes 5 and 7 mm. Input probabilities were derived from prior literature, and 1-way, 2-way, and probabilistic sensitivity analyses (PSA) were performed. In base case calculation and PSA, PED was the dominant strategy for both the size groups, with and without consideration of indirect costs. One-way sensitivity analyses show that the conclusion remained robust when varying the retreatment rate of SAC from 0% to 50%, and only changes when the retreatment rate of PED > 49%. PED remained the more cost-effective strategy when the morbidity and mortality of PED increased by <55% and when those of SAC decreased by <37%. SAC only became cost-effective when the total cost of PED is >$73000 more expensive than the total cost of SAC. With increasing use of PED for treatment of small unruptured anterior circulation aneurysms, our study indicates that PED is cost-effective relative to stent coiling irrespective of aneurysm size. This is due to lower aneurysm recurrence rate, as well as better health outcomes.


In vivo administration of the anticancer agent bryostatin 1 activates platelets and neutrophils and modulates protein kinase C activity.
Bryostatin 1 is a naturally occurring macrocyclic lactone which when applied to cells in culture activates protein kinase C (PKC). In vivo bryostatin 1 functions as an anticancer agent with activity against murine lymphomas, leukemias, and melanoma. Because all organs and tissues contain PKC, normal cells would also be a likely target for this agent. Here we demonstrate that in vivo administration of bryostatin 1 activates platelets over a dose range of 0.4 to 40 micrograms/kg with half-maximal activation occurring at 3 micrograms/kg and stimulation of neutrophils over a similar dose range. This in vivo activation of neutrophils is associated with a rapid decrease in measurable cytosolic PKC, a finding consistent with translocation of the enzyme to the membrane. In contrast, no statistically significant change in PKC location was found in liver, spleen, brain, or L10A B-cell lymphoma. However, in culture the L10A lymphoma did respond to bryostatin 1 with translocation of PKC. To evaluate whether the lack of effect of bryostatin 1 on PKC in organs was secondary to rapid degradation, we developed a bioassay to measure the levels of bryostatin 1 in the blood. To measure the presence of bryostatin 1, human neutrophils were incubated with plasma from mice given injections of different concentrations of bryostatin 1. Using this assay, bryostatin 1 at levels as low as 60 nM could be measured in the plasma. A time course with this bioassay demonstrated that less than 10% of the bryostatin 1 injected was detectable after 2.5 min. These results demonstrate that bryostatin 1 is capable of activating platelets and neutrophils and modulating PKC in vivo. The lack of effect of bryostatin 1 on specific organs may be secondary to the rapid clearance/degradation of this compound from the blood.


Tetramethyleneethane Equivalents: Recursive Reagents for Serialized Cycloadditions.
New reactions and reagents that allow for multiple bond-forming events per synthetic operation are required to achieve structural complexity and thus value with step-, time-, cost-, and waste-economy. Here we report a new class of reagents that function like tetramethyleneethane (TME), allowing for back-to-back [4 + 2] cycloadditions, thereby amplifying the complexity-increasing benefits of Diels-Alder and metal-catalyzed cycloadditions. The parent recursive reagent, 2,3-dimethylene-4-trimethylsilylbutan-1-ol (DMTB), is readily available from the metathesis of ethylene and THP-protected 4-trimethylsilylbutyn-1-ol. DMTB and related reagents engage diverse dienophiles in an initial Diels-Alder or metal-catalyzed [4 + 2] cycloaddition, triggering a subsequent vinylogous Peterson elimination that recursively generates a new diene for a second cycloaddition. Overall, this multicomponent catalytic cascade produces in one operation carbo- and heterobicyclic building blocks for the synthesis of a variety of natural products, therapeutic leads, imaging agents, and materials. Its application to the three step synthesis of a new solvatochromic fluorophore, N-ethyl(6-N,N-dimethylaminoanthracene-2,3-dicarboximide) (6-DMA), and the photophysical characterization of this fluorophore are described.


Environmental Enteric Dysfunction and Growth Failure/Stunting in Global Child Health.
Approximately 25% of the world's children aged <5 years have stunted growth, which is associated with increased mortality, cognitive dysfunction, and loss of productivity. Reducing by 40% the number of stunted children is a global target for 2030. The pathogenesis of stunting is poorly understood. Prenatal and postnatal nutritional deficits and enteric and systemic infections clearly contribute, but recent findings implicate a central role for environmental enteric dysfunction (EED), a generalized disturbance of small intestinal structure and function found at a high prevalence in children living under unsanitary conditions. Mechanisms contributing to growth failure in EED include intestinal leakiness and heightened permeability, gut inflammation, dysbiosis and bacterial translocation, systemic inflammation, and nutrient malabsorption. Because EED has multiple causal pathways, approaches to manage it need to be multifaceted. Potential interventions to tackle EED include: (1) reduction of exposure to feces and contact with animals through programs such as improved water, sanitation, and hygiene; (2) breastfeeding and enhanced dietary diversity; (3) probiotics and prebiotics; (4) nutrient supplements, including zinc, polyunsaturated fatty acids, and amino acids; (5) antiinflammatory agents such as 5-aminosalicyclic acid; and (6) antibiotics in the context of acute malnutrition and infection. Better understanding of the underlying causes of EED and development of noninvasive, practical, simple, and affordable point-of-care diagnostic tools remain key gaps. "Omics" technologies (genomics, epigenomics, transcriptomics, proteomics, and metabolomics) and stable isotope techniques (eg, 13C breath tests) targeted at children and their intestinal microbiota will enhance our ability to successfully identify, manage, and prevent this disorder.


