In vitro analysis of the invasive phenotype of SUM 149, an inflammatory breast cancer cell line.
BACKGROUND: Inflammatory breast cancer (IBC) is the most lethal form of locally invasive breast cancer known. However, very little information is available on the cellular mechanisms responsible for manifestation of the IBC phenotype. To understand the unique phenotype of IBC, we compared the motile and adhesive interactions of an IBC cell line, SUM 149, to the non-IBC cell line SUM 102. RESULTS: Our results demonstrate that both IBC and non-IBC cell lines exhibit similar adhesive properties to basal lamina, but SUM 149 showed a marked increase in adhesion to collagen I. In vitro haptotaxis assays demonstrate that SUM 149 was less invasive, while wound healing assays show a less in vitro migratory phenotype for SUM 149 cells relative to SUM 102 cells. We also demonstrate a role for Rho and E-cadherin in the unique invasive phenotype of IBC. Immunoblotting reveals higher E-cadherin and RhoA expression in the IBC cell line but similar RhoC expression. Rhodamine phalloidin staining demonstrates increased formation of actin stress fibers and larger focal adhesions in SUM 149 relative to the SUM 102 cell line. CONCLUSION: The observed unique actin and cellular architecture as well as the invasive and adhesive responses to the extracellular matrix of SUM 149 IBC cells suggest that the preference of IBC cells for connective tissue, possibly a mediator important for the vasculogenic mimicry via tubulogenesis seen in IBC pathological specimens. Overexpression of E-cadherin and RhoA may contribute to passive dissemination of IBC by promoting cell-cell adhesion and actin cytoskeletal structures that maintain tissue integrity. Therefore, we believe that these findings indicate a passive metastatic mechanism by which IBC cells invade the circulatory system as tumor emboli rather than by active migratory mechanisms.


Multi-tissue transcriptome analysis using hybrid-sequencing reveals potential genes and biological pathways associated with azadirachtin A biosynthesis in neem (azadirachta indica).
Azadirachtin A is a triterpenoid from neem tree exhibiting excellent activities against over 600 insect species in agriculture. The production of azadirachtin A depends on extraction from neem tissues, which is not an eco-friendly and sustainable process. The low yield and discontinuous supply of azadirachtin A impedes further applications. The biosynthetic pathway of azadirachtin A is still unknown and is the focus of our study. We attempted to explore azadirachtin A biosynthetic pathway and identified the key genes involved by analyzing transcriptome data from five neem tissues through the hybrid-sequencing (Illumina HiSeq and Pacific Biosciences Single Molecule Real-Time (SMRT)) approach. Candidates were first screened by comparing the expression levels between the five tissues. After phylogenetic analysis, domain prediction, and molecular docking studies, 22 candidates encoding 2,3-oxidosqualene cyclase (OSC), alcohol dehydrogenase, cytochrome P450 (CYP450), acyltransferase, and esterase were proposed to be potential genes involved in azadirachtin A biosynthesis. Among them, two unigenes encoding homologs of MaOSC1 and MaCYP71CD2 were identified. A unigene encoding the complete homolog of MaCYP71BQ5 was reported. Accuracy of the assembly was verified by quantitative real-time PCR (qRT-PCR) and full-length PCR cloning. By integrating and analyzing transcriptome data from hybrid-seq technology, 22 differentially expressed genes (DEGs) were finally selected as candidates involved in azadirachtin A pathway. The obtained reliable and accurate sequencing data provided important novel information for understanding neem genome. Our data shed new light on understanding the biosynthesis of other triterpenoids in neem trees and provides a reference for exploring other valuable natural product biosynthesis in plants.


The utility of hyperthermia for local recurrence of breast cancer.
Hyperthermia has long been used in combination with chemotherapy or radiation therapy for the treatment of superficial malignancies, in part due to its sensitizing capabilities. Patients who suffer from superficial recurrences of breast cancer have poor clinical outcomes. Skin metastases may particularly impair the quality of life due to the physical appearance, odor and bleeding. A 66-year-old woman underwent mastectomy and axillary lymph node dissection for breast cancer. Nine years post-operatively, local metastases developed in the left axillary area (measuring 5 cm in diameter). Initially the tumor did not respond to radiation therapy and chemotherapy. Therefore, we added hyperthermia combined with them. Eight weeks later, the tumor became nearly flat and the patient noted improved activity in her daily life. Hyperthermia may accelerate the antitumor effects of radiation therapy and chemotherapy. This treatment provides an alternative for unresectable breast cancer skin metastases.


Independent Regulatory Aspects and Posttranslational Modifications of Two beta-Amylases of Rye : Use of a Mutant Inbred Line.
We have examined the occurrence/disappearance, tissue location, and posttranslational modification of beta-amylase proteins in rye (Secale cereale L.) kernels at three physiological stages (development, maturity, germination) with a normal inbred line and a mutant line exhibiting a high but incomplete beta-amylase deficiency. This deficiency corresponds to a lack of accumulation of beta-amylase activity in the endosperm and does not affect the level of activity in the outer pericarp and green tissues as compared to the normal line. Two antigenically related but distinct beta-amylases (I and II) were detected in the normal line (II being the major constituent) and only one (I) in the mutant line. I and II display very similar electrophoretic polymorphism. In both lines, I appears to be ubiquitous, although it disappears from the outer pericarp during ripening. Antigen II was present only in the normal line and appears to be specific for the endosperm and perhaps for the maternal green tissues of the seed. Posttranslational modifications occurring during germination, which are mimicked by the action of papain, affect II but not I. The two groups of beta-amylases are discussed in relation to recent reports indicating the presence of two types of beta-amylase with different functions and gene loci in barley and wheat.


Prospective study of obesity, hypertension, high cholesterol, and risk of restless legs syndrome.
Because previous cross-sectional studies suggest an association between metabolic disorders and restless legs syndrome (RLS), we prospectively evaluated whether obesity, hypercholesterolemia, and hypertension were associated with increased risk of RLS. Our study consisted of 42,728 female participants from the Nurses' Health Study II and 12,812 male participants from the Health Professionals Follow-up Study, free of RLS at baseline (2002 for men and 2005 for women), and free of diabetes and arthritis through follow-up (2002-2008 for men and 2005-2009 for women). RLS symptoms were assessed using the International RLS Study Group's standardized questionnaire. We considered RLS symptoms a "case" if the symptoms occurred ≥5 times/month and met International RLS Study Group criteria. We found that obesity was associated with an increased risk RLS among both men and women (P difference for sex >0.5). The pooled multivariate-adjusted odds ratio (OR) for RLS was 1.57 (95% confidence interval [CI]: 1.33-1.85; P trend <0.0001) for body mass index >30 versus ≤23 kg/m(2) and 1.56 (95% CI: 1.29-1.89; P trend = 0.0001) comparing two extreme waist circumference quintiles, adjusting for age, ethnicity, smoking, physical activity, use of antidepressant, and other covariates. A similar significant association was found for high cholesterol; the pooled adjusted OR for total serum cholesterol >240 versus <159 mg/dL was 1.33 (95% CI: 1.11-1.60; P trend = 0.002). There was no significant association between hypertension and RLS risk (adjusted OR: 0.90; 95% CI: 0.79-1.02). In this large, prospective study, we found that obesity and high cholesterol, but not high blood pressure, were significantly associated with an increased risk of developing RLS. © 2014 International Parkinson and Movement Disorder Society.


Thyroidal radioactive iodide uptake in the lactating rhesus monkey.
Although radioactive iodide uptake (RAIU) is one of the reliable diagnostic methods for thyroid function in adult humans, especially in the diagnosis of thyrotoxicosis, there are limited data for RAIU during pregnancy and lactation in humans and animals. Therefore, we proposed to validate RAIU for the lactating rhesus monkey to further human model studies in thyroid disease. RAIU was performed at 6 and 24 h using 100 microCi of (123)I orally in four lactating monkeys. The thyroid and thigh were counted using a scintillation probe and multichannel analyser. A dose/standard ratio of counts/minute was calculated to compensate for background, utilizing differences in the activity between the dose administered and a standard. Thyroidal RAIU varied significantly among monkeys: 6.71 +/- 2.40% for the 6 h uptake and 15.44 +/- 7.71% for the 24 h uptake. These data showed that the RAIU test may allow a rational clinical approach to thyroid function testing for lactating rhesus monkeys. Additional studies are needed for assessing thyroid function in rhesus monkeys of varying ages and gender with clinical abnormalities.


Are numbers special? An overview of chronometric, neuroimaging, developmental and comparative studies of magnitude representation.
There is a current debate whether the human brain possesses a shared representation for various types of magnitude such as numerical quantities, physical size, or loudness. Here, we critically review evidence from chronometric, neuroimaging, developmental and comparative fields, and supplement it with a meta-analysis of the neuroimaging data. Together, based on such an integrative overview, we discuss limitations inherent in each approach, and the possibility whether shared, or distinct magnitude representation, or both representations exist.


Nectins establish a checkerboard-like cellular pattern in the auditory epithelium.
In the auditory epithelium of the cochlea, the sensory hair cells and supporting cells are arranged in a checkerboard-like fashion, but the mechanism underlying this cellular patterning is unclear. We found that mouse hair cells and supporting cells express the immunoglobulin-like adhesion molecules nectin-1 and -3, respectively, and that their interaction mediates the heterotypic adhesion between these two cell types. Genetic removal of nectin-1 or -3 disrupted the checkerboard-like pattern, inducing aberrant attachment between hair cells. When cells expressing either nectin-1 or -3 were cocultured, they arranged themselves into a mosaic pattern. Thus, nectin-1 and -3 promote the formation of the checkerboard-like pattern of the auditory epithelia.