Role of YAP Activation in Nuclear Receptor CAR-Mediated Proliferation of Mouse Hepatocytes.
Constitutive androstane receptor (CAR) is a xenobiotic-responsive nuclear receptor that is highly expressed in the liver. CAR activation induces hepatocyte proliferation and hepatocarcinogenesis in rodents, but the mechanisms remain unclear. In this study, we investigated the association of CAR-dependent cell proliferation with Yes-associated protein (YAP), which is a transcriptional cofactor controlling organ size and cell growth through the interaction with various transcriptional factors including TEA domain family member (TEAD). In mouse livers, 1,4-bis-(2-[3,5-dichloropyridyloxy])benzene (TCPOBOP) (a mouse CAR [mCAR] activator) treatment increased the nuclear YAP accumulation and mRNA levels of YAP target genes as well as cell-cycle related genes along with liver hypertrophy and verteporfin (an inhibitor of YAP/TEAD interaction) cotreatment tended to attenuate them. Furthermore, in cell-based reporter gene assays, CAR activation enhanced the YAP/TEAD-dependent transcription. To investigate the role of YAP/TEAD activation in the CAR-dependent hepatocyte proliferation, we sought to establish an in vitro system completely reproducing CAR-dependent cell proliferation. Since CAR was only slightly expressed in cultured mouse primary hepatocytes compared with mouse livers and no proliferation was observed after treatment with TCPOBOP, we overexpressed CAR using mCAR expressing adenovirus (Ad-mCAR-V5) in mouse primary hepatocytes. Ad-mCAR-V5 infection and TCPOBOP treatment induced hepatocyte proliferation. Similar results were obtained with immortalized normal mouse hepatocytes as well. In the established in vitro system, CAR-dependent proliferation was strongly inhibited by Yap knockdown and completely abolished by verteporfin treatment. Our present results obtained in in vivo and in vitro experiments suggest that YAP/TEAD activation plays key roles in CAR-dependent proliferation of murine hepatocytes.


Pulmonary tumorlets with surrounding fibrous tissue--suspected carcinoma: case report and review of the literature.
Pulmonary tumorlets are small, often multiple nodular proliferations of pulmonary neuroendocrine cells. They are common incidental findings in chronic inflammatory pulmonary diseases. They can also be found in normal lung parenchyma and as one part of the continuum known as diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. In many cases, they are incidental histologic findings of no importance or clinical consequences, or they can be associated with a very slow progression of either obstructive or mixed obstructive/restrictive impairment with good prognosis. Only rarely, they metastasize to an adjacent lymph node or produce ectopic neuroendocrine products. When found during diagnostic examination, they represent a doubt to be a malignant tumor until proven otherwise, which is often impossible without biopsy or surgical removal of the adjacent lung lobe. Hereby, we present a patient with a persistent nodular lung structure after being treated for nonspecific symptoms, cough with non purulent sputum and pain among the scapulae, for a period of one month. He had otherwise normal clinical and laboratory findings, except for a mild mixed obstructive/restrictive pattern of impairment that was shown by lung spirometry. After 8 months, he underwent lobectomy of the medial lobe of the lung with partial lymphadenectomy, since the diagnostic methods applied could not define the nature of lung nodular infiltration. Histologic examination showed a few tumorlets surrounded by the fibrous tissue with a very dense lymphocyte infiltration. We present a review of the literature and emphasize the necessity to include tumorlets with adjacent fibrosis as part of the differential diagnosis of a solitary nodular lung structure.


Monitoring cell-cell contacts in vivo in transgenic animals.
We used a synthetic genetic system based on ligand-induced intramembrane proteolysis to monitor cell-cell contacts in animals. Upon ligand-receptor interaction in sites of cell-cell contact, the transmembrane domain of an engineered receptor is cleaved by intramembrane proteolysis and releases a protein fragment that regulates transcription in the interacting partners. We demonstrate that the system can be used to regulate gene expression between interacting cells, both in vitro and in vivo, in transgenic Drosophila We show that the system allows for detection of interactions between neurons and glia in the Drosophila nervous system. In addition, we observed that when the ligand is expressed in subsets of neurons with a restricted localization in the brain it leads to activation of transcription in a selected set of glial cells that interact with those neurons. This system will be useful to monitor cell-cell interactions in animals, and can be used to genetically manipulate cells that interact with one another.


Terahertz vibrational modes of the rigid crystal phase of succinonitrile.
Succinonitrile (N ≡ C-CH2-CH2-C ≡ N), an orientationally disordered molecular plastic crystal at room temperature, exhibits rich phase behavior including a solid-solid phase transition at 238 K. In cooling through this phase transition, the high-temperature rotational disorder of the plastic crystal phase is frozen out, forming a rigid crystal that is both spatially and orientationally ordered. Using temperature-dependent terahertz time-domain spectroscopy, we characterize the vibrational modes of this low-temperature crystalline phase for frequencies from 0.3 to 2.7 THz and temperatures ranging from 20 to 220 K. Vibrational modes are observed at 1.122 and 2.33 THz at 90 K. These modes are assigned by solid-state density functional theory simulations, corresponding respectively to the translation and rotation of the molecules along and about their crystallographic c-axis. In addition, we observe a suppression of the phonon modes as the concentration of dopants, in this case a lithium salt (LiTFSI), increases, indicating the importance of doping-induced disorder in these ionic conductors.


Doctor Shopping Behavior for Zolpidem Among Insomnia Patients in Taiwan: A Nationwide Population-Based Study.
Although zolpidem is listed as a controlled drug in Taiwan, patients' behavior has not been restricted and has led to the problem of doctor shopping behavior (DSB), leading to overutilization of medical resources and excess spending. The National Health Insurance Administration in Taiwan has instituted a new policy to regulate physicians' prescribing behavior and decrease DSB. This retrospective study aimed to analyze the DSB for zolpidem by insomnia patients and assess related factors. Data were extracted from the Longitudinal Health Insurance Database in Taiwan. Individuals with a diagnosis of insomnia who received more than one prescription of zolpidem in 2008 were followed for 24 mo. Doctor shopping was defined as ≥ 2 prescriptions by different doctors within ≥ 1 day overlapping in the duration of therapy. The percentage of zolpidem obtained through doctor shopping was used as an indicator of the DSB of each patient. Among the 6,947 insomnia patients who were prescribed zolpidem, 1,652 exhibited DSB (23.78%). The average dose of zolpidem dispensed for each patient during 24 mo was 244.21 daily defined doses. The doctor shopping indicator (DSI) was 0.20 (standard deviation, 0.23) among patients with DSB. Younger age, chronic diseases, high number of diseases, higher premium status, high socioeconomic status, and fewer people served per practicing physicians were all factors significantly related to doctor shopping behavior. Doctor shopping for zolpidem appears to be an important issue in Taiwan. Implementing a proper referral system with efficient data exchange by physician or pharmacist-led medication reconciliation process might reduce DSB.


The endocannabinoid system: a promising target for the management of type 2 diabetes.
Type 2 diabetes is closely related to abdominal obesity and is generally associated with other cardiometabolic risk factors, resulting in a high incidence of cardiovascular complications. Several animal and human observations suggest that the endocannabinoid (EC) system is overactivated in presence of abdominal obesity and/or diabetes, and contributes to disturbances of energy balance and metabolism. Not only it regulates the intake of nutrients through central mechanisms located within the hypothalamus and limbic area, but it also intervenes in transport, metabolism and deposit of the nutrients in the digestive tract, liver, adipose tissue, skeletal muscle, and possibly pancreas. Activation of both central and peripheral CB1 receptors promotes weight gain and associated metabolic changes. Conversely, rimonabant, the first selective CB(1) receptor antagonist in clinical use, has been shown to reduce body weight, waist circumference, triglycerides, blood pressure, insulin resistance and C-reactive protein levels, and to increase HDL cholesterol and adiponectin concentrations in both non-diabetic and diabetic overweight/obese patients. In addition, a 0.5-0.7% reduction in glycated hemoglobin (HbA1c) levels was observed in metformin- or sulfonylurea-treated patients with type 2 diabetes and in drug-naive or insulin-treated diabetic patients. Almost half of metabolic changes occurred beyond weight loss, in agreement with direct peripheral effects. Rimonabant was generally well-tolerated, but with a slightly higher incidence of depressed mood disorders, anxiety, nausea and dizziness compared to placebo. New trials are supposed to confirm the potential role of rimonabant (and other CB1 neutral antagonists or inverse agonists) in overweight/obese patients with type 2 diabetes and high risk cardiovascular disease.


Autotaxin through lysophosphatidic acid stimulates polarization, motility, and transendothelial migration of naive T cells.
Blood-borne lymphocytes home to lymph nodes by interacting with and crossing high endothelial venules (HEVs). The transendothelial migration (TEM) step is poorly understood. Autotaxin (ATX) is an ectoenzyme that catalyzes the conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a bioactive lipid and a close relative of sphingosine 1-phosphate. HEVs produce and secrete ATX into the blood. A prior study implicated ATX in the overall homing process, but the step in which it functions and its mechanism of action have not been defined. In this article, we show that HA130, an inhibitor of the enzymatic activity of ATX, slows T cell migration across lymph node HEVs in vivo. Ex vivo, ATX plus LPC or LPA itself induces the polarization of mouse naive T cells and stimulates their motility on an ICAM-1 substratum. Under physiologic shear conditions in a flow chamber, LPA or ATX/LPC strongly enhances TEM of integrin-arrested T cells across an endothelial monolayer. HA130 blunts the TEM-promoting activity of ATX, paralleling its in vivo effects. T cells possess Mn(+2)-activatable receptors for ATX, which are localized at the leading edge of polarized cells. ATX must bind to these receptors to elicit a maximal TEM response, providing a mechanism to focus the action of LPA onto arrested lymphocytes in flowing blood. Our results indicate that LPA produced via ATX facilitates T cell entry into lymph nodes by stimulating TEM, substantiating an additional step in the homing cascade. This entry role for LPA complements the efflux function of sphingosine 1-phosphate.


Comparative studies of spermatogenesis in fertile and subfertile men.
Testicular biopsy specimens from 16 fertile and 10 subfertile men with normal male karyotype were studied quantitatively to provide histological and cytogenetic data for a basis of reference in assessing abnormalities of spermatogenesis. Histological studies included estimation of the proportion and activity of germinal epithelium and an assessment of tubular morphology. In cytogenetic preparations, counts were made of cells at different stages of meiosis. Studies of cells at diakinesis included chiasma counts and percentage of cells with dissociated sex chromosomes. One fertile and six subfertile men showed decreased germinal activity; the six subfertile men also had decreased MII/MI ratios. Other findings were similar in the two groups.


Contextual influences on polydrug use among young, low-income women: effects of neighborhood and personal networks.
This study assessed contextual risks for polydrug use in a triethnic sample (non-Hispanic white, African American, Hispanic) of young women with a low income. For the current analysis, a total of 712 young women aged 18 to 31 years who sought care in state-funded family planning clinics in southeast Texas from December 2001 to May 2003 participated in the survey. The main outcome of the study was the number of illicit drugs (including marijuana, MDMA [ecstasy], crack cocaine, and other hard drugs) used in the last 12 months. Of the 712 subjects, 198 (28%) reported using illicit drugs in the past 12 months. Neighborhood socioeconomic status was significantly associated with drug use in a bivariate model. The proportion of women living in the most advantaged neighborhoods who reported drug use was more than twice that of women living in the most disadvantaged neighborhoods. However, the significance of neighborhood socioeconomic status was eliminated after controlling for ethnicity or for personal network characteristics in a multivariate ordinal logistic regression model. In contrast, in multivariate models, personal network indicators, such as a larger number of monthly contacts with friends (odds ratio [OR] = 1.32, 95% confidence interval [CI] = 1.11, 1.56) and a larger number of friends who used illicit drugs (OR = 1.47, 95% CI = 1.33, 1.62) were associated with increased drug use. In addition, not being currently married (vs. being married) (OR = 2.73, 95% CI = 1.44, 5.16) was associated with a larger number of drugs used in the last 12 months. In conclusion, we found that neighborhood socioeconomic status was not directly associated with more drug use when controlling for ethnicity or for personal network characteristics. Personal networks may mediate the relationships between neighborhood and drug use. Strategies to reduce polydrug use should target personal networks where friends use illicit drugs.