Mu opiate receptor down-regulation by morphine and up-regulation by naloxone in SH-SY5Y human neuroblastoma cells.
The human neuroblastoma cell line SH-SY5Y was used to demonstrate morphine-induced down-regulation and naloxone-induced up-regulation of opiate receptors in a mu receptor containing neuronally derived preparation capable of desensitization to morphine. Chronic exposure to morphine decreased the number but not the affinity of mu opiate receptors in SH-SY5Y cells. Differentiation of the cells with retinoic acid or with the phorbol agent TPA (12-O-tetradecanoyl-phorbol-13-acetate) increased the number of mu receptors. Morphine-induced down-regulation, however, was observed in the absence of differentiation as well as after differentiation with retinoic acid or TPA. The decrease in the number of receptors was related to time of exposure, with a half-maximum disappearance time (T1/2) of about 3 hr during the initial phase. The receptor decrease was near maximum at 24 hr with no further significant change up to 72 hr. The loss of [3H] DAMGO ([3H]Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol) binding was also dose-dependent, with reductions occurring at 0.3, 1 and 10 microM. The loss of receptors was dependent on temperature, with reductions at 37 but not 23 degrees C. The down-regulation was blocked by naloxone and the mu-selective antagonist CTOP (D-Phe-Cys-Tyr-D(-Trp-)Orn-Thr-Pen-Thr-NH2), but not by the delta antagonist ICI 174864 ([N,N-diallyl-Tyr1,Aib2,3]Leu-enkephalin). Cholinergic ([3H]quinclidinyl benzilate) binding was not affected by the morphine treatment, indicating that the down-regulation was homologous for opiate receptors. In SH-SY5Y cells, unlike other cell models, the opiate antagonist naloxone upregulated mu receptors by more than 50%.(ABSTRACT TRUNCATED AT 250 WORDS)


Modelling the impact of artemisinin combination therapy and long-acting treatments on malaria transmission intensity.
Artemisinin derivatives used in recently introduced combination therapies (ACTs) for Plasmodium falciparum malaria significantly lower patient infectiousness and have the potential to reduce population-level transmission of the parasite. With the increased interest in malaria elimination, understanding the impact on transmission of ACT and other antimalarial drugs with different pharmacodynamics becomes a key issue. This study estimates the reduction in transmission that may be achieved by introducing different types of treatment for symptomatic P. falciparum malaria in endemic areas. We developed a mathematical model to predict the potential impact on transmission outcomes of introducing ACT as first-line treatment for uncomplicated malaria in six areas of varying transmission intensity in Tanzania. We also estimated the impact that could be achieved by antimalarials with different efficacy, prophylactic time, and gametocytocidal effects. Rates of treatment, asymptomatic infection, and symptomatic infection in the six study areas were estimated using the model together with data from a cross-sectional survey of 5,667 individuals conducted prior to policy change from sulfadoxine-pyrimethamine to ACT. The effects of ACT and other drug types on gametocytaemia and infectiousness to mosquitoes were independently estimated from clinical trial data. Predicted percentage reductions in prevalence of infection and incidence of clinical episodes achieved by ACT were highest in the areas with low initial transmission. A 53% reduction in prevalence of infection was seen if 100% of current treatment was switched to ACT in the area where baseline slide-prevalence of parasitaemia was lowest (3.7%), compared to an 11% reduction in the highest-transmission setting (baseline slide prevalence = 57.1%). Estimated percentage reductions in incidence of clinical episodes were similar. The absolute size of the public health impact, however, was greater in the highest-transmission area, with 54 clinical episodes per 100 persons per year averted compared to five per 100 persons per year in the lowest-transmission area. High coverage was important. Reducing presumptive treatment through improved diagnosis substantially reduced the number of treatment courses required per clinical episode averted in the lower-transmission settings although there was some loss of overall impact on transmission. An efficacious antimalarial regimen with no specific gametocytocidal properties but a long prophylactic time was estimated to be more effective at reducing transmission than a short-acting ACT in the highest-transmission setting. Our results suggest that ACTs have the potential for transmission reductions approaching those achieved by insecticide-treated nets in lower-transmission settings. ACT partner drugs and nonartemisinin regimens with longer prophylactic times could result in a larger impact in higher-transmission settings, although their long term benefit must be evaluated in relation to the risk of development of parasite resistance.


A natural biomimetic porous medium mimicking hypomineralized enamel.
In order to evaluate the clinical impact of low viscosity resin infiltration in hypomineralized enamel, it is necessary to obtain a biomimetic porous substrate capable of mimicking enamel. The specifications for the biomimetic porous medium are defined using the literature data on hypomineralized enamel. Based on these specifications, we propose to use deproteinized dentin, the latter being deproteinized by heat treatment. Thermogravimetry analysis (TGA), field emission scanning electron microscopy (FESEM) observations, mercury intrusion porosimetry (MIP) tests and nanoindentation are performed on the deproteinized dentin tissue. Heat treatment is shown to be an effective and reproducible method for removing organic fluids and protein residues in dentin. Deproteinizing dentin also enables forming nanovoids by eliminating its organic matrix. The interconnected open nanoporosities (porosities of less than 100 nm) created at 600°C are distributed between 14 nm and 32 nm and the total porosity is 39% (including 36% due to nanoporosities). At 800°C, they are distributed between 60 nm and 100 nm and total porosity is 37% (including 33% arising from the nanoporosities). The hydroxyapatite crystal structure is transformed less at 600°C, so this temperature should be preferred. Besides providing new understanding of the dentin tissue itself, this study led to characterizing a porous medium made of natural apatite, and proposing and validating its use as a porous medium mimicking hypomineralized enamel. The next logical step of this study is the characterization of resin infiltration in this medium and its mechanical reinforcement.


Aging of running shoes and its effect on mechanical and biomechanical variables: implications for runners.
This study investigates the effect of running shoes' aging on mechanical and biomechanical parameters as a function of midsole materials (viscous, intermediate, elastic) and ground inclination. To this aim, heel area of the shoe (under calcaneal tuberosity) was first mechanically aged at realistic frequency and impact magnitudes based on a 660 km training plan. Stiffness (ST) and viscosity were then measured on both aged and matching new shoes, and repercussions on biomechanical variables (joint kinematics, muscular pre-activation, vertical ground reaction force and tibial acceleration) were assessed during a leg-extended stepping-down task designed to mimic the characteristics of running impacts. Shoes' aging led to increased ST (means: from 127 to 154 N ∙ mm(-1)) and decreased energy dissipation (viscosity) (means: from 2.19 to 1.88 J). The effects induced by mechanical changes on body kinematics were very small. However, they led with the elastic shoe to increased vastus lateralis pre-activation, tibial acceleration peak (means: from 4.5 g to 5.2 g) and rate. Among the three shoes tested, the shoe with intermediate midsole foam provided the best compromise between viscosity and elasticity. The optimum balance remains to be found for the design of shoes regarding at once cushioning, durability and injury prevention.


Common variation in the gene for apolipoprotein B modulates postprandial lipoprotein metabolism: a hypothesis generating study.
We have carried out a pilot study to examine the influence on postprandial lipid and lipoprotein metabolism of common genetic variation in the gene coding for apolipoprotein (apo) B, in a previously described group of 30 individuals who had survived a myocardial infarction (MI) before the age of 45 (normo (NTG)- and hypertriglyceridaemic (HTG) patients) and 11 age-matched healthy individuals. Postprandial lipid or lipoprotein levels were examined by genotypes in the three groups separately and after adjustment for fasting triglycerides (TG) in the whole group combined. For the signal peptide polymorphism in the apo B gene, individuals with one or more SP-24 alleles had a 38% smaller mean area under curve (AUC) (P = 0.06) for postprandial large chylomicron remnants and a 29% smaller mean AUC (P = 0.01) for large very low density lipoproteins (VLDLs) compared to individuals homozygous for the wild type SP-27 allele. Previously in this patient group, small chylomicron remnants (apo B-48 levels in the Sf 20-60 range) were found to relate significantly and positively to progression of coronary atherosclerosis suggesting that these lipoproteins are implicated in progression of atherosclerosis. For the apo B Val591-Ala polymorphism (Ag a1/d), individuals homozygous for the V591 allele had a 33% greater AUC for Sf 20-60 postprandial triglycerides (P = 0.006), with higher postprandial levels of both apo B-48- and apo B-100-containing lipoproteins in this fraction. This pilot study gives insight into the mechanisms of the previously reported associations between polymorphisms in the apo B gene and fasting plasma lipids and lipoproteins.


The effect of polypyrrole with incorporated neurotrophin-3 on the promotion of neurite outgrowth from auditory neurons.
This research aims to improve the nerve-electrode interface of the cochlear implant using polymer technology to encourage neuron survival, elongation and adhesion to the electrodes. Polypyrrole (Ppy) doped with p-toluene sulphonate (pTS) is an electroactive polymer into which neurotrophin-3 (NT3) can be incorporated. Ppy/pTS+/-NT3 was synthesised over gold electrodes and used as a surface for auditory neuron explant culture. Neurite outgrowth from explants grown on Ppy/pTS was equivalent to tissue culture plastic but improved with the incorporation of NT3 (Ppy/pTS/NT3). Electrical stimulation of Ppy/pTS/NT3 with a biphasic current pulse, as used in cochlear implants, significantly improved neurite outgrowth from explants. Using (125)I-NT3, it was shown that low levels of NT3 passively diffused from Ppy/pTS/NT3 during normal incubation and that electrical stimulation enhanced the release of biologically active NT3 in quantities adequate for neuron survival. Furthermore, Ppy/pTS/NT3 and its constituents were not toxic to auditory neurons and the Ppy/pTS/NT3 coating on gold electrodes did not alter impedance. If applied to the cochlear implant, Ppy/pTS/NT3 will provide a biocompatible, low-impedance substrate for storage and release of NT3 to help protect auditory neurons from degradation after sensorineural hearing loss and encourage neurite outgrowth towards the electrodes.


Factors affecting cytokine change after esophagectomy for esophageal cancer.
Esophagectomy for esophageal cancer is one of the most invasive operative procedures. Surgical stress induces the release of proinflammatory cytokines, and overproduction induces a systemic inflammatory response syndrome, which may lead to acute lung injury and multiple organ dysfunction syndrome. In addition, surgical stress may cause immunosuppression, which may affect not only perioperative mortality but also long-term survival. Between 2006 and 2013, levels of perioperative serum cytokines were evaluated in 90 patients who underwent esophagectomy for esophageal carcinoma. The serum interleukin (IL)-6, IL-8, and IL-10 levels were measured by enzyme-linked immunosorbent assays. We reviewed and assessed medical records, including cytokine profiles, and determined the factors affecting postoperative serum cytokine levels. These cytokine levels peaked on postoperative day 1 and decreased gradually. Of the clinicopathologic factors, a thoracoscopic approach was a significant factor in attenuating IL-6 and IL-8 levels on postoperative day 1 in multivariate analysis, and a longer operative time was a significant factor in increasing these levels. During postoperative days 3-7, the thoracoscopic approach and early enteral nutrition were significant factors in attenuating serum cytokine changes in multivariate analysis, and postoperative infectious complications were significant factors in increasing these levels. The thoracoscopic approach and early enteral nutrition could attenuate the cytokine change after esophagectomy, and a longer operative time and postoperative infectious complication could increase it. We should undertake strategies to minimize the surgical stress to reduce potential short-term and long-term consequences for patients.