Altered temporal correlations in parietal alpha and prefrontal theta oscillations in early-stage Alzheimer disease.
Encoding and retention of information in memory are associated with a sustained increase in the amplitude of neuronal oscillations for up to several seconds. We reasoned that coordination of oscillatory activity over time might be important for memory and, therefore, that the amplitude modulation of oscillations may be abnormal in Alzheimer disease (AD). To test this hypothesis, we measured magnetoencephalography (MEG) during eyes-closed rest in 19 patients diagnosed with early-stage AD and 16 age-matched control subjects and characterized the autocorrelation structure of ongoing oscillations using detrended fluctuation analysis and an analysis of the life- and waiting-time statistics of oscillation bursts. We found that Alzheimer's patients had a strongly reduced incidence of alpha-band oscillation bursts with long life- or waiting-times (< 1 s) over temporo-parietal regions and markedly weaker autocorrelations on long time scales (1-25 seconds). Interestingly, the life- and waiting-times of theta oscillations over medial prefrontal regions were greatly increased. Whereas both temporo-parietal alpha and medial prefrontal theta oscillations are associated with retrieval and retention of information, metabolic and structural deficits in early-stage AD are observed primarily in temporo-parietal areas, suggesting that the enhanced oscillations in medial prefrontal cortex reflect a compensatory mechanism. Together, our results suggest that amplitude modulation of neuronal oscillations is important for cognition and that indices of amplitude dynamics of oscillations may prove useful as neuroimaging biomarkers of early-stage AD.


Ca(2+)-independent F-actin assembly and disassembly during Fc receptor-mediated phagocytosis in mouse macrophages.
Phagocytosis of IgG-coated particles by macrophages is presumed to involve the actin-based cytoskeleton since F-actin accumulates beneath forming phagosomes, and particle engulfment is blocked by cytochalasins, drugs that inhibit actin filament assembly. However, it is unknown whether Fc receptor ligation affects the rate or extent of F-actin assembly during phagocytosis of IgG-coated particles. To examine this question we have used a quantitative spectrofluorometric method to examine F-actin dynamics during a synchronous wave of phagocytosis of IgG-coated red blood cells by inflammatory mouse macrophages. We observed a biphasic rise in macrophage F-actin content during particle engulfment, with maxima at 1 and 5 min after the initiation of phagocytosis. F-actin declined to resting levels by 30 min, by which time particle engulfment was completed. These quantitative increases in macrophage F-actin were reflected in localized changes in F-actin distribution. Previous work showed that the number of IgG-coated particles engulfed by macrophages is unaffected by buffering extracellular calcium or by clamping cytosolic free calcium concentration ([Ca2+]i) to very low levels (Di Virgilio, F., B. C. Meyer, S. Greenberg, and S. C. Silverstein. 1988. J. Cell Biol. 106: 657-666). To determine whether clamping [Ca2+]i in macrophages affects the rate of particle engulfment, or the assembly or disassembly of F-actin during phagocytosis, we examined these parameters in macrophages whose [Ca2+]i had been clamped to approximately less than 3 nM with fura 2/AM and acetoxymethyl ester of EGTA. We found that the initial rate of phagocytosis, and the quantities of F-actin assembled and disassembled were similar in Ca(2+)-replete and Ca(2+)-depleted macrophages. We conclude that Fc receptor-mediated phagocytosis in mouse macrophages is accompanied by an ordered sequence of assembly and disassembly of F-actin that is insensitive to [Ca2+]i.


The discovery and development of boceprevir.
Boceprevir was the first direct acting agent developed for the treatment of hepatitis C virus infection. Boceprevir functions by targeting NS3 protease, a viral enzyme essential for replication. This peptidomimetic molecule was optimized from a peptide lead to provide a potent, selective and orally bioavailable drug that can be combined with ribavirin and peg interferon to achieve sustained viral response (undetectable HCV RNA levels for 24 weeks after completion of therapy) in patients infected with Genotype 1 of the virus. This article provides a review of the pre-clinical and clinical discovery of boceprevir. This review includes the role and function of its molecular target, NS3 protease, as well as the assays used to measure in vitro efficacy, compound optimization and clinical studies to demonstrate safety and efficacy. As the first direct acting anti-HCV agent, boceprevir represents an important advance in therapy of this widespread chronic disease. Yet, while this therapy is a valuable approach, it does have limitations. Studies have suggested that 30% of patients do not achieve sustained viral response and 11% of patients have developed anemia and/or neutropenia. Current drug discovery and development efforts are underway to develop novel therapeutic options that address these issues.


Segmental analysis of carotid arterial strain using speckle-tracking.
Increased arterial stiffness has been shown to be associated with aging and cardiovascular risk factors. Speckle-tracking algorithms are being used to measure myocardial strain. The aims of this study were to evaluate whether speckle-tracking could be used to measure carotid arterial strain (CAS) reproducibly in healthy volunteers and to determine if CAS was lesser in individuals with diabetes. Bilateral electrocardiographically gated ultrasound scans of the distal common carotid arteries (three cardiac cycles; 14-MHz linear probe; mean frame rate, 78.7 ± 8.9 frames/sec) were performed twice (2-4 days apart) on 10 healthy volunteers to test repeatability. Differences in CAS between healthy subjects (n = 20) and patients with diabetes (n = 21) were examined. Peak CAS was measured in each of six equal segments, and averages of all segments (i.e., the global average), of the three segments nearest the probe, and of the three segments farthest from the probe (i.e., the far wall average) were obtained. Global CAS (intraclass correlation coefficient = 0.40) and far wall average (intraclass correlation coefficient = 0.63) had the greatest test-retest reliability. Global and far wall averaged CAS values were lower in patients with diabetes (4.29% [SE, 0.27%] and 4.30% [SE, 0.44%], respectively) than in controls (5.48% [SE, 0.29%], P = .001, and 5.58% [SE, 0.44%], P = .003, respectively). This difference persisted after adjustment for age, gender, race, and hemodynamic parameters. Speckle-tracking to measure CAS is feasible and modestly reliable. Patients with diabetes had lower CAS obtained with speckle-tracking compared with healthy controls.


SNP analysis of follistatin gene associated with polycystic ovarian syndrome.
Follistatin has been reported as a candidate gene for polycystic ovarian syndrome (PCOS) based on linkage and association studies. In this study, investigation of polymorphisms in the FST gene was done to determine if genetic variation is associated with susceptibility to PCOS. The nucleotide sequence of human follistatin and the protein sequence of human follistatin were retrieved from the NCBI database using Entrez. The follistatin protein of human was retrieved from the Swiss-Prot database. There are 344 amino acids and the molecular weight is 38,007 Da. The ProtParam analysis shows that the isoelectric point is 5.53 and the aliphatic index is 61.25. The hydropathicity is -0.490. The domains in FST protein are as follows: Pfam-B 5005 domain from 1 to 92; EGF-like subdomain from 93 to 116; Kazal 1 domain, occurred in three places, namely, 118-164, 192-239, and 270-316. There are 31 single-nucleotide polymorphisms (SNPs) for this gene. Some are nonsynonymous, some occur in the intron region, and some in an untranslated region. Two nonsynonymous SNPs, namely, rs11745088 and rs1127760, were taken for analysis. In the SNP rs11745088, the change is E152Q. Likewise, in rs1127760, the change is C239S. SIFT (Sorting Intolerant from Tolerant) showed positions of amino acids and the single letter code of amino acids that can be tolerated or deleterious for each position. There were six SNP results and each result had links to it. The dbSNP id, primary database id, and the type of mutation whether silent and if occurring in coding region are given as phenotype alterations. The FASTA format of protein was given to the nsSNP Analyzer tool, and the variation E152Q and C239S were given as inputs in the SNP data field. E152Q change was neutral and C239S causes disease. Using PANTHER for evolutionary analysis of coding SNPs, the protein sequence was given as input and analyzed for the E152Q and C239S SNPs for deleterious effect on protein function. The genetic association database results showed that FST gene SNPs are linked to PCOS coming under the disease class of metabolic disorders. The list of intronic and synonymous SNPs, with their nucleotide position, amino acid change information, and dbSNP link, is provided for further analysis.


Ptena and ptenb genes play distinct roles in zebrafish embryogenesis.
PTEN is a tumor suppressor gene associated with multiple tumor types. PTEN function is essential for early embryonic development and is involved in the regulation of cell size, number, and survival. By dephosphorylating PIP(3), PTEN normally acts to inhibit the PI3-Kinase/AKT pathway. Here we have identified two zebrafish orthologs, ptena and ptenb, of the single mammalian PTEN gene and analyzed the role of these genes in zebrafish development. Ptena transcripts were expressed throughout the embryo at early somitogenesis. By 24 hpf, expression was predominant in the central nervous system, axial vasculature, retina, branchial arches, ear, lateral line primordium, and pectoral fin bud. Ptenb was also ubiquitously expressed early in somitogenesis, but transcripts became more restricted to the somites and central nervous system as development progressed. By 48 hpf, ptena and ptenb were expressed predominantly in the central nervous system, branchial arches, pectoral fins, and eye. Antisense morpholinos were used to knock down translation of ptena and ptenb mRNA in zebrafish embryos. Knockdown of either pten gene caused increased levels of phosphorylated Akt in morphant embryos, indicating that Ptena and Ptenb each possess PIP(3) lipid phosphatase activity. Ptena morphants had irregularities in notochord shape (73%), vasculogenesis (83%), head shape (72%), and inner ear development (59%). The most noticeable defects in ptenb morphants were upward hooked tails (73%), domed heads (83%), and reduced yolk extensions (90%). These results indicate that ptena and ptenb encode functional enzymes and that each pten gene plays a distinct role during zebrafish embryogenesis.


Emotion Recognition from Skeletal Movements.
Automatic emotion recognition has become an important trend in many artificial intelligence (AI) based applications and has been widely explored in recent years. Most research in the area of automated emotion recognition is based on facial expressions or speech signals. Although the influence of the emotional state on body movements is undeniable, this source of expression is still underestimated in automatic analysis. In this paper, we propose a novel method to recognise seven basic emotional states-namely, happy, sad, surprise, fear, anger, disgust and neutral-utilising body movement. We analyse motion capture data under seven basic emotional states recorded by professional actor/actresses using Microsoft Kinect v2 sensor. We propose a new representation of affective movements, based on sequences of body joints. The proposed algorithm creates a sequential model of affective movement based on low level features inferred from the spacial location and the orientation of joints within the tracked skeleton. In the experimental results, different deep neural networks were employed and compared to recognise the emotional state of the acquired motion sequences. The experimental results conducted in this work show the feasibility of automatic emotion recognition from sequences of body gestures, which can serve as an additional source of information in multimodal emotion recognition.


Diagnosing intramammary infections: evaluating expert opinions on the definition of intramammary infection using conjoint analysis.
The primary purpose of this study was to develop a set of criteria to serve as a pseudo-gold standard for what constitutes an intramammary infection using data from 3 consecutive quarter milk samples taken 1 wk apart. Data from lactating cows in 90 dairy herds in 4 Canadian provinces were used to generate the data sets (profiles) used in the conjoint analysis to elicit expert opinions on the topic. The experts were selected from the participants (n=23) in the 2007 Mastitis Research Workers' Conference in Minneapolis and from a series of mastitis laboratory courses for bovine practitioners (n=25) in the Netherlands. Three-week udder quarter profiles with specific combinations of somatic cell count, bacterial species isolated, and plate colony count were selected and included in the conjoint analysis based on the desire to achieve even distributions in the categories of 6 constructed variables. The participants were presented with 3 sets of cards with 20 cards in each set. On each card, they were asked to assign a probability of infection on the middle day (test day) in the 3-wk profile. Depending on the set of cards, they were asked only to be concerned with the probability of infection with coagulase-negative staphylococci, Escherichia coli, or Staphylococcus aureus. These 3 organisms were chosen to represent a minor pathogen, a major environmental pathogen, and a major contagious pathogen, respectively. The assigned probabilities for each organism were cross-tabulated according to the number of times the organism of interest was isolated in the 3-wk period, how many colonies of the organism of interest were isolated on the test day, and the somatic cell count (<or= or >200,000 cells/mL). There was considerable variation in the assigned probabilities within each of the combinations of factors. The median, minimum, and maximum values of the assigned probabilities for each combination were computed. The combinations with a median probability >50% were considered intramammary infection-positive and included as a criterion in the consensus standard. This yielded 4 possible criteria, which were condensed to the following 2 by consensus at the 2008 Mastitis Research Workers' Conference in Toronto: 1) the organism of interest was isolated on the test day with at least 10 colonies (1,000 cfu/mL), and 2) the organism of interest was isolated at least twice in the 3-wk period.