Brain Network Reconfiguration and Perceptual Decoupling During an Absorptive State of Consciousness.
Trance is an absorptive state of consciousness characterized by narrowed awareness of external surroundings and has long been used-for example, by shamans-to gain insight. Shamans across cultures often induce trance by listening to rhythmic drumming. Using functional magnetic resonance imaging (fMRI), we examined the brain-network configuration associated with trance. Experienced shamanic practitioners (n = 15) listened to rhythmic drumming, and either entered a trance state or remained in a nontrance state during 8-min scans. We analyzed changes in network connectivity. Trance was associated with higher eigenvector centrality (i.e., stronger hubs) in 3 regions: posterior cingulate cortex (PCC), dorsal anterior cingulate cortex (dACC), and left insula/operculum. Seed-based analysis revealed increased coactivation of the PCC (a default network hub involved in internally oriented cognitive states) with the dACC and insula (control-network regions involved in maintaining relevant neural streams). This coactivation suggests that an internally oriented neural stream was amplified by the modulatory control network. Additionally, during trance, seeds within the auditory pathway were less connected, possibly indicating perceptual decoupling and suppression of the repetitive auditory stimuli. In sum, trance involved coactive default and control networks, and decoupled sensory processing. This network reconfiguration may promote an extended internal train of thought wherein integration and insight can occur.


A research agenda for helminth diseases of humans: modelling for control and elimination.
Mathematical modelling of helminth infections has the potential to inform policy and guide research for the control and elimination of human helminthiases. However, this potential, unlike in other parasitic and infectious diseases, has yet to be realised. To place contemporary efforts in a historical context, a summary of the development of mathematical models for helminthiases is presented. These efforts are discussed according to the role that models can play in furthering our understanding of parasite population biology and transmission dynamics, and the effect on such dynamics of control interventions, as well as in enabling estimation of directly unobservable parameters, exploration of transmission breakpoints, and investigation of evolutionary outcomes of control. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. A research and development agenda for helminthiasis modelling is proposed based on identified gaps that need to be addressed for models to become useful decision tools that can support research and control operations effectively. This agenda includes the use of models to estimate the impact of large-scale interventions on infection incidence; the design of sampling protocols for the monitoring and evaluation of integrated control programmes; the modelling of co-infections; the investigation of the dynamical relationship between infection and morbidity indicators; the improvement of analytical methods for the quantification of anthelmintic efficacy and resistance; the determination of programme endpoints; the linking of dynamical helminth models with helminth geostatistical mapping; and the investigation of the impact of climate change on human helminthiases. It is concluded that modelling should be embedded in helminth research, and in the planning, evaluation, and surveillance of interventions from the outset. Modellers should be essential members of interdisciplinary teams, propitiating a continuous dialogue with end users and stakeholders to reflect public health needs in the terrain, discuss the scope and limitations of models, and update biological assumptions and model outputs regularly. It is highlighted that to reach these goals, a collaborative framework must be developed for the collation, annotation, and sharing of databases from large-scale anthelmintic control programmes, and that helminth modellers should join efforts to tackle key questions in helminth epidemiology and control through the sharing of such databases, and by using diverse, yet complementary, modelling approaches.


Acute evaluation of pediatric patients with minor traumatic brain injury.
This review focuses on minor traumatic brain injury (TBI), evaluates the most recent literature regarding clinical prediction rules for the use of cranial computed tomography (CT) in children presenting with minor TBI, reviews the evidence on the need for hospitalization in children with minor TBI, and evaluates the role of S100B testing. The majority of children presenting to an emergency department (ED) after TBI have a Glasgow Coma Scale (GCS) of 14-15, and the rate of clinically significant intracranial injury is exceedingly rare. Nevertheless, the number of cranial CTs performed in the US has increased dramatically over the past two decades. Several clinical prediction rules have been developed to aid the clinician in identifying children with low-risk TBI, but only the Pediatric Emergency Care Applied Research Network (PECARN) rules have been sufficiently validated to warrant clinical application. Two recent studies provide evidence that children with low-risk TBI can be safely discharged from the ED and do not require prolonged hospitalization for neurologic observation. Lastly, studies evaluating the diagnostic utility of S100B in patients with TBI have shown that it may be a useful adjunct to the clinical evaluation and aid in minimizing neuroimaging. Clinical prediction rules, most notably the PECARN rules, can be applied to determine children with low-risk TBI and help decrease unnecessary CT use and hospitalizations. S100B testing requires further investigation, but may serve as an adjunct in determining children with low-risk TBI.


A sensitive core region in the structure of glutathione S-transferases.
A variant form of an Anopheles dirus glutathione S-transferase (GST), designated AdGSTD4-4, possesses a single amino acid change of leucine to arginine (Leu-103-Arg). Although residue 103 is outside of the active site, it has major effects on enzymic properties. To investigate these structural effects, site-directed mutagenesis was used to generate mutants by changing the non-polar leucine to alanine, glutamate, isoleucine, methionine, asparagine, or tyrosine. All of the recombinant GSTs showed approximately the same expression level at 25 degrees C. Several of the mutants lacked glutathione (GSH)-binding affinity but were purified by S-hexyl-GSH-based affinity chromatography. However the protein yields (70-fold lower), as well as the GST activity (100-fold lower), of Leu-103-Tyr and Leu-103-Arg purifications were surprisingly low and precluded the performance of kinetic experiments. Size-exclusion chromatography showed that both GSTs Leu-103-Tyr and Leu-103-Arg formed dimers. Using 1-chloro-2,4-dinitrobenzene (CDNB) and GSH substrates to determine kinetic constants it was demonstrated that the other Leu-103 mutants possessed a greater K (m) towards GSH and a differing K (m) towards CDNB. The V (max) ranged from 44.7 to 87.0 micromol/min per mg (wild-type, 44.7 micromol/min per mg). Substrate-specificity studies showed different selectivity properties for each mutant. The structural residue Leu-103 affects the active site through H-bond and van-der-Waal contacts with six active-site residues in the GSH binding site. Changes in this interior core residue appear to disrupt internal packing, which affects active-site residues as well as residues at the subunit-subunit interface. Finally, the data suggest that Leu-103 is noteworthy as a sensitive residue in the GST structure that modulates enzyme activity as well as stability.


Endothelial progenitor cells enhance islet engraftment, influence β-cell function, and modulate islet connexin 36 expression.
The success of pancreatic islet transplantation is limited by delayed engraftment and suboptimal function in the longer term. Endothelial progenitor cells (EPCs) represent a potential cellular therapy that may improve the engraftment of transplanted pancreatic islets. In addition, EPCs may directly affect the function of pancreatic β-cells. The objective of this study was to examine the ability of EPCs to enhance pancreatic islet transplantation in a murine syngeneic marginal mass transplant model and to examine the mechanisms through which this occurs. We found that cotransplanted EPCs improved the cure rate and initial glycemic control of transplanted islets. Gene expression data indicate that EPCs, or their soluble products, modulate the expression of the β-cell surface molecule connexin 36 and affect glucose-stimulated insulin release in vitro. In conclusion, EPCs are a promising candidate for improving outcomes in islet transplantation, and their mechanisms of action warrant further study.


Involvement of N-methyl-D-aspartate receptor stimulation in the ventral tegmental area and amygdala in behavioral sensitization to cocaine.
Systemic administration of N-methyl-D-aspartate (NMDA) antagonists prevents the development of behavioral sensitization to amphetamine-like psychostimulants. Pretreatment with the noncompetitive NMDA antagonist, MK-801, resulted in a dose-dependent blockade of behavioral sensitization to cocaine. However, pretreatment with the highest dose of MK-801 (0.25 mg/kg i.p.) alone inhibited the behavioral response to a subsequent cocaine challenge 24 hr later. The induction of behavioral sensitization is known to result, at least partly, from an action by psychostimulants in the ventral tegmental area (VTA). To determine whether the dose-dependent inhibition of behavioral sensitization to cocaine by NMDA antagonists resulted from receptor blockade in the VTA, rats were pretreated in the VTA with the MK-801 or the competitive NMDA antagonist, 3-(2-carboxypiperazine-4-yl) propyl-1-phosphonic acid, before systemically administered cocaine (30 mg/kg i.p.). Two to 3 days later rats were challenged with cocaine alone (15 mg/kg i.p.). Pretreatment with either NMDA antagonist into the VTA prevented the manifestation of behavioral sensitization. Intracranial pretreatment with MK-801 was also made into the nucleus accumbens and amygdala which have been implicated in psychostimulant-induced sensitization. Whereas MK-801 was without effect in the nucleus accumbens, when microinjected into the ventral amygdala it prevented the manifestation of behavioral sensitization to a cocaine challenge. The blockade of sensitization by MK-801 in the VTA was produced with a minimum effective dose of 0.01 nmol, whereas the minimum effective dose in the amygdala was 1.0 nmol. These data demonstrate that stimulation of NMDA receptors in the VTA and amygdala is necessary in the development of behavioral sensitization to cocaine.


Surgical Treatment of Subchondral Bone Cysts of the Acetabulum With Calcium Phosphate Bone Substitute Material in Patients Without Advanced Arthritic Hips.
Subchondral acetabular edema and cysts, as a consequence of degenerative changes of the hip, are associated with disability, pain, and worsened function in this joint. The arthroscopic treatment of intra-articular pathologies, such as femoroacetabular impingement syndrome and labral tears, when associated with those alterations, has been suggested to provide inferior outcomes to those in patients without subchondral changes. Yet, the direct treatment of subchondral pathology has been limited. Recently, a technique for insufflating bone substitute into the bone marrow lesions of the knee, Subchondroplasty (Zimmer Knee Creations, Exton, PA), has led to promising results. Subchondroplasty has raised attention as a possible minimally invasive procedure to treat cystic changes in the acetabulum in patients who are not yet candidates for hip replacement. We present the technique of acetabular Subchondroplasty, in which a bone substitute material is injected into subchondral acetabular cysts under fluoroscopic guidance. In this technique, hip arthroscopy is used in conjunction with fluoroscopic guidance to address intra-articular pathologies and assess for possible intra-articular extravasation of the injectable material.


Role of platelet adhesion in homeostasis and immunopathology.
Various molecules expressed on the surface of platelets have been shown to mediate the protective or deleterious role of these cells in immuno-inflammatory mechanisms. Increasing evidence points to the involvement of the cell adhesion molecules, gpIIb-IIIa, P-selectin, CD31, LFA-1, and CD36 in the interaction between platelets and endothelial cells as well as other cell types. The possible role of these molecules in the ability of platelets to support endothelium and to protect against tumour necrosis factor mediated cytolysis or parasitic invasion are reviewed. The involvement of platelets as effectors of tissue damage in cerebral malaria, lipopolysaccharide induced pathology, and pulmonary fibrosis is also discussed. This has then been extended to include the intercellular mechanisms underpinning their pathogenic role in metastasis, transplant rejection, stroke, brain hypoxia, and related conditions. A better understanding of the complex regulation and hierarchical organisation of these various platelet adhesion molecules may prove useful in the development of new approaches to the treatment of such diseases.


Relationships among 5-HTT genotype, life events and gender in the recognition of facial emotions.
Accumulating evidence has shown that a polymorphism in the promoter region of the serotonin-transporter (5-HTTLPR) modulates neural activation during the perceptual processing of emotional facial expressions. Furthermore, behavioral research has shown that attentional bias for negative information is increased in s allele carriers. We examined the interactions among 5-HTTLPR (including SNP rs25531), life events and gender on the detection of facial emotions. We found a main effect of genotype, as well as moderating effects of childhood emotional abuse (CEA) and recent life events (RLE). S homozygous participants recognized negative facial expressions at a lower intensity than the other genotype groups. This effect was more evident in female participants and in participants who had experienced life events. The 5-HTTLPR genotype affects facial emotional perception, a process which is linked to a neurobiological response to threat and vulnerability to emotional disorders.


Novel mutations of epidermolysis bullosa identified using whole-exome sequencing in Indonesian Javanese patients.
Epidermolysis bullosa (EB) is a group of inherited blistering skin diseases known to have heterogenicity of phenotypes and genotypes. There are four main types of EB: simplex, junctional, dystrophic, and Kindler syndrome, which are further classified into 34 distinct subtypes. Twenty different gene mutations are responsible for the loss of function and integrity of the basal membrane zone. In limited-resource settings such as Indonesia, diagnoses of hereditary skin disease often rely on clinical features. This limitation was managed by using the Clinical Diagnostic Matrix EB for clinical diagnosis support and whole-exome sequencing for genetic analysis. This study is the first whole-exome sequencing analysis of Javanese Indonesian patients with EB. The genetic analysis from four patients with EB identified all novel mutations unreported in the dbSNP database. There are Kindler syndrome with FERMT1 frameshift mutation in exon 4, at c.388A (p.I130fs), which causes truncated protein; junctional EB generalized intermediate (JEB-GI) subtype with missense mutation at LAMB3 gene position c.A962C (p.H321P); and recessive dystrophic EB (RDEB) a missense mutation at COL7A1 gene position c.G5000T (p.G1667V). The whole-exome sequencing was further verified by Sanger sequencing. The new mutations' finding is possibly due to the limited genetic database in the Malayo-Polynesian ethnic group. Indonesia has hundreds of ethnic groups, and the Javanese is the largest ethnic group that populates Indonesia. Genetic data of these ethnic groups is important to be established in the international genetic database. This combination of clinical diagnostic and genetic analysis tools with whole-exome sequencing confirmed the challenging diagnosis of epidermolysis bullosa.


Effect of ionic liquids on the Menschutkin reaction: an experimental and theoretical study.
The effect of ionic liquids (ILs) on the Menschutkin reaction between N-methylimidazole and benzyl halides has been investigated. Hammett correlations have been used to obtain information on the reaction mechanism of benzyl chlorides in ionic and molecular solvents. The solvent effects on this reaction have been examined using both multiparameter linear solvation energy relationships and theoretical calculations. These latter have been performed using a supermolecular approach, i.e., the IL is represented by an explicit ionic pair, IP. Two possible different reaction pathways have been obtained changing the position of the IL-IP with respect to the reagents. It is hypothesized that inside the IL the Menschutkin reaction of benzyl chloride with N-methylimidazole can follow different reaction pathways by considering the influence of dynamic heterogeneity in ionic media on the time scale of the lifetime of a transition state.


Adherence to Southern European Atlantic Diet and physical fitness on the atherogenic index of plasma in adolescents.
We sought (i) to evaluate the associations of cardiorespiratory fitness (CRF), muscular fitness (MF) and Southern European Atlantic Diet (SEADiet) with atherogenic index of plasma (AIP) and (ii) to investigate de combined association of MF, CRF and SEADiet on AIP in adolescents. A cross-sectional school-based study was conducted on 493 adolescents (285 girls and 208 boys) aged 15-18 years, from the Portuguese Azorean Archipelago. CRF was measured by shuttle run test and MF by curl up and push up tests. Adherence to SEADiet was assessed with a semi-quantitative food frequency questionnaire (FFQ). The AIP was estimated as log (TG/HDL-C). Measures of pubertal stage and socioeconomic status were assessed. Linear regression showed a significant inverse association between MF (standardized β = -0.165; p < 0.001), CRF (standardized β = -0.081; p < 0.030) and SEADiet (standardized β = -0.081; p < 0.045) with AIP, after adjustments for age, sex, pubertal stage and parental education. Furthermore, participants classified with an optimal as well as those with low adherence to a SEADiet but with LowMF/LowCRF had on average the highest AIP (F(7.482) = 3.270; p = 0.002). Moreover, optimal SEADiet with HighMF/HighCRF group showed the lowest AIP when compared with those with low adherence to a SEADiet with HighMF/HighCRF group (p = 0.03). AIP is inversely associated with MF, CRF and SEADiet. The low MF combined with a low CRF levels seems to overcome the potential healthy effect of having an optimal adherence to the SEADiet on AIP. However, an optimal adherence to SEADiet seems to improve the AIP in those adolescents with high fitness levels.


Women sleep objectively better than men and the sleep of young women is more resilient to external stressors: effects of age and menopause.
The aims of this study were to: (i) assess gender differences of objective sleep patterns in a general population sample; (ii) evaluate the effects of menopause and hormone treatment (HT) on the sleep of the same cohort; and (iii) examine gender differences in sleep resilience towards external stressors. The participants were (i) 1324 subjects without sleep complaints, recruited from the general population of Central Pennsylvania that spent one night in the sleep laboratory and (ii) 66 young, healthy volunteers whose sleep was disturbed during night four by an external stressor, i.e. 24-h blood drawing (average of nights 2 and 3 versus night 4). Women compared with men in the general population sample had significantly higher percentage of sleep time, lower percentage of stage 1, and higher percentage of slow wave sleep. Also, menopause, in the absence of HT, was associated with prolonged sleep latency and decreased deep sleep. Finally, young, healthy women compared with men experienced less sleep disturbance because of blood draws as indicated by a significantly smaller change in per cent sleep time, and percentage of stage 1 sleep. These findings suggest that women without sleep complaints sleep objectively better across age than men and the sleep of young women is more resistant to external stressors. Also, gonadal hormones exert a beneficial effect on women's sleep. This gender dimorphism in sleep regulation may have been to protect women from the demands of infant and child care, and in part, might contribute to women's lower cardiovascular risks and greater longevity.


Recent advances in the management of pulmonary embolism: focus on the critically ill patients.
The aim of this narrative review is to summarize for intensivists or any physicians managing "severe" pulmonary embolism (PE) the main recent advances or recommendations in the care of patients including risk stratification, diagnostic algorithm, hemodynamic management in the intensive care unit (ICU), recent data regarding the use of thrombolytic treatment and retrievable vena cava filters and finally results of direct oral anticoagulants. Thanks to the improvements achieved in the risk stratification of patients with PE, a better therapeutic approach is now recommended from diagnosis algorithm and indication to admission in ICU to indication of thrombolysis and general hemodynamic support in patients with shock. Given at current dosage, thrombolytic therapy is associated with a reduction in the combined end-point of mortality and hemodynamic decompensation in patients with intermediate-risk PE, but this is obtained without a decrease in overall mortality and with a significant increase in major extracranial and intracranial bleeding. In patients with high-intermediate-risk PE, thrombolytic therapy should be given in case of hemodynamic worsening. Vena cava filters are of little help when anticoagulant treatment is not contraindicated, even in patients with PE and features of clinical severity. Finally, direct oral anticoagulants have been shown to be as effective as and safer than the combination of low molecular weight heparin and vitamin K antagonist(s) in patients with venous thromboembolism and low- to intermediate-risk PE.


Fragmentation: a wicked problem with an integrated solution?
Integrated care is central to current health care reforms as policy makers and practitioners struggle to address fragmentation of care planning and delivery. However, those pursuing integration have failed to appreciate the complex nature of fragmentation. We seek to bring some much-needed clarity to current debate by considering fragmentation as a 'wicked problem' requiring a locally driven and multifaceted approach to integration.


Study of the environmental hazard caused by the oil shale industry solid waste.
The environmental hazard was studied of eight soil and solid waste samples originating from a region of Estonia heavily polluted by the oil shale industry. The samples were contaminated mainly with oil products (up to 7231mg/kg) and polycyclic aromatic hydrocarbons (PAHs; up to 434mg/kg). Concentrations of heavy metals and water-extractable phenols were low. The toxicities of the aqueous extracts of solid-phase samples were evaluated by using a battery of Toxkit tests (involving crustaceans, protozoa, rotifers and algae). Waste rock and fresh semi-coke were classified as of "high acute toxic hazard", whereas aged semi-coke and most of the polluted soils were classified as of "acute toxic hazard". Analysis of the soil slurries by using the photobacterial solid-phase flash assay showed the presence of particle-bound toxicity in most samples. In the case of four samples out of the eight, chemical and toxicological evaluations both showed that the levels of PAHs, oil products or both exceeded their respective permitted limit values for the living zone (20mg PAHs/kg and 500mg oil products/kg); the toxicity tests showed a toxic hazard. However, in the case of three samples, the chemical and toxicological hazard predictions differed markedly: polluted soil from the Erra River bank contained 2334mg oil/kg, but did not show any water-extractable toxicity. In contrast, spent rock and aged semi-coke that contained none of the pollutants in hazardous concentrations, showed adverse effects in toxicity tests. The environmental hazard of solid waste deposits from the oil shale industry needs further assessment.