Understanding the Importance of Contact Heterogeneity and Variable Infectiousness in the Dynamics of a Large Norovirus Outbreak.
Large norovirus (NoV) outbreaks are explosive in nature and vary widely in final size and duration, suggesting that superspreading combined with heterogeneous contact may explain these dynamics. Modeling tools that can capture heterogeneity in infectiousness and contact are important for NoV outbreak prevention and control, yet they remain limited. Data from a large NoV outbreak at a Dutch scout jamboree, which resulted in illness among 326 (of 4500 total) individuals from 7 separate camps, were used to examine the contributions of individual variation in infectiousness and clustered contact patterns to the transmission dynamics. A Bayesian hierarchical model of heterogeneous, clustered outbreak transmission was applied to represent (1) between-individual heterogeneity in infectiousness and (2) heterogeneous patterns of contact. We found wide heterogeneity in infectiousness across individuals, suggestive of superspreading. Nearly 50% of individual infectiousness was concentrated in the individual's subcamp of residence, with the remainder distributed over other subcamps. This suggests a source-and-sink dynamic in which subcamps with greater average infectiousness fed cases to those with a lower transmission rate. Although the per capita transmission rate within camps was significantly greater than that between camps, the large pool of susceptible individuals across camps enabled similar numbers of secondary cases generated between versus within camps. The consideration of clustered transmission and heterogeneous infectiousness is important for understanding NoV transmission dynamics. Models including these mechanisms may be useful for providing early warning and guiding outbreak response.


Efficient transformation in characteristics of cations supported-reduced graphene oxide nanocomposites for the destruction of trichloroethane.
Experiments were conducted to investigate the use of graphene-oxide supported metallic nanocomposites for improving the degradation of trichloroethane (TCA) by sodium percarbonate (SPC). Two methods of production, chemical reduction (CR) and solvo-thermal (ST), were tested for preparation of single (Fe) and binary (Fe-Cu) nanocomposites supported by reduced graphene oxide (rGO). A variety of analytical techniques including N2 adsorption Brunauer-Emmett-Teller (BET), x-ray diffraction (XRD), fourier-transfrom infrared spectroscopy (FTIR), and transmisison electron microscopy (TEM) were applied to characterize the physicochemical and microstructural properties of the synthesized nanocomposites. The characterization indicated that the CR method produced nanocomposites that comprised only mesoporous structure. Conversely, both micro and mesoporous structures were present for samples produced with the ST method. The synthesized single and bimetallic composites produced from the ST method showed higher surface areas, i.e. 93.6 m2/g and 119.2 m2/g as compared to the ones synthesized via the CR method, i.e. 13.8 m2/g and 38.0 m2/g respectively. The results of FTIR and XRD analyses confirmed that the ST method produced highly crystalline nanocomposites. SEM and TEM analysis validated that metallic particles with definite morphology well distributed on the surface of rGO. X-ray photoelectron spectroscopy (XPS) analysis confirmed the homogeneity nanocomposites and occurrence of variation in copper oxidation states during degradation process. EDS mapping validate the homogeneous distribution of Cu and Fe at reduced graphene oxide surface. The Fe-Cu/rGO (ST) activated SPC system effectively degraded TCA (92%) in 2.5 h at low nanocomposite dose compared to the Fe-Cu/rGO (CR) and only Fe, for which the maximum degradation efficiencies achieved were 81% and 34%. In conclusion, excellent catalytic characteristics were observed for the ST-synthesized single and bimetallic (Fe/rGO, Fe-Cu/rGO) catalysts. These catalysts were successful in improving the degradation of TCA via activated SPC.


Mitogen-activated protein kinase phosphatase-1 is overexpressed in non-small cell lung cancer and is an independent predictor of outcome in patients.
An increase in the activity of the mitogen-activated protein kinases (MAPKs) has been correlated with a more malignant phenotype in several tumor models in vitro and in vivo. A key regulatory mechanism of the MAPKs [extracellular signal-regulated kinase (ERK); c-jun NH(2)-terminal kinase (JNK); and p38] is the dual specificity phosphatase CL100, also called MAPK phosphatase-1 (MKP-1). This study was designed to examine the involvement of CL100/MKP-1 and stress-related MAPKs in lung cancer. We assessed the expression of CL100/MKP-1 and the activation of the MAPKs in a panel of 18 human cell lines [1 primary normal bronchial epithelium, 8 non-small cell lung cancer (NSCLC), 7 small cell lung cancer (SCLC), and 2 carcinoids] and in 108 NSCLC surgical specimens. In the cell lines, CL100/MKP-1 expression was substantially higher in NSCLC than in SCLC. P-ERK, P-JNK, and P-p38 were activated in SCLC and NSCLC, but the degree of their activation was variable. Immunohistochemistry in NSCLC resection specimens showed high levels of CL100/MKP-1 and activation of the three MAPK compared with normal lung. In univariate analysis, no relationship was found among CL100/MKP-1 expression and P-ERK, P-JNK, or P-p38. Interestingly, high CL100/MKP-1 expression levels independently predicted improved survival in multivariate analysis. JNK activation associated with T(1-2) and early stage, whereas ERK activation correlated with late stages and higher T and N. Neither JNK nor ERK activation were independent prognostic factors when studied for patient survival. Our data indicate the relevance of MAPKs and CL100/MKP-1 in lung cancer and point at CL100/MKP-1 as a potential positive prognostic factor in NSCLC. Finally, our study supports the search of new molecular targets for lung cancer therapy within the MAPK signaling pathway.