Serum immunoglobulins in fixed drug eruption.
The serum globulins IgG, IgA and IgM were studied in the serum of 47 patients with fixed drug eruption due to identified drugs. The diagnosis was established by using as a test the readministration of the responsible drug and the consequent appearance of the eruption. IgM was found in normal amounts in the acute phase and after the remission of the eruption, whereas IgG and IgA were found increased during the acute phase of the eruption though after the remission, levels returned to normal.


Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs.
Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) and cyclooxygenase inhibitor that is frequently used as a research tool to study the process of adipocyte differentiation. Treatment of various preadipocyte cell lines with micromolar concentrations of indomethacin in the presence of insulin promotes their terminal differentiation. However, the molecular basis for the adipogenic actions of indomethacin had remained unclear. In this report, we show that indomethacin binds and activates peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand-activated transcription factor known to play a pivotal role in adipogenesis. The concentration of indomethacin required to activate PPARgamma is in good agreement with that required to induce the differentiation of C3H10T1/2 cells to adipocytes. We demonstrate that several other NSAIDs, including fenoprofen, ibuprofen, and flufenamic acid, are also PPARgamma ligands and induce adipocyte differentiation of C3H10T1/2 cells. Finally, we show that the same NSAIDs that activate PPARgamma are also efficacious activators of PPARalpha, a liver-enriched PPAR subtype that plays a key role in peroxisome proliferation. Interestingly, several NSAIDs have been reported to induce peroxisomal activity in hepatocytes both in vitro and in vivo. Our findings define a novel group of PPARgamma ligands and provide a molecular basis for the biological effects of these drugs on adipogenesis and peroxisome activity.


Unsupervised lineage-based characterization of primate precursors reveals high proliferative and morphological diversity in the OSVZ.
Generation of the primate cortex is characterized by the diversity of cortical precursors and the complexity of their lineage relationships. Recent studies have reported miscellaneous precursor types based on observer classification of cell biology features including morphology, stemness, and proliferative behavior. Here we use an unsupervised machine learning method for Hidden Markov Trees (HMTs), which can be applied to large datasets to classify precursors on the basis of morphology, cell-cycle length, and behavior during mitosis. The unbiased lineage analysis automatically identifies cell types by applying a lineage-based clustering and model-learning algorithm to a macaque corticogenesis dataset. The algorithmic results validate previously reported observer classification of precursor types and show numerous advantages: It predicts a higher diversity of progenitors and numerous potential transitions between precursor types. The HMT model can be initialized to learn a user-defined number of distinct classes of precursors. This makes it possible to 1) reveal as yet undetected precursor types in view of exploring the significant features of precursors with respect to specific cellular processes; and 2) explore specific lineage features. For example, most precursors in the experimental dataset exhibit bidirectional transitions. Constraining the directionality in the HMT model leads to a reduction in precursor diversity following multiple divisions, thereby suggesting that one impact of bidirectionality in corticogenesis is to maintain precursor diversity. In this way we show that unsupervised lineage analysis provides a valuable methodology for investigating fundamental features of corticogenesis.


Pathogenesis of Alzheimer-related neuritic plaques: AT8 immunoreactive dystrophic neurites precede argyrophilic neurites in plaques of the entorhinal region, hippocampal formation, and amygdala.
The hyperphosphorylated microtubule-associated protein tau is a major component of Alzheimer-related intraneuronal cytoskeletal changes. Hyperphosphorylated tau proteins may form straight and paired helical filaments, which can condensate and crosslink, leading to agglomerations called neurofibrillary changes. The non-crosslinked filaments have been shown to precede the neurofibrillary changes in the cell body and dendritic processes of neurons. However, Alzheimer-related cytoskeletal changes are also found in dystrophic neurites of axonal origin. In the present study, occurrence of non-crosslinked and crosslinked cytoskeletal changes in dystrophic neurites of plaques has been investigated in the entorhinal region, hippocampal formation, and amygdala of cases at transentorhinal and limbic stages according to Braak and Braak. Consecutive 7 microm thick paraffin sections have been stained with the Campbell/Switzer and Gallyas silver techniques, as well as AT8 antibody for demonstration of beta-amyloid deposits, neurofibrillary changes, and non-crosslinked filaments, respectively. Most beta-amyloid deposits contained neither AT8-immunoreactive nor Gallyas positive argyrophilic neurites. Furthermore, a considerable proportion of beta-amyloid deposits displayed only AT8-immunoreactive dystrophic neurites. The findings indicate that AT8-immunoreactive neuronal processes located in beta-amyloid deposits precede Gallyas positive argyrophilic neurites in neuritic plaques. Both non-crosslinked and crosslinked forms of Alzheimer-type cytoskeletal changes are likely to develop in beta-amyloid deposits.


The roles of matrix metalloproteinases-2, -7, -10 and tissue inhibitor of metalloproteinase-1 in the pathogenesis of oral lichen planus.
The aim of this study was to investigate the roles of Matrix Metalloproteinases (MMP)-2, Metalloproteinases-7, Metalloproteinases-10 and Tissue Inhibitors of Metalloproteinase-1 (TIMP-1) in the pathogenesis of oral lichen planus (OLP) disease in same tissue samples. Thirty-nine individuals [29 patients with OLP (74%) and 10 healthy control subjects (25%)] were included in our study. The mean age was 48 ± 14.39 with a range of 20-75. MMP-2 and MMP-7 expression was significantly different in the patient and control groups in the epithelium and the connective tissue (P<0. 05). The ratio of MMP-2/TIMP-1 and MMP-7/TIMP-1 were higher in patient with OLP group than control group. Along with the exposure of the role of MMPs activity on diseases characterized by the tissue destruction, several studies were conducted on the pharmacological control of MMPs activity. However, understanding of the biological functions of MMPs is very important for the development and implementation of MMP inhibitors in the treatment of diseases. According to the results of this study, we suggest that MMP-2, MMP-7, and TIMP-1 may be involved in the formation of OLP lesions. Further studies on MMPs may be useful for understanding and treating the diseases such as OLP.


Inactivated porcine reproductive and respiratory syndrome virus vaccine adjuvanted with Montanide™ Gel 01 ST elicits virus-specific cross-protective inter-genotypic response in piglets.
The efficacy of a novel BEI-inactivated porcine reproductive and respiratory syndrome virus (PRRSV) candidate vaccine in pigs, developed at RIBSP Republic of Kazakhstan and delivered with an adjuvant Montanide™ Gel 01 ST (D/KV/ADJ) was compared with a commercial killed PRRSV vaccine (NVDC-JXA1, C/KV/ADJ) used widely in swine herds of the Republic of Kazakhstan. Clinical parameters (body temperature and respiratory disease scores), virological and immunological profiles [ELISA and virus neutralizing (VN) antibody titers], macroscopic lung lesions and viral load in the lungs (quantitative real-time PCR and cell culture assay) were assessed in vaccinated and both genotype 1 and 2 PRRSV challenged pigs. Our results showed that the commercial vaccine failed to protect pigs adequately against the clinical disease, viremia and lung lesions caused by the challenged field isolates, Kazakh strains of PRRSV type 1 and type 2 genotypes. In contrast, clinical protection, absence of viremia and lung lesions in D/KV/ADJ vaccinated pigs was associated with generation of VN antibodies in both homologous vaccine strain LKZ/2010 (PRRSV type 2) and a heterogeneous type 1 PRRSV strain (CM/08) challenged pigs. Thus, our data indicated the induction of cross-protective VN antibodies by D/KV/ADJ vaccine, and importantly demonstrated that an inactivated PRRSV vaccine could also induce cross-protective response across the viral genotype.


Denosumab, an Alternative to Bisphosphonates but also Associated with Osteonecrosis of the Jaw--What is the Risk?.
Most dental professionals will have, or will soon, encounter patients prescribed this novel alternative antiresorptive drug to bisphosphonates, denosumab (Prolia®, Xgeva®). Denosumab is licensed in the UK for the prevention of osteoporotic fractures in postmenopausal women and the prevention of skeletal-related events (SRE) in adults with bone metastases. The presence of osteonecrosis of the jaw in patients receiving non-bisphosphonate antiresorptives has led to the introduction of the term antiresorptive-related osteonecrosis of the jaw or ARONJ. This paper discusses the basic physiology of bone remodelling, the pharmacology of bisphosphonates and denosumab, and the risk of ARONJ. CPD/CLINICAL RELEVANCE: What is the potential risk of ARONJ arising from dental treatment that we should be advising for our patients?


Bis(phosphinic)diamido yttrium amide, alkoxide, and aryloxide complexes: an evaluation of lactide ring-opening polymerization initiator efficiency.
The synthesis and characterization of a series of bis(phosphinic)diamido yttrium alkoxide, amide, and aryloxide initiators are reported. The new complexes are characterized using multinuclear nuclear magnetic resonance (NMR) spectroscopy, elemental analysis, and, in some cases, X-ray crystallography. The alkoxide complexes are all dimeric in both the solid state and in solution, as are the amide complexes substituted with iso-propyl or phenyl groups on the phosphorus atoms. On the other hand, increasing the steric hindrance of the phosphorus substituents (tert-butyl), enables isolation of mononuclear yttrium amide complexes with either 2,2-dimethylpropylene or ethylene diamido ligand backbones. The complex of 2,6-di-tert-butyl-4-methylphenoxide is also mononuclear. All the new complexes are efficient initiators for rac-lactide ring-opening polymerization. The polymerization kinetics are compared and pseudo first order rate constants, k(obs), determined. The polymerization control is also discussed, by monitoring the number-averaged molecular weight, M(n), and polydispersity index, PDI, obtained using gel permeation chromatography (GPC). The alkoxide complexes are the most efficient initiators, showing very high rates and good polymerization control, behavior consistent with rapid rates of initiation. The phenoxide and amide complexes are less efficient as manifest by nonlinear regions in the kinetic plots, lower values for k(obs), and reduced polymerization control. One of the mononuclear yttrium amide complexes shows heteroselectivity in the polymerization of rac-lactide; however, this effect is reduced on changing the initiating group to phenoxide or on changing the ancillary ligand diamido backbone group.