A comparison of the vastus splitting and median parapatellar approaches in total knee arthroplasty.
This prospective randomized study was undertaken to evaluate the vastus splitting approach as an alternative to the median parapatellar approach in primary total knee arthroplasty. Fifty-one knees in 42 patients were randomized preoperatively. Clinical parameters were evaluated preoperatively and at regular postoperative intervals. Electromyography was performed preoperatively and postoperatively to evaluate each approach relative to its effect on the innervation of the quadriceps mechanism. There were no significant preoperative differences. Postoperatively, there were no significant differences regarding strength, range of motion, knee scores, tourniquet time, proprioception, or patellar replacement. There were significantly more lateral releases performed and greater blood loss in the patients in the parapatellar group. The results of all preoperative electromyograms were normal, as were all of the results of postoperative electromyograms in the patients in the parapatellar group. However, the results of nine of 21 (43%) of the electromyograms performed postoperatively on patients who had the vastus splitting approach were abnormal. Significantly fewer lateral releases were performed and there was less blood loss in the patients in the vastus group. However, the postoperative electromyographic results revealed neurologic injuries in the vastus medialis muscle that only were present after the vastus splitting approach. The clinical significance of denervation of the vastus medialis muscle by the vastus approach remains to be determined by longer term clinical and electromyographic studies.


Entrainment of a semilunar rhythm by a simulated moonlight cycle in the terrestrial crab, Sesarma haematocheir.
Sesarma haematocheir is a species of terrestrial crabs inhabiting hillsides and paddy fields near the sea. Females show a semilunar rhythm of zoea-release coinciding with days of spring tides and in addition with the time of high water occurring at the nearby seacoast about dusk. Nature of environmental stimuli or zeitgebers that induce the semilunar rhythm of zoea-release was examined experimentally. In case that a population of males and females was kept under the condition of a 24-h light-dark cycle (LD 14:10) only, females showed a free-running semilunar rhythm of egg-laying and zoea-release synchronized from field conditions. On the other hand, a semilunar rhythm of egg-laying and zoea-release was entrained by the combination of the 24-h LD and a simulated 24.8-hr moonlight cycle of which the phase was shifted in relation to the natural lunar cycle. This result suggests that the 24.8-h moonlight cycle acts as a zeitgeber of a semilunar rhythm. The 12.4-h tidal cycle parallels with the 24.8-h moonlight cycle in the field. On the basis of the perception of a distinct phase relationship between the 24-h LD and the 24.8-h moonlight cycle, it is considered that crabs substitute the 24.8-h moonlight cycle for the 12.4-h cycle of tides as a zeitgeber to synchronize the phase of the semilunar rhythm with a tidal situation.


Melding a High-Risk Patient for Continuous Flow Left Ventricular Assist Device into a Low-Risk Patient.
The model for end-stage liver disease (MELD) has been used as a predictor of mortality after left ventricular assist device (LVAD) placement. However, improvement or worsening of MELD and how those changes affect outcomes is unknown. We performed a retrospective analysis of 244 patients implanted with a continuous flow (CF) LVAD. Patients were dichotomized at admission into low- or high-risk categories using a cutoff of MELD ≥ 19, and they were reclassified at day of implant forming four groups: Group LL (low to low, remained low risk), LH (low to high, worsened to high risk), HH (high to high, remained high risk), and HL (high to low, improved to low risk). Patients who improved to a low risk (group HL) had the same 1 year survival as those that remained low risk (group LL; 80% vs. 77%; p = 0.6). However, patients who were initially classified as low risk and worsened to a high risk (group LH) had a survival that was worse than those that were consistently high risk (group HH; 55% vs. 10%; p = 0.01). Model for end-stage liver disease reclassification after adjusting for commonly attributed risk factors remained an independent predictor for mortality, including patients classified as Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) 1 and 2. In conclusion, our MELD score reclassification is an independent and powerful predictor of mortality in patients undergoing LVAD implantation.


The impact of regulatory T cells on T-cell immunity following hematopoietic cell transplantation.
Regulatory T cells (Tregs) prevent graft-versus-host disease (GvHD) by inhibiting the proliferation and function of conventional T cells (Tcons). However, the impact of Tregs on T-cell development and immunity following hematopoietic cell transplantation (HCT) is unknown. Using a murine GvHD model induced by Tcons, we demonstrate that adoptive transfer of Tregs leads to (1) abrogration of GvHD, (2) preservation of thymic and peripheral lymph node architecture, and (3) an accelerated donor lymphoid reconstitution of a diverse TCR-Vbeta repertoire. The resultant enhanced lymphoid reconstitution in Treg recipients protects them from lethal cytomegalovirus (MCMV) infection. By contrast, mice that receive Tcons alone have disrupted lymphoid organs from GvHD and remain lymphopenic with a restricted TCR-Vbeta repertoire and rapid death on MCMV challenge. Lymphocytes from previously infected Treg recipients generate secondary response specific to MCMV, indicating long-term protective immunity with transferred Tregs. Thymectomy significantly reduces survival after MCMV challenge in Treg recipients compared with euthymic controls. Our results indicate that Tregs enhance immune reconstitution by preventing GvHD-induced damage of the thymic and secondary lymphoid microenvironment. These findings provide new insights into the role of Tregs in affording protection to lymphoid stromal elements important for T-cell immunity.


Multivesicular liposomes. Sustained release of the antimetabolite cytarabine in the eye.
We entrapped the antimetabolite cytarabine hydrochloride in a multivesicular liposome for sustained drug delivery to the eye. The in vitro half-life of cytarabine release from these liposomes was 359 hours. Following subconjunctival administration of 6 mg of cytarabine to 12 rabbits, the tissue half-life of drug at the injection site was 52.5 hours in the six rabbits treated with liposomes compared with 0.2 hours in the six nonliposome controls treated with the same amount of drug in normal saline solution. The aqueous humor drug concentration peaked after 1.5 hours in both the experimental (0.4 mg/L) and control (19 mg/L) groups. In control eyes, the cytarabine level of both the tissue and aqueous humor had decreased to less than 1% of peak value by eight hours. In the liposome-treated eyes, almost 30% of the cytarabine remained in the conjunctiva and episcleral tissue after 72 hours. The difference in cytarabine levels in tissue between the liposome-treated group and controls was highly significant. By controlling the rate of drug release, it may be possible to reduce the ocular toxicity and increase the efficacy of this drug for treating ocular proliferative disorders.


Learned self-regulation of EEG frequency components affects attention and event-related brain potentials in humans.
Learned enhancement of EEG frequency components in the lower beta range by means of biofeedback has been reported to alleviate attention deficit hyperactivity disorder (ADHD) symptoms. In order to elucidate frequency-specific behavioural effects and neurophysiological mediators, this study applied neurofeedback protocols to healthy volunteers, and assessed impact on behavioural and electrocortical attention measures. Operant enhancement of a 12-15 Hz component was associated with reduction in commission errors and improved perceptual sensitivity on a continuous performance task (CPT), while the opposite relation was found for 15-18 Hz enhancement. Both 12-15 Hz and 15-18 Hz enhancement were associated with significant increases in P300 event-related brain potential amplitudes in an auditory oddball task. These relations are interpreted as stemming from band-specific effects on perceptual and motor aspects of attention measures.


Envelope and waveguide methods: a comparative study of PbF(2) and CeO(2) birefringent films.
We have characterized low-birefringence, PbF(2) coatings to permit, first, agreement between envelope and prism-coupler waveguide methods under the standard isotropic assumption. In essentially the same measurement conditions, for obliquely deposited (58.3°) CeO(2) coatings the isotropic model becomes unsustainable. Explicit consideration of the film microstructure is then required for good correlation between thickness results from TE (503 ± 9 nm) and TM (504 ± 10 nm) modes in the waveguide experiment as well as between refractive-index results from envelope (n(2) = 1.78 ± 0.03) and waveguide (n(2) = 1.794 ± 0.002) techniques. We considered uniaxial and biaxial models to achieve consistency, and the refractive indices along the principal axes of symmetry were determined.


Ultrasound-guided retrieval of plant awns.
In dogs, surgical removal of plant awns causing a foreign body granuloma or abscess may be challenging. The inability to localize the foreign body during surgical removal often leads to abscess recurrence. In this report, we describe ultrasound-guided retrieval as an alternative to standard surgical retrieval in animals where the plant awn can be identified sonographically. This procedure was used in six dogs with a superficial abscess due to a plant awn, and in all dogs the foreign body was successfully retrieved with Hartmann forceps. No complication was observed and no abscess recurred. Minimally invasive ultrasound-guided plant awn retrieval appears to be a safe effective method of retrieving superficially located plant awns in the dog.


Evidence for the involvement of the posterior parietal cortex in coordination of fingertip forces for grasp stability in manipulation.
Grasp stability during object manipulation is achieved by the grip forces applied normal to the grasped surfaces increasing and decreasing in phase with increases and decreases of destabilizing load forces applied tangential to the grasped surfaces. This force coordination requires that the CNS anticipates the grip forces that match the requirements imposed by the self-generated load forces. Here, we use functional MRI (fMRI) to study neural correlates of the grip-load force coordination in a grip-load force task in which six healthy humans attempted to lift an immovable test object held between the tips of the right index finger and thumb. The recorded brain activity was compared with the brain activity obtained in two control tasks in which the same pair of digits generated forces with similar time courses and magnitudes; i.e., a grip force task where the subjects only pinched the object and did not apply load forces, and a load force task, in which the subjects applied vertical forces to the object without generating grip forces. Thus neither the load force task nor the grip force task involved coordinated grip-load forces, but together they involved the same grip force and load force output. We found that the grip-load force task was specifically associated with activation of a section of the right intraparietal cortex, which is the first evidence for involvement of the posterior parietal cortex in the sensorimotor control of coordinated grip and load forces in manipulation. We suggest that this area might represents a node in the network of cortical and subcortical regions that implement anticipatory control of fingertip forces for grasp stability.


Silent infarcts in children with sickle cell anemia and abnormal cerebral artery velocity.
A substantial minority of neurologically normal children with sickle cell disease have lesions consistent with cerebral infarction as seen on magnetic resonance imaging (MRI). To determine if transfusion therapy affects the rate at which silent infarcts develop and to evaluate the contribution of MRI of the brain to stroke prediction by transcranial Doppler (TCD) ultrasonography. Children with elevated TCD ultrasonographic velocity were randomized to receive long-term transfusion therapy or standard care. Magnetic resonance imaging of the brain was obtained at randomization, annually, and with clinical neurologic events. The risk for new silent lesions and/or stroke was compared for each treatment arm. Among the 37% of subjects with silent infarcts, those receiving standard care were significantly more likely to develop new silent lesions or stroke than were those who received transfusion therapy. For subjects receiving standard care, those with lesions at baseline were significantly more likely to develop stroke or new silent lesions than those whose MRI studies showed no abnormality. Transfusion therapy lowers the risk for new silent infarct or stroke for children having both abnormal TCD ultrasonographic velocity and silent infarct. However, those with both abnormalities who are not provided transfusion therapy are at higher risk for developing a new silent infarct or stroke than are those whose initial MRI showed no abnormality. The finding of a silent infarct reinforces the need for TCD ultrasonographic screening and consideration of transfusion therapy if the abnormalities are seen. Similarly, elevated TCD ultrasonographic velocity warrants MRI of the brain because children with both abnormalities seem to be at increased risk for developing new silent infarct or stroke.