Endothelial cell proliferation is suppressed by plasma but not serum from women with preeclampsia.
Evidence has been sought for a circulating factor derived from the placenta that suppresses endothelial cell proliferation and hence contributes to the maternal endothelial cell disturbances of preeclampsia. The effects of sera and plasmas from women with proteinuric preeclampsia and from matched normal pregnant control women on endothelial cell proliferation were compared. The recovery of endothelial cell inhibitory activity from syncytiotrophoblast microvesicles added to male blood and prepared as plasma or serum was determined to investigate the possible placental origin of the inhibitory factor. Sera from women with preeclampsia did not inhibit endothelial cell proliferation. In contrast, plasma from preeclamptic women significantly suppressed endothelial cell growth at 20% dilution compared with controls, and suppression was more pronounced in severe preeclampsia. The inhibitory activity of syncytiotrophoblast microvesicles added to blood could not be recovered from serum, only from plasma, which may explain why there was no suppression with sera from preeclamptic women. These results confirm that there is a blood-borne endothelial cell suppressive factor in preeclampsia that may be derived from the placenta.


Diagnosis of and therapy for solid tumors with radiolabeled antibodies and immune fragments.
Antibodies which are directed against human tumor-associated antigens can potentially be used as carriers of radioactivity for in vivo diagnosis (radioimmunodetection) or treatment (radioimmunotherapy) of solid tumors, including colon, hepatoma, cholangiocarcinoma, and melanoma. Murine monoclonal antibodies (MOAB), produced by the hybridoma technique of Kohler and Milstein, are replacing conventional heterosera as sources of antibodies, because MOAB can be produced in large quantities as reproducible reagents with homogeneous binding properties. We have studied human melanoma using MOAB IgG and Fab fragments that recognize the human melanoma-associated antigens p97 and "high-molecular-weight antigen." Both antigens are found in the membrane of melanomas at much larger concentrations than in normal adult tissues. We have performed radioimmunodetection studies with whole immunoglobulin and have detected 88% of lesions greater than 1.5 cm. We have used Fab fragments for radioimmunotherapy and have found that large doses of radiolabeled antibodies (up to 342 mCi) can be repetitively given to patients without excessive end-organ toxicity. Two of three patients treated with high-dose radiolabeled antimelanoma Fab showed an effect from the treatment. Although both technical and biologic problems remain, the use of radiolabeled antibodies that are directed against tumor-associated antigens holds future promise as a new therapeutic approach to solid tumors that are resistant to conventional therapy.


Signal coverage approach to the detection probability of hypothetical extraterrestrial emitters in the Milky Way.
The lack of evidence for the existence of extraterrestrial life, even the simplest forms of animal life, makes it is difficult to decide whether the search for extraterrestrial intelligence (SETI) is more a high-risk, high-payoff endeavor than a futile attempt. Here we insist that even if extraterrestrial civilizations do exist and communicate, the likelihood of detecting their signals crucially depends on whether the Earth lies within a region of the galaxy covered by such signals. By considering possible populations of independent emitters in the galaxy, we build a statistical model of the domain covered by hypothetical extraterrestrial signals to derive the detection probability that the Earth is within such a domain. We show that for general distributions of the signal longevity and directionality, the mean number of detectable emitters is less than one even for detection probabilities as large as 50%, regardless of the number of emitters in the galaxy.


Association Between Perceived Barriers to Diabetes Self-management and Diabetic Retinopathy in Asian Patients With Type 2 Diabetes.
A patient's perceived barriers to diabetes self-management (DSM) may affect his or her risk of diabetic retinopathy (DR); however, few studies have examined this association. To examine the association between perceived barriers to DSM and the severity spectrum of DR in Asian patients with type 2 diabetes. A cross-sectional clinic-based study, the Singapore Diabetes Management Project, was conducted from December 28, 2010, to March 20, 2013, at the Singapore National Eye Centre, a tertiary eye care institute. After excluding patients with type 1 diabetes and ungradable fundus images, 361 participants were included in the analyses. Statistical analysis was conducted from July 20 to September 8, 2017. The degree of perceived barriers to DSM was assessed using a 23-item questionnaire comprising items about knowledge of DSM, access to care, and confidence in health care professionals. Rasch analysis was used to optimize the scale's psychometric properties, with lower scores indicating a higher degree of self-perceived barriers. Diabetic retinopathy was graded from 2-field retinal images into categories of no DR (Early Treatment Diabetic Retinopathy Study levels 10-15; n = 154), mild to moderate DR (levels 20-43; n = 112), and severe DR (levels ≥53 and/or presence of clinically significant macular edema; n = 95) using the modified Airlie House classification system of DR. Multinomial logistic regression models were used to assess the association between perceived barriers and severity of DR in the worse-affected eye. Among the 361 participants (105 women and 256 men; mean [SD] age, 57 [8] years), a greater magnitude of perceived barriers to DSM was independently associated with higher odds of having any DR (odds ratio, 1.32; 95% CI, 1.06-1.66), mild to moderate DR (odds ratio, 1.30; 95% CI, 1.01-1.68), and severe DR (odds ratio, 1.36; 95% CI, 1.03-1.79). This association was independent of diabetes control (hemoglobin A1c, blood pressure, and lipid levels), presenting visual acuity, and socioeconomic indicators. These results suggest that greater perceived barriers to DSM are independently associated with severity of DR. Although longitudinal data are needed, these findings suggest that evidence-based interventions to reduce patient-, practitioner-, and system-related barriers to diabetes care may help reduce the risk of DR.


Community-specific evaluation of tool affordances in wild chimpanzees.
The notion of animal culture, defined as socially transmitted community-specific behaviour patterns, remains controversial, notably because the definition relies on surface behaviours without addressing underlying cognitive processes. In contrast, human cultures are the product of socially acquired ideas that shape how individuals interact with their environment. We conducted field experiments with two culturally distinct chimpanzee communities in Uganda, which revealed significant differences in how individuals considered the affording parts of an experimentally provided tool to extract honey from a standardised cavity. Firstly, individuals of the two communities found different functional parts of the tool salient, suggesting that they experienced a cultural bias in their cognition. Secondly, when the alternative function was made more salient, chimpanzees were unable to learn it, suggesting that prior cultural background can interfere with new learning. Culture appears to shape how chimpanzees see the world, suggesting that a cognitive component underlies the observed behavioural patterns.


Cutaneous Allergic reactions to pine processionary caterpillar (Thaumetopoea Pityocampa): a complicated cutaneous reaction in an infant and review of the literature.
Thaumetopoea Pityocampa (TP) are frequent in the Mediterranean region especially affecting forest workers in pinewood areas. The common symptoms include swelling, rash or burns like any form of dermatitis. The reactions can be triggered by mechanical, chemical or allergic factors and the `allergic` reaction is caused by sensitization to a hair protein named `thaumetopoein`. This protein triggers the IgE mediated reaction resulting in the mast cell degranulation causing urticaria. Different kinds of allergic reactions like urticaria or anaphylaxis have been reported previously commonly in adults, especially in forest workers while severe reactions without direct contact are rare in pediatric population. A 28 month old healthy boy was admitted to Near East University Pediatric Allergy and Immunology Outpatient Clinic in March with complaints of pain, hyperemia and swelling on the left hand. His complaints had started the day before his admission just after walking around in their garden which is surrounded by pine trees. On admission, his physical examination revealed serious edema and hyperemia on his left hand limiting his finger movements with a few bullae on the skin. His temperature was 38 C and the other vital parameters were normal. Based on hyperemia, swelling and high acute phase reactants he was hospitalized with the differential diagnosis of soft tissue inflammation and cellulitis. The case was treated with iv antihistamines, systemic steroids and antibiotics. Pine processionary (PP) is an important irritant and allergen especially in endemic areas like Cyprus which is a Mediterranean Country. It must be kept in mind in case of local or generalized urticaria, dermatitis, bullae and other allergic reactions even if there had been no direct contact with PP. Systemic involvement with fever and elevated acute phase reactants in infancy may necessitate hospitalization and intravenous treatment. Hereby, we reported an infant who presented with fever in addition to severe cutaneous lesions following the exposure to TP without direct contact. This is the first case reported from North Cyprus.


Single pixel transmissive and reflective liquid crystal display using broadband cholesteric liquid crystal film.
We propose a single mode transflective liquid crystal display (LCD) which is operated as the transmissive and reflective modes in a single pixel without dividing into sub-pixels. The single pixel transflective LCD was composed of the cross-polarized nematic LCD as a light modulator and the broadband cholesteric liquid crystal film (BCLCF) as a half mirror. The BCLCF, simply prepared by the exposure of ultraviolet light to the mixture of the nematic LC and the reactive mesogen with chirality, selectively reflects a certain circular polarization but transmits the orthogonal circular polarization in entire visible light. The electro-optical properties in both transmissive and reflective modes coincide with each other.


Exercise Performance and 22q11.2 Deletion Status Affect Quality of Life in Tetralogy of Fallot.
To identify mediators of health status and quality of life (QOL) in children and adolescents aged 8-18 years old following surgical repair for tetralogy of Fallot (TOF), including resource use, exercise performance, and 22q11.2 deletion status. We performed a corollary study to a cross-sectional analysis of subjects following repair for TOF that completed cardiac magnetic resonance imaging, cardiopulmonary exercise tests, and instruments assessing health status and QOL. General linear models were used to test for mediation. A total of 29 of 151 (19%) patients carried a 22q11.2 deletion. Parents of children with a deletion compared with those without a deletion reported worse physical and psychosocial functioning on the Child Health Questionnaire. The patients with a 22q11.2 deletion and their parents reported lower total and Disease Impact scores compared with the group without a deletion on the Pediatric Cardiac Quality of Life Inventory. Medical care use negatively correlated with measures of health status/QOL. Greater maximum work correlated with better patient health status and QOL, regardless of deletion status. Exercise performance mediated the association between deletion status and parent-reported outcomes (unstandardized effects ranging from 2.4 to 4.2) and patient-reported Disease Impact (0.99; 95% CI 0.02-2.70). Children and adolescents following repair for TOF seem to suffer significant challenges to their health status and QOL, which is amplified markedly in the context of the 22q11.2 deletion syndrome, and related to exercise performance.


ERP evidence for different strategies in the processing of case markers in native speakers and non-native learners.
The present experiments were designed to test how the linguistic feature of case is processed in Japanese by native and non-native listeners. We used a miniature version of Japanese as a model to compare sentence comprehension mechanisms in native speakers and non-native learners who had received training until they had mastered the system. In the first experiment we auditorily presented native Japanese speakers with sentences containing incorrect double nominatives and incorrect double accusatives, and with correct sentences. In the second experiment we tested trained non-natives with the same material. Based on previous research in German we expected an N400-P600 biphasic ERP response with specific modulations depending on the violated case and whether the listeners were native or non-native. For native Japanese participants the general ERP response to the case violations was an N400-P600 pattern. Double accusatives led to an additional enhancement of the P600 amplitude. For the learners a native-like P600 was present for double accusatives and for double nominatives. The additional negativity, however, was present in learners only for double nominative violations, and it was characterized by a different topographical distribution. The results indicate that native listeners use case markers for thematic as well as syntactic structure building during incremental sentence interpretation. The modulation of the P600 component for double accusatives possibly reflects case specific syntactic restrictions in Japanese. For adult language learners later processes, as reflected in the P600, seem to be more native-like compared to earlier processes. The anterior distribution of the negativity and its selective emergence for canonical sentences were taken to suggest that the non-native learners resorted to a rather formal processing strategy whereby they relied to a large degree on the phonologically salient nominative case marker.


Digital Subtraction Angiography Use During Epidural Steroid Injections Does Not Reliably Distinguish Artery from Vein.
Epidural steroid injections (ESIs) are among the most common procedures performed in an interventional pain management practice. It is well known that tragic complications may arise from ESIs, most commonly those performed using a transforaminal approach. Digital subtraction angiography (DSA) has been hailed as a fluoroscopic technique that can be used to detect arterial placement of the injection needle, and therefore as a safety measure that can decrease the incidence of catastrophic sequelae of these procedures. The objective of this article was to review existing scientific pain literature to determine if DSA can distinguish arterial vs. venous uptake. Narrative review. The current narrative review of DSA in interventional spine was completed with a PUBMED search using the key words: digital subtraction angiography, epidural, fluoroscopy, intravascular injection, paraplegia, and quadriplegia in accordance with Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guidelines. After identification of duplicate articles, 383 articles were screened by title, abstract, and/or full article review. Ten of these articles were deemed appropriate, after applying inclusion and exclusion criteria, as they specifically looked at the use of digital subtraction angiography in interventional spine epidural injections. This included 4 case reports, 3 prospective studies, one retrospective analysis, one prospective cohort study, and one meta-analysis. All of the available studies claiming that DSA was capable of detecting vascular spread are likely accurate, but no significant detection of specifically arterial spread has been reported. The known catastrophic complications related to ESIs are purported to be due to arterial injection of insoluble steroids or local anesthetic and detection of arterial spread of contrast during fluoroscopy would be of obvious benefit to the interventionalist. Small study size, non-randomized studies between DSA and real time fluoroscopy. Existing studies do not support that DSA can predict arterial spread. In fact, DSA exposes the practitioner and the patient to higher levels of radiation without objective evidence of any safety parameters. Digital subtraction angiography, real-time fluoroscopy, transforaminal epidural injection, particulate steroids, cervical radicular artery, lumbar radicular artery, spinal cord injury.


Aging into Perceptual Control: A Dynamic Causal Modeling for fMRI Study of Bistable Perception.
Aging is accompanied by stereotyped changes in functional brain activations, for example a cortical shift in activity patterns from posterior to anterior regions is one hallmark revealed by functional magnetic resonance imaging (fMRI) of aging cognition. Whether these neuronal effects of aging could potentially contribute to an amelioration of or resistance to the cognitive symptoms associated with psychopathology remains to be explored. We used a visual illusion paradigm to address whether aging affects the cortical control of perceptual beliefs and biases. Our aim was to understand the effective connectivity associated with volitional control of ambiguous visual stimuli and to test whether greater top-down control of early visual networks emerged with advancing age. Using a bias training paradigm for ambiguous images we found that older participants (n = 16) resisted experimenter-induced visual bias compared to a younger cohort (n = 14) and that this resistance was associated with greater activity in prefrontal and temporal cortices. By applying Dynamic Causal Models for fMRI we uncovered a selective recruitment of top-down connections from the middle temporal to Lingual gyrus (LIN) by the older cohort during the perceptual switch decision following bias training. In contrast, our younger cohort did not exhibit any consistent connectivity effects but instead showed a loss of driving inputs to orbitofrontal sources following training. These findings suggest that perceptual beliefs are more readily controlled by top-down strategies in older adults and introduce age-dependent neural mechanisms that may be important for understanding aberrant belief states associated with psychopathology.


Generalized paired-agent kinetic model for in vivo quantification of cancer cell-surface receptors under receptor saturation conditions.
New precision medicine drugs oftentimes act through binding to specific cell-surface cancer receptors, and thus their efficacy is highly dependent on the availability of those receptors and the receptor concentration per cell. Paired-agent molecular imaging can provide quantitative information on receptor status in vivo, especially in tumor tissue; however, to date, published approaches to paired-agent quantitative imaging require that only 'trace' levels of imaging agent exist compared to receptor concentration. This strict requirement may limit applicability, particularly in drug binding studies, which seek to report on a biological effect in response to saturating receptors with a drug moiety. To extend the regime over which paired-agent imaging may be used, this work presents a generalized simplified reference tissue model (GSRTM) for paired-agent imaging developed to approximate receptor concentration in both non-receptor-saturated and receptor-saturated conditions. Extensive simulation studies show that tumor receptor concentration estimates recovered using the GSRTM are more accurate in receptor-saturation conditions than the standard simple reference tissue model (SRTM) (% error (mean ± sd): GSRTM 0 ± 1 and SRTM 50 ± 1) and match the SRTM accuracy in non-saturated conditions (% error (mean ± sd): GSRTM 5 ± 5 and SRTM 0 ± 5). To further test the approach, GSRTM-estimated receptor concentration was compared to SRTM-estimated values extracted from tumor xenograft in vivo mouse model data. The GSRTM estimates were observed to deviate from the SRTM in tumors with low receptor saturation (which are likely in a saturated regime). Finally, a general 'rule-of-thumb' algorithm is presented to estimate the expected level of receptor saturation that would be achieved in a given tissue provided dose and pharmacokinetic information about the drug or imaging agent being used, and physiological information about the tissue. These studies suggest that the GSRTM is necessary when receptor saturation exceeds 20% and highlight the potential for GSRTM to accurately measure receptor concentrations under saturation conditions, such as might be required during high dose drug studies, or for imaging applications where high concentrations of imaging agent are required to optimize signal-to-noise conditions. This model can also be applied to PET and SPECT imaging studies that tend to suffer from noisier data, but require one less parameter to fit if images are converted to imaging agent concentration (quantitative PET/SPECT).


HIV status and age at first marriage among women in Cameroon.
Recent research has highlighted the risk of HIV infection for married teenage women compared with their unmarried counterparts (Clark, 2004). This study assesses whether a relationship exists, for women who have completed their adolescence (age 20-29 years), between HIV status with age at first marriage and the length of time between first sex and first marriage. Multivariate analysis utilizing the nationally representative 2004 Cameroon Demographic and Health Survey shows that late-marrying women and those with a longer period of pre-marital sex have the highest risk of HIV. Although women in urban areas overall marry later than their rural counterparts, the positive relationship between age at marriage and HIV risk is stronger in rural areas. The higher wealth status and greater number of lifetime sexual partners of late-marrying women contribute to their higher HIV risk. Given that the age at first marriage and the gap between first marriage and first sex have increased in recent years, focusing preventive efforts on late-marrying women will be of much importance in reducing HIV prevalence among females.


Inflexibly focused under stress: acute psychosocial stress increases shielding of action goals at the expense of reduced cognitive flexibility with increasing time lag to the stressor.
Dynamically adjusting the right amount of goal shielding to varying situational demands is associated with the flexibility of cognitive control, typically linked with pFC functioning. Although stress hormones are found to also bind to prefrontal receptors, the link between stress and cognitive control remains elusive. Based on that, we aimed at investigating effects of acute psychosocial stress on dynamic control adjustments. Forty-eight healthy volunteers were exposed to either a well-established stress induction protocol (the Trier Social Stress Test, TSST) or a standardized control situation before a selective attention (Simon) task involving response conflicts. The individual physiological stress response was monitored by analyzing levels of free cortisol and α-amylase activity in saliva samples showing that the TSST reliably induced an increase of endogenous stress hormone levels. Acute stress did not inevitably impair cognitive functioning, however, as stressed participants showed tonically increased goal shielding (to reduce interference) at the expense of decreased cognitive flexibility. Importantly, as a novel finding in humans, stress effects on cognitive functions were not present immediately after the stress experience but developed gradually over time and, therefore, paralleled the time course of the hypothalamus-pituitary-adrenal (HPA) stress response. In addition, the total increase of individual cortisol levels reflecting HPA activity, but not the total changes in α-amylase activity associated with sympathetic activity, was reversely related to the amount of cognitive flexibility in the final block of testing. Our study provides evidence for a stress-induced time-dependent decrease of cognitive flexibility that might be related to changes in cortisol levels.


Transforming Nepal's primary health care delivery system in global health era: addressing historical and current implementation challenges.
Nepal's Primary Health Care (PHC) is aligned vertically with disease control programs at the core and a vast network of community health workers at the periphery. Aligning with the globalization of health and the factors affecting global burden of diseases, Nepal echoes the progressive increase in life expectancy, changes in diseases patterns, including the current impact of COVID-19. Nepal's health system is also accommodating recent federalization, and thus it is critical to explore how the primary health care system is grappling the challenges amidst these changes. In this review, we conducted a narrative synthesis of literature to explore the challenges related to transformation of Nepal's primary health care delivery system to meet the demands incurred by impact of globalization and recent federalization, covering following database: PubMED, Embase and Google Scholar. Of the 49 articles abstracted for full text review, 37 were included in the analyses. Existing theories were used for constructing the conceptual framework to explain the study findings. The results are divided into four themes. Additional searches were conducted to further support the narrative synthesis: a total of 46 articles were further included in the articulation of main findings. Transforming Nepal's primary health care system requires a clear focus on following priority areas that include i) Revised efforts towards strengthening of community based primary health care units; ii) Adapting vertical programs to federal governance; iii) Reinforcing the health insurance scheme; and iv) Strengthening an existing network of community health workers and health human resources. This review discusses how these broad goals bear challenges and opportunities.


Inhibitors of V-ATPase proton transport reveal uncoupling functions of tether linking cytosolic and membrane domains of V0 subunit a (Vph1p).
Vacuolar ATPases (V-ATPases) are important for many cellular processes, as they regulate pH by pumping cytosolic protons into intracellular organelles. The cytoplasm is acidified when V-ATPase is inhibited; thus we conducted a high-throughput screen of a chemical library to search for compounds that acidify the yeast cytosol in vivo using pHluorin-based flow cytometry. Two inhibitors, alexidine dihydrochloride (EC(50) = 39 μM) and thonzonium bromide (EC(50) = 69 μM), prevented ATP-dependent proton transport in purified vacuolar membranes. They acidified the yeast cytosol and caused pH-sensitive growth defects typical of V-ATPase mutants (vma phenotype). At concentrations greater than 10 μM the inhibitors were cytotoxic, even at the permissive pH (pH 5.0). Membrane fractions treated with alexidine dihydrochloride and thonzonium bromide fully retained concanamycin A-sensitive ATPase activity despite the fact that proton translocation was inhibited by 80-90%, indicating that V-ATPases were uncoupled. Mutant V-ATPase membranes lacking residues 362-407 of the tether of Vph1p subunit a of V(0) were resistant to thonzonium bromide but not to alexidine dihydrochloride, suggesting that this conserved sequence confers uncoupling potential to V(1)V(0) complexes and that alexidine dihydrochloride uncouples the enzyme by a different mechanism. The inhibitors also uncoupled the Candida albicans enzyme and prevented cell growth, showing further specificity for V-ATPases. Thus, a new class of V-ATPase inhibitors (uncouplers), which are not simply ionophores, provided new insights into the enzyme mechanism and original evidence supporting the hypothesis that V-ATPases may not be optimally coupled in vivo. The consequences of uncoupling V-ATPases in vivo as potential drug targets are discussed.


Normalization is a general neural mechanism for context-dependent decision making.
Understanding the neural code is critical to linking brain and behavior. In sensory systems, divisive normalization seems to be a canonical neural computation, observed in areas ranging from retina to cortex and mediating processes including contrast adaptation, surround suppression, visual attention, and multisensory integration. Recent electrophysiological studies have extended these insights beyond the sensory domain, demonstrating an analogous algorithm for the value signals that guide decision making, but the effects of normalization on choice behavior are unknown. Here, we show that choice models using normalization generate significant (and classically irrational) choice phenomena driven by either the value or number of alternative options. In value-guided choice experiments, both monkey and human choosers show novel context-dependent behavior consistent with normalization. These findings suggest that the neural mechanism of value coding critically influences stochastic choice behavior and provide a generalizable quantitative framework for examining context effects in decision making.


Optimality of Upper-Arm Reaching Trajectories Based on the Expected Value of the Metabolic Energy Cost.
When we move our body to perform a movement task, our central nervous system selects a movement trajectory from an infinite number of possible trajectories under constraints that have been acquired through evolution and learning. Minimization of the energy cost has been suggested as a potential candidate for a constraint determining locomotor parameters, such as stride frequency and stride length; however, other constraints have been proposed for a human upper-arm reaching task. In this study, we examined whether the minimum metabolic energy cost model can also explain the characteristics of the upper-arm reaching trajectories. Our results show that the optimal trajectory that minimizes the expected value of energy cost under the effect of signal-dependent noise on motor commands expresses not only the characteristics of reaching movements of typical speed but also those of slower movements. These results suggest that minimization of the energy cost would be a basic constraint not only in locomotion but also in upper-arm reaching.


Mendelian randomization study of interleukin-6 in chronic obstructive pulmonary disease.
Cross-sectional studies have demonstrated that increased levels of interleukin-6 (IL6) are present in the airways and blood samples of patients with chronic obstructive pulmonary disease (COPD). To investigate the association between IL6 and the risk of COPD using a Mendelian randomization approach. Eight common single-nucleotide polymorphisms (SNPs) in the region of the IL6 gene were genotyped using both TaqMan and Illumina in the Rotterdam Study, a prospective population-based cohort study consisting of 7,983 participants aged 55 years or older, including 928 COPD patients. At baseline, blood was drawn in a random sample of 714 subjects to measure the IL6 plasma level. Analysis of variance, logistic regression, and Cox proportional hazard models--adjusted for age, gender, pack years, and BMI--were used for analyses. High levels of IL6 (>2.4 pg/ml, the highest tertile) were associated with a three-fold increased risk of developing COPD, in comparison to low levels (<1.4 pg/ml, the lowest tertile). The rs2056576 SNP was associated with a 10% increase in the risk of COPD per additional T allele. However, the association was no longer significant after adjustment. No association was found with other common SNPs in the IL6 gene and COPD. Although increased IL6 plasma levels at baseline are associated with the risk of developing COPD during follow-up, there was no strong evidence for an association between common variation in the IL6 gene and the risk of COPD.


Identification of a vacuolar proton channel that triggers the bioluminescent flash in dinoflagellates.
In 1972, J. Woodland Hastings and colleagues predicted the existence of a proton selective channel (HV1) that opens in response to depolarizing voltage across the vacuole membrane of bioluminescent dinoflagellates and conducts protons into specialized luminescence compartments (scintillons), thereby causing a pH drop that triggers light emission. HV1 channels were subsequently identified and demonstrated to have important functions in a multitude of eukaryotic cells. Here we report a predicted protein from Lingulodinium polyedrum that displays hallmark properties of bona fide HV1, including time-dependent opening with depolarization, perfect proton selectivity, and characteristic ΔpH dependent gating. Western blotting and fluorescence confocal microscopy of isolated L. polyedrum scintillons immunostained with antibody to LpHV1 confirm LpHV1's predicted organellar location. Proteomics analysis demonstrates that isolated scintillon preparations contain peptides that map to LpHV1. Finally, Zn2+ inhibits both LpHV1 proton current and the acid-induced flash in isolated scintillons. These results implicate LpHV1 as the voltage gated proton channel that triggers bioluminescence in L. polyedrum, confirming Hastings' hypothesis. The same channel likely mediates the action potential that communicates the signal along the tonoplast to the scintillon.


Intra-abdominal pressure monitoring as a guideline in the nonoperative management of blunt hepatic trauma.
Nonoperative management has been validated as a standard of care for patients with blunt hepatic trauma. We herein study the correlation of intra-abdominal pressure (IAP) and other clinical parameters to predict the failure of nonoperative management, and attempt to use IAP to determine further therapeutic options. During a 9-month period, 25 hemodynamically stable patients sustaining grades III to V blunt hepatic injuries were prospectively studied. They were admitted to the intensive care unit for clinical reevaluation, and hemodynamic and IAP monitoring. If the patient developed an IAP greater than 25 cm H(2)O, then an emergent laparotomy or laparoscopy was performed to achieve hemostasis and decompression of intra-abdominal hypertension (IAH). On the basis of an IAP of 25 cm H(2)O, the correlation between the IAP and an estimated amount of liver-related transfusion, the Pao(2)/Fio(2) ratio and peritoneal signs were analyzed. Of the 25 patients being studied, 20 (80%) had an IAP below 25 cm H(2)O, 1 of whom was found to have a pelvic abscess from an amputated segment of liver. On the other hand, five other patients with an IAP greater than 25 cm H(2)O received decompression and laparoscopic examinations, and one needed an open hepatorrhaphy. In general, though, 19 patients (76%) were successfully treated without operation. All recovered well after different therapeutic regimens; however, two developed liver abscesses, for a morbidity rate of 8% (2 of 25). This analysis revealed a strong association between the IAP value and the presence of peritoneal signs (Phi coefficient = 0.890, p < 0.001), but not in the estimated amount of liver-related transfusion and Pao(2)/Fio(2) ratio. This preliminary investigation suggests that IAH or abdominal compartment syndrome can develop while patients receive nonoperative management for grade III to V blunt hepatic injuries. There were no parameters that precisely reflected ongoing hepatic hemorrhage or predicted hemodynamic instability. Although the amount of hepatic hemorrhage was not accurately measured by the IAP, it could be reflected by an increased IAP. During nonoperative management, IAP monitoring may be a simple and objective guideline to suggest further intervention for patients with blunt hepatic trauma. Laparoscopic hepatic evaluation and abdominal decompression may be helpful in this situation.


Breaking away from dopamine deficiency: an essential new direction for Parkinson's disease.
For the past 40 years Parkinson's disease (PD) has been intrinsically associated with dopamine (DA) deficiency of the nigrostriatal DA system. One of the fundamental strengths of this theoretical approach is based on a presumed relationship between the degree of DA deficiency and the severity of motor impairment in the disease and its models. However, detailed examination of a substantial number of exemplary preclinical and clinical studies reveals that any such interpretation is overoptimistic and suggests that DA deficiency may be merely an epiphenomenon of a larger process underlying this disorder. Such a conclusion is based on numerous examples of miscarriage of basic principles of good scientific practice including (i) failure to thoroughly examine the adverse effects of DA replacement, (ii) drawing of statistical inference without recognising excessive spread of measure thereby lessening the importance of outliers, (iii) confounding independent and dependent variables within the scientific paradigm, (iv) overlooking fundamental principles of modern pharmacology, (v) confusing correlation with causation in linking cause and effect and (vi) disinclination to incorporate conflicting findings thereby infringing the quintessential scientific principle of tertium quid. This review demonstrates the inherent risks and dangers in the incontrovertible defence of DA deficiency theory and serves to address the ethical problems that emerge from the clinical application of scientific findings. There is increasing interest in new directions for PD research by dimming down the current emphasis on the importance of DA deficiency and its replacement. This would provide genuine hope and a new direction for the sufferers of a most debilitating disease.